Imidazolopyrimidine derivatives, preparation methods thereof and their application in medicine

Abstract

The present disclosure relates to imidazopyrimidine derivatives, preparation methods thereof and their applications in medicine. Specifically, the present disclosure relates to an imidazopyrimidine derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, in particular, its use as an ATR kinase inhibitor and its use in the preparation of a drug for treating or preventing hyperproliferative diseases. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of medicine and relates to an imidazopyrimidine derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and the use thereof as a therapeutic agent, in particular, the use thereof as an ATR kinase inhibitor and the use thereof in the preparation of a drug for treating and preventing hyperproliferative diseases. Background Art

[0002] Thousands of DNA damages occur every day in both normal cells and tumor cells. This makes DNA damage repair play a vital role in maintaining genome stability and cell survival. Compared with normal cells, tumor cells are under greater replication pressure, carry more endogenous DNA damage, and often lack one or more DNA damage repair pathways. This makes the survival of tumor cells more dependent on the smooth progress of DNA damage repair.

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

[0004] The patent applications for ATR inhibitors that have been disclosed include WO2010071837, WO2011154737, WO2016020320, WO2016130581, WO2017121684, WO2017118734, WO2018049400, WO2019050889 and WO2014140644, etc. Summary of the invention

[0005] The object of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0006]

[0007] in:

[0008] R 0 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, and a cycloalkylalkyl group;

[0009] R 1 and R 2 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, heterocyclyloxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkoxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0010] R 3 is selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0011] R 4 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0012] R 5 is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl and cycloalkylalkyl;

[0013] n is 0, 1, 2 or 3.

[0014] In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (Ia) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0015]

[0016] Among them, R 0 , R 1 , R 2 , R 3 , R 4 and n are as defined in the general formula (I).

[0017] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 is a heteroaryl group, which is optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro and cycloalkyl.

[0018] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 is a five-membered heteroaryl group, wherein the five-membered heteroaryl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 The alkyl group is substituted with one or more substituents.

[0019] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 is selected from pyrazolyl, imidazolyl, pyrrolyl and triazolyl, preferably pyrazolyl, wherein the pyrazolyl, imidazolyl, pyrrolyl and triazolyl are optionally selected from halogen, C 1-6 Alkyl and halogenated C 1-6 The alkyl group is substituted with one or more substituents.

[0020] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 2 for Preferably R 2a Selected from hydrogen atoms, C 1-6 Alkyl and halogenated C 1-6 Alkyl; preferably, R 2a It is methyl or ethyl.

[0021] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 3 is a heteroaryl group, which is optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro and cycloalkyl.

[0022] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 3 is a five-membered heteroaryl group, wherein the five-membered heteroaryl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 The alkyl group is substituted with one or more substituents.

[0023] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from pyrazolyl, imidazolyl, pyrrolyl and triazolyl, preferably pyrazolyl, wherein the pyrazolyl, imidazolyl, pyrrolyl and triazolyl are optionally selected from halogen, C 1-6 Alkyl and halogenated C 1-6 The alkyl group is substituted with one or more substituents.

[0024] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 3 for Preferably R 3aSelected from hydrogen atoms, C 1-6 Alkyl and halogenated C 1-6 Alkyl; preferably, R 3a A hydrogen atom.

[0025] In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0026]

[0027] in:

[0028] R 6 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0029] R 7 are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0030] p and q are the same or different and are each independently selected from 0, 1, 2 or 3;

[0031] R 0 , R 1 , R 4 and n are as defined in the general formula (I).

[0032] In some embodiments of the present disclosure, the compound represented by the general formula (I), (Ia) or (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 0 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group and a cyano group; preferably, R 0 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl and cyano; more preferably a hydrogen atom or C 1-6 alkyl.

[0033] In some embodiments of the present disclosure, the compound represented by the general formula (I), (Ia) or (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, heterocyclyloxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino and cycloalkyl; wherein the alkyl, alkoxy, heterocyclyloxy and cycloalkyl are each independently substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino and nitro;

[0034] Preferably, R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0035] More preferably, R 1 A hydrogen atom.

[0036] In some embodiments of the present disclosure, the compound represented by the general formula (I), (Ia) or (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 4 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino and cycloalkyl; wherein the alkyl, alkoxy and cycloalkyl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino and nitro;

[0037] Preferably, R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0038] More preferably, R 4 A hydrogen atom.

[0039] In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 5 is alkyl or halogenated alkyl; preferably C 1-6 Alkyl; more preferably methyl.

[0040] In some embodiments of the present disclosure, the compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 6 are the same or different and are independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino and nitro; preferably, R 6 are the same or different and are independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; more preferably C 1-6 Alkyl; more preferably methyl.

[0041] In some embodiments of the present disclosure, the compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 7 are the same or different and are independently selected from hydrogen, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino and nitro; preferably, R 7 are the same or different and are independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 An alkyl group; more preferably a hydrogen atom.

[0042] In some embodiments of the present disclosure, the compound represented by the general formula (I), (Ia) or (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1, preferably 1.

[0043] In some embodiments of the present disclosure, the compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0044] In some embodiments of the present disclosure, the compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1, preferably 1.

[0045] In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 0 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Hydroxyalkyl and cyano; R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; R 2 is a five-membered heteroaryl group, wherein the five-membered heteroaryl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 The alkyl group is substituted by one or more substituents; R 3 is a five-membered heteroaryl group, wherein the five-membered heteroaryl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy and halogenated C 1-6 The alkyl group is substituted by one or more substituents; R 4 is a hydrogen atom; R 5 C 1-6 alkyl; n is 0 or 1. In some embodiments of the present disclosure, the compound represented by the general formula (Ia) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 0 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl and cyano; R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; R 2 for R 2a Selected from hydrogen atoms, C 1-6 Alkyl and halogenated C 1-6 Alkyl; R 3 for R 3a Selected from hydrogen atoms, C 1-6 Alkyl and halogenated C 1-6 Alkyl; R 4 is a hydrogen atom; n is 0 or 1.

[0046] In some embodiments of the present disclosure, the compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or pharmaceutically acceptable salt thereof, wherein R 0 A hydrogen atom or C 1-6 Alkyl; R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; R 4 is a hydrogen atom; R 6are the same or different and are independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; R 7 are the same or different and are independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and halogenated C 1-6 Alkyl; n is 0 or 1; p is 1; q is 1.

[0047] Table A Typical compounds of the present disclosure include, but are not limited to:

[0048]

[0049]

[0050] or its tautomer, meso racemate, racemate, enantiomer, diastereomer, or mixture thereof, or its pharmaceutically acceptable salt.

[0051] Another aspect of the present disclosure relates to a compound represented by the general formula (IA) or a tautomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0052]

[0053] in:

[0054] X is a hydrogen atom or a halogen; preferably a halogen; more preferably Br;

[0055] R 0 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group, and a cycloalkylalkyl group;

[0056] R 1 and R 2 are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, heterocyclyloxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkoxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0057] R 4are the same or different, and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclic, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl and heteroaryl are each independently optionally substituted by one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0058] R 5 is selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl and cycloalkylalkyl;

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

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

[0061]

[0062] in:

[0063] X is a hydrogen atom or a halogen; preferably a halogen; more preferably Br;

[0064] R 0 , R 1 , R 2 , R 4 and n are as defined in the general formula (Ia).

[0065] Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0066]

[0067] in:

[0068] X is a hydrogen atom or a halogen; preferably a halogen; more preferably Br;

[0069] R 0 , R 1 , R 4 , R 6 , n and p are as defined in the general formula (II).

[0070] Typical intermediate compounds of the present disclosure include, but are not limited to:

[0071]

[0072]

[0073]

[0074] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0075]

[0076] A compound of the general formula (IA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a compound of the general formula (IB) undergo a coupling reaction to obtain a compound of the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0077] in:

[0078] X is halogen; preferably Br;

[0079] Y is

[0080] R is a hydrogen atom or an alkyl group;

[0081] R 0 , R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined in the general formula (I).

[0082] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (Ia) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0083]

[0084] A compound of the general formula (I-aA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a compound of the general formula (IB) undergo a coupling reaction to obtain a compound of the general formula (Ia) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0085] in:

[0086] X is halogen; preferably Br;

[0087] Y is

[0088] R is a hydrogen atom or an alkyl group;

[0089] R 0 , R 1 , R 2 , R 3 , R 4 and n are as defined in the general formula (Ia).

[0090] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0091]

[0092] The compound of the general formula (IIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, and the compound of the general formula (IIB) undergo coupling reaction to obtain the compound of the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0093] in:

[0094] X is halogen; preferably Br;

[0095] Y is

[0096] R is a hydrogen atom or an alkyl group;

[0097] R 0 , R 1 , R 4 , R 6 , R 7 , n, p and q are as defined in the general formula (II).

[0098] Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a compound of the present disclosure represented by general formula (I), (Ia), (II) or Table A, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0099] The present disclosure further relates to the use of a compound represented by the general formula (I), (Ia), (II) or Table A, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting ATR kinase.

[0100] The present disclosure further relates to the use of a compound of formula (I), (Ia), (II) or shown in Table A or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same in the preparation of a medicament for treating or preventing a hyperproliferative disease.

[0101] The present disclosure further relates to the use of a compound of the general formula (I), (Ia), (II) or shown in Table A or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same in the preparation of a medicament for treating or preventing tumors.

[0102] The present disclosure further relates to the use of a compound of the general formula (I), (Ia), (II) or shown in Table A or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same in the preparation of a drug for treating tumors.

[0103] The present disclosure also relates to a method for inhibiting ATR kinase, which comprises administering to a patient in need thereof an effective inhibitory amount of a compound of the general formula (I), (Ia), (II) or shown in Table A, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0104] The present disclosure also relates to a method for treating or preventing a hyperproliferative disease, comprising administering to a patient in need thereof an effective amount of a compound of the general formula (I), (Ia), (II) or shown in Table A, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0105] The present disclosure also relates to a method for treating or preventing tumors, comprising administering to a patient in need thereof an effective amount of a compound of the general formula (I), (Ia), (II) or shown in Table A, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0106] The present disclosure further relates to a compound of formula (I), (Ia), (II) or shown in Table A or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same, which is used as a drug.

[0107] The present disclosure also relates to compounds represented by general formula (I), (Ia), (II) or Table A, or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, which are used as ATR kinase inhibitors.

[0108] The present disclosure also relates to compounds represented by general formula (I), (Ia), (II) or Table A, or their tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in treating or preventing hyperproliferative diseases.

[0109] The present disclosure further relates to a compound represented by the general formula (I), (Ia), (II) or Table A, or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in treating tumors.

[0110] The tumor described in the present disclosure is preferably selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, glioma, sarcoma, bone cancer, endometrial cancer, head and neck tumor, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor, bladder cancer and gallbladder cancer.

[0111] The active compound can be prepared into a form suitable for administration by any appropriate route, and the composition of the present disclosure can be prepared by conventional methods using one or more pharmaceutically acceptable carriers. Therefore, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compound of the present disclosure can be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges or syrups.

[0112] As a general guide, the active compounds of the present disclosure are preferably in a unit dose form, or in a form that a patient can self-administer in a single dose. The unit dose of the compounds or compositions of the present disclosure can be expressed in tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid formulations. Suitable unit doses can be 0.1 to 1000 mg.

[0113] The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0114] Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

[0115] Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.

[0116] Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

[0117] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or a mineral oil. Oil suspensions may contain a thickening agent. Sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

[0118] Pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, or a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

[0119] The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, and the injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0120] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared with suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable nontoxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

[0121] The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0122] The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by the addition of water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

[0123] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the severity of the disease, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound or the type of pharmaceutically acceptable salt can be verified according to traditional treatment regimens.

[0124] Terminology

[0125] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0126] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available attachment point, and the substituents are preferably independently selected from one or more substituents of H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0127] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group, which is a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, and is a straight or branched group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and the like. The alkylene group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, the substituents preferably being independently selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and oxo.

[0128] The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above. Alkenyl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents of hydrogen atom, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0129] The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above. Alkynyl can be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents in hydrogen atom, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0130] 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, preferably 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, and 8), and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include cycloalkyls of spirocyclic, condensed, and bridged rings.

[0131] The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 yuan, a carbon atom (called spiral atom) shared between monocyclic rings, which may contain one or more double bonds. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0132]

[0133] The term "condensed cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5 yuan / 5 yuan or 5 yuan / 6 yuan bicyclic alkyl. Non-limiting examples of condensed cycloalkyl include:

[0134]

[0135] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, it is 6 to 14 members, and more preferably, it is 7 to 10 members (e.g., 7, 8, 9, or 10 members). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic, or tetracyclic, more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0136]

[0137] The cycloalkyl ring includes a cycloalkyl group as described above (including a monocyclic ring, a spirocyclic ring, a condensed ring and a bridged ring) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include etc.; preferably

[0138] The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0139] The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from H atoms, D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

[0140] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxidized (i.e. forming a sulfoxide or sulfone), but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms being 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 ring atoms (e.g. 3, 4, 5, 6, 7 and 8), of which 1-3 are heteroatoms (e.g. 1, 2 and 3); more preferably, it contains 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably, it contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

[0141] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiral atom) is shared between 5 to 20 monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of spiral atoms shared between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. It is more preferably a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0142]

[0143] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 yuan, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5 yuan / 5 yuan or 5 yuan / 6 yuan bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0144]

[0145]

[0146] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxoed (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into 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:

[0147]

[0148] The heterocyclic ring includes a heterocyclic group as described above (including a monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples of which include:

[0149] wait.

[0150] The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic group, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl, heteroaryl.

[0151] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent carbon atom pairs) group with a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and its non-limiting examples include:

[0152]

[0153]

[0154] The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

[0155] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9, or 10 yuan), more preferably 5 yuan or 6 yuan, such as furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

[0156]

[0157] The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from one or more substituents of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0158] The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from a parent ring atom by removing one hydrogen atom, or residues derived from the same or two different ring atoms of the parent by removing two hydrogen atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

[0159] The term "amino protecting group" is to protect the amino group with an easily removable group in order to keep the amino group unchanged when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro. The term "hydroxy protecting group" is a suitable group for hydroxy protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed.TWGreene & P.GMWuts) in the hydroxyl protecting group. As an example, preferably, the hydroxyl protecting group can be (C 1-10 alkyl or aryl) 3 silyl, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, etc.; it can be C 1-10 Alkyl or substituted alkyl, preferably alkoxy substituted alkyl or aryl substituted alkyl, more preferably C 1-6 Alkoxy substituted C 1-6 Alkyl or phenyl substituted C 1-6 Alkyl, most preferably C 1-4 Alkoxy substituted C 1-4 Alkyl, for example: methyl, tert-butyl, benzyl, methoxymethyl (MOM), ethoxyethyl; can be (C 1-10 alkyl or aromatic) acyl, for example: formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.; can be (C 1-6 Alkyl or C 6-10 Aryl)sulfonyl; can also be (C 1-6 Alkoxy or C 6-10 aryloxy)carbonyl.

[0160] The term "cycloalkyloxy" refers to a cycloalkyl-O- group wherein cycloalkyl is as defined above.

[0161] The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

[0162] The term "aryloxy" refers to an aryl-O- group in which aryl is as defined above.

[0163] The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

[0164] The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

[0165] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0166] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0167] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0168] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0169] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0170] The term "hydroxy" refers to -OH.

[0171] The term "thiol" refers to -SH.

[0172] The term "amino" refers to -NH2.

[0173] The term "cyano" refers to -CN.

[0174] The term "nitro" refers to -NO2.

[0175] The term "oxo" or "oxo" refers to "=0".

[0176] The term "carbonyl" refers to C=O.

[0177] The term "carboxy" refers to -C(O)OH.

[0178] The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined above.

[0179] The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure of the present disclosure except that hydrogen is replaced by "deuterium" or "tritium", or by 18 F-fluorine labeling ( 18 F isotope) instead of fluorine, or with 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or14 C-carbon labeling; 11 C-, 13 C-, or 14 Compounds in which a carbon atom is replaced by a C-isotope) are within the scope of the present disclosure. Such compounds can be used as analytical tools or probes in, for example, biological assays, or can be used as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics or receptor studies. The present disclosure also includes various deuterated compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated compounds with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing deuterated compounds, or they can be synthesized using deuterated reagents using conventional techniques, and deuterated reagents include but are not limited to deuterated borane, trideuterated borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated substances can generally retain activity comparable to undeuterated compounds, and when deuterated at certain specific sites, better metabolic stability can be achieved, thereby obtaining certain therapeutic advantages.

[0180] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0181] "Substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently by a corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0182] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0183] "Pharmaceutically acceptable salts" refer to salts of the disclosed compounds that are safe and effective for use in mammals and have the desired biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

[0184] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0185] The term "solvate" as used herein refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. The physical association includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated into the lattice of a crystalline solid, the solvate will be separated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0186] "Prodrug" refers to a compound that can be transformed in vivo under physiological conditions, for example, by hydrolysis in the blood, to yield the active prodrug.

[0187] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio, and effective for the intended use.

[0188] As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

[0189] When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by those skilled in the art, when a parameter is not critical, numbers are generally given only for illustrative purposes and not for limitation.

[0190] Synthesis method of the disclosed compound

[0191] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0192] Solution 1

[0193] The method for preparing the compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprises the following steps:

[0194]

[0195] The compound of the general formula (IA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof and the compound of the general formula (IB) undergo coupling reaction in the presence of a catalyst under alkaline conditions to obtain the compound of the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0196] in:

[0197] X is halogen; preferably Br;

[0198] Y is

[0199] R is a hydrogen atom or an alkyl group;

[0200] R 0 , R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined in the general formula (I).

[0201] Solution 2

[0202] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (Ia) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0203]

[0204] A compound of the general formula (I-aA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a compound of the general formula (IB) undergo a coupling reaction in the presence of a catalyst under alkaline conditions to obtain a compound of the general formula (Ia) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

[0205] in:

[0206] X is halogen; preferably Br;

[0207] Y is

[0208] R is a hydrogen atom or an alkyl group;

[0209] R 0 , R 1 , R 2 , R 3 , R 4 and n are as defined in the general formula (Ia).

[0210] Option 3

[0211] The method for preparing the compound represented by the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, comprises the following steps:

[0212]

[0213] The compound of general formula (IIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof and the compound of general formula (IIB) undergo coupling reaction in the presence of a catalyst under alkaline conditions to obtain the compound of general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof,

[0214] in:

[0215] X is halogen; preferably Br;

[0216] Y is

[0217] R is a hydrogen atom or an alkyl group;

[0218] R 0 , R 1 , R 4 , R 6 , R 7 , n, p and q are as defined in the general formula (II).

[0219] 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, lithium diisopropylamide, lithium bistrimethylsilylamide, 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, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide, preferably sodium carbonate or anhydrous sodium carbonate.

[0220] The catalyst described in the above synthesis scheme includes but is not limited to palladium / carbon, tetrakistriphenylphosphine palladium, palladium dichloride, palladium acetate, bis(dibenzylideneacetone)palladium, chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex, 1,1′-bis(dibenzylphosphine)dichloroferrocenepalladium or tris(dibenzylideneacetone)dipalladium, preferably [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex.

[0221] The above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water or N,N-dimethylformamide. DETAILED DESCRIPTION

[0222] The present disclosure is further described below in conjunction with embodiments, but these embodiments do not limit the scope of the present disclosure.

[0223] Example

[0224] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 or Bruker AVANCENEO 500M NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measurement solvent, and tetramethylsilane (TMS) as the internal standard.

[0225] MS was determined using Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC / MS (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS); Waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector); THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0226] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0227] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0228] High performance liquid chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

[0229] Chiral preparative chromatography was performed using a Shimadzu LC-20AP preparative chromatograph.

[0230] The CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

[0231] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0232] Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0233] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0234] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0235] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0236] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0237] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1L.

[0238] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0239] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0240] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0241] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0242] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0243] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of the column chromatography used for purifying the compound and the developing solvent system of the thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0244] Example 1

[0245] (R)-3-methyl-4-(6-methyl-2-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-4-yl)morpholine 1

[0246]

[0247]

[0248] first step

[0249] N-((4,6-dioxo-1,4,5,6-tetrahydropyrimidin-2-yl)methyl)acetamide 1c

[0250] Under argon atmosphere, malonamide 1a (8.6 g, 84.2 mmol, Shanghai BiDe), acetylglycine ethyl ester 1b (12.9 g, 88.87 mmol) and sodium methoxide (11.2 g, 207.3 mmol) were added to methanol (150 mL), refluxed for 14 hours, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1c (12 g). The product was used directly in the next reaction without purification.

[0251] MS m / z(ESI):184.1[M+1].

[0252] Step 2

[0253] 2,4-Dichloro-6-methylimidazo[1,5-a]pyrimidine 1d

[0254] The crude compound 1c (12 g, 65.5 mmol) was dissolved in toluene (50 mL), phosphorus oxychloride (36 mL, 393.1 mmol) was added, N, N-diisopropylethylamine (33 mL, 196.5 mmol) was slowly added, and the mixture was reacted at 90°C for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and stirred for 0.5 hours with dichloromethane (500 mL), filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1d (8 g), which was directly used in the next step without purification.

[0255] MS m / z(ESI):202.1[M+1].

[0256] Step 3

[0257] (R)-4-(2-Chloro-6-methylimidazo[1,5-a]pyrimidin-4-yl)-3-methylmorpholine 1f

[0258] The crude compound 1d (8 g, 39.59 mmol) was dissolved in 80 mL of acetonitrile, and N,N-diisopropylethylamine (232.12 mmol, 39 mL) and (R)-3-methylmorpholine (1e) (8 g, 79.0 mmol, Shanghai Bidex) were added, and the mixture was reacted at 75°C for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, extracted with water (150 mL), extracted with ethyl acetate (80 mL×2), and purified by silica gel column chromatography with eluent system C to obtain the title compound 1f (500 mg, yield: 4.7%).

[0259] MS m / z(ESI):267.2[M+1].

[0260] Step 4

[0261] (R)-3-methyl-4-(6-methyl-2-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-4-yl)morpholine 1g

[0262] Compound 1f (40 mg, 0.15 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (56 mg, 0.44 mmol, Shanghai Bid) were dissolved in a mixed solution of 4 mL of dioxane and water (v:v=3:1), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (19 mg, 0.022 mmol) and anhydrous sodium carbonate (60 mg, 0.56 mmol) were added, and the temperature was raised to 100°C for reaction for 2 hours. After cooling to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 1g (40 mg, yield: 85.3%).

[0263] MS m / z(ESI):313.1[M+1].

[0264] Step 5

[0265] (R)-4-(8-Bromo-6-methyl-2-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-4-yl)-3-methylmorpholine 1h

[0266] Compound 1g (40 mg, 0.13 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran, cooled to -78°C, N-bromosuccinimide (23 mg, 0.13 mmol) was added, and stirred for 10 minutes. The reaction solution was warmed to room temperature, 3 mL of saturated sodium bicarbonate solution was added, and ethyl acetate was extracted (10 mL×3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude title product 1h (40 mg, yield: 79.2%), which was used directly in the next step without purification.

[0267] MS m / z(ESI):391.1[M+1].

[0268] Step 6

[0269] (R)-3-methyl-4-(6-methyl-2-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-4-yl)morpholine 1

[0270] The crude compound 1h (40 mg, 0.102 mmol) was dissolved in a mixed solution of 4 mL of dioxane and water (v:v=3:1), (1H-pyrazol-3-yl)boronic acid 1i (23 mg, 0.204 mmol, Shanghai Bidex), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (17 mg, 0.02 mmol) and anhydrous sodium carbonate (27 mg, 0.26 mmol) were added, and the mixture was heated to 90°C and stirred for 2 hours. After cooling to room temperature, the reaction solution was filtered and concentrated under reduced pressure. The crude product was purified by high performance liquid preparative chromatography (Waters 2545-2767, elution system: ammonium bicarbonate, acetonitrile, water) to obtain the title product 1 (6 mg, yield: 15.6%).

[0271] MS m / z(ESI):379.2[M+1].

[0272] 1 H NMR (400MHz, CDCl3): δ7.77(s, 1H), 7.57(s, 1H), 6.89(s, 1H), 6.71(s, 1H), 6.49(s, 1H), 4.43(s, 3H), 4 .01 (d, 2H), 3.93 (s, 1H), 3.44-3.40 (m, 2H), 3.23 (d, 1H), 3.00 (s, 3H), 2.95-2.92 (m, 1H), 1.25 (d, 3H).

[0273] Example 2

[0274] (R)-4-(6-ethyl-2-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-4-yl)-3-methylmorpholine

[0275]

[0276] first step

[0277] N-((4,6-dioxo-1,4,5,6-tetrahydropyrimidin-2-yl)methyl)propanamide 2b

[0278] Under argon atmosphere, compound 1a (5 g, 48.9 mmol, Shanghai BiDe), compound 2a (8.5 g, 53.4 mmol, prepared by the method disclosed in Intermediate 3 on page 76 of the specification of patent application "WO2015095788"), and sodium methoxide (6.6 g, 122.16 mmol) were added to methanol (25 mL), refluxed for 3 hours, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 2b (9.6 g), which was used directly in the next reaction without purification.

[0279] MS m / z(ESI):198.0[M+1].

[0280] Step 2

[0281] 2,4-Dichloro-6-ethylimidazo[1,5-a]pyrimidine 2c

[0282] The crude compound 2b (9.6 g, 48.6 mmol) was dissolved in toluene (80 mL), phosphorus oxychloride (27 mL, 292.1 mmol) was added, N, N-diisopropylethylamine (33 mL, 194.7 mmol) was slowly added, and the mixture was reacted at 90°C for 3 hours. The reaction solution was concentrated under reduced pressure, dichloromethane (500 mL) was added, stirred for 0.5 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 2c (10 g), which was directly used in the next step without purification.

[0283] MS m / z(ESI):216.1[M+1].

[0284] Step 3

[0285] (R)-4-(2-chloro-6-ethylimidazo[1,5-a]pyrimidin-4-yl)-3-methylmorpholine 2d

[0286] The crude compound 2c (10 g, 46.3 mmol) was dissolved in 80 mL of acetonitrile, and N,N-diisopropylethylamine (185.12 mmol, 32 mL) and compound 1e (23 g, 227.4 mmol) were added, and the mixture was reacted at 75°C for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, extracted with water (150 mL), extracted with ethyl acetate (80 mL×2), and purified by silica gel column chromatography with eluent system C to obtain the title compound 2d (1.3 g, yield: 10%).

[0287] MS m / z(ESI):281.2[M+1].

[0288] Step 4

[0289] (R)-4-(6-ethyl-2-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-4-yl)-3-methylmorpholine 2e

[0290] Compound 2d (300 mg, 1.07 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (555 mg, 2.67 mmol, Shanghai Bidex) were dissolved in a mixed solution of 6 mL of dioxane and water (v:v=5:1), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (135 mg, 0.16 mmol) and anhydrous sodium carbonate (339 mg, 3.19 mmol) were added, and the mixture was reacted at 100°C for 2 hours. After cooling to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 2e (300 mg, yield: 86%).

[0291] MS m / z(ESI):327.1[M+1].

[0292] Step 5

[0293] (R)-4-(8-Bromo-6-ethyl-2-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-4-yl)-3-methylmorpholine 2f

[0294] Compound 2e (300 mg, 919.13 μmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, cooled to -78°C, N-bromosuccinimide (114 mg, 640.51 μmol) was added, and stirred for 10 minutes. The reaction solution was warmed to room temperature, 3 mL of saturated sodium bicarbonate solution was added, and ethyl acetate was used for extraction (10 mL × 3). The organic phases were combined and concentrated under reduced pressure to obtain the crude title compound 2f (240 mg), which was used directly in the next step without purification.

[0295] MS m / z(ESI):405.1[M+1].

[0296] Step 6

[0297] (R)-4-(6-ethyl-2-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-4-yl)-3-methylmorpholine

[0298] Under argon atmosphere, crude compound 2f (370 mg, 912.9 μmol) was dissolved in 10 mL 1,4-dioxane and 2 mL water, compound 1i (204 mg, 1.82 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (116 mg, 137 μmol) and sodium carbonate (193 mg, 1.82 mmol) were added in sequence, and stirred at 90° C. for 4 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was purified by high performance liquid preparative chromatography (Waters 2545-2767, elution system: ammonium bicarbonate, acetonitrile, water) to obtain the title compound 2 (98 mg, yield: 27.3%).

[0299] MS m / z(ESI):393.0[M+1].

[0300] 1H NMR (500MHz, CD3OD): δ7.65 (s, 1H), 7.56 (d, 1H), 7.09-6.97 (m, 1H), 6.90 (d, 2H), 4.39 (d, 3H), 4.10-3.73(m, 4H), 3.62-3.37(m, 4H), 2.95(ddd, 1H), 1.44(t, 3H), 1.13-1.02(m, 3H).

[0301] Example 3

[0302] (R)-4-(2-(1-ethyl-1H-pyrazol-5-yl)-6-methyl-8-(1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-4-yl)-3-methylmorpholine 3

[0303]

[0304] first step

[0305] (R)-4-(2-(1-ethyl-1H-pyrazol-5-yl)-6-methylimidazo[1,5-a]pyrimidin-4-yl)-3-methylmorpholine 3b

[0306] Compound 1f (100 mg, 0.37 mmol) and 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3a) (166 mg, 0.75 mmol, Shanghai Bidex) were dissolved in a mixed solution of 4 mL of dioxane and water (v:v=3:1), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (47 mg, 0.055 mmol) and anhydrous sodium carbonate (119 mg, 1.12 mmol) were added, and the mixture was reacted at 100°C for 2 hours. After cooling to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 3b (100 mg, yield: 81.7%).

[0307] MS m / z(ESI):327.3[M+1].

[0308] Step 2

[0309] (R)-4-(8-Bromo-2-(1-ethyl-1H-pyrazol-5-yl)-6-methylpyrazolo[1,5-a]pyrimidin-4-yl)-3-methylmorpholine 3c

[0310] Compound 3b (100 mg, 0.3 mmol) was dissolved in 2 mL of anhydrous tetrahydrofuran, cooled to -78°C, N-bromosuccinimide (27 mg, 0.15 mmol) was added, and stirred for 20 minutes. The reaction solution was warmed to room temperature, 3 mL of saturated sodium bicarbonate solution was added, and ethyl acetate was extracted (10 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain a crude title compound 3c (100 mg, yield: 80%), which was used directly in the next step without purification.

[0311] MS m / z(ESI):405.0[M+1].

[0312] Step 3

[0313] (R)-4-(2-(1-ethyl-1H-pyrazol-5-yl)-6-methyl-8-(1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-4-yl)-3-methylmorpholine 3

[0314] Compound 3c (100 mg, 0.247 mmol) was dissolved in 4 mL of a mixed solution of dioxane and water (v:v=3:1), and compound 1i (55 mg, 0.491 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (31 mg, 0.04 mmol) and anhydrous sodium carbonate (78 mg, 0.74 mmol) were added, and stirred at 90°C for 2 hours. After cooling to room temperature, the reaction solution was filtered and concentrated under reduced pressure, and the obtained residue was purified by high performance liquid preparative chromatography (Waters 2545-2767, elution system: ammonium bicarbonate, acetonitrile, water) to obtain compound 3 (30 mg, yield: 30.9%).

[0315] MS m / z(ESI):393.0[M+1].

[0316] 1 H NMR (500MHz, CD3OD): δ7.85-7.45(m, 2H), 7.03(s, 1H), 6.95-6.43(m, 2H), 4.91(d, 2H), 4.20-3.56(m, 4H), 3.55-3.33(m, 2H), 3.01(s, 4H), 1.50(t, 3H), 1.05(d, 3H).

[0317] Example 4

[0318] (R)-3-methyl-4-(2-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-4-yl)morpholine

[0319]

[0320] first step

[0321] 2,4-Dihydroxyimidazo[1,5-a]pyrimidine-8-carboxylic acid methyl ester 4b

[0322] Under argon atmosphere, dimethyl malonate (700 mg, 5.3 mmol), methyl 5-amino-1H-imidazole-4-carboxylate (4a) (500 mg, 3.5 mmol, Shanghai Hanhong), cesium carbonate (2.3 g, 7.08 mmol) were added to N, N-dimethylformamide (15 mL) and stirred at 110°C for 15 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 4b (1.2 g), which was directly used in the next step without purification.

[0323] MS m / z(ESI):210.1[M+1].

[0324] Step 2

[0325] 2,4-Dichloroimidazo[1,5-a]pyrimidine-8-carboxylic acid methyl ester 4c

[0326] The crude compound 4b (1.0 g, 4.78 mmol) was dissolved in toluene (20 mL), phosphorus oxychloride (3 mL, 35.1 mmol) was added, and the mixture was reacted at 100°C for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and stirred for 0.5 hours with dichloromethane (500 mL), filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 4c (3.2 g), which was used directly in the next step without purification.

[0327] MS m / z(ESI):246.0[M+1].

[0328] Step 3

[0329] (()-2-Chloro-4-(3-methylmorpholine)imidazo[1,5-a]pyrimidine-8-carboxylic acid methyl ester 4d

[0330] The crude compound 4c (1.0 g, 1.6 mmol) was dissolved in 20 mL of acetonitrile, and N,N-diisopropylethylamine (1.05 g, 8.0 mmol) and compound 1e (822 mg, 8 mmol) were added, and the mixture was reacted at 75°C for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, extracted with water (50 mL), extracted with ethyl acetate (50 mL×2), and purified by silica gel column chromatography with eluent system C to obtain the title compound 4d (120 mg), with a yield of 23.7%.

[0331] MS m / z(ESI):311.1[M+1].

[0332] Step 4

[0333] (R)-2-(1-methyl-1H-pyrazol-5-yl)-4-(3-methylmorpholino)imidazo[1,5-a]pyrimidine-8-carboxylic acid methyl ester 4e

[0334] Compound 4d (100 mg, 0.39 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (160 mg, 0.772 mmol) were dissolved in a mixed solution of 4 mL of dioxane and water (v:v=3:1), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (49 mg, 0.06 mmol) and anhydrous sodium carbonate (122 mg, 1.15 mmol) were added, and the temperature was raised to 100°C for reaction for 2 hours. After cooling to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 4e (40 mg, yield: 87.2%).

[0335] MS m / z(ESI):357.3[M+1].

[0336] Step 5

[0337] (R)-2-(1-methyl-1H-pyrazol-5-yl)-4-(3-methylmorpholino)imidazo[1,5-a]pyrimidine-8-carboxylic acid 4f

[0338] Compound 4e (120 mg, 0.336 mmol) was dissolved in a mixed solution of 4 mL of methanol and water (v:v=3:1), lithium hydroxide monohydrate (70 mg, 1.68 mmol) was added, and stirred for 15 hours. The reaction solution was concentrated under reduced pressure, diluted with 5 mL of water, adjusted to pH=5 with 1N hydrochloric acid, extracted with ethyl acetate (10 mL×3), and the organic phases were combined and concentrated under reduced pressure to obtain a crude title product 4f (60 mg, yield: 52.1%), which was used directly in the next step without purification.

[0339] MS m / z(ESI):343.1[M+1].

[0340] Step 6

[0341] (R)-4-(8-Bromo-2-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-4-yl)-3-methylmorpholine 4g

[0342] The crude compound 4f (60 mg, 0.175 mmol) was dissolved in 4 mL of N, N-dimethylformamide, cooled to -78 °C, anhydrous sodium bicarbonate (30 mg, 0.35 mmol) and N-bromosuccinimide (35 mg, 0.184 mmol) were added, and stirred for 10 minutes. The reaction solution was warmed to room temperature, 10 mL of saturated sodium bicarbonate solution was added, and ethyl acetate was extracted (10 mL × 3), the organic phases were combined, and concentrated under reduced pressure to obtain the crude title product 4g (30 mg, yield: 45.4%), which was used directly in the next step without purification.

[0343] MS m / z(ESI):377.2[M+1].

[0344] Step 7

[0345] (R)-3-methyl-4-(2-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-4-yl)morpholine

[0346] The crude compound 4g (30 mg, 0.079 mmol) was dissolved in a mixed solution of 4 mL of dioxane and water (v:v=3:1), and compound 1i (27 mg, 0.238 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (10 mg, 0.02 mmol) and anhydrous sodium carbonate (27 mg, 0.26 mmol) were added, and the mixture was heated to 90°C and stirred for 2 hours. After cooling to room temperature, the reaction solution was filtered and concentrated under reduced pressure, and the crude product was purified by high performance liquid preparative chromatography (Waters 2545-2767, elution system: ammonium bicarbonate, acetonitrile, water) to obtain the title product 4 (5 mg, yield: 17.2%).

[0347] MS m / z(ESI):365.2[M+1].

[0348] 1 H NMR (400MHz, CDCl3): δ7.75 (s, 1H), 7.52 (s, 1H), 7.13 (s, 2H), 7.02 (s, 1H), 6.90 (s, 1H), 4.23 (s, 3H), 4.03 (d, 2H), 3.95 (s, 1H), 3.66-3.64 (m, 2H), 3.53 (d, 1H), 3.39 (d, 1H), 1.33 (d, 3H).

[0349] Test example:

[0350] Biological evaluation

[0351] Test Example 1: Inhibitory activity of the disclosed compounds on ATR enzyme

[0352] The following method was used to determine the inhibitory activity of the disclosed compounds on the ATR enzyme.

[0353] The experimental method is briefly described as follows:

[0354] 1. Experimental Materials and Instruments

[0355] 1. ATR enzyme (Eurofins Pharma Discovery Services, 14-953-M)

[0356] 2. GST-tagged P53 protein (Eurofins Pharma Discovery Services, 14-952-M)

[0357] 3. 384-well plate (Thermo Scientific, 267462)

[0358] 4. U-bottom 96-well plate (Corning, 3795)

[0359] 5. Labeling of europium cryptate anti-phosphorylated P53 protein antibody (cisbio, 61P08KAE)

[0360] 6. Anti-GST antibody linked to D2 (Cisbio, 61GSTDLF)

[0361] 7. ATP solution (Promega, V916B)

[0362] 8. EDTA (Thermo Scientific, AM9260G)

[0363] 9. HEPES (Gibco, 15630-080)

[0364] 10. Microplate reader (BMG, PHERAsta)

[0365] 2. Experimental steps

[0366] 1nM ATR enzyme, 50nM P53 protein, 7.435μM ATP and different concentrations of the disclosed compound (first concentration 1μM, 3-fold gradient dilution 11 concentrations) were mixed and incubated at room temperature for 2 hours, then the stop solution (12.5mM HEPES, 250mM EDTA) was added and mixed, and then 0.42ng / well of the labeled europium cryptate anti-phosphorylated P53 protein antibody and 25ng / well of the linked d2 anti-GST antibody were added. After incubation at room temperature overnight, the 620nm and 665nm fluorescence signals were detected with PHERAstar. The data were processed using GraphPad software.

[0367] 3. Experimental Data

[0368] The inhibitory activity of the disclosed compounds on ATR enzyme can be determined by the above test. The blank experimental wells without ATR enzyme are set as 100% inhibition, and the inhibition rate of the compound is calculated by the formula 100×[1-(compound signal-background signal) / (DMSO well signal-background signal)]. The measured IC 50 The values ​​and maximum inhibition rates are shown in Table 1.

[0369] Table 1 IC of the compounds disclosed herein for ATR enzyme inhibition 50

[0370] Example No. <![CDATA[IC 50 / nM]]> Maximum inhibition rate (%) 1 8 99 2 3 100 3 13 99 4 101 96

[0371] Conclusion: The disclosed compounds have good inhibitory activity against ATR enzyme.

[0372] Test Example 2: Selectivity test of the disclosed compounds for ATR enzyme

[0373] The following methods were used to measure the inhibitory activities of the disclosed compounds on ATM enzyme, DNA-PK enzyme and PI3K enzyme, respectively, to illustrate that the disclosed compounds have selectivity for ATR enzyme.

[0374] The experimental method is briefly described as follows:

[0375] (I) Inhibitory effect of the disclosed compounds on ATM enzyme

[0376] 1. Experimental Materials and Instruments

[0377] 1. ATM enzyme (Eurofins Pharma Discovery Services, 14-933-M)

[0378] 2. GST-tagged P53 protein (Eurofins Pharma Discovery Services, 14-952-M)

[0379] 3. 384-well plate (Thermo Scientific, 267462)

[0380] 4. U-bottom 96-well plate (Corning, 3795)

[0381] 5. Labeling of europium cryptate anti-phosphorylated P53 protein antibody (cisbio, 61P08KAE)

[0382] 6. Anti-GST antibody linked to D2 (Cisbio, 61GSTDLF)

[0383] 7. ATP solution (Promega, V916B)

[0384] 8. EDTA (Thermo Scientific, AM9260G)

[0385] 9. HEPES (Gibco, 15630-080)

[0386] 10. Microplate reader (BMG, PHERAsta)

[0387] 2. Experimental steps

[0388] 1nM ATM enzyme, 30nM P53 protein, 11μM ATP and different concentrations of the disclosed compound (first concentration 10μM, 3-fold gradient dilution 11 concentrations) were mixed and incubated at room temperature for 2 hours, then the stop solution (12.5mM HEPES, 250mM EDTA) was added and mixed, and then 0.42ng / well of the labeled europium cryptate anti-phosphorylated P53 protein antibody and 25ng / well of the linked d2 anti-GST antibody were added. After incubation at room temperature overnight, the 620nm and 665nm fluorescence signals were detected with PHERAstar. The data were processed using GraphPad software. IC inhibition of the disclosed compound on ATM enzyme 50 The values ​​are shown in Table 2 below.

[0389] (II) Inhibitory effect of the disclosed compounds on DNA-PK enzyme

[0390] 1. Experimental Materials and Instruments

[0391] 1. DNA-PK enzyme (Eurofins Pharma Discovery Services, 14-950-M)

[0392] 2. GST-tagged P53 protein (Eurofins Pharma Discovery Services, 14-952-M)

[0393] 3. 384-well plate (Thermo Scientific, 267462)

[0394] 4. U-bottom 96-well plate (Corning, 3795)

[0395] 5. Labeling of europium cryptate anti-phosphorylated P53 protein antibody (cisbio, 61P08KAE)

[0396] 6. Anti-GST antibody linked to D2 (Cisbio, 61GSTDLF)

[0397] 7. ATP solution (Promega, V916B)

[0398] 8. EDTA (Thermo Scientific, AM9260G)

[0399] 9. HEPES (Gibco, 15630-080)

[0400] 10. Microplate reader (BMG, PHERAsta)

[0401] 2. Experimental steps

[0402] 0.02nM DNA-PK enzyme, 50nM P53 protein, 7.3μM ATP and different concentrations of the disclosed compound (first concentration 10μM, 3-fold gradient dilution 11 concentrations) were mixed and incubated at room temperature for 1 hour, then the stop solution (12.5mM HEPES, 250mM EDTA) was added and mixed, and then 0.42ng / well of the labeled europium cryptate anti-phosphorylated P53 protein antibody and 25ng / well of the linked d2 anti-GST antibody were added. After incubation at room temperature overnight, the 620nm and 665nm fluorescence signals were detected with PHERAstar. The data were processed using GraphPad software. IC inhibition of the disclosed compound on DNA-PK enzyme 50 The values ​​are shown in Table 2 below.

[0403] (III) Inhibitory effect of the disclosed compounds on PI3K enzyme

[0404] 1. Experimental Materials and Instruments

[0405] 1. PIK3CA / PIK3R1 (p110 alpha / p85 alpha) kinase (Invitrogen, PV4788)

[0406] 2. PIP2:PS Lipid substrate (Invitrogen, PV5100)

[0407] 3. DTT (Sigma, 43815-1G)

[0408] 4. Tris-HCl (1M, pH 7.5) (Beijing Tianenze Biotechnology Co., Ltd., 101205-100)

[0409] 5. ATP solution (Promega, V916B)

[0410] 6. Magnesium chloride hexahydrate (Sigma, M2393)

[0411] 7. Sodium chloride (Sinopharm Chemical Reagent Co., Ltd., 10019318)

[0412] 8. CHAPS (Sigma, C3023-5G)

[0413] 9. HEPES (Gibco, 15630-080)

[0414] 10. ADP-Glo TM Kinase assay kit (Promega, V9102)

[0415] 11. 384-well plate (Thermo Scientific, 267462)

[0416] 12. U-bottom 96-well plate (Corning, 3795)

[0417] 13. Microplate reader (BMG, PHERAstar)

[0418] 2. Experimental steps

[0419] The final concentration of PIK3CA / PIK3R1 (p110 alpha / p85 alpha) kinase was 0.625 nM, mixed with different concentrations (initial concentration 10 μM, 3-fold gradient dilution to 10 concentrations) of the compound of the present invention, incubated at room temperature for 30 minutes, then added PIP2:PSLipid substrate (final concentration 50 μM) and 1xATP (final concentration 50 μM), mixed, incubated at 37°C for 30 minutes, and then added detection reagent ADP-Glo ​​(Promega, V9102) and mixed. After incubation at room temperature for 40 minutes, ADP-Glo ​​was added. TM The detection reagent of the kinase assay kit (Promega, V9102) was incubated at room temperature for 40 minutes. The fluorescence signal was detected using PHERAstar, and the data were processed using GraphPad software. The inhibitory IC of the disclosed compounds on PI3K enzyme 50 The values ​​are shown in Table 2 below.

[0420] Table 2 IC values ​​of the compounds disclosed herein for inhibition of ATM enzyme, DNA-PK enzyme and PI3K enzyme 50 value

[0421]

[0422] Conclusion: The inhibitory activity of the disclosed compounds on ATM enzyme, DNA-PK enzyme and PI3K enzyme is weak. Comparison of test examples 1 and 2 shows that the disclosed compounds are selective for ATR enzyme.

[0423] Test Example 3: LoVo cell proliferation experiment

[0424] The following method detects the intracellular ATP content according to IC 50 The inhibitory effect of the disclosed compounds on the proliferation of LoVo cells was evaluated.

[0425] The experimental method is briefly described as follows:

[0426] 1. Experimental Materials and Instruments

[0427] 1. LoVo, human colon cancer tumor cells (Nanjing Kebai, CBP60032)

[0428] 2. Fetal bovine serum (GIBCO, 10091-148)

[0429] 3. F-12K medium (Gibco, 21127030)

[0430] 4. CellTite-Glo reagent (Promega, G7573)

[0431] 5. 96-well cell culture plate (corning, 3903)

[0432] 6. Pancreatin (Invitrogen, 25200-072)

[0433] 7. Microplate reader (BMG, PHERAsta)

[0434] 8. Cell counter (Shanghai Ruiyu Biotechnology Co., Ltd., IC1000)

[0435] 2. Experimental steps

[0436] LoVo cells were cultured in F-12K medium containing 10% FBS and passaged 2-3 times a week at a passage ratio of 1:3 or 1:5. During passage, the cells were digested with trypsin and transferred to a centrifuge tube. Centrifuged at 1200 rpm for 3 minutes, the supernatant medium was discarded, and fresh medium was added to resuspend the cells. 90 μL of the cell suspension was added to a 96-well cell culture plate at a density of 3.88×10 4 cells / ml, only 100 μL of complete culture medium was added to the periphery of the 96-well plate, and the culture plate was cultured in an incubator for 24 hours (37° C., 5% CO 2 ).

[0437] The compound to be tested was diluted to 2 mM with DMSO, and diluted 3 times in sequence to 10 concentrations, and blank wells (no cells and no compounds) and control wells (with cells and no compounds) were set. Take 5 μL of the compound solution prepared in gradient concentrations and add it to 95 μL of fresh culture medium to prepare a culture medium solution containing the compound. Then add 10 μL of the above-mentioned drug-containing culture medium solution to the culture plate. Incubate the culture plate in an incubator for 3 days (37°C, 5% CO2). In a 96-well cell culture plate, add 50 μL of CellTiter-Glo reagent to each well, place it at room temperature away from light for 5-10 minutes, read the chemiluminescent signal value in PHERAstar, and process the data using GraphPad software.

[0438] 3. Experimental Data

[0439] The inhibitory activity of the disclosed compounds on LoVo cell proliferation can be determined by the above test. The blank well is set as 100% inhibition, and the inhibition rate of the compound is calculated by the formula 100×[1-(compound signal-blank well signal) / (control well signal-blank well signal)]. The measured IC 50 The values ​​and maximum inhibition rates are shown in Table 3 below.

[0440] Table 3 IC of the compounds disclosed herein on the inhibition of LoVo cell proliferation 50

[0441] Example No. <![CDATA[IC 50 / nM]]> Maximum inhibition rate (%) 1 47 84 2 9.4 95 3 40 94

[0442] Conclusion: The disclosed compounds have good inhibitory activity on LoVo cell proliferation.

[0443] Pharmacokinetic evaluation

[0444] Test Example 4: Pharmacokinetic Test of the Disclosed Compounds

[0445] 1. Summary

[0446] Nude mice were used as test animals, and the drug concentration in plasma at different time points after oral administration of the compound of Example 1 was determined by LC / MS / MS method. The pharmacokinetic behavior of the disclosed compound in nude mice was studied, and its pharmacokinetic characteristics were evaluated.

[0447] 2. Experimental plan

[0448] 2.1 Test samples

[0449] Example 1 Compound.

[0450] 2.2 Experimental animals

[0451] Nine healthy adult female nude mice were purchased from Weitonglihua Experimental Animal Co., Ltd.

[0452] 2.3 Sample preparation

[0453] A certain amount of the compound of Example 1 was weighed, a predetermined volume of PEG400 (final volume ratio 15%, Nanjing Well Chemical Co., Ltd.) was added, a stirrer was added and ultrasonic stirring was performed until the sample was completely dissolved, and then a certain volume (final volume ratio 85%) of a prepared 1% HPMC K100LV solution (HPMC K100LV powder was purchased from DOW, USA, and the 1% HPMC K100LV solution was prepared in-house) was added to prepare the compound of Example 1 into a dosing solution with a concentration of 0.5 mg / mL.

[0454] 2.4 Administration

[0455] The nude mice were fasted overnight and then gavaged with the drug. The dosage was 10 mg / kg and the dosage volume was 0.2 mL / 10 g.

[0456] 3. Operation

[0457] Nude mice were orally administered with the compound of Example 1. 0.1 mL of blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, and the blood was placed in an EDTA-K2 anticoagulant tube. The tube was centrifuged at 4°C and 10,000 rpm for 1 minute. The plasma was separated within 1 hour and stored at -20°C for testing. The blood collection and centrifugation process were performed in an ice bath.

[0458] Determine the content of the test compound in the plasma of nude mice after oral administration of drugs of different concentrations: take 25 μL of nude mouse plasma at each time after administration, add 50 μL of internal standard solution (100 ng / mL camptothecin) and 200 μL of acetonitrile, vortex mix for 5 minutes, centrifuge for 10 minutes (4000 rpm), and take 0.1 μL of the supernatant of the plasma sample for LC / MS / MS analysis.

[0459] 4. Pharmacokinetic parameter results

[0460] The pharmacokinetic parameters of the disclosed compounds are shown in Table 4 below.

[0461] Table 4 Pharmacokinetic parameters of the disclosed compounds

[0462]

[0463] Conclusion: The compounds disclosed herein have good pharmacokinetic absorption and have obvious pharmacokinetic advantages.

Claims

1. A compound represented by general formula (I) or its tautomer or a pharmaceutically acceptable salt thereof: in: R 0 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl and cyano groups; R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 2 is a five-membered heteroaryl group, wherein the five-membered heteroaryl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 is substituted by one or more substituents in a haloalkyl group; R 3 is a five-membered heteroaryl group, wherein the five-membered heteroaryl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 is substituted by one or more substituents in a haloalkyl group; R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 5 C 1-6 Alkyl or C 1-6 Haloalkyl; n is 0, 1, 2 or 3.

2. The compound represented by the general formula (I) according to claim 1, or its tautomer, or its pharmaceutically acceptable salt, which is a compound represented by the general formula (II) or its tautomer, or its pharmaceutically acceptable salt: in: R 6 are the same or different and are independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 7 are the same or different and are independently selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; p and q are the same or different and are each independently selected from 0, 1, 2 or 3; R 0 , R 1 , R 4 and n is as defined in claim 1.

3. The compound represented by the general formula (I) according to claim 1, or its tautomer, or its pharmaceutically acceptable salt, wherein R 0 A hydrogen atom or C 1-6 alkyl.

4. The compound represented by the general formula (I) according to claim 1, or its tautomer, or its pharmaceutically acceptable salt, wherein R 1 A hydrogen atom.

5. The compound represented by the general formula (I) according to claim 1, or its tautomer, or its pharmaceutically acceptable salt, wherein R 4 A hydrogen atom.

6. The compound represented by the general formula (I) according to claim 1, or its tautomer, or its pharmaceutically acceptable salt, wherein R 5 C 1-6 alkyl.

7. The compound represented by the general formula (I) according to claim 1, or its tautomer, or its pharmaceutically acceptable salt, wherein R 5 It is methyl.

8. The compound represented by the general formula (I) according to claim 2, or its tautomer or its pharmaceutically acceptable salt, wherein R 6 C 1-6 alkyl.

9. The compound represented by the general formula (I) according to claim 2, or its tautomer or its pharmaceutically acceptable salt, wherein R 6 It is methyl.

10. The compound represented by the general formula (I) according to claim 2, or its tautomer or its pharmaceutically acceptable salt, wherein R 7 A hydrogen atom.

11. A compound represented by the general formula (I) according to any one of claims 1 to 10, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from any one of the following compounds:

12. A compound represented by the general formula (IA) or a pharmaceutically acceptable salt thereof, in: X is a hydrogen atom or a halogen; R 0 Selected from hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl and cyano groups; R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 2 is a five-membered heteroaryl group, wherein the five-membered heteroaryl group is optionally selected from halogen, C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 is substituted by one or more substituents in a haloalkyl group; R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; R 5 C 1-6 Alkyl or C 1-6 Haloalkyl; n is 0, 1, 2 or 3.

13. The compound represented by the general formula (IA) or a pharmaceutically acceptable salt thereof according to claim 12, wherein X is a halogen.

14. The compound represented by the general formula (IA) or a pharmaceutically acceptable salt thereof according to claim 12, wherein X is Br.

15. The compound represented by the general formula (IA) according to claim 12 or a pharmaceutically acceptable salt thereof, which is selected from any one of the following compounds:

16. A method for preparing the compound represented by general formula (I) according to claim 1 or its tautomer or its pharmaceutically acceptable salt, the method comprising: The compound of general formula (IA) or its pharmaceutically acceptable salt and the compound of general formula (IB) undergo coupling reaction to obtain the compound of general formula (I) or its tautomer or its pharmaceutically acceptable salt, in: X is a halogen; Y is R is a hydrogen atom or C 1-6 alkyl; R 0 , R 1 , R 2 , R 3 , R 4 , R 5 and n is as defined in claim 1.

17. A pharmaceutical composition comprising a compound represented by general formula (I) according to any one of claims 1 to 11 or its tautomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

18. Use of the compound represented by the general formula (I) according to any one of claims 1 to 11 or its tautomer or its pharmaceutically acceptable salt or the pharmaceutical composition according to claim 17 in the preparation of a medicament for inhibiting ATR kinase.

19. Use of a compound represented by general formula (I) according to any one of claims 1 to 11 or its tautomer or its pharmaceutically acceptable salt or a pharmaceutical composition according to claim 17 in the preparation of a medicament for treating or preventing a hyperproliferative disease.

20. Use of the compound represented by general formula (I) according to any one of claims 1 to 11 or its tautomer or its pharmaceutically acceptable salt or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating or preventing tumors.

21. The use according to claim 20, wherein the tumor is selected from brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, glioma, sarcoma, bone cancer, endometrial cancer, head and neck tumors, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, bladder cancer and gallbladder cancer.

22. The use according to claim 21, wherein the skin cancer is melanoma.

23. The use according to claim 21, wherein the head and neck tumor is a thyroid tumor.

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