A pyrazolo heteroaryl derivative, a preparation method thereof, and a medical use thereof

Abstract

This disclosure relates to pyrazolone aryl derivatives, their preparation methods, and their pharmaceutical applications. Specifically, this disclosure relates to a pyrazolone aryl derivative of general formula (I), its preparation method, pharmaceutical compositions containing the derivative, and its use as a therapeutic agent, particularly as an ATR kinase inhibitor, and in the preparation of medicaments for treating and / or preventing hyperproliferative diseases. The definitions of the groups in general formula (I) are the same as in the specification.

Description

[Technical Field]

[0001] This disclosure pertains to the pharmaceutical field and relates to a pyrazolone aryl derivative of general formula (I), a method for its preparation, pharmaceutical compositions containing the derivative, and its use as a therapeutic agent, particularly as an ATR kinase inhibitor and in the preparation of medicaments for treating and / or preventing hyperproliferative diseases. [Previous Technology]

[0002] Whether in normal or tumor cells, DNA damage occurs thousands of times every day. This makes DNA damage repair crucial for maintaining genome stability and cell survival. Compared to normal cells, tumor cells experience greater replication stress, carry more endogenous DNA damage, and often exhibit the absence of one or more DNA damage repair pathways. This makes the survival of tumor cells even more dependent on the successful completion of DNA damage repair.

[0003] Homologous recombination repair is the main repair mechanism for DNA double-strand breaks. It uses the homologous sequence of an undamaged sister chromatid as a template to replicate the damaged DNA sequence, precisely repairing the DNA. This repair mechanism mainly occurs in the G2 and S phases of the cell cycle. ATR is a key enzyme in the homologous recombination repair pathway, belonging to the PIKK family. When the ATR / ATRIP complex binds to damaged DNA covered by replication protein A (RPA), ATR is activated and regulates various checkpoints in the cell cycle by phosphorylating downstream proteins such as Chk1 and SMARCAL, causing cell cycle arrest; ensuring the stability of damaged DNA; and increasing dNTP concentration, thus promoting DNA damage repair. DNA damage repair occurring in the S phase of the cell cycle is mainly completed by the ATR pathway, indicating that ATR is crucial for ensuring cell proliferation. Analysis of clinical tumor samples shows that elevated ATR expression levels have been observed in various tumor tissues, such as gastric cancer, liver cancer, colorectal cancer, ovarian cancer, and pancreatic cancer. Furthermore, in patients with ovarian cancer and pancreatic cancer, high ATR levels are often accompanied by lower survival rates. This demonstrates that ATR is an important target for cancer treatment.

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

[0005] The object of this disclosure is to provide a compound of general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0005] Among them:

[0005] G1 and G2 are the same or different, and each is independently CH or N, provided that G1 and G2 are not both CH at the same time;

[0005] Ring A is a heteroaryl group;

[0005] R1 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, -NR4R5, -CONR4R5, -SO2NR4R5, -R6N-CO-NR4R5, -COOR7, -SO2R7, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein each of the alkyl, alkoxy, amino, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, -NR4R5, -CONR4R5, -SO2NR4R5, -R6N-CO-NR4R5, -COOR7, -SO2R7, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0005] R2 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein each of the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0005] R3 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein each of the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0005] R4 and R5 may be the same or different, and each is independently selected from hydrogen atom, alkyl, haloalkyl, hydroxyl, amino, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0005] R6 is selected from hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

[0005] R7 is selected from hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

[0005] n is 0, 1, 2 or 3.

[0006] In some embodiments of this disclosure, the compound represented by general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyrazolyl, pyrroleyl, and imidazolyl.

[0007] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically acceptable salts, are compounds represented by general formula (II) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts:

[0007] Among them:

[0007] G1, G2, R1, R2, R3 and n are as defined in general formula (I).

[0008] In some preferred embodiments of this disclosure, the compound represented by general formula (I) or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by general formula (III) or general formula (IV) or a tautomer, meso compound, racemic mixture, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0008]

[0008] Where R1, R2, R3 and n are as defined in general formula (I).

[0009] In some embodiments of this disclosure, the compound represented by general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl; wherein each of the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl groups.

[0010] In some embodiments of this disclosure, the compound represented by general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from alkyl, cycloalkyl, and heterocyclic groups; wherein the alkyl group is optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, and the cycloalkyl and heterocyclic groups are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. The aryl group is substituted with one or more substituents; preferably, R1 is a C1-C6 alkyl or a 3- to 6-membered cycloalkyl; wherein the C1-C6 alkyl and the 3- to 6-membered cycloalkyl are each independently optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-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; more preferably, R1 is a C1-C6 alkyl or a 3- to 6-membered cycloalkyl; wherein the C1-C6 alkyl and the 3- to 6-membered cycloalkyl are each independently optionally substituted with a cyano; most preferably, R1 is or

[0011] In some embodiments of this disclosure, the compound represented by general formula (I) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R2 is a hydrogen atom or an alkyl group; preferably an alkyl group; more preferably a C1-6 alkyl group.

[0012] In some embodiments of this disclosure, the compound represented by general formula (I) or its tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically acceptable salts, wherein R2 is an alkyl group.

[0013] In some embodiments of this disclosure, the compound represented by general formula (I) or its tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutically acceptable salts, wherein R3 is a hydrogen atom.

[0014] Typical compounds disclosed herein include, but are not limited to:

[0014]

[0014]

[0014]

[0015] Another aspect of this disclosure relates to compounds of general formula (IA) or tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0015] Among them:

[0015] X is a halogen; preferably Br;

[0015] G1 and G2 may be the same or different, and each can be CH or N independently, provided that G1 and G2 are not both CH at the same time;

[0015] R1 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, -NR4R5, -CONR4R5, -SO2NR4R5, -R6N-CO-NR4R5, -COOR7, -SO2R7, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein each of the alkyl, alkoxy, amino, cycloalkyl, heterocyclic, aryl and heteroaryl is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, -NR4R5, -CONR4R5, -SO2NR4R5, -R6N-CO-NR4R5, -COOR7, -SO2R7, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0015] R2 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein each of the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0015] R4 and R5 may be the same or different, and each is independently selected from hydrogen atom, alkyl, haloalkyl, hydroxyl, amino, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0015] R6 is selected from hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

[0015] R7 is selected from hydrogen atoms, alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0016] Another aspect of this disclosure relates to compounds of general formula (IIIC) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0016]

[0016] Where X, R1 and R2 are as defined in general formula (IA).

[0017] Another aspect of this disclosure relates to compounds of general formula (IIA) or tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0017] Among them:

[0017] Ra is an amino protecting group;

[0017] G1 and G2 may be the same or different, and each can be CH or N independently, provided that G1 and G2 are not both CH at the same time;

[0017] R1 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, -NR4R5, -CONR4R5, -SO2NR4R5, -R6N-CO-NR4R5, -COOR7, -SO2R7, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein each of the alkyl, alkoxy, amino, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, -NR4R5, -CONR4R5, -SO2NR4R5, -R6N-CO-NR4R5, -COOR7, -SO2R7, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0017] R2 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein each of the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0017] R3 is selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein each of the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl groups is independently and optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl groups;

[0017] R4 and R5 may be the same or different, and each is independently selected from hydrogen atom, alkyl, haloalkyl, hydroxyl, amino, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0017] R6 is selected from hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

[0017] R7 is selected from hydrogen atoms, alkyl groups, haloalkyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups;

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

[0018] Another aspect of this disclosure relates to compounds of general formula (IIGA) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0018]

[0018] Where G1, G2, R1, R2, R3, Ra and n are as defined in general formula (IIA).

[0019] Another aspect of this disclosure relates to compounds of general formula (IIIA) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0019]

[0019] Where Ra, R1, R2, R3 and n are as defined in general formula (IIA).

[0020] Another aspect of this disclosure relates to compounds of general formula (IIIGA) or their tautomers, meso compounds, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof.

[0020]

[0020] Where Ra, R1, R2, R3 and n are as defined in general formula (IIIA).

[0021] Typical intermediate compounds disclosed herein include, but are not limited to:

[0021]

[0021]

[0021]

[0022] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0022]

[0022] A compound of general formula (IA) and a compound of general formula (IB) undergo a coupling reaction to give a compound of general formula (I).

[0022] Among them:

[0022] X is a halogen; preferably Br;

[0022] Rb is OR;

[0022] Rings A, G1, G2, R1, R2, R3 and n are as defined in general formula (I).

[0023] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0023]

[0023] A compound of general formula (IA) and a compound of general formula (IID) undergo a coupling reaction to give a compound of general formula (II).

[0023] Among them:

[0023] X is a halogen; preferably Br;

[0023] Rb is OR;

[0023] G1, G2, R1, R2, R3 and n are as defined in general formula (II).

[0024] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0024]

[0024] A compound of general formula (IIIC) and a compound of general formula (IID) undergo a coupling reaction to give a compound of general formula (III).

[0024] Among them:

[0024] X is a halogen; preferably Br;

[0024] Rb is OR;

[0024] R1, R2, R3 and n are as defined in general formula (III).

[0025] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0025]

[0025] A compound of general formula (IVC) and a compound of general formula (IID) undergo a coupling reaction to give a compound of general formula (IV).

[0025] Among them:

[0025] X is a halogen; preferably Br;

[0025] Rb is OR;

[0025] R1, R2, R3 and n are as defined in general formula (IV).

[0026] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IIA) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0026]

[0026] A compound of general formula (IA) and a compound of general formula (IIB) undergo a coupling reaction to give a compound of general formula (IIA).

[0026] Among them:

[0026] X is a halogen; preferably Br;

[0026] Ra is an amino protecting group;

[0026] Rb is OR;

[0026] G1, G2, R1, R2, R3 and n are as defined in general formula (II).

[0027] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0027]

[0027] The compound of general formula (IIA) is deamined to obtain the compound of general formula (II).

[0027] Among them:

[0027] Ra is an amino protecting group;

[0027] G1, G2, R1, R2, R3 and n are as defined in general formula (II).

[0028] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IIGA) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0028]

[0028] A compound of general formula (IA) and a compound of general formula (IIGB) undergo a coupling reaction to give a compound of general formula (IIGA).

[0028] Among them:

[0028] X is a halogen; preferably Br;

[0028] Ra is an amino protecting group;

[0028] Rb is OR;

[0028] G1, G2, R1, R2, R3 and n are as defined in general formula (IIGA).

[0029] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0029]

[0029] Compounds of general formula (IIGA) are deamined to obtain compounds of general formula (II).

[0029] Among them:

[0029] Ra is an amino protecting group;

[0029] G1, G2, R1, R2, R3 and n are as defined in general formula (II).

[0030] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IIIA) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0030]

[0030] A compound of general formula (IIIC) and a compound of general formula (IIB) undergo a coupling reaction to give a compound of general formula (IIIA).

[0030] Among them:

[0030] X is a halogen; preferably Br;

[0030] Ra is an amino protecting group;

[0030] Rb is OR;

[0030] R1, R2, R3 and n are as defined in general formula (III).

[0031] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0031]

[0031] Compounds of general formula (IIIA) are deamined to obtain compounds of general formula (III).

[0031] Among them:

[0031] Ra is an amino protecting group;

[0031] R1, R2, R3 and n are as defined in general formula (III).

[0032] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IIIGA) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0032]

[0032] A compound of general formula (IIIC) and a compound of general formula (IIGB) undergo a coupling reaction to give a compound of general formula (IIIGA).

[0032] Among them:

[0032] X is a halogen; preferably Br;

[0032] Ra is an amino protecting group;

[0032] Rb is OR;

[0032] R1, R2, R3 and n are as defined in general formula (IIIG).

[0033] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0033]

[0033] The compound of general formula (IIIGA) is deamined to obtain the compound of general formula (III).

[0033] Among them:

[0033] Ra is an amino protecting group;

[0033] R1, R2, R3 and n are as defined in general formula (III).

[0034] Another aspect of this disclosure relates to a method for preparing a compound of general formula (IV) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0034]

[0034] Compounds of general formula (IVA) are deamined to obtain compounds of general formula (IV).

[0034] Among them:

[0034] Ra is an amino protecting group;

[0034] R1, R2, R3 and n are as defined in general formula (IV).

[0035] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound represented by formula (I) of this disclosure or a tautomer, meso compound, racemic compound, enantiomer, diastereomer or mixture thereof or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0036] This disclosure further relates to the use of a compound of general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising thereof in the preparation of a medicament for inhibiting ATR kinase.

[0037] This disclosure further relates to the use of compounds of general formula (I) or their tautomers, meso compounds, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising thereof in the preparation of medicaments for the treatment and / or prevention of hyperproliferative diseases.

[0038] This disclosure further relates to the use of compounds of general formula (I) or their tautomers, meso compounds, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising thereof in the preparation of medicaments for the treatment and / or prevention of tumors.

[0039] This disclosure further relates to the use of a compound of general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising thereof in the preparation of a medicament for treating tumors.

[0040] This disclosure also relates to a method of inhibiting ATR kinase, comprising administering to a desired patient an effective amount of a compound of general formula (I) or a tautomer thereof, meso compound, racemic compound, enantiomer, diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0041] This disclosure also relates to a method of treating and / or preventing hyperproliferative diseases, comprising administering to a desired patient an effective amount of a compound of general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0042] This disclosure also relates to a method of treating and / or preventing tumors, comprising administering to a desired patient an effective amount of a compound of general formula (I) or a tautomer thereof, meso compound, racemic compound, enantiomer, diastereomer thereof or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof.

[0043] This disclosure further relates to a compound of general formula (I) or a tautomer, meso compound, racemic compound, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, for use as a medicament. The medicament may be used to treat and / or prevent hyperproliferative diseases, particularly tumors.

[0044] This disclosure also relates to compounds of general formula (I) or tautomers, meso compounds, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutical salts thereof, or pharmaceutical compositions comprising thereof, which are used as ATR kinase inhibitors.

[0045] This disclosure also relates to compounds of general formula (I) or tautomers, meso compounds, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutical salts thereof, or pharmaceutical compositions comprising thereof, for the treatment and / or prevention of hyperproliferative diseases.

[0046] This disclosure further relates to compounds of general formula (I) or tautomers, meso compounds, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutical salts thereof, or pharmaceutical compositions comprising thereof, for the treatment of tumors.

[0047] In this disclosure, the tumor 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 tumors, bladder cancer, and gallbladder cancer.

[0048] The active compound may be formulated in a form suitable for administration by any appropriate route, preferably in a unit dose manner, or in a manner that allows the patient to self-administer a single dose. The unit dose of the compounds or compositions disclosed herein may be expressed as tablets, capsules, sachets, bottled liquids, powders, granules, lozenges, suppositories, regenerated powders, or liquid formulations.

[0049] The dosage of the compounds or compositions used in the treatment methods disclosed herein will generally vary depending on the severity of the disease, the patient's weight, and the relative efficacy of the compounds. However, as a general guideline, a suitable unit dose may be 0.1 to 1000 mg.

[0050] In addition to the active compound, the pharmaceutical composition disclosed herein may contain one or more excipients selected from the following components: fillers (diluents), binders, wetting agents, disintegrants, or excipients, etc. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0051] Pharmaceutical compositions containing an active ingredient may be in forms suitable for oral administration, such as tablets, sugar tablets, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide an appealing and palatable pharmaceutical formulation. Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0052] Oral formulations may also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0053] The aqueous suspension contains an active substance and excipients suitable for preparing the aqueous suspension for mixing. Such excipients are suspending agents, dispersing agents, or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0054] Oil suspensions can be prepared by suspending the active ingredient in vegetable oil or mineral oil. Oil suspensions may contain thickeners. The aforementioned sweeteners and flavoring agents may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0055] The addition of water provides active ingredients and dispersants or wetting agents, suspending agents, or one or more preservatives suitable for preparing aqueous suspensions to dispersible powders and granules. Suitable dispersants or wetting agents and suspending agents can be illustrated by the examples above. Other excipients such as sweeteners, flavoring agents, and coloring agents may also be added. These compositions are preserved by the addition of antioxidants such as ascorbic acid.

[0056] The pharmaceutical composition disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0057] The pharmaceutical composition of this disclosure may be in the form of a sterile injectable aqueous solution. Acceptable solvents or media that can be used include 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, which can be injected into the patient's bloodstream by local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds of this disclosure. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0058] The pharmaceutical composition of this disclosure can be in the form of a sterile injectable aqueous or oil suspension for intramuscular and subcutaneous administration. This suspension can be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulation can also be a sterile injectable solution or suspension prepared in a parenteral-acceptable, non-toxic diluent or solvent. Furthermore, a sterile fixative oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixative oil can be used. Additionally, fatty acids can also be used to prepare injectable formulations.

[0059] The disclosed compounds may be administered in suppository form for rectal administration. These pharmaceutical compositions may be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.

[0060] 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 activity of the specific compound used, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment mode, such as the treatment pattern, the daily dosage of the general formula compound (I) or the type of pharmaceutically acceptable salt, can be verified based on conventional treatment protocols.

[0060] [Detailed Description of the Invention]

[0061] Unless otherwise stated, the terms used in the specification and the claims have the following meanings.

[0062] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched 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, tributyl, dibutyl, 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 their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tributyl, dibutyl, 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, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents chosen from H atom, D atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0063] The term "alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. It is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups 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-), etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent can be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents chosen from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0064] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in its molecule, wherein the definition of alkyl is as described above. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from one or more substituents selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0065] The term "alkynyl" refers to a molecule containing at least one carbon-carbon triple bond, wherein the definition of alkyl is as described above. The alkynyl group can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from one or more substituents selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0066] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7 or 8) carbon atoms, and even more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocyclic, fused-ring, and bridged-ring cycloalkyl.

[0067] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 rings sharing a single carbon atom (called a spiro atom), which may contain one or more double bonds. Preferably, it consists of 6 to 14 rings, more preferably 7 to 10 rings (e.g., 7, 8, 9, or 10 rings). Spirocycloalkyl groups are classified as monospirocycloalkyl, bispirocycloalkyl, or polyspirocycloalkyl groups based on the number of shared spiro atoms between rings, with monospirocycloalkyl and bispirocycloalkyl groups being more preferred. More preferably, they are 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0067]

[0068] The term "fused cycloalkyl" refers to a 5 to 20-membered polycyclic group of carbon atoms in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 4, 5 / 5, 5 / 6, 6 / 3, 6 / 4, 6 / 5, and 6 / 6 bicyclic alkyl. Non-limiting examples of fused cycloalkyl include:

[0068]

[0069] The term "bridged cycloalkyl" refers to a polycyclic carbon group with 5 to 20 rings, in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. Preferably, it has 6 to 14 rings, more preferably 7 to 10 rings (e.g., 7, 8, 9, or 10 rings). Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

[0069]

[0070] The cycloalkyl ring includes cycloalkyl groups (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the ring connected to the parent structure is a cycloalkyl group, and non-limiting examples include indenyl, tetrahydronaphthyl, phenylcyclopentyl, and benzocycloheptyl; preferably phenylcyclopentyl and tetrahydronaphthyl.

[0071] The cycloalkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0072] 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 groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from one or more substituents selected from H, D, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl. The term "heterocyclic" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, S, S(O), and S(O)2, but excluding the ring moiety of -OO-, -OS-, or -SS-, 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 to 3 (e.g., 1, 2, or 3) are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0073] The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 rings sharing a single atom (called a spiro atom), 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 consists of 6 to 14 rings, more preferably 7 to 10 rings. Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups based on the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being more preferred. More preferably, it consists of 4 / 4, 4 / 5, 4 / 6, 5 / 5, or 5 / 6 monospirocyclic groups. Non-limiting examples of spirocyclic groups include:

[0073]

[0074] The term "fused heterocyclic group" refers to a 5 to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings 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). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 4, 5 / 5, 5 / 6, 6 / 3, 6 / 4, 6 / 5 and 6 / 6 bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0074]

[0075] The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It 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). Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0075]

[0076] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0076]

[0077] The heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0078] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0078]

[0079] The aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0080] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 members (e.g., 5, 6, 7, 8, 9, and 10), more preferably 5 or 6 members, such as furanyl, thiophene, pyridinyl, pyrrolithyl, N-alkylpyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl group fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0080]

[0080]

[0081] The heteroaryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any usable connection point. The substituent is preferably independently selected independently from one or more substituents chosen from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0082] The above-mentioned cycloalkyl, heterocyclic, aryl and heteroaryl groups have one residue derived from removing one hydrogen atom from a parent ring atom, or two residues derived from removing two hydrogen atoms from the same or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", "heteroaryl".

[0083] The term "amine protecting group" is used to protect the amine group with an easily removable group so that the amine group remains unchanged when other parts of the molecule react. Non-limiting examples include tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl, etc. These groups may optionally be replaced by 1 to 3 substituents selected from halogens, alkoxy groups, or nitro groups. The amine protecting group is preferably tetrahydropyranyl.

[0084] The term “cycloalkyloxy” refers to cycloalkyl-O-, wherein the cycloalkyl group is as defined above.

[0085] The term “haloalkyl” means an alkyl group that is substituted with one or more halogens, wherein the alkyl group is as defined above.

[0086] The term “deuterated alkyl” means that an alkyl group is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0087] The term “hydroxyl group” refers to the -OH group.

[0088] The term “hydroxyalkyl” refers to an alkyl group that has been substituted with a hydroxyl group, wherein the alkyl group is as defined above.

[0089] The term “halogen” refers to fluorine, chlorine, bromine or iodine.

[0090] The term “amine group” refers to -NH2.

[0091] The term “cyano” refers to -CN.

[0092] The term “nitro” refers to -NO2.

[0093] The term “carbonyl” refers to C=O.

[0094] The term “carboxyl group” refers to -C(O)OH.

[0095] The term “carboxylic acid ester group” refers to -C(O)O (alkyl) or -C(O)O (cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0096] THP is tetrahydropyranyl.

[0097] The compounds disclosed herein can exist as tautomers. For the purposes of this disclosure, references to compounds of formula (I) refer to the compound itself, any one of its tautomers, or a mixture of two or more tautomers. For example, a reference to a pyrazolyl group should be understood to include any one or a mixture of two of the following structures.

[0098] The compounds disclosed herein include their isotopic derivatives. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of this disclosure, in which hydrogen is replaced by "deuterium" or "tritium," or fluorine is replaced by 18F-fluorine labeling (18F isotope), or carbon atoms are replaced by 11C-, 13C-, or 14C-enriched carbon (11C-, 13C-, or 14C-carbon labeling; 11C-, 13C-, or 14C-isotope), are within the scope of this disclosure. Such compounds can be used as analytical tools or probes, for example, in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamic, pharmacokinetic, or receptor studies. This disclosure includes various deuterated forms of compounds of formula (I). Each available hydrogen atom bonded 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 to prepare the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques with deuterated reagents, including but not limited to deuterated boranes, trideuterated borane tetrahydrofuran solutions, deuterated lithium aluminum hydride, deuterated iodoethane, and deuterated iodomethane.

[0099] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and this description includes the case where the event or environment occurs or does not occur. For example, "optionally alkyl-substituted heterocyclic group" means that the alkyl group may but does not have to be present, and this description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.

[0100] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino group or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0101] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically / pharmacologically acceptable salts or prodrugs, along with other chemical components, such as physiologically / pharmacologically acceptable carriers and excipients. The purpose of pharmaceutical compositions is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0102] "Medicinal salts" refers to salts of the compounds disclosed herein, which are safe and effective when used in mammals and have the appropriate biological activity.

[0103] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but achieves the desired effect. The determination of the effective amount varies from person to person, depending on the recipient's age and general condition, as well as on the specific active substance. The appropriate effective amount in a case can be determined by a person skilled in the art based on routine testing.

[0103] [Synthetic method of the compounds disclosed herein]

[0104] In order to achieve the purpose of this disclosure, the following technical solution is adopted:

[0104] Option 1

[0104] A method for preparing the compound or its salt represented by general formula (I) of this disclosure includes the following steps:

[0104]

[0105] Compounds of general formula (IA) and (IB) undergo a coupling reaction under basic conditions in the presence of a catalyst to give a compound of general formula (I).

[0105] Among them:

[0105] X is a halogen; preferably Br;

[0105] Rb is OR;

[0105] Rings A, G1, G2, R1, R2, R3 and n are as defined in general formula (I).

[0106] Option Two

[0106] A method for preparing the compound or its salt represented by general formula (II) of this disclosure includes the following steps:

[0106]

[0107] Compounds of general formula (IA) and (IID) undergo a coupling reaction under basic conditions in the presence of a catalyst to give a compound of general formula (II).

[0107] Among them:

[0107] X is a halogen; preferably Br;

[0107] Rb is OR;

[0107] G1, G2, R1, R2, R3 and n are as defined in general formula (II).

[0108] Option 3

[0108] A method for preparing the compound or its salt represented by general formula (II) of this disclosure includes the following steps:

[0108]

[0109] A compound of general formula (IA) and a compound of general formula (IIB) undergo a coupling reaction under basic conditions in the presence of a catalyst to give a compound of general formula (IIA).

[0109] The compound of general formula (IIA) is deamined under acidic conditions to obtain the compound of general formula (II);

[0109] Among them:

[0109] X is a halogen; preferably Br;

[0109] Rb is OR;

[0109] G1, G2, R1, R2, R3 and n are as defined in general formula (II).

[0110] Option Four

[0110] A method for preparing the compound or its salt represented by general formula (II) of this disclosure includes the following steps:

[0110]

[0111] A compound of general formula (IA) and a compound of general formula (IIGB) undergo a coupling reaction under basic conditions in the presence of a catalyst to give a compound of general formula (IIGA).

[0111] The compound of general formula (IIGA) is deamined under acidic conditions to obtain the compound of general formula (II);

[0111] Among them:

[0111] X is a halogen; preferably Br;

[0111] Rb is OR;

[0111] G1, G2, R1, R2, R3 and n are as defined in general formula (II).

[0112] Option Five

[0112] A method for preparing the compound or its salt represented by formula (III) of this disclosure includes the following steps:

[0112]

[0113] Compounds of general formula (IIIC) and compounds of general formula (IID) undergo a coupling reaction under basic conditions in the presence of a catalyst to give compounds of general formula (III).

[0113] Among them:

[0113] X is a halogen; preferably Br;

[0113] Rb is OR;

[0113] R1, R2, R3 and n are as defined in general formula (III).

[0114] Option Six

[0114] A method for preparing the compound or its salt represented by formula (III) of this disclosure includes the following steps:

[0114]

[0115] Compounds of general formula (IIIC) and compounds of general formula (IIB) undergo a coupling reaction under basic conditions in the presence of a catalyst to give compounds of general formula (IIIA).

[0115] A compound of general formula (IIIA) is deamined under acidic conditions to obtain a compound of general formula (III);

[0115] Among them:

[0115] X is a halogen; preferably Br;

[0115] Ra is an amino protecting group;

[0115] Rb is OR;

[0115] R1, R2, R3 and n are as defined in general formula (III).

[0116] Option Seven

[0116] A method for preparing the compound or its salt represented by general formula (III) of this disclosure includes the following steps:

[0116]

[0117] A compound of general formula (IIIC) and a compound of general formula (IIGB) undergo a coupling reaction under basic conditions in the presence of a catalyst to give a compound of general formula (IIIGA).

[0117] A compound of general formula (IIIGA) is deamined under acidic conditions to obtain a compound of general formula (III);

[0117] Among them:

[0117] X is a halogen; preferably Br;

[0117] Ra is an amino protecting group;

[0117] Rb is OR;

[0117] R1, R2, R3 and n are as defined in general formula (III).

[0118] Option Eight

[0118] A method for preparing the compound or its salt represented by formula (IV) of this disclosure includes the following steps:

[0118]

[0119] Compounds of general formula (IVC) and compounds of general formula (IID) undergo a coupling reaction under basic conditions in the presence of a catalyst to give a compound of general formula (IV).

[0119] Among them:

[0119] X is a halogen; preferably Br;

[0119] Rb is OR;

[0119] R1, R2, R3 and n are as defined in general formula (IV).

[0120] Option Nine

[0120] A method for preparing the compound or its salt represented by formula (IV) of this disclosure includes the following steps:

[0120]

[0121] Compounds of general formula (IVC) and compounds of general formula (IIB) undergo a coupling reaction under basic conditions in the presence of a catalyst to give compounds of general formula (IVA).

[0121] Compounds of general formula (IVA) are deamined under acidic conditions to obtain compounds of general formula (IV);

[0121] Among them:

[0121] X is a halogen; preferably Br;

[0121] Ra is an amino protecting group;

[0121] Rb is OR;

[0121] R1, R2, R3 and n are as defined in general formula (IV).

[0122] Plan Ten

[0122] A method for preparing the compound or its salt represented by formula (IV) of this disclosure includes the following steps:

[0122]

[0123] A compound of general formula (IVC) and a compound of general formula (IIGB) undergo a coupling reaction under basic conditions in the presence of a catalyst to give a compound of general formula (IVGA).

[0123] Compounds of general formula (IVGA) are deamined under acidic conditions to obtain compounds of general formula (IV);

[0123] Among them:

[0123] X is a halogen; preferably Br;

[0123] Ra is an amino protecting group;

[0123] Rb is OR;

[0123] R1, R2, R3 and n are as defined in general formula (IV).

[0124] 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, diisopropylaminolithium, bistrimethylsilylaminolithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, and sodium n-butoxide. The inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and lithium hydroxide.

[0125] The catalysts described in the above synthesis schemes include, but are not limited to, palladium / carbon, tetra-triphenylphosphine palladium, palladium dichloride, palladium acetate, bis(triphenylphosphine)palladium(II) dichloride, bis(dibenzylacetone)palladium, chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium, [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride, 1,1'-bis(dibenzylphosphine)dichlorodipentadienylferropalladium or tri(dibenzylacetone)dipalladium, preferably tetra-triphenylphosphine palladium or bis(triphenylphosphine)palladium(II) dichloride.

[0126] The reagents providing acidic conditions in the above synthesis scheme include, but are not limited to, hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-benzenesulfonic acid, Me3SiCl, and TMSOTf, with trifluoroacetic acid being preferred.

[0127] In the above synthetic schemes, the amine protecting group includes, but is not limited to, tetrahydropyranyl (THP), tert-butoxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl. These groups may optionally be replaced by 1-3 substituents selected from halogen, alkoxy, or nitro. Tetrahydropyranyl is preferred.

[0128] The above reaction is preferably carried out in a solvent, including but 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.

Implementation Method

[0129] The present disclosure is further described below with reference to embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0129] [Example]

[0130] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer with deuterated dimethyl monoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0131] MS determination was performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometry system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a waters ACQuity UPLC-QD / SQD system (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0132] High performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high performance liquid chromatograph.

[0133] Chiral HPLC analysis was performed using an Agilent 1260 DAD high-performance liquid chromatograph.

[0134] High performance liquid chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

[0135] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0136] The CombiFlash rapid preparation instrument uses the CombiFlash Rf200 (TELEDYNE ISCO).

[0137] The thin-layer chromatography silica gel plates used are Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used for thin-layer chromatography (TLC) have a size of 0.15mm~0.2mm, and the size used for thin-layer chromatography separation and purification of products is 0.4mm~0.5mm.

[0138] Silicone column chromatography generally uses Yantai Huanghai silicone 200~300 mesh silicone as the carrier.

[0139] The average inhibition rate and IC50 value of the kinase were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0140] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals.

[0141] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0142] Argon atmosphere or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen balloon with a volume of about 1L.

[0143] Hydrogen atmosphere refers to a reaction flask connected to a hydrogen balloon with a volume of about 1L.

[0144] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0145] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and the operation is repeated 3 times.

[0146] The microwave reaction uses a CEM Discover-S 908860 microwave reactor.

[0147] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0148] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0149] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the column chromatography extraction solvent system used to purify the compounds, and the thin-layer chromatography developing solvent system included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system. The volume ratio of the solvent was adjusted according to the polarity of the compounds. Small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0150] THP is tetrahydropyranyl.

[0151] Example 1

[0151] (R)-2-methyl-2-(1-methyl-5-(3-methylmorpholino)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propionitrile 1

[0151]

[0151]

[0152] Step 1

[0152] (R,E)-1-methyl-4-((1-(3-methylmorpholine)ethoxy)amino)-1H-pyrazole-5-carboxylic acid methyl ester 1c

[0152] Compound (R)-1-(3-methylmorpholine) ethyl-1-one 1b (2.5 g, 17.7 mmol, prepared by the method disclosed in the example of intermediate-1 on page 86 of the specification of patent application "WO2016020320A1") was dissolved in 1,2-dichloroethane, protected by argon, cooled in ice water, and phosphorus oxychloride (7.4 g, 48.3 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. Then, compound methyl 4-amino-1-methyl-1H-pyrazole-5-carboxylate 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. Cool to room temperature, concentrate under reduced pressure, dilute the residue with dichloromethane (200 mL), cool in ice water, neutralize to pH 8-9 with saturated sodium bicarbonate solution, wash the organic phase with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, and purify the filtrate by silica gel column chromatography with extraction solvent system C to obtain the title compound 1c (4.8 g), yield: 94%.

[0152] MS m / z (ESI): 281.2 [M+1].

[0153] Step Two

[0153] (R)-1-Methyl-5-(3-methylmorpholino)-1H-pyrazolo[4,3-b]pyridine-7-phenol 1d

[0153] Compound 1c (2.6 g, 9.3 mmol) was dissolved in tetrahydrofuran (20 mL), cooled in ice water, and bis(trimethylsilylaminolithium) (27.8 mL, 1 M tetrahydrofuran solution, 27.8 mmol) was slowly added. The reaction was carried out at 0 °C for 1 hour. The reaction was quenched with methanol (10 mL), and purified by silica gel column chromatography using extractant system A to give the title compound 1d (400 mg), yield: 55.8%.

[0153] MS m / z (ESI): 249.0 [M+1].

[0154] Step 3

[0154] (R)-4-(7-chloro-1-methyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylmorpholine 1e

[0154] Compound 1d (400 mg, 1.6 mmol) was dissolved in 3.0 mL of phosphorus oxychloride and heated to 90 °C with stirring for 2.0 h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with dichloromethane (50 mL), cooled in ice water, neutralized to pH 8-9 with saturated sodium bicarbonate solution, and stirred for 0.5 h. The mixture was allowed to stand and separated, the organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography using a refrigerant system C to give the title compound 1e (240 mg), yield: 56%.

[0154] MS m / z (ESI): 267.0 [M+1].

[0155] Step 4

[0155] (R)-2-methyl-2-(1-methyl-5-(3-methylmorpholino)-1H-pyrazolo[4,3-b]pyridin-7-yl)propionitrile 1g

[0155] Compound 1e (240 mg, 0.91 mmol) and compound isobutyronitrile 1f (620 mg, 8.9 mmol, Shanghai Bide) were dissolved in 30 mL of tetrahydrofuran. Under a nitrogen atmosphere, the mixture was cooled in an acetone bath on dry ice. Bistrimethylsilylaminolithium (8.9 mL, 1 M tetrahydrofuran solution, 8.9 mmol) was added dropwise. The mixture was stirred at low temperature for 0.5 hours, then allowed to rise naturally to room temperature and stirred for 1 hour. The reaction was quenched with water. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a refrigerant system C to obtain 1 g (200 mg) of the title compound, yield: 74%.

[0155] MS m / z (ESI): 300.1 [M+1].

[0156] Step 5

[0156] (R)-2-(3-bromo-1-methyl-5-(3-methylmorpholino)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropionitrile 1h

[0156] 1 g (200 mg, 0.67 mmol) was dissolved in 5 mL of 1,4-dioxane, and sodium hydroxide solution (0.66 mL, 2 M solution, 1.32 mmol) was added. The mixture was cooled with ice water, and liquid bromine (427 mg, 2.67 mmol) was added. The mixture was stirred at low temperature for 10 minutes, and then allowed to rise naturally to room temperature with stirring for 1 hour. The mixture was diluted with ethyl acetate, and the organic phase was washed with saturated sodium thiosulfate solution, then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography using a buffer system C to give the title compound 1 h (140 mg), yield: 55%.

[0156] MS m / z (ESI): 377.9 [M+1].

[0157] Step Six

[0157] 2-Methyl-2-(1-methyl-5-((R)-3-methylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propionitrile 1i

[0157] 1h (20 mg, 0.05 mmol), tetraphenylphosphine 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-dioxoboronacyclopentan-2-yl)-1H-pyrazole (29 mg, 0.10 mmol, Shanghai Bide) were dissolved in 4 mL of ethylene glycol dimethyl ether. 1 mL of water was added, and the mixture was heated to 120 °C for 1 hour under an argon atmosphere using microwave heating. 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 filtrate was purified by silica gel column chromatography using a buffer system C to give the title compound 1i (20 mg), yield: 84%.

[0157] MS m / z (ESI): 450.1 [M+1].

[0158] Step Seven

[0158] (R)-2-methyl-2-(1-methyl-5-(3-methylmorpholino)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propionitrile 1

[0158] Compound 1i (20 mg, 0.04 mmol) was dissolved in 5 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added dropwise. After the addition was complete, the mixture was stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 8-9 by adding 7 M amine methanol solution. The solution was then concentrated under reduced pressure and purified by silica gel column chromatography using extraction solvent system A to give title compound 1 (7.0 mg), yield: 43%.

[0158] MS m / z (ESI): 366.0 [M+1].

[0158] 1H NMR (400MHz, CD3OD): δ 7.58(s,1H),7.03(s,1H),6.86(s,1H),4.39(s,4H),4.04-3.82(m,2H),3.74(s,2H),3.58(td,1H),3.26(dd,1H),1.88(d,6H),1.19(d,3H).

[0159] Example 2

[0159] (R)-1-(1-methyl-5-(3-methylmorpholino)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropionitrile 2

[0159]

[0159]

[0160] Step 1

[0160] (R)-1-(1-methyl-5-(3-methylmorpholino)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropionitrile 2a

[0160] 1e (86 mg, 0.32 mmol), cyclopropionitrile (65 mg, 0.97 mmol), tris(dibenzylacetone)palladium (30 mg, 0.03 mmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (40 mg, 0.06 mmol) were dissolved in 2 mL of tetrahydrofuran. Under an argon atmosphere, bis(trimethylsilylaminolithium) (1.0 mL, 1 M tetrahydrofuran solution, 1.0 mmol) was added. The mixture was sealed and heated to 80 °C with stirring 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, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a retort system C to give the title compound 2a (80 mg), yield: 84%.

[0160] MS m / z (ESI): 298.3 [M+1].

[0161] Second Step

[0161] (R)-1-(3-bromo-1-methyl-5-(3-methylmorpholino)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropionitrile 2b

[0161] 2a (30 mg, 0.1 mmol) was dissolved in 5 mL of 1,4-dioxane, and sodium hydroxide solution (0.1 mL, 2 M, 0.2 mmol) was added. The mixture was cooled with ice water, and liquid bromine (64 mg, 0.4 mmol) was added. The mixture was stirred at low temperature for 10 minutes, and then allowed to rise naturally to room temperature with stirring for 1 hour. The mixture was diluted with 20 mL of ethyl acetate, and the organic phase was washed with saturated sodium thiosulfate solution, then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a buffer system C to give the title compound 2b (30 mg), yield: 80%.

[0161] MS m / z (ESI): 376.4 [M+1].

[0162] Step 3

[0162] 1-(1-methyl-5-((R)-3-methylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropionitrile 2c

[0162] 2b (30 mg, 0.08 mmol), tetraphenylphosphine 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-dioxoboronacyclopentan-2-yl)-1H-pyrazole (44 mg, 0.16 mmol) were dissolved in 4.0 mL of ethylene glycol dimethyl ether. 1.0 mL of water was added, and the mixture was heated to 120 °C 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 using a buffer system C to give the title compound 2c (30 mg), yield: 84%.

[0162] MS m / z (ESI): 448.3 [M+1].

[0163] Step 4

[0163] (R)-1-(1-methyl-5-(3-methylmorpholino)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropionitrile 2

[0163] Compound 2c (30 mg, 0.07 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added dropwise. After the addition was complete, the mixture was stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 8-9 by adding 7 M amine methanol solution. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using extraction solvent system A to give title compound 2 (13.5 mg), yield: 55%.

[0163] MS m / z (ESI): 364.3 [M+1].

[0163] 1H NMR (400MHz, CD3OD): δ 7.58(d,1H),7.01(d,1H),6.93(s,1H),4.40(d,1H),4.38(s,3H),3.95(dd,2H),3.79-3.68( m,2H),3.57(td,1H),3.30-3.25(m,1H),1.92-1.80(m,2H),1.72-1.58(m,2H),1.18(d,3H).

[0164] Example 3

[0164] (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

[0164]

[0165] Step 1

[0165] (R)-3-methyl-4-(1-methyl-7-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)morpholine 3a

[0165] 1e (250 mg, 0.94 mmol), bis(triphenylphosphine)-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-dioxoboronyl-2-yl)-1H-pyrazole (390 mg, 1.87 mmol) were dissolved in 8.0 mL of ethylene glycol dimethyl ether. 2.0 mL of water was added, and the mixture was microwaved at 120 °C for 2 hours under an argon atmosphere. The reaction solution was then cooled to room temperature. The mixture was diluted with 20 mL of water, extracted with ethyl acetate (20 mL × 3), and the organic phases were combined. The mixture was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a refrigerant system C to give the title compound 3a (290 mg), yield: 99%.

[0165] MS m / z (ESI): 313.2 [M+1].

[0166] Step Two

[0166] (R)-4-(3-bromo-1-methyl-7-(1-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylmorpholine 3b

[0166] 3a (300 mg, 0.97 mmol) was dissolved in 5 mL of N,N-dimethylformamide, cooled in ice water, and N-bromobutyldiimide (205 mg, 1.2 mmol) was added. The mixture was stirred at low temperature for 10 minutes, then allowed to rise naturally to room temperature and stirred for 1 hour. The mixture was diluted with 20 mL of ethyl acetate, washed with saturated sodium thiosulfate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography using a buffer system C to give the title compound 3b (115 mg), yield: 30%.

[0166] MS m / z (ESI): 391.1 [M+1].

[0167] Step 3

[0167] (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

[0167] 3b (35 mg, 0.09 mmol), tetraphenylphosphine 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-dioxoboronacyclopentan-2-yl)-1H-pyrazole (50 mg, 0.18 mmol) were dissolved in 5.0 mL of ethylene glycol dimethyl ether. 1 mL of water was added, and the mixture was heated to 120 °C for 1 hour under an argon atmosphere and 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 using a buffer system C to give the title compound 3c (20 mg), yield: 48%.

[0167] MS m / z (ESI): 463.4 [M+1].

[0168] Step Four

[0168] (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

[0168] 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 for 4 hours. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 8-9 by adding 7 M amine methanol solution. The solution was then concentrated under reduced pressure and purified by silica gel column chromatography using extraction solvent system A to give the title compound 3 (20 mg), yield: 40.7%.

[0168] MS m / z (ESI): 379.2 [M+1].

[0168] 1H NMR (400MHz, CD3OD): δ 7.58(d,1H),7.57(d,1H),7.03(d,1H),6.90(s,1H),6.48(d,1H),4.38(d,1H),4.02-3.88(m ,2H),3.72(s,2H),3.65(s,3H),3.57(td,1H),3.50(s,3H),3.27-3.22(m,1H),1.19(d,3H).

[0169] Example 4

[0169] (R)-2-(1-Ethyl-5-(3-methylmorpholino)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropionitrile 4

[0169]

[0169]

[0170] Step 1

[0170] Methyl 1-ethyl-4-nitro-1H-pyrazole-5-carboxylic acid ester 4b

[0170] Methyl 1-ethyl-4-nitro-1H-pyrazole-5-carboxylate 4a (5 g, 25.1 mmol, Shanghai Bide) was dissolved in 100 mL of methanol, and 10% palladium / carbon (1 g) was added. The mixture was purged three times with hydrogen and stirred for 14 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude title compound 4b (4.2 g). The product was used directly in the next reaction without purification.

[0170] MS m / z (ESI): 170.1 [M+1].

[0171] Step Two

[0171] (R,E)-1-Ethyl-4-((1-(3-methylmorpholine)ethoxy)amino)-1H-pyrazole-5-carboxylic acid methyl ester 4c

[0171] 1b (3.3 g, 23.0 mmol) was dissolved in 1,2-dichloroethane and cooled in ice water under an argon atmosphere. Phosphorus oxychloride (5.4 g, 35.2 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 30 minutes. 4b (2.5 g, 16.1 mmol) was added, and the mixture was heated to 80 °C and stirred for 2 hours. The mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with dichloromethane (200 mL). The mixture was cooled in ice water and neutralized to pH 8-9 with saturated sodium bicarbonate solution. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was purified by silica gel column chromatography using a retort system C to give the title compound 4c (2.3 g), yield: 66.1%.

[0171] MS m / z (ESI): 295.2 [M+1].

[0172] Step 3

[0172] (R)-1-Ethyl-5-(3-methylmorpholino)-1H-pyrazolo[4,3-b]pyridine-7-phenol 4d

[0172] 4c (1 g, 3.39 mmol) was dissolved in tetrahydrofuran (20 mL), cooled in ice water, and bis(trimethylsilylaminolithium) (10 mL, 1 M tetrahydrofuran solution, 10 mmol) was slowly added. The reaction was carried out at 0 °C for 1 hour. The reaction was quenched with methanol (10 mL), and purified by silica gel column chromatography using extractant system A to give the title compound 4d (250 mg), yield: 28.1%.

[0172] MS m / z (ESI): 263.1 [M+1].

[0173] Step Four

[0173] (R)-4-(7-chloro-1-ethyl-1H-pyrazolo[4,3-b]pyridin-5-yl)-3-methylmorpholine 4e

[0173] 4d (250 mg, 0.95 mmol) was dissolved in 2.0 mL of phosphorus oxychloride and heated to 90 °C with stirring for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with dichloromethane (50 mL). The solution was cooled in ice water, neutralized to pH 8-9 with saturated sodium bicarbonate solution, and stirred for 0.5 hours. The mixture was allowed to stand and separated, and the organic phase was collected, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and purified by silica gel column chromatography using a retort system C to give the title compound 4e (120 mg), yield: 42.5%.

[0173] MS m / z (ESI): 281.3 [M+1].

[0174] Step 5

[0174] (R)-2-(1-Ethyl-5-(3-methylmorpholino)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropionitrile 4g

[0174] Compound 4e (120 mg, 0.43 mmol) and compound 1f (295 mg, 4.3 mmol, Shanghai Bide) were dissolved in 30 mL of tetrahydrofuran. Under an argon atmosphere, the mixture was cooled in an ice-acetone bath. Bistrimethylsilylaminolithium (1.7 mL, 1 M tetrahydrofuran solution, 1.7 mmol) was added dropwise. The mixture was stirred at low temperature for 0.5 hours, then allowed to rise naturally to room temperature and stirred for 1 hour. The reaction was quenched with water. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a refrigerant system C to obtain compound 4 g (95 mg), yield: 74%.

[0174] MS m / z (ESI): 314.1 [M+1].

[0175] Step Six

[0175] (R)-2-(3-bromo-1-ethyl-5-(3-methylmorpholino)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropionitrile 4h

[0175] 4 g (95 mg, 0.67 mmol) was dissolved in 5 mL of 1,4-dioxane, and sodium hydroxide solution (0.3 mL, 2 M, 0.6 mmol) was added. The mixture was cooled with ice water, and liquid bromine (194 mg, 1.2 mmol) was added. The mixture was stirred at low temperature for 10 minutes, and then allowed to rise naturally to room temperature with stirring for 1 hour. The mixture was diluted with ethyl acetate, and the organic phase was washed with saturated sodium thiosulfate solution, then washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a buffer system C to give the title compound 4h (41 mg), yield: 34%.

[0175] MS m / z (ESI): 392.1 [M+1].

[0176] Step Seven

[0176] 2-(1-Ethyl-5-((R)-3-methylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropionitrile 4i

[0176] 4h (40 mg, 0.1 mmol), tetraphenylphosphine 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-dioxoboronyl-2-yl)-1H-pyrazole (32 mg, 0.20 mmol, Shanghai Bide) were dissolved in 4 mL of dioxane. 1 mL of water was added, and the mixture was heated to 120 °C for 1 hour under an argon atmosphere using microwave heating. 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 using a retort system C to give the title compound 4i (40 mg), yield: 85%.

[0176] MS m / z (ESI): 464.1 [M+1].

[0177] Step 8

[0177] (R)-2-(1-Ethyl-5-(3-methylmorpholino)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropionitrile 4

[0177] Compound 4i (20 mg, 0.04 mmol) was dissolved in 5 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added dropwise. After the addition was complete, the mixture was stirred for 4 hours. The reaction solution was concentrated under reduced pressure, and the pH was adjusted to 8-9 by adding 7 M amine methanol solution. The solution was then concentrated under reduced pressure and purified by silica gel column chromatography using extraction solvent system A to give compound 4 (15 mg), yield: 45%.

[0177] MS m / z (ESI): 380.2 [M+1].

[0177] 1H NMR (400MHz, CD3OD): δ 7.57(s,1H),7.04(s,1H),6.85(s,1H),4.66-4.64(m,2H),4.39-4.38(m,1H),3.97-3.91(m,2 H),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).

[0178] Example 5

[0178] (R)-1-(1-ethyl-5-(3-methylmorpholino)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropionitrile 5

[0178]

[0179] Step 1

[0179] (R)-1-(1-ethyl-5-(3-methylmorpholino)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropionitrile 5a

[0179] 4e (500 mg, 1.78 mmol), cyclopropionitrile (239 mg, 3.56 mmol), tris(dibenzylacetone)palladium (162 mg, 0.18 mmol), and 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (222 mg, 0.36 mmol) were dissolved in 2 mL of tetrahydrofuran. Under an argon atmosphere, bis(trimethylsilylaminolithium) (5.3 mL, 1 M tetrahydrofuran solution, 5.3 mmol) was added. The mixture was sealed and heated to 80 °C with stirring 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, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a retort system C to give the title compound 5a (360 mg), yield: 64.9%.

[0179] MS m / z (ESI): 312.2 [M+1].

[0180] Step Two

[0180] (R)-1-(3-bromo-1-ethyl-5-(3-methylmorpholino)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropionitrile 5b

[0180] 5a (377 mg, 1.2 mmol) was dissolved in 5 mL of tetrahydrofuran, cooled with ice water, and N-bromosuccinimide (215 mg, 1.2 mmol) was added. The mixture was stirred at low temperature for 10 minutes, then allowed to rise naturally to room temperature and stirred for 2 hours. The mixture was diluted with 20 mL of ethyl acetate, washed with saturated sodium thiosulfate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a retort system C to give the title compound 5b (100 mg), yield: 21%.

[0180] MS m / z (ESI): 390.3 [M+1].

[0181] Step 3

[0181] (R)-1-(1-ethyl-5-(3-methylmorpholino)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)cyclopropionitrile 5

[0181] 5b (100 mg, 0.25 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (43 mg, 0.05 mmol), sodium carbonate (81 mg, 0.78 mmol), and (1H-pyrazol-3-yl)boronic acid (43 mg, 0.38 mmol, Shanghai Bide) were dissolved in 4.0 mL of dioxane. 1.0 mL of water was added, and the mixture was stirred at 100 °C for 2 hours under an argon atmosphere. The reaction solution was then cooled to room temperature. 20 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using extraction solvent system A to give title compound 5 (10 mg), yield: 10%.

[0181] 1H NMR (400MHz, CD3OD): δ 7.82(s,1H),7.04-7.12(m,2H),4.84-4.82(m,2H),4.51-4.50(m,1H),4.09-4.05(m,2H),3.86-3.85(m ,2H),3.69-3.66(m,1H),3.43-3.42(m,1H),1.97(d,2H),1.80-1.78(m,2H),1.67(t,3H),1.32(d,3H).

[0182] Example 6

[0182] (R)-2-methyl-2-(5-(3-methylmorpholino)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propionitrile 6

[0182]

[0182]

[0183] Step 1

[0183] Methyl 1-benzyl-4-nitro-1H-pyrazole-5-carboxylic acid 6b

[0183] Methyl 4-nitro-1H-pyrazole-3-carboxylic acid 6a (2 g, 11.69 mmol, Merrill) was dissolved in 30 mL of N,N-dimethylformamide, and potassium carbonate (1.75 g, 12.66 mmol) and benzyl bromide (2.04 g, 11.93 mmol) were added. The mixture was stirred at room temperature for 17 hours. The reaction solution was added to 80 mL of ethyl acetate, washed with water (30 mL × 3), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using a buffer system C to give the title compound 6b (710 mg), yield: 23.3%.

[0183] MS m / z (ESI): 262.0 [M+1].

[0184] Step Two

[0184] Methyl 4-amino-1-benzyl-1H-pyrazole-5-carboxylic acid 6c

[0184] 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 mixture was heated to reflux and stirred for 17 hours. The reaction mixture was cooled to room temperature and filtered through a Buchner funnel pre-lined with diatomaceous earth. The solid was washed with ethyl acetate, and the filtrates were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a buffer system C to give the title compound 6c (650 mg, containing ethanol transesterification product), yield: 100%.

[0184] MS m / z (ESI): 232.2[M+1], 246.2[M+1].

[0185] Step 3

[0185] (R)-1-(4-amino-1-benzyl-1H-pyrazol-5-yl)-3-(3-methylmorpholino)propane-1,3-dione 6d

[0185] A 11.29 mL solution of bis(trimethylsilyl)aminolithium (11.29 mmol, 1 M tetrahydrofuran solution) was placed in a three-necked flask. Under a nitrogen atmosphere, the reaction solution was cooled to an internal temperature between -10°C and 0°C. 0.65 g, 4.54 mmol, 1.6 mL of 2-methyltetrahydrofuran solution (1b) was added dropwise, and the reaction was maintained at this temperature for 40 minutes. Then, 0.65 g, 2.81 mmol, 2.6 mL of 2-methyltetrahydrofuran solution (6c) was added dropwise, and the reaction was maintained at this temperature for 1 hour. 10 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a buffer system C to give the title compound 6d (440 mg), yield: 45.7%.

[0185] MS m / z (ESI): 343.2 [M+1].

[0186] Step Four

[0186] (R)-1-Benzyl-7-chloro-5-(3-methylmorpholino)-1H-pyrazolo[4,3-b]pyridine 6e

[0186] Compound 6d (0.44 g, 1.29 mmol) was dissolved in 5 mL of acetonitrile, and N,N-diisopropylethylamine (0.5 g, 3.87 mmol) was added. The reaction mixture was cooled to an internal temperature between -5 °C and 0 °C. Phosphorus oxychloride (0.79 g, 5.15 mmol) was added dropwise, and the reaction was maintained at this temperature for 1.5 h, then increased to 65 °C and reacted for another 4 h. The reaction mixture was cooled to room temperature and poured into 20 mL of saturated sodium carbonate solution. The solution was 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 using a buffer system C to give the title compound 6e (180 mg), yield: 40.8%.

[0186] MS m / z (ESI): 343.1 [M+1].

[0187] Step 5

[0187] (R)-2-methyl-2-(5-(3-methylmorpholino)-1H-pyrazolo[4,3-b]pyridin-7-yl)propionitrile 6g

[0187] 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 below -70 °C under a nitrogen atmosphere. Bis(trimethylsilyl)aminolithium (3.15 mL, 1 M tetrahydrofuran solution, 3.15 mmol) was added dropwise, and the reaction was maintained at this temperature for 30 minutes, then allowed to rise 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 using a buffer system C to give the title compound 6 g (80 mg), yield: 53.3%.

[0187] MS m / z (ESI): 286.2 [M+1].

[0188] Step Six

[0188] (R)-2-(3-bromo-5-(3-methylmorpholino)-1H-pyrazolo[4,3-b]pyridin-7-yl)-2-methylpropionitrile 6h

[0188] 6 g (80 mg, 0.28 mmol) of compound was dissolved in 2 mL of tetrahydrofuran, and N-bromosuccinimide (50 mg, 0.28 mmol) was added. 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). The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a buffer system C to give the title compound 6h (40 mg), yield: 39.2%.

[0188] MS m / z (ESI): 364.1 [M+1].

[0189] Step Seven

[0189] 2-Methyl-2-(5-((R)-3-methylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propionitrile 6j

[0189] Compound 6h (40 mg, 0.11 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboranecyclopentan-2-yl)-1H-pyrazole 6i (61 mg, 0.22 mmol, Shanghai Bide) and sodium carbonate (24 mg, 0.22 mmol) were placed in a three-necked flask, 2 mL of 1,4-dioxane and 0.5 mL of water were added, and the mixture was purged with nitrogen three times. Then, bis(triphenylphosphine)palladium(II) dichloride (16 mg, 22.8 μmol) was added, and the mixture was purged 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, and the mixture was extracted with ethyl acetate (10 mL × 3). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with a retort system C to give the title compound 6j (25 mg), yield: 52.3%.

[0189] MS m / z (ESI): 436.3 [M+1].

[0190] Step 8

[0190] 2-Methyl-2-(5-((R)-3-methylmorpholino)-3-(1H-pyrazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)propionitrile 6

[0190] Compound 6j (22 mg, 50.51 μmol) was dissolved in 3 mL of isopropanol, and trifluoroacetic acid (404 mg, 3.54 mmol) was added. 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, and then extracted with ethyl acetate (10 mL × 3). The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography using solvent system C to give the title compound 6 (5 mg), yield: 28.2%.

[0190] MS m / z (ESI): 352.1 [M+1].

[0190] 1H NMR (500MHz, CDCl3): δ 7.77(s,1H),7.18(s,1H),6.93(s,1H),4.42-4.43(d,1H),4.14-4.11(m,1H),4.01-3.98(m,1 H),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).

[0191] Comparative Example 1 (Example 7)

[0191] (R)-2-(1-Methyl-5-(3-methylmorpholino)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)prop-2-ol 7

[0191]

[0192] Step 1

[0192] (R)-1-Methyl-5-(3-methylmorpholino)-1H-pyrazolo[4,3-b]pyridin-7-yltrifluoromethanesulfonate 7a

[0192] 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)imine (790 mg, 2.2 mmol) were added and the mixture was stirred for 2.0 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silicone column chromatography using a buffer system C to give the title compound 7a (600 mg), yield: 78.3%.

[0192] MS m / z (ESI): 381.3 [M+1].

[0193] Step Two

[0193] (R)-1-Methyl-5-(3-methylmorpholino)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic acid methyl ester 7b

[0193] Compound 7a (400 mg, 1.05 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloromethane complex (178 mg, 0.21 mmol, Shanghai Bide), and triethylamine (210 mg, 2.09 mmol) were dissolved in 8 mL of methanol. The mixture was stirred at 65 °C for 15 hours under a carbon monoxide atmosphere, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a buffer system C to obtain the title compound 7b (90 mg), yield: 29.5%.

[0193] MS m / z (ESI): 291.1 [M+1].

[0194] Step 3

[0194] (R)-3-bromo-1-methyl-5-(3-methylmorpholine)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic acid methyl ester 7c

[0194] Compound 7b (90 mg, 0.31 mmol) was dissolved in 5 mL of tetrahydrofuran, and N-bromosuccinimide (110 mg, 0.62 mmol) was added. 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). The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude title compound 7c (180 mg). The product was used directly in the next reaction without purification.

[0194] MS m / z (ESI): 369.1 [M+1].

[0195] Step 4

[0195] Methyl-5-((R)-3-methylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridine-7-carboxylic acid methyl ester 7d

[0195] 7c (180 mg, 0.316 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride 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-dioxoborhexacyclopentan-2-yl)-1H-pyrazole (176 mg, 0.632 mmol, Shanghai Bide) were dissolved in 4 mL of dioxane, 1 mL of water was added, and the mixture was heated to 120 °C for 1 hour under an argon atmosphere using a microwave. 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 a retort system C to give the title compound 7d (45 mg), yield: 32.3%.

[0195] MS m / z (ESI): 441.2 [M+1].

[0196] Step 5

[0196] 2-(1-Methyl-5-((R)-3-methylmorpholino)-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)prop-2-ol 7e

[0196] Compound 7d (45 mg, 0.102 mmol) was dissolved in 5 mL of tetrahydrofuran, and 1 M methyl magnesium bromide solution in tetrahydrofuran (36 mg, 0.301 mmol, Shanghai Bide) was added dropwise in an ice bath. After the addition was complete, the mixture was stirred for 2 hours. The reaction solution was then extracted with 10 mL of saturated ammonium chloride solution and ethyl acetate (10 mL × 3). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using extraction solvent system A to give the title compound 7e (40 mg), yield: 88.9%.

[0196] MS m / z (ESI): 441.6 [M+1].

[0197] Step Six

[0197] (R)-2-(1-Methyl-5-(3-methylmorpholino)-3-(1H-pyrazol-3-yl)-1H-pyrazolo[4,3-b]pyridin-7-yl)prop-2-ol 7

[0197] Compound 7e (40 mg, 90 μmol) was dissolved in 3 mL of methanol, and dioxane hydrochloride solution (1 mL, 4 N) was added. The mixture was stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography using solvent system C to give the title compound 7 (10 mg), yield: 30.9%.

[0197] MS m / z (ESI): 357.6 [M+1].

[0197] 1H NMR (400MHz, CD3OD): δ 7.68(s,1H),7.43(s,1H),7.11(s,1H),4.50-4.42(m,2H),4.21(s,3H),4.10-3.99(m,4H),3.84(d,2H),3.68(td,2H),1.28(d,6H).

[0198] Test Example:

[0198] Biological Evaluation

[0198] Test Example 1: The inhibitory effect of the disclosed compound on ATR enzyme.

[0198] The following method was used to determine the inhibitory effect of the disclosed compound on ATR enzymes. The experimental method is briefly described below:

[0199] I. Experimental Materials and Instruments

[0199] 1. ATR enzyme (Eurofins Pharma Discovery Services, 14-953-M)

[0199] 2. GST-tagged P53 protein (Eurofins Pharma Discovery Services, 14-952-M)

[0199] 3.384 well plate (Thermo Scientific, 267462)

[0199] 4. U-shaped bottom 96-hole plate (Corning, 3795)

[0199] 5. Antibody against phosphorylated P53 protein labeled with europium cavitation compound (cisbio, 61P08KAE)

[0199] 6. Anti-GST antibody linked to d2 (cisbio, 61GSTDLF)

[0199] 7. ATP solution (Promega, V916B)

[0199] 8.EDTA (Thermo Scientific, AM9260G)

[0199] 9.HEPES (Gibco, 15630-080)

[0199] 10. Microplate reader (BMG, Pherasta)

[0200] II. Experimental Procedure

[0200] A mixture of 1 nM ATR enzyme, 50 nM P53 protein, 7.435 μM ATP, and small molecule compounds at different concentrations (initial concentration 1 μM, 11 concentrations obtained through 3-fold serial dilutions) was incubated at room temperature for 2 hours. Then, stop solution (12.5 mM HEPES, 250 mM EDTA) was added and mixed. Next, 0.42 ng / well of labeled europium cavitation compound anti-phosphorylated P53 protein antibody and 25 ng / well of linked d2 anti-GST antibody were added. After incubation overnight at room temperature, fluorescence signals at 620 nm and 665 nm were detected using Pherastar. Data were processed using GraphPad software.

[0201] III. Experimental Data

[0201] The inhibitory activity of the compound against ATR enzyme can be determined by the above tests, and the measured IC50 values ​​are shown in Table 1.

[0201]

[0201] Conclusion: Compared with Control Example 1, the compound disclosed herein has better inhibitory activity against ATR enzymes.

[0202] Test Example 2: Cell Proliferation Experiment

[0202] The following method evaluates the inhibitory effect of the disclosed compound on LoVo cell proliferation by detecting intracellular ATP content and based on IC50 value. The experimental method is briefly described below:

[0203] I. Experimental Materials and Instruments

[0203] 1. LoVo, human colon cancer tumor cells (Nanjing Kebai, CBP60032)

[0203] 2. Fetal bovine serum (FBS) (GIBCO, 10091-148)

[0203] 3. F-12K medium (Gibco, 21127030)

[0203] 4. CellTite-Glo reagent (Promega, G7573)

[0203] 5.96-well cell culture plate (corning, 3903)

[0203] 6. Pancreatic enzyme (invitrogen, 25200-072)

[0203] 7. Microplate reader (BMG, PHERAstar)

[0203] 8. Cell counter (Shanghai Ruiyu Biotechnology Co., Ltd., IC1000)

[0204] II. Experimental Procedure

[0204] LoVo cells were cultured in F-12K medium containing 10% FBS, subcultured 2-3 times per week at a subculture ratio of 1:3 or 1:5. During subculture, cells were digested with trypsin and transferred to centrifuge tubes, centrifuged at 1200 rpm for 3 minutes, and the supernatant was discarded. Fresh medium was added to resuspend the cells. 90 μL of the cell suspension was added to each 96-well cell culture plate at a density of 3.88 × 10⁴ cells / ml. Only 100 μL of complete medium was added to the outer edge of the 96-well plate. The culture plate was incubated for 24 hours (37℃, 5% CO₂).

[0205] The test sample was diluted to 2 mM with DMSO, and then serially diluted 3-fold to 10 concentrations, with blank and control wells set up. 5 μL of the prepared gradient concentration test compound solution was added to 95 μL of fresh culture medium. Then, 10 μL of the above drug-containing culture medium solution was added to the culture plate. The culture plate was incubated in an incubator for 3 days (37℃, 5% CO2). In a 96-well cell culture plate, 50 μL of CellTiter-Glo reagent was added to each well, and the plate was incubated at room temperature in the dark for 5-10 min. The chemiluminescence signal value was read in Pherastar, and the data were processed using GraphPad software.

[0206] III. Experimental Data

[0206] The inhibitory activity of the compound of this disclosure on the proliferation of LoVo cells can be determined by the above experiments, and the measured IC50 values ​​are shown in Table 2.

[0206]

[0206] Conclusion: Compared with Control Example 1, the compound disclosed herein has a better inhibitory effect on LoVo cell proliferation.

[0207] Pharmacokinetic Evaluation

[0207] Test Example 3: Pharmacokinetic Test of the Compounds of this Disclosure

[0207] 1. Abstract

[0207] Using rats as test animals, the plasma drug concentrations at different time points after oral administration of the compounds of Example 1, Example 2, and Example 3 were determined by LC / MS / MS. The pharmacokinetic behavior of these compounds in rats was studied to evaluate their pharmacokinetic characteristics.

[0208] 2. Test Plan

[0208] 2.1 Test Drugs

[0208] Compounds of Example 1, Example 2 and Example 3.

[0209] 2.2 Experimental Animals

[0209] Twelve healthy adult SD rats, half male and half female, were randomly divided into three groups of four rats each and purchased from Vital River Laboratory Animal Co., Ltd.

[0210] 2.3 Drug Preparation

[0210] Weigh a certain amount of the drug and add 5% DMSO, 5% Tween 80 and 90% physiological saline to prepare a colorless and clear solution.

[0211] 2.4 Administration

[0211] SD rats were fasted overnight and then administered the drug by gavage. The dosage was 2 mg / kg and the volume was 10.0 mL / kg.

[0212] 3. Operation

[0212] Rats were administered compounds of Example 1, Example 2 and Example 3 by gavage. Blood samples of 0.2 mL were collected from the orbital cavity before administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0 and 24.0 hours after administration. The plasma was placed in EDTA-K2kk anticoagulant tubes, centrifuged at 11000 rpm for 5 minutes at 4°C, and stored at -20°C. The rats were fed 2 hours after administration.

[0213] Determination of the content of the target compound in rat plasma after gavage administration of different concentrations of the drug: Take 25 μL of rat plasma at each time point 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.

[0214] 4. Results of pharmacokinetic parameters

[0214]

[0214] Conclusion: The compound disclosed herein exhibits good drug metabolism and absorption, and has significant pharmacokinetic advantages.

Claims

1. A compound of general formula (I) or a meso compound, racemic mixture, or mixture thereof, or a pharmaceutically acceptable salt thereof, 1. Among them: G1 and G2 may be the same or different, each independently being CH or N, provided that G1 and G2 are not both CH; ring A is a 5-membered heteroaryl; R1 is a C1-C6 alkyl or a 3 to 6-membered cycloalkyl; wherein each of the C1-C6 alkyl or the 3 to 6-membered cycloalkyl is independently substituted by one or more cyano groups; R2 is selected from hydrogen atoms and C1-C6 alkyl; R3 is selected from hydrogen atoms; n is 0.

2. A compound of formula (I) as described in claim 1, or a meso compound, racemic compound, mixture thereof, or pharmaceutically acceptable salt thereof, wherein ring A is selected from pyrazolyl, pyrroleyl, and imidazolyl.

3. A compound of general formula (I) as claimed in claim 1, or a meso compound, racemic mixture thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of general formula (II) is a meso compound, racemic mixture thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

3. Among them: G1, G2, R1, R2, R3 and n are as defined in request item 1.

4. A compound of formula (I) as claimed in claim 1, or a meso compound, racemic mixture thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (III) or formula (IV), or a meso compound, racemic mixture thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

4. Among them: R1, R2, R3, and n are as defined in request item 1.

5. A compound of general formula (I) as claimed in any one of claims 1 to 4, or a meso compound, racemic compound, mixture thereof, or pharmaceutically acceptable salt thereof, wherein R1 is or.

6. A compound of general formula (I) as claimed in any one of claims 1 to 4, or a meso compound, racemic mixture thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R2 is a hydrogen atom.

7. A compound of general formula (I) as claimed in any one of claims 1 to 4, or a meso compound, racemic mixture, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R2 is a C1-C6 alkyl group.

8. A compound or its meso compound, racemic mixture, mixture thereof, or pharmaceutically acceptable salt thereof, selected from any of the following compounds:

9. A compound of general formula (IA) or a meso compound, racemic mixture, or mixture thereof, or a pharmaceutically acceptable salt thereof.

9. Among them: X is a halogen; G1 and G2 may be the same or different, each being CH or N independently, provided that G1 and G2 are not both CH; R1 is a C1-C6 alkyl or a 3- to 6-membered cycloalkyl; wherein the C1-C6 alkyl or the 3- to 6-membered cycloalkyl is substituted by one or more cyano groups; R2 is selected from hydrogen atoms and C1-C6 alkyl.

10. A compound of formula (IA) as claimed in claim 9, or a meso compound, racemic compound, mixture thereof, or pharmaceutically acceptable salt thereof, wherein X is Br.

11. A compound of general formula (IIA) or a meso compound, racemic mixture, or mixture thereof, or a pharmaceutically acceptable salt thereof.

11. Among them: Ra is an amino protecting group, wherein the amino protecting group is tetrahydropyranyl; G1 and G2 may be the same or different, each independently being CH or N, provided that G1 and G2 are not both CH; R1 is a C1-C6 alkyl or a 3 to 6-membered cycloalkyl; wherein each of the C1-C6 alkyl or the 3 to 6-membered cycloalkyl is independently substituted by one or more cyano groups; R2 is selected from hydrogen atoms and C1-C6 alkyl; R3 is selected from hydrogen atoms; n is 0.

12. A compound of general formula (IIGA) or a meso compound, racemic mixture, or mixture thereof, or a pharmaceutically acceptable salt thereof.

12. Among them: G1, G2, R2, R3, Ra, and n are as defined in request item 11; R1 is OR.

13. A compound of formula (IA) as claimed in claim 9, or a meso compound, racemic mixture, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from any of the following compounds:

14. A compound of formula (IIA) as claimed in claim 11, or a meso compound, racemic mixture, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from any of the following compounds:

15. A compound or its meso compound, racemic mixture, mixture thereof, or pharmaceutically acceptable salt thereof, selected from the following compounds:

16. A method for preparing a compound of general formula (I) as claimed in claim 1, or a meso compound, racemic mixture, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

16. A compound of general formula (IA) and a compound of general formula (IB) undergo a coupling reaction to give a compound of general formula (I), wherein: X is a halogen; Rb is halogenated or halogenated; and rings A, G1, G2, R1, R2, R3 and n are as defined in claim 1.

17. A method for preparing a compound of general formula (IIA) as claimed in claim 11, or a meso compound, racemic mixture, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

17. A compound of formula (IA) and a compound of formula (IIB) undergo a coupling reaction to give a compound of formula (IIA), wherein: X is a halogen; Ra is an amino protecting group, said amino protecting group being tetrahydropyranyl; Rb is or; G1, G2, R1, R2, R3 and n are as defined in claim 11.

18. A method for preparing a compound of general formula (IIGA) or a meso compound, racemic mixture, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

18. A compound of formula (IA) and a compound of formula (IIGB) undergo a coupling reaction to give a compound of formula (IIGA), wherein: X is a halogen; Ra is an amino protecting group, said amino protecting group being tetrahydropyranyl; Rb is or; G1, G2, R1, R2, R3 and n are as defined in claim 12.

19. The method of any one of claims 16 to 18, wherein X is Br.

20. A method for preparing a compound of general formula (II) or a meso compound, racemic mixture, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

20. A compound of general formula (IIA) is deaminoprotected to obtain a compound of general formula (II), wherein: R6 is an aminoprotecting group, said aminoprotecting group being tetrahydropyranyl; G1, G2, R1, R2, R3 and n are as defined in claim 3.

21. A method for preparing a compound of general formula (II) or a meso compound, racemic mixture, or mixture thereof or a pharmaceutically acceptable salt thereof, the method comprising:

21. A compound of general formula (IIGA) is deamined to obtain a compound of general formula (II), wherein: Ra is an amino protecting group, said amino protecting group being tetrahydropyranyl; G1, G2, R1, R2, R3 and n are as defined in claim 12.

22. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 9, or a meso, racemic, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

23. A pharmaceutical composition comprising 0.1 to 1000 mg of the following compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients:

24. A pharmaceutical composition comprising 0.1 to 99% by weight of the following compounds or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients:

25. Use of a compound of general formula (I) as claimed in any one of claims 1 to 8, or a meso compound, racemic mixture thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in any one of claims 22 to 24, in the preparation of a medicament for inhibiting ATR kinase.

26. Use of a compound of general formula (I) as claimed in any one of claims 1 to 8, or a meso compound, racemic mixture thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in any one of claims 22 to 24, in the preparation of a medicament for the treatment and / or prevention of hyperproliferative diseases.

27. Use of a compound of general formula (I) as claimed in any one of claims 1 to 8, or a meso compound, racemic mixture thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in any one of claims 22 to 24, in the preparation of a medicament for the treatment and / or prevention of tumors.