TW202214642A - Imidazolopyrimidine derivatives, preparation method and medical use thereof - Google Patents

Abstract

The present disclosure relates to imidazopyrimidine derivatives, preparation method and medical use thereof. Specifically, the present disclosure relates to an imidazopyrimidine derivative represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the same, and its use as a therapeutic agent, especially as an ATR kinase inhibitor, as well as its use in the preparation of a medicament for the treatment or prevention of hyperproliferative diseases.

Description

咪唑并嘧啶類衍生物、其製備方法及其在醫藥上的應用 Imidazopyrimidine derivatives, their preparation method and their application in medicine

本揭露屬於醫藥領域，係關於一種通式(I)所示的咪唑并嘧啶類衍生物、其製備方法、含有該衍生物的醫藥組成物以及其作為治療劑的用途，特別是作為ATR激酶抑制劑的用途和用於製備治療和預防過度增殖性疾病的藥物中的用途。 The present disclosure belongs to the field of medicine, and relates to an imidazopyrimidine derivative represented by the general formula (I), its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as an inhibitor of ATR kinase Use of the agent and in the manufacture of a medicament for the treatment and prevention of hyperproliferative diseases.

無論是正常細胞還是腫瘤細胞中，每天都會出現成千上萬次DNA的損傷。這使得DNA損傷修復在維持基因組的穩定性和細胞存活方面起到至關重要的作用。相比較於正常細胞，腫瘤細胞承受了更大的複製壓力，攜帶更多的內源性DNA損傷，並且經常出現一個或多個DNA損傷修復通路的缺失。這使得腫瘤細胞的存活更加依賴於DNA損傷修復的順利進行。 DNA damage occurs thousands of times every day in both normal and tumor cells. This makes DNA damage repair crucial in maintaining genome stability and cell survival. Compared to normal cells, tumor cells are under greater replication stress, carry more endogenous DNA damage, and often exhibit the loss of one or more DNA damage repair pathways. This makes the survival of tumor cells more dependent on the smooth progress of DNA damage repair.

同源重組修復是DNA雙鏈斷裂的主要修復方式，以未受損的姐妹染色單體的同源序列作為其修復的模板複製受損處的DNA序列，精確修復DNA。這種修復方式主要發生在細胞的G2期和S期。ATR是同 源重組修復通路中的關鍵酶，屬於PIKK家族。當ATR/ATRIP複合物與覆蓋了複製蛋白A(RPA)的受損DNA結合後，ATR被激活並藉由磷酸化下游蛋白Chk1和SMARCAL等，調節細胞週期各個檢查點，引起細胞週期阻滯，保證受損DNA的穩定性，提高dNTP濃度，促使DNA損傷得以修復。細胞週期S期中出現的DNA損傷修復主要由ATR通路完成，說明ATR對於保證細胞增殖非常重要。對於臨床腫瘤樣品的分析結果表明在多種腫瘤組織中，例如胃癌、肝癌、結直腸癌、卵巢癌、胰腺癌等，均觀察到ATR表達水平升高。並且在卵巢癌、胰腺癌病人中，高水平的ATR往往伴隨著較低的存活率。由此可見ATR是一個重要的腫瘤治療的靶標。 Homologous recombination repair is the main repair method for DNA double-strand breaks. The homologous sequence of the undamaged sister chromatid is used as the template for its repair to replicate the DNA sequence at the damaged place, and the DNA is accurately repaired. This repair mode mainly occurs in the G2 and S phases of cells. ATR is the same It is a key enzyme in the original recombination repair pathway and belongs to the PIKK family. When the ATR/ATRIP complex binds to damaged DNA covered with replication protein A (RPA), ATR is activated and regulates various checkpoints in the cell cycle by phosphorylating downstream proteins Chk1 and SMARCAL, resulting in cell cycle arrest, Ensure the stability of damaged DNA, increase the concentration of dNTPs, and promote the repair of DNA damage. DNA damage repair in the S phase of the cell cycle is mainly completed by the ATR pathway, indicating that ATR is very important to ensure cell proliferation. Analysis of clinical tumor samples showed that in various tumor tissues, such as gastric cancer, liver cancer, colorectal cancer, ovarian cancer, pancreatic cancer, etc., elevated ATR expression levels were observed. And in patients with ovarian cancer and pancreatic cancer, high levels of ATR are often associated with lower survival rates. It can be seen that ATR is an important target for tumor therapy.

現已公開的ATR抑制劑的專利申請包括WO2010071837、WO2011154737、WO2016020320、WO2016130581、WO2017121684、WO2017118734、WO2018049400、WO2019050889和WO2014140644等。 Published patent applications for ATR inhibitors include WO2010071837, WO2011154737, WO2016020320, WO2016130581, WO2017121684, WO2017118734, WO2018049400, WO2019050889, and WO2014140644, among others.

本揭露的目的在於提供一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽： The purpose of the present disclosure is to provide a compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , or a pharmaceutically acceptable salt thereof:

其中， in,

R⁰選自氫原子、烷基、鹵烷基、羥烷基、氰基和環烷基烷基； R ⁰ is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group and a cycloalkylalkyl group;

R¹和R²相同或不同，各自獨立地選自氫原子、鹵素、烷基、烯基、烷氧基、雜環基氧基、鹵烷基、鹵烷氧基、羥基、羥烷基、氰基、胺基、環烷基、雜環基、芳基和雜芳基；其中，該烷基、烷氧基、雜環基氧基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要被選自鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R ¹ and R ² are the same or different, each independently selected from hydrogen atom, 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 selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl substituted by one or more substituents in the base;

R³選自氫原子、鹵素、烷基、烯基、烷氧基、鹵烷基、鹵烷氧基、羥基、羥烷基、氰基、胺基、環烷基、雜環基、芳基和雜芳基；其中，該烷基、烷氧基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要被選自鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； ^R is selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, substituted with one or more substituents of hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁴相同或不同，各自獨立地選自氫原子、鹵素、烷基、烯基、烷氧基、鹵烷基、鹵烷氧基、羥基、羥烷基、氰基、胺基、環烷基、雜環基、芳基和雜芳基；其中，該烷基、烷氧基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要被選自鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R ⁴ are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl , heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkane substituted with one or more substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁵選自烷基、鹵烷基、羥烷基和環烷基烷基； R ⁵ is selected from alkyl, haloalkyl, hydroxyalkyl and cycloalkylalkyl;

n為0、1、2或3。 n is 0, 1, 2 or 3.

在本揭露的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其為通式(I-a)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽： In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form, or its pharmaceutically acceptable salt, it is the compound represented by general formula (I-a) or its tautomer, meso, racemate, enantiomer, diastereomer Constituents, or mixtures thereof, or pharmaceutically acceptable salts thereof:

其中，R⁰、R¹、R²、R³、R⁴和n如通式(I)中所定義。 wherein R ⁰ , R ¹ , R ² , R ³ , R ⁴ and n are as defined in general formula (I).

在本揭露的一些實施方案中，該通式(I)或(I-a)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R²為雜芳基，該雜芳基視需要地被選自鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基和環烷基中的一個或多個取代基所取代。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, diastereomer structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is a heteroaryl group optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, Substituted with one or more substituents of hydroxyalkyl, cyano, amino, nitro and cycloalkyl.

在本揭露的一些實施方案中，該通式(I)或(I-a)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R²為五員雜芳基，所述的五員雜芳基視需要地被選自鹵素、C_1-6烷基、C_1-6烷氧基和鹵C_1-6烷基中的一個或多個取代基所取代。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is a five-membered heteroaryl group optionally selected from halogen, C _1-6 alkyl, Substituted with one or more substituents of C _1-6 alkoxy and halo C _1-6 alkyl.

在本揭露的一些實施方案中，該通式(I)或(I-a)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R²選自吡唑基、咪唑基、吡咯基和***基，較佳為吡唑基，該吡唑基、咪唑基、吡咯基和***基視需要地被選自鹵素、C_1-6烷基和鹵C_1-6烷基中的一個或多個取代基所取代。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is selected from pyrazolyl, imidazolyl, pyrrolyl and triazolyl, preferably pyrazolyl, the pyrazolyl, imidazolyl , pyrrolyl and triazolyl are optionally substituted with one or more substituents selected from halogen, C _1-6 alkyl and halo C _1-6 alkyl.

在本揭露的一些實施方案中，該通式(I)或(I-a)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、 或其混合物形式、或其可藥用的鹽，其中，R²為

，較佳為

， R^2a選自氫原子、C_1-6烷基和鹵C_1-6烷基；較佳地，R^2a為甲基或乙基。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or its mixture form, or its pharmaceutically acceptable salt, wherein, R ² is

, preferably

, R ^2a is selected from hydrogen atom, C _1-6 alkyl and halogen C _1-6 alkyl; preferably, R ^2a is methyl or ethyl.

在本揭露的一些實施方案中，該通式(I)或(I-a)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R³為雜芳基，該雜芳基視需要地被選自鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基和環烷基中的一個或多個取代基所取代。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, diastereomer structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is a heteroaryl group optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, Substituted with one or more substituents of hydroxyalkyl, cyano, amino, nitro and cycloalkyl.

在本揭露的一些實施方案中，該通式(I)或(I-a)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R³為五員雜芳基，該五員雜芳基視需要地被選自鹵素、C_1-6烷基、C_1-6烷氧基和鹵C_1-6烷基中的一個或多個取代基所取代。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is a five-membered heteroaryl group optionally selected from halogen, C _1-6 alkyl, C _{1 -6} alkoxy and one or more substituents of _{haloC 1-6} alkyl.

在本揭露的一些實施方案中，該通式(I)或(I-a)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式或其可藥用的鹽，其中，R³選自吡唑基、咪唑基、吡咯基和***基，較佳為吡唑基，該吡唑基、咪唑基、吡咯基和***基視需要地被選自鹵素、C_1-6烷基和鹵C_1-6烷基中的一個或多個取代基所取代。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or its mixture form or its pharmaceutically acceptable salt, wherein, R ³ is selected from pyrazolyl, imidazolyl, pyrrolyl and triazolyl, preferably pyrazolyl, the pyrazolyl, imidazolyl, The pyrrolyl and triazolyl groups are optionally substituted with one or more substituents selected from halogen, C _1-6 alkyl, and halo C _1-6 alkyl.

在本揭露的一些實施方案中，該通式(I)或(I-a)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、 或其混合物形式、或其可藥用的鹽，其中，R³為

，較佳為

， R^3a選自氫原子、C_1-6烷基和鹵C_1-6烷基；較佳地，R^3a為氫原子。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or its mixture form, or its pharmaceutically acceptable salt, wherein, R ³ is

, preferably

, R ^3a is selected from a hydrogen atom, a C _1-6 alkyl group and a halogenated C _1-6 alkyl group; preferably, R ^3a is a hydrogen atom.

在本揭露的一些實施方案中，該通式(I)或(I-a)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其為通式(II)所示的化合物或其互變 異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽： In some embodiments of the present disclosure, the compound represented by the general formula (I) or (I-a) or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or its interconversion Isomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

其中， in,

R⁶相同或不同，各自獨立地選自氫原子、鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基； R ⁶ are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁷相同或不同，各自獨立地選自氫原子、鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基； R ⁷ are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

p和q相同或不同，各自獨立地選自0、1、2或3； p and q are the same or different, each independently selected from 0, 1, 2 or 3;

R⁰、R¹、R⁴和n如通式(I)中所定義。 R ⁰ , R ¹ , R ⁴ and n are as defined in general formula (I).

在本揭露的一些實施方案中，該通式(I)、(I-a)或(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R⁰選自氫原子、烷基、鹵烷基、羥烷基和氰基；較佳地，R⁰選自氫原子、C_1-6烷基、C_1-6鹵烷基、C_1-6羥烷基和氰基；更佳為氫原子或C_1-6烷基。 In some embodiments of the present disclosure, the compound represented by the general formula (I), (Ia) or (II) or its tautomer, meso, racemate, enantiomer, Diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ is selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group and cyano group; preferably, R ⁰ is selected from from a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 hydroxyalkyl group and a cyano group; more preferably a hydrogen atom or a C _1-6 alkyl group.

在本揭露的一些實施方案中，該通式(I)、(I-a)或(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R¹選自氫原子、鹵素、烷基、烷氧基、雜環基氧基、鹵烷基、鹵烷氧基、羥基、羥烷基、氰基、胺基和環烷基；其中，該烷基、烷氧基、雜環基氧基和環烷基各自獨立地視 需要被選自鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基中的一個或多個取代基所取代； In some embodiments of the present disclosure, the compound represented by the general formula (I), (Ia) or (II) or its tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from hydrogen atom, halogen, alkyl, alkoxy, heterocyclyloxy, haloalkyl, haloalkane oxy, hydroxy, hydroxyalkyl, cyano, amino and cycloalkyl; wherein the alkyl, alkoxy, heterocyclyloxy and cycloalkyl are each independently optionally selected from halogen, alkyl , substituted by one or more substituents in alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amine, nitro;

較佳地，R¹選自氫原子、鹵素、C_1-6烷基和鹵C_1-6烷基； Preferably, R ¹ is selected from hydrogen atom, halogen, C _1-6 alkyl and halogen C _1-6 alkyl;

更佳地，R¹為氫原子。 More preferably, R ¹ is a hydrogen atom.

在本揭露的一些實施方案中，該通式(I)、(I-a)或(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R⁴相同或不同，各自獨立地選自氫原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、羥基、羥烷基、氰基、胺基和環烷基；其中，該烷基、烷氧基和環烷基各自獨立地視需要被選自鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基和硝基中的一個或多個取代基所取代； In some embodiments of the present disclosure, the compound represented by the general formula (I), (Ia) or (II) or its tautomer, meso, racemate, enantiomer, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁴ are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, halo alkoxy, hydroxy, hydroxyalkyl, cyano, amino and cycloalkyl; wherein the alkyl, alkoxy and cycloalkyl are each independently optionally selected from halogen, alkyl, alkoxy, Substituted with one or more substituents of haloalkyl, hydroxy, hydroxyalkyl, cyano, amine and nitro;

較佳地，R⁴選自氫原子、鹵素、C_1-6烷基和鹵C_1-6烷基； Preferably, R ⁴ is selected from hydrogen atom, halogen, C _1-6 alkyl and halogen C _1-6 alkyl;

更佳地，R⁴為氫原子。 More preferably, R ⁴ is a hydrogen atom.

在本揭露的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R⁵為烷基或鹵烷基；較佳為C_1-6烷基；更佳為甲基。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein, R ⁵ is alkyl or haloalkyl; preferably C _1-6 alkyl; more preferably methyl.

在本揭露的一些實施方案中，該通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R⁶相同或不同，各自獨立地選自氫原子、鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基和硝基；較佳地，R⁶相同或不同，各自獨立地選自氫原子、鹵素、C_1-6烷基和鹵C_1-6烷基；進一步較佳為C_1-6烷基；更佳為甲基。 In some embodiments of the present disclosure, the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form, or its pharmaceutically acceptable salt, wherein, R ⁶ is the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, Amine group and nitro group; preferably, R ⁶ is the same or different, each independently selected from hydrogen atom, halogen, C _1-6 alkyl group and halogen C _1-6 alkyl group; more preferably C _1-6 alkane group; more preferably methyl.

在本揭露的一些實施方案中，該通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R⁷相同或不同，各自獨立地選自氫原子、鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基和硝基；較佳地，R⁷相同或不同，各自獨立地選自氫原子、鹵素、C_1-6烷基和鹵C_1-6烷基；更佳為氫原子。 In some embodiments of the present disclosure, the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or A mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amine group and nitro group; preferably, R ⁷ is the same or different, each independently selected from hydrogen atom, halogen, C _1-6 alkyl group and halogen C _1-6 alkyl group; more preferably hydrogen atom.

在本揭露的一些實施方案中，該通式(I)、(I-a)或(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，n為0或1，較佳為1。 In some embodiments of the present disclosure, the compound represented by the general formula (I), (I-a) or (II) or its tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1, preferably 1.

在本揭露的一些實施方案中，該通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，p為1。 In some embodiments of the present disclosure, the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein p is 1.

在本揭露的一些實施方案中，該通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，q為0或1，較佳為1。 In some embodiments of the present disclosure, the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1, preferably 1.

在本揭露的一些實施方案中，該通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R⁰選自氫原子、C_1-6烷基、C_1-6鹵烷基、C_1-6羥烷基和氰基；R¹選自氫原子、鹵素、C_1-6烷基和鹵C_1-6烷基；R²為五員雜芳基，該五員雜芳基視需要地被選自鹵素、C_1-6烷基、C_1-6烷氧基和鹵C_1-6烷基中的一個或多個取代基所取代；R³為五員雜芳基，該五員雜芳基視需要地被選自鹵素、C_1-6烷基、C_1-6烷氧基和鹵C_1-6烷基中的一個或多個取代基所取代；R⁴為氫原子；R⁵為C_1-6烷基；n為0或1。在本揭露的一些實施方案中，該通式(I-a)所示的化合物或其互變異構體、內 消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R⁰選自氫原子、C_1-6烷基、C_1-6鹵烷基、C_1-6羥烷基和 氰基；R¹選自氫原子、鹵素、C_1-6烷基和鹵C_1-6烷基；R²為

，R^2a 選自氫原子、C_1-6烷基和鹵C_1-6烷基；R³為

，R^3a選自氫原子、 C_1-6烷基和鹵C_1-6烷基；R⁴為氫原子；n為0或1。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form, or its pharmaceutically acceptable salt, wherein, R ⁰ is selected from hydrogen atom, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl and cyano; R ¹ is selected from hydrogen atom, halogen, C _1-6 alkyl and halogen C _1-6 alkyl; R ² is a five-membered heteroaryl group optionally selected from halogen, C _1-6 alkyl , C _1-6 alkoxy and one or more substituents in halogen C _1-6 alkyl substituted; R ³ is a five-membered heteroaryl, and the five-membered heteroaryl is optionally selected from halogen, Substituted by one or more substituents in C _1-6 alkyl, C _1-6 alkoxy and halogen C _1-6 alkyl; R ⁴ is a hydrogen atom; R ⁵ is 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, meso, racemate, enantiomer, diastereomer, or Its mixture form, or its pharmaceutically acceptable salt, wherein, R ⁰ is selected from hydrogen atom, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl and cyano; R ¹ is selected From hydrogen atom, halogen, C _1-6 alkyl and halogen C _1-6 alkyl; R ² is

, R ^2a is selected from hydrogen atom, C _1-6 alkyl and halogen C _1-6 alkyl; R ³ is

, R ^3a is selected from hydrogen atom, C _1-6 alkyl and halogen C _1-6 alkyl; R ⁴ is hydrogen atom; n is 0 or 1.

在本揭露的一些實施方案中，該通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R⁰為氫原子或C_1-6烷基；R¹選自氫原子、鹵素、C_1-6烷基和鹵C_1-6烷基；R⁴為氫原子；R⁶相同或不同，各自獨立地選自氫原子、鹵素、C_1-6烷基和鹵C_1-6烷基；R⁷相同或不同，各自獨立地選自氫原子、鹵素、C_1-6烷基和鹵C_1-6烷基；n為0或1；p為1；q為1。 In some embodiments of the present disclosure, the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or Its mixture form, or its pharmaceutically acceptable salt, wherein, R ⁰ is hydrogen atom or C _1-6 alkyl; R ¹ is selected from hydrogen atom, halogen, C _1-6 alkyl and halogen C _1-6 alkyl ; R ⁴ is a hydrogen atom; R ⁶ is the same or different, each independently selected from hydrogen atom, halogen, C _1-6 alkyl and halogen C _1-6 alkyl; R ⁷ is the same or different, each independently selected from hydrogen Atom, halogen, C _1-6 alkyl and halogen C _1-6 alkyl; n is 0 or 1; p is 1; q is 1.

表A 本揭露的典型化合物包括但不限於： Table A Typical compounds of the present disclosure include, but are not limited to:

或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽。 or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

本揭露的另一方面係關於通式(IA)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， Another aspect of the present disclosure pertains to compounds of formula (IA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof,

其中， in,

X為氫原子或鹵素；較佳為鹵素；更佳為Br； X is hydrogen atom or halogen; preferably halogen; more preferably Br;

R⁰選自氫原子、烷基、鹵烷基、羥烷基、氰基和環烷基烷基； R ⁰ is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group and a cycloalkylalkyl group;

R¹和R²相同或不同，各自獨立地選自氫原子、鹵素、烷基、烯基、烷氧基、雜環基氧基、鹵烷基、鹵烷氧基、羥基、羥烷基、氰基、胺基、環烷基、雜環基、芳基和雜芳基；其中，該烷基、烷氧基、雜環基氧基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要被選自鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R ¹ and R ² are the same or different, each independently selected from hydrogen atom, 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 selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl substituted by one or more substituents in the base;

R⁴相同或不同，各自獨立地選自氫原子、鹵素、烷基、烯基、烷氧基、鹵烷基、鹵烷氧基、羥基、羥烷基、氰基、胺基、環烷基、雜環基、芳基和雜芳基；其中，該烷基、烷氧基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要被選自鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R ⁴ are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl , heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkane substituted with one or more substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R⁵選自烷基、鹵烷基、羥烷基和環烷基烷基； R ⁵ is selected from alkyl, haloalkyl, hydroxyalkyl and cycloalkylalkyl;

n為0、1、2或3。 n is 0, 1, 2 or 3.

本揭露的另一方面係關於通式(I-aA)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， Another aspect of the present disclosure relates to the compound represented by general formula (I-aA) or its tautomer, meso, racemate, enantiomer, diastereomer, or in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中， in,

X為氫原子或鹵素；較佳為鹵素；更佳為Br； X is hydrogen atom or halogen; preferably halogen; more preferably Br;

R⁰、R¹、R²、R⁴和n如通式(I-a)中所定義。 R ⁰ , R ¹ , R ² , R ⁴ and n are as defined in general formula (Ia).

本揭露的另一方面係關於通式(IIA)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， Another aspect of the present disclosure relates to the compound represented by general formula (IIA) or its tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof form, or a pharmaceutically acceptable salt thereof,

其中， in,

X為氫原子或鹵素；較佳為鹵素；更佳為Br； X is hydrogen atom or halogen; preferably halogen; more preferably Br;

R⁰、R¹、R⁴、R⁶、n和p如通式(II)中所定義。 R ⁰ , R ¹ , R ⁴ , R ⁶ , n and p are as defined in general formula (II).

本揭露的典型中間體化合物包括但不限於： Typical intermediate compounds of the present disclosure include, but are not limited to:

本揭露的另一方面係關於一種製備通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的方法，該方法包括： Another aspect of the present disclosure relates to a preparation of the compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or A method for its mixture form, or a pharmaceutically acceptable salt thereof, comprising:

通式(IA)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽和通式(IB)化合物發生偶聯反應，得到通式(I)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， A compound of general formula (IA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and The compound of general formula (IB) undergoes a coupling reaction to obtain the compound of general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中， in,

X為鹵素；較佳為Br； X is halogen; preferably Br;

Y為

或

； Y is

or

;

R為氫原子或烷基； R is a hydrogen atom or an alkyl group;

R⁰、R¹、R²、R³、R⁴、R⁵和n如通式(I)中所定義。 R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are as defined in general formula (I).

本揭露的另一方面係關於一種製備通式(I-a)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的方法，該方法包括： Another aspect of the present disclosure relates to a preparation of the compound represented by general formula (I-a) or its tautomer, meso, racemate, enantiomer, diastereomer, or A method for its mixture form, or a pharmaceutically acceptable salt thereof, comprising:

通式(I-aA)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽和通式(IB)化合物發生偶聯反應，得到通式(I-a)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， Compounds of general formula (I-aA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable forms thereof The salt and the compound of general formula (IB) undergo coupling reaction to obtain the compound of general formula (I-a) or its tautomer, meso, racemate, enantiomer and diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中， in,

X為鹵素；較佳為Br； X is halogen; preferably Br;

Y為

或

； Y is

or

;

R為氫原子或烷基； R is a hydrogen atom or an alkyl group;

R⁰、R¹、R²、R³、R⁴和n如通式(I-a)中所定義。 R ⁰ , R ¹ , R ² , R ³ , R ⁴ and n are as defined in general formula (Ia).

本揭露的另一方面係關於一種製備通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的方法，該方法包括： Another aspect of the present disclosure relates to a preparation of the compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or A method for its mixture form, or a pharmaceutically acceptable salt thereof, comprising:

通式(IIA)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽和通式(IIB)化合物發生偶聯反應，得到通式(II)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， A compound of general formula (IIA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and The compound of general formula (IIB) undergoes a coupling reaction to obtain the compound of general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中， in,

X為鹵素；較佳為Br； X is halogen; preferably Br;

Y為

或

； Y is

or

;

R為氫原子或烷基； R is a hydrogen atom or an alkyl group;

R⁰、R¹、R⁴、R⁶、R⁷、n、p和q如通式(II)中所定義。 R ⁰ , R ¹ , R ⁴ , R ⁶ , R ⁷ , n, p and q are as defined in general formula (II).

本揭露的另一方面係關於一種醫藥組成物，該醫藥組成物含有本揭露通式(I)、(I-a)、(II)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑。 Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound represented by the general formula (I), (I-a), (II) or Table A of the present disclosure or a tautomer, meso isomer thereof isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients .

本揭露進一步係關於通式(I)、(I-a)、(II)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽或者包含其的醫藥組成物在製備用於抑制ATR激酶的藥物中的用途。 The present disclosure further relates to compounds of general formula (I), (I-a), (II) or Table A, or tautomers, mesomers, racemates, enantiomers, unpaired Use of an enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for inhibiting ATR kinase.

本揭露進一步係關於通式(I)、(I-a)、(II)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構 體、或其混合物形式、或其可藥用的鹽或者包含其的醫藥組成物在製備用於治療或預防過度增殖性疾病的藥物中的用途。 The present disclosure further relates to compounds of general formula (I), (I-a), (II) or Table A, or tautomers, mesomers, racemates, enantiomers, unpaired enantiomer Use of the form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment or prevention of a hyperproliferative disease.

本揭露進一步係關於通式(I)、(I-a)、(II)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽或者包含其的醫藥組成物在製備用於治療或預防腫瘤的藥物中的用途。 The present disclosure further relates to compounds of general formula (I), (I-a), (II) or Table A, or tautomers, mesomers, racemates, enantiomers, unpaired Use of an enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment or prevention of tumors.

本揭露進一步係關於通式(I)、(I-a)、(II)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽或者包含其的醫藥組成物在製備治療腫瘤的藥物中的用途。 The present disclosure further relates to compounds of general formula (I), (I-a), (II) or Table A, or tautomers, mesomers, racemates, enantiomers, unpaired Use of an enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for treating tumors.

本揭露還係關於一種抑制ATR激酶的方法，其包括給予有需要的患者抑制有效量的通式(I)、(I-a)、(II)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，或包含其的醫藥組成物。 The present disclosure also relates to a method for inhibiting ATR kinase, comprising administering to a patient in need thereof an effective amount of the compound of general formula (I), (I-a), (II) or Table A or a tautomer thereof, Meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

本揭露還係關於一種治療或預防過度增殖性疾病的方法，其包括給予有需要的患者治療或預防有效量的通式(I)、(I-a)、(II)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，或包含其的醫藥組成物。 The present disclosure also relates to a method of treating or preventing a hyperproliferative disease, comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a compound of general formula (I), (I-a), (II) or Table A or A tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

本揭露還係關於一種治療或預防腫瘤的方法，其包括給予有需要的患者治療或預防有效量的通式(I)、(I-a)、(II)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，或包含其的醫藥組成物。 The present disclosure also relates to a method for treating or preventing tumors, comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of a compound of general formula (I), (I-a), (II) or Table A or a tautomer thereof A isomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

本揭露進一步係關於一種通式(I)、(I-a)、(II)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映 異構體、或其混合物形式、或其可藥用的鹽或包含其的醫藥組成物，其用作藥物。 The present disclosure further relates to a compound represented by the general formula (I), (I-a), (II) or Table A or its tautomer, meso, racemate, enantiomer, non- antithetical Isomers, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

本揭露還係關於通式(I)、(I-a)、(II)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽或包含其的醫藥組成物，其用作ATR激酶抑制劑。 The present disclosure also relates to compounds represented by the general formula (I), (I-a), (II) or Table A, or tautomers, mesomers, racemates, enantiomers, unpaired isomers thereof An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as an ATR kinase inhibitor.

本揭露還係關於通式(I)、(I-a)、(II)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽或包含其的醫藥組成物，其用於治療或預防過度增殖性疾病。 The present disclosure also relates to compounds represented by the general formula (I), (I-a), (II) or Table A, or tautomers, mesomers, racemates, enantiomers, unpaired isomers thereof An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment or prevention of a hyperproliferative disease.

本揭露進一步係關於通式(I)、(I-a)、(II)或表A所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽或包含其的醫藥組成物，其用於治療腫瘤。 The present disclosure further relates to compounds of general formula (I), (I-a), (II) or Table A, or tautomers, mesomers, racemates, enantiomers, unpaired An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment of tumors.

本揭露中，該腫瘤較佳自黑色素瘤、腦瘤、食管癌、胃癌、肝癌、胰腺癌、結腸直腸癌、肺癌、腎癌、乳腺癌、子宮頸癌、卵巢癌、***癌、皮膚癌、神經母細胞瘤、神經膠質瘤、肉瘤、骨癌、子宮內膜癌、頭頸腫瘤、多發性骨髓瘤、B-細胞淋巴瘤、真性紅細胞增多症、白血病、甲狀腺腫瘤、膀胱癌和膽囊癌。 In the present disclosure, the tumor 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 tumors, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumors, bladder cancer, and gallbladder cancer.

可將活性化合物製成適合於藉由任何適當途徑給藥的形式，藉由一般方法使用一種或多種藥學上可接受的載體來配製本揭露的組成物。因此，本揭露的活性化合物可以配製成用於口服給藥、注射(例如靜脈內、肌肉內或皮下)給藥、吸入或吹入給藥的各種劑型。本揭露的化合 物可以配製成例如片劑、硬或軟膠囊、水性或油性混懸液、乳劑、注射液、可分散性粉末或顆粒、栓劑、錠劑或糖漿等劑型。 The active compounds can be formulated in a form suitable for administration by any suitable route, and the compositions of the present disclosure can be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure can be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular, or subcutaneous) administration, inhalation, or insufflation. Compounds of the present disclosure The drug can be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injection solutions, dispersible powders or granules, suppositories, lozenges or syrups.

作為一般性指導，本揭露活性化合物較佳是以單位劑量的方式，或者是以患者可以以單劑自我給藥的方式。本揭露化合物或組成物的單位劑量的表達方式可以是片劑、膠囊、扁囊劑、瓶裝藥水、粉末劑、顆粒劑、錠劑、栓劑、再生粉末或液體製劑。合適的單位劑量可以是0.1至1000mg。 As a general guide, the active compounds of the present disclosure are preferably presented in unit dosage form or in a form that the patient can self-administer in a single dose. Unit doses of a compound or composition of the present disclosure can be expressed as tablets, capsules, cachets, vials, powders, granules, lozenges, suppositories, reconstituted powders, or liquid preparations. A suitable unit dose may be 0.1 to 1000 mg.

本揭露的醫藥組成物除活性化合物外，可含有一種或多種輔料，該輔料選自以下成分：填充劑(稀釋劑)、黏合劑、潤濕劑、崩解劑或賦形劑等。根據給藥方法的不同，組成物可含有0.1至99重量%的活性化合物。 In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients and the like. Depending on the method of administration, the composition may contain from 0.1 to 99% by weight of active compound.

片劑含有活性成分和用於混合的適宜製備片劑的無毒的可藥用的賦形劑。這些賦形劑可以是惰性賦形劑、造粒劑、崩解劑、黏合劑和潤滑劑。這些片劑可以不包衣或可藉由掩蓋藥物的味道或在胃腸道中延遲崩解和吸收，因而在較長時間內提供緩釋作用的已知技術將其包衣。 Tablets contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binders and lubricants. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained release over an extended period of time.

也可用其中活性成分與惰性固體稀釋劑或其中活性成分與水溶性載體或油溶媒混合的軟明膠膠囊提供口服製劑。 Oral formulations can also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble or oily vehicle.

水混懸液含有活性物質和用於混合的適宜製備水懸浮液的賦形劑。此類賦形劑是懸浮劑、分散劑或濕潤劑。水混懸液也可以含有一種或多種防腐劑、一種或多種著色劑、一種或多種矯味劑和一種或多種甜味劑。 Aqueous suspensions contain the active substances in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. The 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.

油混懸液可藉由使活性成分懸浮於植物油或礦物油配製而成。油混懸液可含有增稠劑。可加入甜味劑和矯味劑以提供可口的製劑。可藉由加入抗氧化劑保存這些組成物。 Oily suspensions can be formulated by suspending the active ingredient in vegetable or mineral oils. The oily suspensions may contain thickening agents. Sweetening and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

本揭露的醫藥組成物也可以是水包油乳劑的形式。油相可以是植物油、或礦物油、或其混合物。適宜的乳化劑可以是天然產生的磷脂，乳劑也可以含有甜味劑、矯味劑、防腐劑和抗氧劑。此類製劑也可含有緩和劑、防腐劑、著色劑和抗氧劑。 The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase can be vegetable oil, or mineral oil, or a mixture thereof. Suitable emulsifying agents may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.

本揭露的醫藥組成物可以是無菌注射水溶液形式。可以使用的可接受的溶媒或溶劑有水、林格氏液和等滲氯化鈉溶液。無菌注射製劑可以是其中活性成分溶於油相的無菌注射水包油微乳，可藉由局部大量注射將注射液或微乳注入患者的血流中。或者，最好按可保持本揭露化合物恆定循環濃度的方式給予溶液和微乳。為保持這種恆定濃度，可使用連續靜脈內遞藥裝置。這種裝置的實例是Deltec CADD-PLUS.TM.5400型靜脈注射泵。 The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Among the acceptable vehicles or solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oily phase, and the injectable solution or microemulsion can be injected into the bloodstream of a patient by local bulk injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous drug delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous pump.

本揭露的醫藥組成物可以是用於肌內和皮下給藥的無菌注射水或油混懸液的形式。可按已知技術，用適宜的分散劑或濕潤劑和懸浮劑配製該混懸液。無菌注射製劑也可以是在腸胃外可接受的無毒稀釋劑或溶劑中製備的無菌注射溶液或混懸液。此外，可方便地用無菌固定油作為溶劑或懸浮介質。為此目的，可使用任何調和固定油。此外，脂肪酸也可以製備注射劑。 The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any blending and fixing oil can be used. In addition, fatty acids are also available in the preparation of injectables.

可按用於直腸給藥的栓劑形式給予本揭露化合物。可藉由將藥物與在普通溫度下為固體但在直腸中為液體，因而在直腸中會溶化而釋放藥物的適宜的無刺激性賦形劑混合來製備這些醫藥組成物。 The compounds of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

可藉由加入水來製備水混懸的可分散粉末和顆粒給予本揭露化合物。可藉由將活性成分與分散劑或濕潤劑、懸浮劑或一種或多種防腐劑混合來製備這些醫藥組成物。 The compounds of the present disclosure can be administered by the addition of water to prepare dispersible powders and granules for aqueous suspension. These pharmaceutical compositions can be prepared by admixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

如所屬技術領域中具有通常知識者所熟知的，藥物的給藥劑量依賴於多種因素，包括但並非界定於以下因素：所用具體化合物的活性、疾病的嚴重性、患者的年齡、患者的體重、患者的健康狀況、患者的行為、患者的飲食、給藥時間、給藥方式、***的速率、藥物的組合等；另外，最佳的治療方式如治療的模式、化合物的日用量或可藥用的鹽的種類可以根據傳統的治療方案來驗證。 As is well known to those of ordinary skill in the art, the dosage of a drug administered depends on a variety of factors including, but not limited to, the activity of the particular compound used, the severity of the disease, the age of the patient, the weight of the patient, The patient's health status, the patient's behavior, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment mode such as the mode of treatment, the daily dose of the compound or the pharmaceutically acceptable The type of salt can be verified according to traditional treatment protocols.

術語說明Glossary

除非有相反陳述，在說明書和申請專利範圍中使用的術語具有下述含義。 Unless stated to the contrary, terms used in the specification and claims have the following meanings.

術語「烷基」指飽和脂肪族烴基團，其為包含1至20個碳原子的直鏈或支鏈基團，較佳為含有1至12個(例如1、2、3、4、5、6、7、8、9、10、11和12個)碳原子的烷基，更佳為含有1至6個碳原子的烷基。非限制性實例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、 正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各種支鏈異構體等。更佳的是含有1至6個碳原子的低級烷基，非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，該取代基較佳為獨立地視需要選自H原子、D原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基中的一個或多個取代基。 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 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, more preferably alkyl groups 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-dimethyhexyl Methylpentyl, 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 isomers thereof, etc. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, th Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl , 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2- Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methyl pentyl, 2,3-dimethylbutyl, etc. Alkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently and optionally selected from H atoms, D atoms, halogens, alkanes alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, One or more substituents in aryl, heteroaryl.

術語「伸烷基」指飽和的直鏈或支鏈脂肪族烴基，其為從母體烷的相同碳原子或兩個不同的碳原子上除去兩個氫原子所衍生的殘基，其為包含1至20個碳原子的直鏈或支鏈基團，較佳為含有1至12個(例如1、2、3、4、5、6、7、8、9、10、11和12個)碳原子，更佳為含有1至6個碳原子的伸烷基。伸烷基的非限制性實例包括但不限於伸甲基(-CH₂-)、1,1-亞乙基(-CH(CH₃)-)、1,2-伸乙基(-CH₂CH₂)-、1,1-亞丙基(-CH(CH₂CH₃)-)、1,2-伸丙基(-CH₂CH(CH₃)-)、1,3-伸丙基(-CH₂CH₂CH₂-)、1,4-伸丁基(-CH₂CH₂CH₂CH₂-)等。伸烷基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，該取代基較佳為獨立地視需要選自烷基、烯基、炔基、烷氧基、鹵烷氧基、環烷基氧基、雜環基氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基和側氧基中的一個或多個取代基。 The term "alkylene" refers to a saturated straight or branched chain aliphatic hydrocarbon group, which is a residue derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which is a residue containing 1 Straight or branched chain groups of up to 20 carbon atoms, preferably containing 1 to 12 (eg 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbons atom, more preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylidene ( _-CH2- ), 1,1-ethylene (-CH( _CH3 )-), 1,2-ethylidene ( _-CH2) CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylidene (-CH ₂ CH(CH ₃ )-), 1,3-propylidene (-CH ₂ CH ₂ CH ₂ -), 1,4-butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), and the like. Alkylene may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from alkyl, alkenyl, alkynyl , alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl , aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and one or more substituents of pendant oxy.

術語「烯基」指分子中含有至少一個碳碳雙鍵的烷基化合物，其中，烷基的定義如上所述。烯基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自氫原子、烷基、烷氧基、鹵素、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基。 The term "alkenyl" refers to an alkyl compound having at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyls, one of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, or multiple substituents.

術語「炔基」指分子中含有至少一個碳碳三鍵的烷基化合物，其中，烷基的定義如上所述。炔基可以是取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自氫原子、烷基、烷氧基、鹵素、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基。 The term "alkynyl" refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from hydrogen atoms, alkyl groups, alkoxy groups, halogens, haloalkyls, one of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl, or multiple substituents.

術語「環烷基」指飽和或部分不飽和單環或多環環狀烴取代基，環烷基環包含3至20個碳原子，較佳為包含3至12個碳原子，較佳為包含3至8個碳原子(例如3、4、5、6、7和8個)，更佳為包含3至6個碳原子。單環環烷基的非限制性實例包括環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基、環辛基等；多環環烷基包括螺環、稠環和橋環的環烷基。 The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably containing 3 to 8 carbon atoms (eg 3, 4, 5, 6, 7 and 8), more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.

術語「螺環烷基」指5至20員，單環之間共用一個碳原子(稱螺原子)的多環基團，其可以含有一個或多個雙鍵。較佳為6至14員，更佳為7至10員(例如7、8、9或10員)。根據環與環之間共用螺原子的數目將螺環烷基分為單螺環烷基、雙螺環烷基或多螺環烷基，較佳為單螺環烷基和雙螺環烷基。更佳為4員/4員、4員/5員、4員/6員、5員/5員或5員/6員單螺環烷基。螺環烷基的非限制性實例包括： The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group containing one carbon atom (called a spiro atom) between the monocyclic rings, which may contain one or more double bonds. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl, double-spirocycloalkyl or poly-spirocycloalkyl, preferably mono-spirocycloalkyl and double-spirocycloalkyl . More preferably 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-/5-member or 5-/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

術語「稠環烷基」指5至20員，系統中的每個環與體系中的其他環共享毗鄰的一對碳原子的全碳多環基團，其中，一個或多個環可以含有一個或多個雙鍵。較佳為6至14員，更佳為7至10員(例如7、8、9或10員)。根據組成環的數目可以分為雙環、三環、四環或多環稠環烷基，較佳為雙環或三環，更佳為5員/5員或5員/6員雙環烷基。稠環烷基的非限制性實例包括： The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, each ring in the system sharing an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain a or multiple double bonds. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

術語「橋環烷基」指5至20員，任意兩個環共用兩個不直接連接的碳原子的全碳多環基團，其可以含有一個或多個雙鍵。較佳為6至14員，更佳為7至10員(例如7、8、9或10員)。根據組成環的數目可以分為雙環、三環、四環或多環橋環烷基，較佳為雙環、三環或四環，更佳為雙環或三環。橋環烷基的非限制性實例包括： The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly attached carbon atoms, which may contain one or more double bonds. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

該環烷基環包括如上所述的環烷基(包括單環、螺環、稠環和橋環)稠合於芳基、雜芳基或雜環烷基環上，其中，與母體結構連接在一起 的環為環烷基，非限制性實例包括

、

、

等等； 較佳為

或

。 The cycloalkyl ring includes a cycloalkyl group (including monocyclic, spirocyclic, fused and bridged rings) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the parent structure is attached Rings together are cycloalkyl, non-limiting examples include

,

,

etc.; preferably

or

.

環烷基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，該取代基較佳為獨立地視需要選自氫原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基中的一個或多個取代基。 Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently and optionally selected from hydrogen atoms, halogens, alkyls, Alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl , one or more substituents in a heteroaryl group.

術語「烷氧基」指-O-(烷基)，其中，烷基的定義如上所述。烷氧基的非限制性實例包括：甲氧基、乙氧基、丙氧基、丁氧基。烷氧基可以是視需要取代的或非取代的，當被取代時，取代基較佳為一個或多個以下基團，其獨立地選自H原子、D原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基。 The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from H atom, D atom, halogen, alkyl, alkoxy alkyl, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heterocyclyl Aryl.

術語「雜環基」指飽和或部分不飽和單環或多環環狀取代基，其包含3至20個環原子，其中，一個或多個環原子為選自氮、氧和硫的雜原子，該硫可視需要被氧化(即形成亞碸或碸)，但不包括-O-O-、-O-S-或-S-S-的環部分，其餘環原子為碳。較佳為包含3至12個環原子，其中，1至4個(例如1、2、3和4個)是雜原子；更佳為包含3至8個環原子(例如3、4、5、6、7和8個)，其中，1至3個是雜原子(例如1、2和3個)；更佳為包含3至6個環原子，其中，1至3個是雜原子；最佳為包含5或6個環原子，其中，1至3個是雜原子。單環雜環基的非限制性實例包括吡咯烷基、四氫吡喃基、1,2,3,6-四氫吡啶基、哌啶基、哌嗪基、嗎 啉基、硫嗎啉基、高哌嗪基等。多環雜環基包括螺環、稠環和橋環的雜環基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing from 3 to 20 ring atoms, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur , the sulfur is optionally oxidized (ie, to form arsenic or arsenic), but does not include ring moieties of -O-O-, -O-S-, or -S-S-, the remaining ring atoms being carbon. Preferably it contains 3 to 12 ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are heteroatoms; more preferably 3 to 8 ring atoms (eg 3, 4, 5, 6, 7 and 8), of which 1 to 3 are heteroatoms (eg 1, 2 and 3); more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms; most preferred is containing 5 or 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, Linoyl, thiomorpholine, homopiperazinyl, etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

術語「螺雜環基」指5至20員的單環之間共用一個原子(稱螺原子)的多環雜環基團，其中，一個或多個環原子為選自氮、氧和硫的雜原子，該硫可視需要被氧化(即形成亞碸或碸)，其餘環原子為碳。其可以含有一個或多個雙鍵。較佳為6至14員，更佳為7至10員(例如7、8、9或10員)。根據環與環之間共用螺原子的數目將螺雜環基分為單螺雜環基、雙螺雜環基或多螺雜環基，較佳為單螺雜環基和雙螺雜環基。更佳為4員/4員、4員/5員、4員/6員、5員/5員或5員/6員單螺雜環基。螺雜環基的非限制性實例包括： The term "spiroheterocyclyl" refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen and sulfur. A heteroatom, the sulfur can be oxidized if desired (ie, to form arsenic or arsenic), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of spiro atoms shared between rings, spiroheterocyclyl groups are classified into mono-spiroheterocyclyl, bis-spiro-heterocyclyl or poly-spiro-heterocyclyl, preferably mono-spiroheterocyclyl and bis-spiro-heterocyclyl . More preferably a 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-/5-member or 5-/6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:

術語「稠雜環基」指5至20員，系統中的每個環與體系中的其他環共享毗鄰的一對原子的多環雜環基團，一個或多個環可以含有一個或多個雙鍵，其中，一個或多個環原子為選自氮、氧和硫的雜原子，該硫可視需要被氧化(即形成亞碸或碸)，其餘環原子為碳。較佳為6至14員，更佳為7至10員(例如7、8、9或10員)。根據組成環的數目可以分為雙環、三環、四環或多環稠雜環基，較佳為雙環或三環，更佳為5員/5員或5員/6員雙環稠雜環基。稠雜環基的非限制性實例包括： The term "fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more A double bond in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxidized (ie, to form sulfite or sulfite), and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 7, 8, 9 or 10 members). According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group . Non-limiting examples of fused heterocyclyl groups include:

術語「橋雜環基」指5至14員，任意兩個環共用兩個不直接連接的原子的多環雜環基團，其可以含有一個或多個雙鍵，其中，一個或多個環原子為選自氮、氧和硫的雜原子，該硫可視需要被氧化(即形成亞碸或碸)，其餘環原子為碳。較佳為6至14員，更佳為7至10員(例如7、8、9或10員)。根據組成環的數目可以分為雙環、三環、四環或多環橋雜環基，較佳為雙環、三環或四環，更佳為雙環或三環。橋雜環基的非限制性實例包括： The term "bridged heterocyclyl" 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 rings The atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, which can be optionally oxidized (ie, to form selenium or susceptibility), and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members (eg 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 heterocyclyl groups include:

該雜環基環包括如上所述的雜環基(包括單環、螺雜環、稠雜環和橋雜環)稠合於芳基、雜芳基或環烷基環上，其中，與母體結構連接在一起的環為雜環基，其非限制性實例包括： The heterocyclyl ring includes the above-mentioned heterocyclyl (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) fused to an aryl, heteroaryl or cycloalkyl ring, wherein, with the parent The rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:

和

等。

and

Wait.

雜環基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，該取代基較佳為獨立地視需要選自氫原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基中的一個或多個取代基。 Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from the group consisting of hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl , one or more substituents in a heteroaryl group.

術語「芳基」指具有共軛的π電子體系的6至14員全碳單環或稠合多環(稠合多環是共享毗鄰碳原子對的環)基團，較佳為6至10員，例如苯基和萘基。該芳基環包括如上所述的芳基環稠合於雜芳基、雜環基或環烷基環上，其中，與母體結構連接在一起的環為芳基環，其非限制性實例包括： The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic are rings that share adjacent pairs of carbon atoms) groups having a conjugated pi electron system, preferably 6 to 10 members, such as phenyl and naphthyl. The aryl ring includes an aryl ring fused to a heteroaryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include :

芳基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，該取代基較佳為獨立地視需要選自氫原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基中的一個或多個取代基。 Aryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently and optionally selected from hydrogen atoms, halogens, alkyl groups, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, One or more substituents in a heteroaryl group.

術語「雜芳基」指包含1至4個(例如1、2、3和4個)雜原子、5至14個環原子的雜芳族體系，其中，雜原子選自氧、硫和氮。雜芳基較佳為5至10員(例如5、6、7、8、9或10員)，更佳為5員或6員，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、噠嗪基、咪唑基、吡唑基、***基、四唑基等。該雜芳基環包括如上述的雜芳基稠合於芳基、雜環基或環烷基環上，其中，與母體結構連接在一起的環為雜芳基環，其非限制性實例包括： The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 (eg 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 members (eg 5, 6, 7, 8, 9 or 10 members), more preferably 5 or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N- Alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl group fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include :

雜芳基可以是取代的或非取代的，當被取代時，其可以在任何可使用的連接點上被取代，該取代基較佳為獨立地視需要選自氫原子、鹵素、烷基、烷氧基、鹵烷基、鹵烷氧基、環烷基氧基、雜環基氧基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基、雜芳基中的一個或多個取代基。 Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently and optionally selected from the group consisting of hydrogen atoms, halogens, alkyls, Alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl , one or more substituents in a heteroaryl group.

上述環烷基、雜環基、芳基和雜芳基包括從母體環原子上除去一個氫原子所衍生的殘基，或從母體的相同或兩個不同的環原子上除去兩個氫原子所衍生的殘基，即「二價環烷基」、「二價雜環基」、「伸芳基」和「伸雜芳基」。 The aforementioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atom, or by removing two hydrogen atoms from the same or two different ring atoms of the parent. Derivative residues, namely "divalent cycloalkyl", "divalent heterocyclyl", "arylidene" and "heteroaryl".

術語「胺基保護基」是為了使分子其它部位進行反應時胺基保持不變，用易於脫去的基團對胺基進行保護。非限制性實施例包含(三甲基矽)乙氧基甲基、四氫吡喃基、第三丁氧羰基、乙醯基、苄基、烯丙基和對甲氧苄基等。這些基團可視需要地被選自鹵素、烷氧基或硝基中的1-3個取代基所取代。術語「羥基保護基」是本領域已知的適當的用於羥基保護的基團，參見文獻(「Protective Groups in Organic Synthesis」，5^Th Ed.T.W.Greene&P.G.M.Wuts)中的羥基保護基團。作為示例，較佳地，該 羥基保護基可以是(C_1-10烷基或芳基)₃矽烷基，例如：三乙基矽基、三異丙基矽基、第三丁基二甲基矽基、第三丁基二苯基矽基等；可以是C_1-10烷基或取代烷基，較佳為烷氧基取代的烷基或芳基取代的烷基，更佳為C_1-6烷氧基取代的C_1-6烷基或苯基取代的C_1-6烷基，最佳為C_1-4烷氧基取代的C_1-4烷基，例如：甲基、第三丁基、苄基、甲氧基甲基(MOM)、乙氧基乙基；可以是(C_1-10烷基或芳香基)醯基，例如：甲醯基、乙醯基、苯甲醯基、對硝基苯甲醯基等；可以是(C_1-6烷基或C_6-10芳基)磺醯基；也可以是(C_1-6烷氧基或C_6-10芳基氧基)羰基。 The term "amine protecting group" is used to protect the amine group with a group that is easy to remove in order to keep the amine group unchanged when the other parts of the molecule are reacted. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups are optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro. The term "hydroxyl protecting group" is a suitable group known in the art for hydroxyl protection, see literature ("Protective Groups in Organic Synthesis", 5 ^Th Ed. TW Greene & P. GMWuts) for hydroxyl protecting groups. As an example, preferably, the hydroxyl protecting group can be a (C _1-10 alkyl or aryl) ₃ silyl group, such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl Silicon, tert-butyldiphenylsilyl, etc.; 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, preferably C _1-4 alkoxy substituted C _1-4 alkyl, for example: methyl, th Tributyl, benzyl, methoxymethyl (MOM), ethoxyethyl; can be (C _1-10 alkyl or aryl) aryl, such as: methyl, acetyl, benzyl Acyl, p-nitrobenzyl, etc.; can be (C _1-6 alkyl or C _6-10 aryl) sulfonyl; can also be (C _1-6 alkoxy or C _6-10 aryl) oxy) carbonyl.

術語「環烷基氧基」指環烷基-O-，其中，環烷基如上所定義。 The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.

術語「雜環基氧基」指雜環基-O-，其中，雜環基如上所定義。 The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

術語「芳基氧基」指芳基-O-，其中，芳基如上所定義。 The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.

術語「雜芳基氧基」指雜芳基-O-，其中，雜芳基如上所定義。 The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

術語「烷硫基」指烷基-S-，其中，烷基如上所定義。 The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above.

術語「鹵烷基」指烷基被一個或多個鹵素取代，其中，烷基如上所定義。 The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

術語「鹵烷氧基」指烷氧基被一個或多個鹵素取代，其中，烷氧基如上所定義。 The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

術語「氘代烷基」指烷基被一個或多個氘原子取代，其中，烷基如上所定義。 The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

術語「羥烷基」指烷基被一個或多個羥基取代，其中，烷基如上所定義。 The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

術語「鹵素」指氟、氯、溴或碘。 The term "halogen" refers to fluorine, chlorine, bromine or iodine.

術語「羥基」指-OH。 The term "hydroxy" refers to -OH.

術語「巰基」指-SH。 The term "thiol" refers to -SH.

術語「胺基」指-NH₂。 The term "amino" refers to _-NH2 .

術語「氰基」指-CN。 The term "cyano" refers to -CN.

術語「硝基」指-NO₂。 The term "nitro" refers to _-NO2 .

術語「側氧基」或「側氧」指「=O」。 The term "pendant oxygen" or "pendant oxygen" refers to "=O".

術語「羰基」指C=O。 The term "carbonyl" refers to C=O.

術語「羧基」指-C(O)OH。 The term "carboxy" refers to -C(O)OH.

術語「羧酸酯基」指-C(O)O(烷基)、-C(O)O(環烷基)、(烷基)C(O)O-或(環烷基)C(O)O-，其中，烷基、環烷基如上所定義。 The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl, cycloalkyl are as defined above.

本揭露的化合物還可包含其同位素衍生物。術語「同位素衍生物」指結構不同僅在於存在一種或多種同位素富集原子的化合物。例如，具有本揭露的結構，除了用「氘」或「氚」代替氫，或者用¹⁸F-氟標記(¹⁸F同位素)代替氟，或者用¹¹C-、¹³C-、或者¹⁴C-富集的碳(¹¹C-、¹³C-、或者¹⁴C-碳標記；¹¹C-、¹³C-、或¹⁴C-同位素)代替碳原子的化合物在本揭露的範圍內。這樣的化合物可用作例如生物學測定中的分析工具或探針，或者可以用作疾病的體內診斷成像示蹤劑，或者作為藥效學、藥動學或受體研究的示蹤劑。本揭露還包括各種氘化形式的化合物。與碳原子連接的各個可用的氫原子可獨立地被氘原子替換。所屬技術領域中具有通常知識者能夠參考相關文獻合成氘化形式的化合物。在製備氘代形式的化合物時可使用市售的氘代起始物質，或它們可使用一般技術採用氘代試劑合成，氘代試劑包括但不限於氘代硼烷、三氘代硼烷四氫呋喃溶液、氘代氫化鋰鋁、氘代碘乙烷和氘代碘甲烷等。氘代物通常可以保留與未氘代的化合物相當的活性，並且當氘代在某些特定位點時可以取得更好的代謝穩定性，從而獲得某些治療優勢。 The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivatives" refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms. For example, there are structures of the present disclosure, except that "deuterium" or "tritium" is used in place of hydrogen, or ^18F -fluorine label ( ^18F isotope) is used instead of fluorine, ^or11C- , ^13C- , ^or14C -rich Compounds that set carbon ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C-, or ¹⁴ C-isotopes) in place of carbon atoms are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The present disclosure also includes compounds in various deuterated forms. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. One of ordinary skill in the art can refer to the relevant literature to synthesize the deuterated form of the compound. Commercially available deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using general techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran , Deuterated lithium aluminum hydride, deuterated iodoethane and deuterated iodomethane, etc. Deuterated compounds generally retain comparable activity to undeuterated compounds, and when deuterated at certain specific sites can achieve better metabolic stability, resulting in certain therapeutic advantages.

「視需要」或「視需要地」意味著隨後所描述的事件或環境可以但不必發生，該說明包括該事件或環境發生或不發生地場合。例如，「視需要被烷基取代的雜環基團」意味著烷基可以但不必須存在，該說明包括雜環基團被烷基取代的情形和雜環基團不被烷基取代的情形。 "Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that 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 the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .

「取代的」指基團中的一個或多個氫原子，較佳為1至5個，更佳為1至3個氫原子彼此獨立地被相應數目的取代基取代。所屬技術領域中具有通常知識者能夠在不付出過多努力的情況下(藉由實驗或理論)確定可能或不可能的取代。例如，具有游離氫的胺基或羥基與具有不飽和(如烯屬)鍵的碳原子結合時可能是不穩定的。 "Substituted" means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, are substituted with the corresponding number of substituents. Those of ordinary skill in the art can determine possible or impossible substitutions without undue effort (either experimentally or theoretically). For example, amine groups or hydroxyl groups with free hydrogens may be unstable when bound to carbon atoms with unsaturated (eg, olefinic) bonds.

「醫藥組成物」表示含有一種或多種本文所述化合物或其生理學上/可藥用的鹽或前體藥物與其他化學組分的混合物，以及其他組分例如生理學/可藥用的載體和賦形劑。醫藥組成物的目的是促進對生物體的給藥，利於活性成分的吸收進而發揮生物活性。 "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

「可藥用的鹽」是指本揭露化合物的鹽，這類鹽用於哺乳動物體內時具有安全性和有效性，且具有應有的生物活性。可以在化合物的最終分離和純化過程中，或藉由使合適的基團與合適的鹼或酸反應來單獨製備鹽。通常用於形成藥學上可接受的鹽的鹼包括無機鹼，例如氫氧化鈉和氫氧化鉀，以及有機鹼，例如胺。通常用於形成藥學上可接受的鹽的酸包括無機酸以及有機酸。 "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which are safe and effective when used in mammals, and have the desired biological activity. The salts can be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate 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 amines. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

針對藥物或藥理學活性劑而言，術語「治療有效量」是指無毒的但能達到預期效果的藥物或藥劑的足夠用量。有效量的確定因人而異，取決於受體的年齡和一般情況，也取決於具體的活性物質，個案中合適的有效量可以由所屬技術領域中具有通常知識者根據一般試驗確定。 With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a non-toxic but sufficient amount of the drug or agent to 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, and the appropriate effective amount in a case can be determined by those of ordinary knowledge in the art based on general experiments.

本文所用的術語「溶劑化物」是指本揭露的化合物與一種或多種，較佳地為1至3種，無論是有機的還是無機的溶劑分子的物理結合。該物理結合包括氫鍵。在某些情況下，例如，當在結晶固體的晶格中摻入一種或多種，較佳為1至3種溶劑分子時，溶劑化物將被分離。示例性的溶劑化物包括但不限於水合物、乙醇化物、甲醇化物和異丙醇化物。溶劑化方法是本領域公知的。 The term "solvate" as used herein refers to a physical association of a compound of the present disclosure with one or more, preferably 1 to 3, solvent molecules, whether organic or inorganic. This physical bond includes hydrogen bonding. In some cases, for example, when one or more, preferably 1 to 3, solvent molecules are incorporated into the crystal lattice of the crystalline solid, the solvate will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

「前藥」是指可以在生理條件下，例如藉由在血液中水解，在體內轉化以產生活性原藥化合物。 "Prodrug" means a compound that can be transformed in vivo under physiological conditions, such as by hydrolysis in blood, to yield the active prodrug compound.

本文所用的術語「藥學上可接受的」是指這些化合物、材料、組成物和/或劑型，在合理的醫學判斷範圍內，適用於與患者組織接觸而沒有過度毒性、刺激性、過敏反應或其他問題或併發症，具有合理的獲益/風險比，並且對預期的用途是有效。 The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with patient tissue without undue toxicity, irritation, allergic response or Other problems or complications with a reasonable benefit/risk ratio and are effective for the intended use.

本文所使用的，單數形式的「一個」、「一種」和「該」包括複數引用，反之亦然，除非上下文另外明確指出。 As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

當將術語「約」應用於如pH、濃度、溫度等的參數時，表明該參數可以變化±10%，並且有時更佳地在±5%之內。如所屬技術領域中具有通常知識者將理解的，當參數不是關鍵的時，通常僅出於說明目的給出數字，而不是限制。 When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is indicated that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As will be understood by one of ordinary skill in the art, when parameters are not critical, numbers are generally given for illustrative purposes only, and not limitations.

本揭露化合物的合成方法Synthetic methods of compounds of the present disclosure

為了完成本揭露的目的，本揭露採用如下技術方案： In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

方案一 Option One

本揭露通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的製備方法，包括以下步驟： The compound represented by the general formula (I) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The preparation method of the salt used comprises the following steps:

通式(IA)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽和通式(IB)化合物在催化劑存在下，在鹼性條件下發生偶聯反應，得到通式(I)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， A compound of general formula (IA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and In the presence of a catalyst, the compound of general formula (IB) undergoes a coupling reaction under basic conditions to obtain the compound of general formula (I) or its tautomer, meso, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中， in,

X為鹵素；較佳為Br； X is halogen; preferably Br;

Y為

或

； Y is

or

;

R為氫原子或烷基； R is a hydrogen atom or an alkyl group;

R⁰、R¹、R²、R³、R⁴、R⁵和n如通式(I)中所定義。 R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are as defined in general formula (I).

方案二 Option II

本揭露的另一方面係關於一種製備通式(I-a)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的方法，該方法包括： Another aspect of the present disclosure relates to a preparation of the compound represented by general formula (I-a) or its tautomer, meso, racemate, enantiomer, diastereomer, or A method for its mixture form, or a pharmaceutically acceptable salt thereof, comprising:

通式(I-aA)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽和通式(IB)化合物在催化劑存在下，在鹼性條件下發生偶聯反應，得到通式(I-a)的化 合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， A compound of general formula (I-aA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable form thereof In the presence of a catalyst, the salt and the compound of the general formula (IB) undergo a coupling reaction under basic conditions to obtain the compound of the general formula (I-a). compound or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中， in,

X為鹵素；較佳為Br； X is halogen; preferably Br;

Y為

或

； Y is

or

;

R為氫原子或烷基； R is a hydrogen atom or an alkyl group;

R⁰、R¹、R²、R³、R⁴和n如通式(I-a)中所定義。 R ⁰ , R ¹ , R ² , R ³ , R ⁴ and n are as defined in general formula (Ia).

方案三 third solution

本揭露通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的製備方法，包括以下步驟： The compound represented by the general formula (II) of the present disclosure or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The preparation method of the salt used comprises the following steps:

通式(IIA)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽和通式(IIB)化合物在催化劑存在下，在鹼性條件下發生偶聯反應，得到通式(II)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， A compound of general formula (IIA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and The compound of general formula (IIB) undergoes a coupling reaction under basic conditions in the presence of a catalyst to obtain the compound of general formula (II) or its tautomer, meso, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中， in,

X為鹵素；較佳為Br； X is halogen; preferably Br;

Y為

或

； Y is

or

;

R為氫原子或烷基； R is a hydrogen atom or an alkyl group;

R⁰、R¹、R⁴、R⁶、R⁷、n、p和q如通式(II)中所定義。 R ⁰ , R ¹ , R ⁴ , R ⁶ , R ⁷ , n, p and q are as defined in general formula (II).

以上合成方案中提供鹼性條件的試劑包括有機鹼和無機鹼類，該有機鹼類包括但不限於三乙胺、N,N-二異丙基乙胺、正丁基鋰、二異丙基胺基鋰、雙三甲基矽基胺基鋰、醋酸鉀、第三丁醇鈉、第三丁醇鉀和正丁醇鈉，該無機鹼類包括但不限於氫化鈉、磷酸鉀、碳酸鈉、碳酸鉀、醋酸鉀、碳酸絕、氫氧化鈉和氫氧化鋰，較佳為碳酸鈉或無水碳酸鈉。 The reagents that provide 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, diisopropyl Lithium amide, lithium bistrimethylsilyl amide, 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, carbonic acid, sodium hydroxide and lithium hydroxide, preferably sodium carbonate or anhydrous sodium carbonate.

以上合成方案中，該催化劑包括但不限於鈀/碳、四三苯基膦鈀、二氯化鈀、醋酸鈀、雙(二亞苄基丙酮)鈀、氯(2-二環己基膦基-2',4',6'-三異丙基-1,1'-聯苯基)[2-(2'-胺基-1,1'-聯苯)]鈀、[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀、[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物、1,1’-雙(二苄基磷)二氯二茂鐵鈀或三(二亞苄基丙酮)二鈀，較佳為[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物。 In the above synthesis scheme, the catalyst 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]dichloropalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex, 1,1'- Bis(dibenzylphosphorus)dichloroferrocene palladium or tris(dibenzylideneacetone)dipalladium, preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium Chloromethane complex.

上述反應較佳在溶劑中進行，所用溶劑包括但不限於：乙二醇二甲醚、醋酸、甲醇、乙醇、正丁醇、甲苯、四氫呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亞碸、1,4-二噁烷、水或N,N-二甲基甲醯胺。 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 , dimethylsulfoxide, 1,4-dioxane, water or N,N-dimethylformamide.

以下結合實施例進一步描述本揭露，但這些實施例並非限制著本揭露的範圍。 The present disclosure is further described below with reference to the embodiments, but these embodiments do not limit the scope of the present disclosure.

實施例 Example

化合物的結構是藉由核磁共振(NMR)或/和質譜(MS)來確定的。NMR位移(δ)以10^-6(ppm)的單位給出。NMR的測定是用Bruker AVANCE-400或Bruker AVANCE NEO 500M核磁儀，測定溶劑為氘代二甲基亞碸(DMSO-d ₆ )、氘代氯仿(CDCl₃)、氘代甲醇(CD₃OD)，內標為四甲基矽烷(TMS)。 The structures of the compounds were determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" ⁶ > (ppm). NMR was measured by Bruker AVANCE-400 or Bruker AVANCE NEO 500M nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) , the internal standard is tetramethylsilane (TMS).

MS的測定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液質聯用儀(生產商：Agilent，MS型號：6110/6120 Quadrupole MS)；waters ACQuity UPLC-QD/SQD(生產商：waters，MS型號：waters ACQuity Qda Detector/waters SQ Detector)；THERMO Ultimate 3000-Q Exactive(生產商：THERMO，MS型號：THERMO Q Exactive)。 The determination of MS was performed with an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS instrument (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).

高效液相層析法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相層析儀。 High performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD and a Waters HPLC e2695-2489 high performance liquid chromatograph.

手性HPLC分析測定使用Agilent 1260 DAD高效液相層析儀。 Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.

高效液相製備層析法使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281製備型層析儀。 High performance liquid preparative chromatography used Waters 2545-2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

手性製備層析法使用Shimadzu LC-20AP製備型層析儀。 Chiral preparative chromatography used a Shimadzu LC-20AP preparative chromatograph.

CombiFlash快速製備儀使用Combiflash Rf200(TELEDYNE ISCO)。 The CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

薄層層析矽膠板使用煙臺黃海HSGF254或青島GF254矽膠板，薄層層析法(TLC)使用的矽膠板採用的規格是0.15mm至0.2mm，薄層層析分離純化產品採用的規格是0.4mm至0.5mm。 The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm to 0.2mm, and the specification used for TLC separation and purification products is 0.4 mm to 0.5mm.

矽膠管柱層析法一般使用煙臺黃海矽膠200至300目矽膠為載體。 Silica gel column chromatography generally uses Yantai Huanghai silica gel 200 to 300 mesh silica gel as the carrier.

激酶平均抑制率及IC₅₀值的測定用NovoStar酶標儀(德國BMG公司)。 The average inhibition rate and IC ₅₀ value of kinases were measured with NovoStar microplate reader (BMG, Germany).

本揭露的已知的起始原料可以採用或按照本領域已知的方法來合成，或可購買自ABCR GmbH & Co.KG、Acros Organics、Aldrich Chemical Company、韶遠化學科技(Accela ChemBio Inc)、達瑞化學品等公司。 The known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.

實施例中無特殊說明，反應能夠均在氬氣氛或氮氣氛下進行。 There is no special description in the examples, and the reactions can all be carried out in an argon atmosphere or a nitrogen atmosphere.

氬氣氛或氮氣氛是指反應瓶連接一個約1L容積的氬氣或氮氣氣球。 Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

氫氣氛是指反應瓶連接一個約1L容積的氫氣氣球。 Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

加壓氫化反應使用Parr 3916EKX型氫化儀和清藍QL-500型氫氣發生器或HC2-SS型氫化儀。 The pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.

氫化反應通常抽真空，充入氫氣，反復操作3次。 The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

微波反應使用CEM Discover-S 908860型微波反應器。 The microwave reaction used a CEM Discover-S 908860 microwave reactor.

實施例中無特殊說明，溶液是指水溶液。 There is no special description in the examples, and the solution refers to an aqueous solution.

實施例中無特殊說明，反應的溫度為室溫，為20℃至30℃。 There is no special description in the examples, and the reaction temperature is room temperature, ranging from 20°C to 30°C.

實施例中的反應進程的監測採用薄層層析法(TLC)，反應所使用的展開劑，純化化合物採用的管柱層析法的沖提劑的體系和薄層層析法的展開劑體系包括：A：二氯甲烷/甲醇體系，B：正己烷/乙酸乙酯體系，C：石油醚/乙酸乙酯體系，溶劑的體積比根據化合物的極性不同而進行調節，也可以加入少量的三乙胺和醋酸等鹼性或酸性試劑進行調節。 The monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), the developing agent used in the reaction, the eluent system of the column chromatography method and the developing agent system of the thin layer chromatography method used to purify the compound. Including: 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 trichloroethylene can also be added. Adjust with basic or acidic reagents such as ethylamine and acetic acid.

實施例1 Example 1

(R)-3-甲基-4-(6-甲基-2-(1-甲基-1H-吡唑-5-基)-8-(1H-吡唑-5-基)咪唑并[1,5-a]嘧啶-4-基)嗎啡啉1 ( R )-3-Methyl-4-(6-methyl-2-(1-methyl- 1H -pyrazol-5-yl)-8-( 1H -pyrazol-5-yl)imidazole [1,5- a ]pyrimidin-4-yl)morpholine 1

第一步 first step

N-((4,6-二側氧-1,4,5,6-四氫嘧啶-2-基)甲基)乙醯胺1c N -((4,6-Dioxy-1,4,5,6-tetrahydropyrimidin-2-yl)methyl)acetamide 1c

在氬氣氛下，將丙二醯胺1a(8.6g，84.2mmol，上海畢得)、乙醯基甘胺酸乙酯1b(12.9g，88.87mmol)、甲醇鈉(11.2g，207.3mmol)加入甲醇(150mL)中，回流14小時，冷卻至室溫，過濾，濾液減壓濃縮，得到標題產物1c(12g)，產品不經純化直接用於下一步反應。 Under an argon atmosphere, malonamide 1a (8.6 g, 84.2 mmol, Shanghai Bide), ethyl acetylglycinate 1b (12.9 g, 88.87 mmol), sodium methoxide (11.2 g, 207.3 mmol) were added In 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), which was used in the next reaction without purification.

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

第二步 second step

2,4-二氯-6-甲基咪唑并[1,5-a]嘧啶1d 2,4-Dichloro-6-methylimidazo[1,5- a ]pyrimidine 1d

將粗品化合物1c(12g，65.5mmol)溶於甲苯(50mL)，加入三氯氧磷(36mL，393.1mmol)，緩慢加入N,N-二異丙基乙胺(33mL，196.5mmol)，90℃反應2小時。反應液冷卻至室溫，減壓濃縮，加二氯甲烷(500mL)攪拌0.5小時，過濾，濾液減壓濃縮，得到標題產物1d(8g)，產品不經純化直接用於下一步反應。 The crude compound 1c (12 g, 65.5 mmol) was dissolved in toluene (50 mL), phosphorous oxychloride (36 mL, 393.1 mmol) was added, N , N -diisopropylethylamine (33 mL, 196.5 mmol) was added slowly, 90° C. React for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added with dichloromethane (500 mL) and stirred for 0.5 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1d (8 g), which was used in the next reaction without purification.

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

第三步 third step

(R)-4-(2-氯-6-甲基咪唑并[1,5-a]嘧啶-4-基)-3-甲基嗎啡啉1f ( R )-4-(2-Chloro-6-methylimidazo[1,5- a ]pyrimidin-4-yl)-3-methylmorpholine 1f

將粗品化合物1d(8g,39.59mmol)溶於80mL乙腈中，加入N,N-二異丙基乙胺(232.12mmol，39mL)和(R)-3-甲基嗎啡啉(1e)(8g，79.0mmol，上海畢得)，75℃反應4小時。反應液冷卻至室溫，減壓濃縮，加水(150mL)萃取，乙酸乙酯萃取(80mL×2)，用矽膠管柱層析法以沖提劑體系C純化得到標題化合物1f(500mg，收率：4.7%)。 Crude compound 1d (8 g, 39.59 mmol) was dissolved in 80 mL of acetonitrile, N , N -diisopropylethylamine (232.12 mmol, 39 mL) and ( R )-3-methylmorpholine ( 1e ) (8 g, 79.0 mmol, Shanghai Bide), react 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%).

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

第四步 the fourth step

(R)-3-甲基-4-(6-甲基-2-(1-甲基-1H-吡唑-5-基)咪唑并[1,5-a]嘧啶-4-基)嗎啡啉1g ( R )-3-methyl-4-(6-methyl-2-(1-methyl- 1H -pyrazol-5-yl)imidazo[1,5- a ]pyrimidin-4-yl) Morphine 1g

將化合物1f(40mg，0.15mmol)、1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊-2-基)-1H-吡唑(56mg，0.44mmol，上海畢得)溶於4mL二噁烷和水(v：v=3：1)的混合溶液中，加入[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物(19mg，0.022mmol)和無水碳酸鈉(60mg，0.56mmol)，升溫至100℃反應2小時。冷卻至室溫，反應液過濾，濾液減壓濃縮，所得殘餘物用矽膠管柱層析法以沖提劑體系C純化，得到標題化合物1g(40mg，收率：85.3%)。 Compound 1f (40 mg, 0.15 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) -1H - Pyrazole (56 mg, 0.44 mmol, Shanghai Bide) was dissolved in 4 mL of a mixed solution of dioxane and water (v:v=3:1), and [1,1'-bis(diphenylphosphine)di Ferrocene] palladium dichloride dichloromethane complex (19 mg, 0.022 mmol) and anhydrous sodium carbonate (60 mg, 0.56 mmol), the temperature was raised to 100° C. and reacted for 2 hours. After cooling to room temperature, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography with eluent system C to obtain 1 g of the title compound (40 mg, yield: 85.3%).

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

第五步 the fifth step

(R)-4-(8-溴-6-甲基-2-(1-甲基-1H-吡唑-5-基)咪唑并[1,5-a]嘧啶-4-基)-3-甲基嗎啡啉1h ( R )-4-(8-Bromo-6-methyl-2-(1-methyl- 1H -pyrazol-5-yl)imidazo[1,5- a ]pyrimidin-4-yl)- 3-Methylmorpholine 1h

將化合物1g(40mg，0.13mmol)溶於5mL無水四氫呋喃中，降溫至-78℃，加入N-溴代丁二醯亞胺(23mg，0.13mmol)，攪拌10分鐘。反應液升至室溫，加入3mL飽和碳酸氫鈉溶液，乙酸乙酯萃取(10mL×3)，合併有機相，減壓濃縮，得到粗品標題產物1h(40mg，收率：79.2%)，產物不經純化直接用於下步反應。 Compound 1 g (40 mg, 0.13 mmol) was dissolved in 5 mL of anhydrous tetrahydrofuran, the temperature was lowered to -78°C, N -bromosuccinimide (23 mg, 0.13 mmol) was added, and the mixture was stirred for 10 minutes. The reaction solution was warmed to room temperature, 3 mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated under reduced pressure to obtain the crude title product for 1 h (40 mg, yield: 79.2%), the product was not It was used directly in the next step after purification.

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

第六步 Step 6

(R)-3-甲基-4-(6-甲基-2-(1-甲基-1H-吡唑-5-基)-8-(1H-吡唑-5-基)咪唑并[1,5-a]嘧啶-4-基)嗎啡啉1 ( R )-3-Methyl-4-(6-methyl-2-(1-methyl- 1H -pyrazol-5-yl)-8-( 1H -pyrazol-5-yl)imidazole [1,5- a ]pyrimidin-4-yl)morpholine 1

將粗品化合物1h(40mg，0.102mmol)溶於4mL二噁烷和水(v：v=3：1)的混合溶液中，加入(1H-吡唑-3-基)硼酸1i(23mg，0.204mmol，上海畢得)、[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物(17mg，0.02mmol)和無水碳酸鈉(27mg，0.26mmol)，升溫至90攪拌2小時。冷卻至室溫，反應液過濾，減壓濃縮，所得粗品用高效液相製備層析法(Waters 2545-2767，沖提體系：碳酸氫銨、乙腈、水)純化，得到標題產物1(6mg，收率：15.6%)。 The crude compound 1h (40 mg, 0.102 mmol) was dissolved in 4 mL of a mixed solution of dioxane and water (v:v=3:1), and ( 1H -pyrazol-3-yl)boronic acid 1i (23 mg, 0.204) was added mmol, Shanghai Bide), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (17 mg, 0.02 mmol) and anhydrous sodium carbonate (27 mg, 0.26 mmol) , heated to 90 and stirred for 2 hours. Cooled to room temperature, the reaction solution was filtered, concentrated under reduced pressure, the obtained 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%).

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

¹H NMR(400MHz,CDCl₃)：δ 7.77(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)。 ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.77(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).

實施例2 Example 2

(R)-4-(6-乙基-2-(1-甲基-1H-吡唑-5-基)-8-(1H-吡唑-5-基)咪唑并[1,5-a]嘧啶-4-基)-3-甲基嗎啡啉2 ( 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 2

第一步 first step

N-((4,6-二側氧-1,4,5,6-四氫嘧啶-2-基)甲基)丙醯胺2b N -((4,6-Dioxy-1,4,5,6-tetrahydropyrimidin-2-yl)methyl)propionamide 2b

在氬氣氛下，將化合物1a(5g，48.9mmol，上海畢得)、化合物2a(8.5g，53.4mmol，採用專利申請「WO2015095788」中說明書第76頁的中間體3公開的方法製備而得)、甲醇鈉(6.6g，122.16mmol)加入甲醇(25mL)中，回流3小時，冷卻至室溫，過濾，濾液減壓濃縮，得到標題產物2b(9.6g)，產品不經純化直接用於下一步反應。 Under an argon atmosphere, compound 1a (5 g, 48.9 mmol, Shanghai Bide) and compound 2a (8.5 g, 53.4 mmol, prepared by the method disclosed in the intermediate 3 on page 76 of the patent application "WO2015095788") , sodium methoxide (6.6 g, 122.16 mmol) was 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 step without purification. one-step reaction.

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

第二步 second step

2,4-二氯-6-乙基咪唑并[1,5-a]嘧啶2c 2,4-Dichloro-6-ethylimidazo[1,5- a ]pyrimidine 2c

將粗品化合物2b(9.6g，48.6mmol)溶於甲苯(80mL)，加入三氯氧磷(27mL，292.1mmol)，緩慢加入N,N-二異丙基乙胺(33mL， 194.7mmol)，90℃反應3小時。反應液減壓濃縮，加二氯甲烷(500mL)攪拌0.5小時，過濾，濾液減壓濃縮，得到標題產物2c(10g)，產品不經純化直接用於下一步反應。 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, 90 °C for 3 hours. The reaction solution was concentrated under reduced pressure, added with dichloromethane (500 mL), stirred for 0.5 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 2c (10 g), which was used in the next reaction without purification.

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

第三步 third step

(R)-4-(2-氯-6-乙基咪唑并[1,5-a]嘧啶-4-基)-3-甲基嗎啡啉2d ( R )-4-(2-Chloro-6-ethylimidazo[1,5- a ]pyrimidin-4-yl)-3-methylmorpholine 2d

將粗品化合物2c(10g，46.3mmol)溶於80mL乙腈中，加入N,N-二異丙基乙胺(185.12mmol，32mL)和化合物1e(23g，227.4mmol)，75℃反應1小時。反應液冷卻至室溫，減壓濃縮，加水(150mL)萃取，乙酸乙酯萃取(80mL×2)，用矽膠管柱層析法以沖提劑體系C純化得到標題化合物2d(1.3g，收率：10%)。 Crude compound 2c (10 g, 46.3 mmol) was dissolved in 80 mL of acetonitrile, N , N -diisopropylethylamine (185.12 mmol, 32 mL) and compound 1e (23 g, 227.4 mmol) were added, and the reaction was carried out 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), purified by silica gel column chromatography with eluent system C to obtain the title compound 2d (1.3 g, obtained rate: 10%).

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

第四步 the fourth step

(R)-4-(6-乙基-2-(1-甲基-1H-吡唑-5-基)咪唑并[1,5-a]嘧啶-4-基)-3-甲基嗎啡啉2e ( R )-4-(6-ethyl-2-(1-methyl- 1H -pyrazol-5-yl)imidazo[1,5- a ]pyrimidin-4-yl)-3-methyl Morphine 2e

將化合物2d(300mg，1.07mmol)、1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊-2-基)-1H-吡唑(555mg，2.67mmol，上海畢得)溶於6mL二噁烷和水(v：v=5：1)的混合溶液中，加入[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物(135mg，0.16mmol)和無水碳酸鈉(339mg，3.19mmol)，100℃反應2小時。冷卻至室溫，反應液過濾，濾液減壓濃縮，所得殘餘物用矽膠管柱層析法以沖提劑體系A純化，得到標題化合物2e(300mg，收率：86%)。 Compound 2d (300 mg, 1.07 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) -1H - Pyrazole (555mg, 2.67mmol, Shanghai Bide) was dissolved in 6mL of a mixed solution of dioxane and water (v:v=5:1), and [1,1'-bis(diphenylphosphine)di Ferrocene] palladium dichloride dichloromethane complex (135 mg, 0.16 mmol) and anhydrous sodium carbonate (339 mg, 3.19 mmol) were reacted at 100° C. for 2 hours. Cooled to room temperature, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 2e (300 mg, yield: 86%).

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

第五步 the fifth step

(R)-4-(8-溴-6-乙基-2-(1-甲基-1H-吡唑-5-基)咪唑并[1,5-a]嘧啶-4-基)-3-甲基嗎啡啉2f ( R )-4-(8-Bromo-6-ethyl-2-(1-methyl- 1H -pyrazol-5-yl)imidazo[1,5- a ]pyrimidin-4-yl)- 3-Methylmorpholine 2f

將化合物2e(300mg，919.13μmol)溶於10mL無水四氫呋喃中，降溫至-78℃，加入N-溴代丁二醯亞胺(114mg，640.51μmol)，攪拌10分鐘。反應液升至室溫，加入3mL飽和碳酸氫鈉溶液，乙酸乙酯萃取(10mL×3)，合併有機相，減壓濃縮，得到粗品標題化合物2f(240mg)，產物不經純化直接用於下步反應。 Compound 2e (300 mg, 919.13 μmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, the temperature was lowered to -78° C., N -bromosuccinimide (114 mg, 640.51 μmol) was added, and the mixture was stirred for 10 minutes. The reaction solution was warmed to room temperature, 3 mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (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. step reaction.

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

第六步 Step 6

(R)-4-(6-乙基-2-(1-甲基-1H-吡唑-5-基)-8-(1H-吡唑-5-基)咪唑并[1,5-a]嘧啶-4-基)-3-甲基嗎啡啉2 ( 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 2

在氬氣氛下，將粗品化合物2f(370mg，912.9μmol)溶於10mL 1,4-二噁烷和2mL水中，依次加入化合物1i(204mg，1.82mmol)、[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物(116mg，137μmol)和碳酸鈉(193mg，1.82mmol)，在90℃攪拌4小時。反應液冷卻至室溫，藉由矽藻土過濾，將濾液減壓濃縮，粗品用高效液相製備層析法(Waters 2545-2767，沖提體系：碳酸氫銨、乙腈、水)純化，得到標題化合物2(98mg，收率：27.3%)。 Under argon atmosphere, the crude compound 2f (370 mg, 912.9 μmol) was dissolved in 10 mL of 1,4-dioxane and 2 mL of water, followed by the addition of compound 1i (204 mg, 1.82 mmol), [1,1′-bis(diphenylene)] (116 mg, 137 μmol) and sodium carbonate (193 mg, 1.82 mmol), and stirred at 90° C. for 4 hours. The reaction solution was cooled to room temperature, filtered through celite, the filtrate was 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 compound 2 (98 mg, yield: 27.3%).

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

1H NMR(500MHz,CD₃OD)：δ 7.65(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)。 1H NMR (500MHz, _CD3OD ): δ 7.65(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).

實施例3 Example 3

(R)-4-(2-(1-乙基-1H-吡唑-5-基)-6-甲基-8-(1H-吡唑-5-基)咪唑并[1,5-a]嘧啶-4-基)-3-甲基嗎啡啉3 ( 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

第一步 first step

(R)-4-(2-(1-乙基-1H-吡唑-5-基)-6-甲基咪唑并[1,5-a]嘧啶-4-基)-3-甲基嗎啡啉3b ( R )-4-(2-(1-ethyl- 1H -pyrazol-5-yl)-6-methylimidazo[1,5- a ]pyrimidin-4-yl)-3-methyl Morphine 3b

將化合物1f(100mg,0.37mmol)和1-乙基-5-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊-2-基)-1H-吡唑(3a)(166mg，0.75mmol，上海畢得)溶於4mL二噁烷和水(v：v=3：1)的混合溶液中，加入[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物(47mg，0.055mmol)和無水碳酸鈉(119mg，1.12mmol)，100℃反應2小時。冷卻至室溫，反應液過濾，濾液減壓濃縮，所得殘餘物用矽膠管柱層析法以沖提劑體系A純化，得到標題化合物3b(100mg，收率：81.7%)。 Compound 1f (100 mg, 0.37 mmol) and 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) -1H - Pyrazole ( 3a ) (166 mg, 0.75 mmol, Shanghai Bide) was dissolved in 4 mL of a mixed solution of dioxane and water (v:v=3:1), and [1,1'-bis(diphenyl) Phosphine)ferrocene]dichloropalladium dichloromethane complex (47mg, 0.055mmol) and anhydrous sodium carbonate (119mg, 1.12mmol) were reacted at 100°C for 2 hours. Cooled to room temperature, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 3b (100 mg, yield: 81.7%).

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

第二步 second step

(R)-4-(8-溴-2-(1-乙基-1H-吡唑-5-基)-6-甲基吡唑并[1,5-a]嘧啶-4-基)-3-甲基嗎啡啉3c ( R )-4-(8-Bromo-2-(1-ethyl- 1H -pyrazol-5-yl)-6-methylpyrazolo[1,5- a ]pyrimidin-4-yl) -3-Methylmorpholine 3c

將化合物3b(100mg，0.3mmol)溶於2mL無水四氫呋喃中，降溫至-78℃，加入N-溴代丁二醯亞胺(27mg，0.15mmol)，攪拌20 分鐘。反應液升至室溫，加入3mL飽和碳酸氫鈉溶液，乙酸乙酯萃取(10mL×3)，合併有機相，減壓濃縮，得到粗品標題化合物3c(100mg，收率：80%)，產物不經純化直接用於下步反應。 Compound 3b (100 mg, 0.3 mmol) was dissolved in 2 mL of anhydrous tetrahydrofuran, the temperature was lowered to -78°C, N -bromosuccinimide (27 mg, 0.15 mmol) was added, and the mixture was stirred for 20 minutes. The reaction solution was warmed to room temperature, 3 mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated under reduced pressure to obtain the crude title compound 3c (100 mg, yield: 80%), the product was not It was used directly in the next step after purification.

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

第三步 third step

(R)-4-(2-(1-乙基-1H-吡唑-5-基)-6-甲基-8-(1H-吡唑-5-基)咪唑并[1,5-a]嘧啶-4-基)-3-甲基嗎啡啉3 ( 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

將化合物3c(100mg，0.247mmol)溶於4mL二噁烷和水(v：v=3：1)的混合溶液中，加入化合物1i(55mg，0.491mmol)、[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物(31mg，0.04mmol)和無水碳酸鈉(78mg，0.74mmol)，在90℃攪拌2小時。冷卻至室溫，反應液過濾，減壓濃縮，所得殘餘物用高效液相製備層析法(Waters 2545-2767，沖提體系：碳酸氫銨、乙腈、水)純化，得到化合物3(30mg，收率：30.9%)。 Compound 3c (100 mg, 0.247 mmol) was dissolved in a mixed solution of 4 mL of dioxane and water (v:v=3:1), and compound 1i (55 mg, 0.491 mmol), [1,1'-bis(bis(bis(bis(bis(bis(di(bis(di(bis(di(di(diox)))) were)) Phenylphosphine)ferrocene]dichloropalladium dichloromethane complex (31 mg, 0.04 mmol) and anhydrous sodium carbonate (78 mg, 0.74 mmol) were stirred at 90°C for 2 hours. Cooled to room temperature, the reaction solution was filtered, concentrated under reduced pressure, and the obtained residue was purified by high-performance liquid phase preparative chromatography (Waters 2545-2767, elution system: ammonium bicarbonate, acetonitrile, water) to obtain compound 3 (30 mg, Yield: 30.9%).

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

¹H NMR(500MHz,CD₃OD)：δ 7.85-7.45(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)。 ¹ H NMR (500 MHz, CD ₃ OD): δ 7.85-7.45 (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).

實施例4 Example 4

(R)-3-甲基-4-(2-(1-甲基-1H-吡唑-5-基)-8-(1H-吡唑-5-基)咪唑并[1,5-a]嘧啶-4-基)嗎啡啉4 ( R )-3-Methyl-4-(2-(1-methyl- 1H -pyrazol-5-yl)-8-( 1H -pyrazol-5-yl)imidazo[1,5 - a ]pyrimidin-4-yl)morpholine 4

第一步 first step

2,4-二經基咪唑并[1,5-a]嘧啶-8-羧酸甲酯4b 2,4-Dimethylimidazo[1,5- a ]pyrimidine-8-carboxylate 4b

在氬氣氛下，將丙二酸二甲酯(700mg，5.3mmol)、5-胺基-1H-咪唑-4-羧酸甲酯(4a)(500mg，3.5mmol，上海瀚鴻)、碳酸銫(2.3g，7.08mmol)加入N,N-二甲基甲醯胺(15mL)中，110℃攪拌15小時。反應液冷卻至室溫，過濾，濾液減壓濃縮，得到標題產物4b(1.2g)，產品不經純化直接用於下一步反應。 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), carbonic acid Cesium (2.3 g, 7.08 mmol) was added to N , N -dimethylformamide (15 mL), and the mixture was 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 reaction without purification.

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

第二步 second step

2,4-二氯咪唑并[1,5-a]嘧啶-8-羧酸甲酯4c 2,4-Dichloroimidazo[1,5- a ]pyrimidine-8-carboxylate methyl ester 4c

將粗品化合物4b(1.0g，4.78mmol)溶於甲苯(20mL)，加入三氯氧磷(3mL，35.1mmol)，100℃反應2小時。反應液冷卻至室溫，減壓濃縮，加二氯甲烷(500mL)攪拌0.5小時，過濾，濾液減壓濃縮，得到標題產物4c(3.2g)，產品不經純化直接用於下一步反應。 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 reaction was carried out at 100° C. for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added with dichloromethane (500 mL), stirred for 0.5 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 4c (3.2 g), which was used in the next reaction without purification.

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

第三步 third step

(R)-2-氯-4-(3-甲基嗎啡啉)咪唑并[1,5-a]嘧啶-8-羧酸甲酯4d ( R )-Methyl 2-chloro-4-(3-methylmorpholine)imidazo[1,5- a ]pyrimidine-8-carboxylate 4d

將粗品化合物4c(1.0g，1.6mmol)溶於20mL乙腈中，加入N,N-二異丙基乙胺(1.05g，8.0mmol)和化合物1e(822mg，8mmol)，75℃反應4小時。反應液冷卻至室溫，減壓濃縮，加水(50mL)萃取，乙酸乙酯萃取(50mL×2)，用矽膠管柱層析法以沖提劑體系C純化，得到標題化合物4d(120mg)，產率：23.7%。 The crude compound 4c (1.0 g, 1.6 mmol) was dissolved in 20 mL of acetonitrile, N , N -diisopropylethylamine (1.05 g, 8.0 mmol) and compound 1e (822 mg, 8 mmol) were added, and the reaction was carried out 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), Yield: 23.7%.

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

第四步 the fourth step

(R)-2-(1-甲基-1H-吡唑-5-基)-4-(3-甲基嗎啡啉)咪唑并[1,5-a]嘧啶-8-羧酸甲酯4e ( R )-Methyl 2-(1-methyl- 1H -pyrazol-5-yl)-4-(3-methylmorpholine)imidazo[1,5- a ]pyrimidine-8-carboxylate 4e

將化合物4d(100mg，0.39mmol)和1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼雜環戊-2-基)-1H-吡唑(160mg，0.772mmol)溶於4mL二噁烷和水(v：v=3：1)的混合溶液中，加入[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物(49mg，0.06mmol)和無水碳酸鈉(122mg，1.15mmol)，升溫至100℃反應2小時。冷卻至室溫，反應液過濾，濾液減壓濃縮，所得殘餘物用矽膠管柱層析法以沖提劑體系C純化，得到標題化合物4e(40mg，收率：87.2%)。 Compound 4d (100 mg, 0.39 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl) -1H - Pyrazole (160 mg, 0.772 mmol) was dissolved in 4 mL of a mixed solution of dioxane and water (v:v=3:1), and [1,1'-bis(diphenylphosphino)ferrocene]di Palladium chloride dichloromethane complex (49 mg, 0.06 mmol) and anhydrous sodium carbonate (122 mg, 1.15 mmol) were heated to 100° C. and reacted for 2 hours. Cooled to room temperature, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 4e (40 mg, yield: 87.2%).

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

第五步 the fifth step

(R)-2-(1-甲基-1H-吡唑-5-基)-4-(3-甲基嗎啡啉)咪唑并[1,5-a]嘧啶-8-羧酸4f ( R )-2-(1-Methyl- 1H -pyrazol-5-yl)-4-(3-methylmorpholine)imidazo[1,5- a ]pyrimidine-8-carboxylic acid 4f

將化合物4e(120mg，0.336mmol)溶於4mL甲醇和水(v：v=3：1)的混合溶液中，加入氫氧化鋰一水合物(70mg，1.68mmol)，攪 拌15小時。反應液減壓濃縮，加水5mL稀釋，1N鹽酸調節至pH=5，乙酸乙酯萃取(10mL×3)，合併有機相，減壓濃縮，得到粗品標題產物4f(60mg，收率：52.1%)，產物不經純化直接用於下步反應。 Compound 4e (120 mg, 0.336 mmol) was dissolved in 4 mL of a mixed solution of methanol and water (v:v=3:1), lithium hydroxide monohydrate (70 mg, 1.68 mmol) was added, and the mixture was stirred for 15 hours. The reaction solution was concentrated under reduced pressure, diluted with 5 mL of water, adjusted to pH=5 with 1 N hydrochloric acid, extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated under reduced pressure to obtain the crude title product 4f (60 mg, yield: 52.1%) ), the product was directly used in the next step without purification.

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

第六步 Step 6

(R)-4-(8-溴-2-(1-甲基-1H-吡唑-5-基)咪唑并[1,5-a]嘧啶-4-基)-3-甲基嗎啡啉4g ( R )-4-(8-Bromo-2-(1-methyl- 1H -pyrazol-5-yl)imidazo[1,5- a ]pyrimidin-4-yl)-3-methylmorphine Phosphine 4g

將粗品化合物4f(60mg，0.175mmol)溶於4mL N,N-二甲基甲醯胺中，降溫至-78℃，加入無水碳酸氫鈉(30mg，0.35mmol)和N-溴代丁二醯亞胺(35mg，0.184mmol)，攪拌10分鐘。反應液升至室溫，加入10mL飽和碳酸氫鈉溶液，乙酸乙酯萃取(10mL×3)，合併有機相，減壓濃縮，得到粗品標題產物4g(30mg，收率：45.4%)，產物不經純化直接用於下步反應。 The crude compound 4f (60 mg, 0.175 mmol) was dissolved in 4 mL of N , N -dimethylformamide, cooled to -78°C, and anhydrous sodium bicarbonate (30 mg, 0.35 mmol) and N -bromobutanediamide were added. imine (35 mg, 0.184 mmol), stirred for 10 minutes. The reaction solution was warmed to room temperature, 10 mL of saturated sodium bicarbonate solution was added, extracted with ethyl acetate (10 mL×3), the organic phases were combined and concentrated under reduced pressure to obtain 4 g of the crude title product (30 mg, yield: 45.4%), the product was not It was used directly in the next step after purification.

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

第七步 Step 7

(R)-3-甲基-4-(2-(1-甲基-1H-吡唑-5-基)-8-(1H-吡唑-5-基)咪唑并[1,5-a]嘧啶-4-基)嗎啡啉4 ( R )-3-Methyl-4-(2-(1-methyl- 1H -pyrazol-5-yl)-8-( 1H -pyrazol-5-yl)imidazo[1,5 - a ]pyrimidin-4-yl)morpholine 4

將粗品化合物4g(30mg，0.079mmol)溶於4mL二噁烷和水(v：v=3：1)的混合溶液中，加入化合物1i(27mg，0.238mmol)、[1,1'-雙(二苯基膦)二茂鐵]二氯化鈀二氯甲烷絡合物(10mg，0.02mmol)和無水碳酸鈉(27mg，0.26mmol)，升溫至90℃攪拌2小時。冷卻至室溫，反應液過濾，減壓濃縮，所得粗品用高效液相製備層析法(Waters 2545-2767，沖提體系：碳酸氫銨、乙腈、水)純化，得到標題產物4(5mg，收率：17.2%)。 The crude compound 4g (30mg, 0.079mmol) was dissolved in a mixed solution of 4mL of dioxane and water (v:v=3:1), compound 1i (27mg, 0.238mmol), [1,1'-bis( Diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex (10 mg, 0.02 mmol) and anhydrous sodium carbonate (27 mg, 0.26 mmol) were heated to 90°C and stirred for 2 hours. Cooled to room temperature, the reaction solution was filtered, concentrated under reduced pressure, the obtained 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%).

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

¹H NMR(400MHz,CDCl₃)：δ 7.75(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)。 ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.75(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).

測試例： Test case:

生物學評價 Biological evaluation

測試例1、本揭露化合物對ATR酶的抑制活性 Test Example 1. Inhibitory activity of compounds of the present disclosure on ATR enzyme

以下方法用來測定本揭露化合物對ATR酶的抑制活性。 The following method was used to determine the inhibitory activity of the compounds of the present disclosure on ATR enzyme.

實驗方法簡述如下： The experimental method is briefly described as follows:

一、實驗材料及儀器 1. Experimental materials and instruments

1、ATR酶(Eurofins Pharma Discovery Services，14-953-M) 1. ATR enzyme (Eurofins Pharma Discovery Services, 14-953-M)

2、GST標籤P53蛋白(Eurofins Pharma Discovery Services，14-952-M) 2. GST-tagged P53 protein (Eurofins Pharma Discovery Services, 14-952-M)

3、384孔板(Thermo Scientific，267462) 3. 384-well plate (Thermo Scientific, 267462)

4、U型底96孔板(Corning，3795) 4. U-bottom 96-well plate (Corning, 3795)

5、標記銪穴狀化合物抗磷酸化P53蛋白抗体(cisbio，61P08KAE) 5. Anti-phosphorylated P53 protein antibody labeled with europium cryptate (cisbio, 61P08KAE)

6、鏈接d2的抗GST抗体(cisbio，61GSTDLF) 6. Anti-GST antibody linked to d2 (cisbio, 61GSTDLF)

7、ATP溶液(Promega，V916B) 7. ATP solution (Promega, V916B)

8、EDTA(Thermo Scientific，AM9260G) 8. EDTA (Thermo Scientific, AM9260G)

9、HEPES(Gibco，15630-080) 9. HEPES (Gibco, 15630-080)

10、酶標儀(BMG，PHERAsta) 10. Microplate reader (BMG, PHERAsta)

二、實驗步驟 2. Experimental steps

將1nM ATR酶、50nM P53蛋白、7.435μM ATP和不同濃度(首濃度1μM，3倍梯度稀釋11個濃度)的本揭露化合物混合，室溫孵育2小時，然後加入終止液(12.5mM HEPES，250mM EDTA)混勻，再 加入0.42ng/孔的標記銪穴狀化合物抗磷酸化P53蛋白抗體和25ng/孔的鏈接d2的抗GST抗體。室溫孵育過夜後用PHERAstar檢測620nm和665nm螢光信號。數據使用GraphPad軟件處理。 1 nM ATR enzyme, 50 nM P53 protein, 7.435 μM ATP and different concentrations (1 μM initial concentration, 11 concentrations of 3-fold serial dilution) of the disclosure compound were mixed, incubated at room temperature for 2 hours, and then a stop solution (12.5 mM HEPES, 250 mM) was added. EDTA), mix well, and then 0.42ng/well of labeled europium cryptate anti-phospho-P53 protein antibody and 25ng/well of d2-linked anti-GST antibody were added. Fluorescence signals at 620 nm and 665 nm were detected with PHERAstar after overnight incubation at room temperature. Data were processed using GraphPad software.

三、實驗數據 3. Experimental data

本揭露化合物對ATR酶的抑制活性可藉由以上的試驗進行測定。設定未加ATR酶的空白實驗孔為100%抑制，藉由公式100×[1-(化合物信號-背景信號)/(DMSO孔信號-背景信號)]計算化合物的抑制率。測得的IC₅₀值和最大抑制率見下表1。 The inhibitory activity of the compounds of the present disclosure on ATR enzyme can be determined by the above test. The blank experimental well without ATR enzyme was set as 100% inhibition, and the inhibition rate of the compound was calculated by the formula 100×[1-(compound signal-background signal)/(DMSO well signal-background signal)]. Measured _IC50 values and maximal inhibition are shown in Table 1 below.

表1 本揭露化合物對ATR酶抑制的IC₅₀

Table 1 IC ₅₀ of the disclosed compounds for ATR enzyme inhibition

結論：本揭露化合物對ATR酶的抑制活性好。 Conclusion: The disclosed compounds have good inhibitory activity on ATR enzyme.

測試例2、本揭露化合物對ATR酶的選擇性測試 Test Example 2. Selectivity test of compounds of the present disclosure for ATR enzyme

以下方法分別測定了本揭露化合物對ATM酶、DNA-PK酶和PI3K酶的抑制活性，用以說明本揭露化合物對ATR酶具有選擇性。 The following methods were used to measure the inhibitory activities of the compounds of the present disclosure on ATM enzyme, DNA-PK enzyme and PI3K enzyme, to demonstrate that the compounds of the present disclosure have selectivity for ATR enzyme.

實驗方法簡述如下： The experimental method is briefly described as follows:

(一)本揭露化合物對ATM酶的抑制作用 (1) Inhibitory effect of the disclosed compounds on ATM enzyme

一、實驗材料及儀器 1. Experimental materials and instruments

1、ATM酶(Eurofins Pharma Discovery Services，14-933-M) 1. ATM enzyme (Eurofins Pharma Discovery Services, 14-933-M)

2、GST標籤P53蛋白(Eurofins Pharma Discovery Services，14-952-M) 2. GST-tagged P53 protein (Eurofins Pharma Discovery Services, 14-952-M)

3、384孔板(Thermo Scientific，267462) 3. 384-well plate (Thermo Scientific, 267462)

4、U型底96孔板(Corning，3795) 4. U-bottom 96-well plate (Corning, 3795)

5、標記銪穴狀化合物抗磷酸化P53蛋白抗体(cisbio，61P08KAE) 5. Anti-phosphorylated P53 protein antibody labeled with europium cryptate (cisbio, 61P08KAE)

6、鏈接d2的抗GST抗体(cisbio，61GSTDLF) 6. Anti-GST antibody linked to d2 (cisbio, 61GSTDLF)

7、ATP溶液(Promega，V916B) 7. ATP solution (Promega, V916B)

8、EDTA(Thermo Scientific，AM9260G) 8. EDTA (Thermo Scientific, AM9260G)

9、HEPES(Gibco，15630-080) 9. HEPES (Gibco, 15630-080)

10、酶標儀(BMG，PHERAsta) 10. Microplate reader (BMG, PHERAsta)

二、實驗步驟 2. Experimental steps

將1nM ATM酶、30nM P53蛋白、11μM ATP以及不同濃度(首濃度10μM，3倍梯度稀釋11個濃度)的本揭露化合物混合，室溫孵育2小時，然後加入終止液(12.5mM HEPES，250mM EDTA)混勻，再加入0.42ng/孔的標記銪穴狀化合物抗磷酸化P53蛋白抗體和25ng/孔的鏈接d2的抗GST抗體。室溫孵育過夜後用PHERAstar檢測620nm和665nm螢光信號。數據使用GraphPad軟件處理。本揭露化合物對ATM酶的抑制IC₅₀值見下表2。 Mix 1 nM ATM enzyme, 30 nM P53 protein, 11 μM ATP and different concentrations (10 μM initial concentration, 11 concentrations of 3-fold serial dilution) of the disclosed compounds, incubate at room temperature for 2 hours, and then add stop solution (12.5 mM HEPES, 250 mM EDTA) ) and mix well, and then add 0.42ng/well of labeled europium cryptate anti-phosphorylated P53 protein antibody and 25ng/well of d2-linked anti-GST antibody. Fluorescence signals at 620 nm and 665 nm were detected with PHERAstar after overnight incubation at room temperature. Data were processed using GraphPad software. The _IC50 values of the compounds of the present disclosure for the inhibition of ATM enzymes are shown in Table 2 below.

(二)本揭露化合物對DNA-PK酶的抑制作用 (2) Inhibitory effect of the disclosed compounds on DNA-PK enzyme

一、實驗材料及儀器 1. Experimental materials and instruments

1、DNA-PK酶(Eurofins Pharma Discovery Services，14-950-M) 1. DNA-PK enzyme (Eurofins Pharma Discovery Services, 14-950-M)

2、GST標籤P53蛋白(Eurofins Pharma Discovery Services，14-952-M) 2. GST-tagged P53 protein (Eurofins Pharma Discovery Services, 14-952-M)

3、384孔板(Thermo Scientific，267462) 3. 384-well plate (Thermo Scientific, 267462)

4、U型底96孔板(Corning，3795) 4. U-bottom 96-well plate (Corning, 3795)

5、標記銪穴狀化合物抗磷酸化P53蛋白抗体(cisbio，61P08KAE) 5. Anti-phosphorylated P53 protein antibody labeled with europium cryptate (cisbio, 61P08KAE)

6、鏈接d2的抗GST抗体(cisbio，61GSTDLF) 6. Anti-GST antibody linked to d2 (cisbio, 61GSTDLF)

7、ATP溶液(Promega，V916B) 7. ATP solution (Promega, V916B)

8、EDTA(Thermo Scientific，AM9260G) 8. EDTA (Thermo Scientific, AM9260G)

9、HEPES(Gibco，15630-080) 9. HEPES (Gibco, 15630-080)

10、酶標儀(BMG，PHERAsta) 10. Microplate reader (BMG, PHERAsta)

二、實驗步驟 2. Experimental steps

將0.02nM DNA-PK酶、50nM P53蛋白、7.3μM ATP以及不同濃度(首濃度10μM，3倍梯度稀釋11個濃度)的本揭露化合物混合，室溫孵育1小時，然後加入終止液(12.5mM HEPES，250mM EDTA)混勻，再加入0.42ng/孔的標記銪穴狀化合物抗磷酸化P53蛋白抗體和25ng/孔的鏈接d2的抗GST抗體。室溫孵育過夜後用PHERAstar檢測620nm和665nm螢光信號。數據使用GraphPad軟件處理。本揭露化合物對DNA-PK酶的抑制IC₅₀值見下表2。 Mix 0.02nM DNA-PK enzyme, 50nM P53 protein, 7.3μM ATP and different concentrations (10μM initial concentration, 11 concentrations of 3-fold serial dilution) of the disclosure compound, incubate at room temperature for 1 hour, and then add stop solution (12.5mM) HEPES, 250mM EDTA) and mixed, and then added 0.42ng/well of labeled europium cryptate anti-phospho-P53 protein antibody and 25ng/well of d2-linked anti-GST antibody. Fluorescence signals at 620 nm and 665 nm were detected with PHERAstar after overnight incubation at room temperature. Data were processed using GraphPad software. The _IC50 values of the compounds of the present disclosure for the inhibition of DNA-PK enzymes are shown in Table 2 below.

(三)本揭露化合物對PI3K酶的抑制作用 (3) Inhibitory effect of the disclosed compounds on PI3K enzyme

一、實驗材料及儀器 1. Experimental materials and instruments

1、PIK3CA/PIK3R1(p110 alpha/p85 alpha)激酶(Invitrogen，PV4788) 1. PIK3CA/PIK3R1 (p110 alpha/p85 alpha) kinase (Invitrogen, PV4788)

2、PIP2：PS Lipid底物(Invitrogen，PV5100) 2. PIP2: PS Lipid substrate (Invitrogen, PV5100)

3、DTT(Sigma，43815-1G) 3. DTT (Sigma, 43815-1G)

4、Tris-Hcl(1M，pH7.5)(北京天恩澤生物技術有限公司，101205-100) 4. Tris-HCl (1M, pH7.5) (Beijing Tianenze Biotechnology Co., Ltd., 101205-100)

5、ATP溶液(Promega，V916B) 5. ATP solution (Promega, V916B)

6、氯化鎂六水合物(Sigma，M2393) 6. Magnesium chloride hexahydrate (Sigma, M2393)

7、氯化鈉(國藥集團化學試劑有限公司，10019318) 7. Sodium chloride (Sinopharm Chemical Reagent Co., Ltd., 10019318)

8、CHAPS(Sigma，C3023-5G) 8. CHAPS (Sigma, C3023-5G)

9、HEPES(Gibco，15630-080) 9. HEPES (Gibco, 15630-080)

10、ADP-Glo^TM激酶試驗試劑盒(Promega，V9102) 10. ADP-Glo ^TM Kinase Assay Kit (Promega, V9102)

11、384孔板(Thermo Scientific，267462) 11. 384-well plate (Thermo Scientific, 267462)

12、U型底96孔板(Corning，3795) 12. U-bottom 96-well plate (Corning, 3795)

13、酶標儀(BMG，PHERAstar) 13. Microplate reader (BMG, PHERAstar)

二、實驗步驟 2. Experimental steps

PIK3CA/PIK3R1(p110 alpha/p85 alpha)激酶終濃度为0.625nM，與不同浓度(首濃度10μM，3倍梯度稀釋10个浓度)的本發明化合物混合，室溫孵育30分鐘，再加入PIP2：PS Lipid底物(終濃度50μM)和1x ATP(終濃度50μM)，混合，37孵育30分鐘，然後加入檢測試劑ADP-Glo(Promega，V9102)混匀，室溫孵育40分鐘後，加入ADP-Glo^TM激酶試驗試劑盒(Promega，V9102)的檢測試劑，室溫孵育40分鐘。用PHERAstar檢測螢光信號，數據使用GraphPad軟體處理。本揭露化合物對PI3K酶的抑制IC₅₀值見下表2。 The final concentration of PIK3CA/PIK3R1 (p110 alpha/p85 alpha) kinase was 0.625nM, mixed with the compounds of the present invention at different concentrations (the initial concentration of 10 μM, 3-fold serial dilution for 10 concentrations), incubated at room temperature for 30 minutes, and then added PIP2:PS Lipid substrate (final concentration 50 μM) and 1x ATP (final concentration 50 μM), mix, incubate for 30 minutes at 37, then add detection reagent ADP-Glo (Promega, V9102) and mix well, incubate at room temperature for 40 minutes, then add ADP-Glo Detection reagent for ^TM Kinase Assay Kit (Promega, V9102), incubated at room temperature for 40 minutes. Fluorescence signals were detected with PHERAstar and data were processed using GraphPad software. The IC ₅₀ values of the compounds of the present disclosure for the inhibition of PI3K enzymes are shown in Table 2 below.

表2 本揭露化合物對ATM酶、DNA-PK酶和PI3K酶的抑制的IC₅₀值

Table 2 _IC50 values of the compounds of the present disclosure for the inhibition of ATM enzymes, DNA-PK enzymes and PI3K enzymes

結論：本揭露化合物對ATM酶、DNA-PK酶和PI3K酶的抑制活性弱，對比測試例1和2可以看出本揭露化合物對ATR酶具有選擇性。 Conclusion: The disclosed compounds have weak inhibitory activity on ATM enzyme, DNA-PK enzyme and PI3K enzyme. Comparing Test Examples 1 and 2, it can be seen that the disclosed compounds are selective for ATR enzyme.

測試例3、LoVo細胞增殖實驗 Test example 3, LoVo cell proliferation experiment

以下方法藉由檢測細胞內ATP含量，根據IC₅₀大小評價本揭露化合物對LoVo細胞增殖的抑制效果。 The following method evaluates the inhibitory effect of the compounds of the present disclosure on the proliferation of LoVo cells by detecting the content of intracellular ATP according to the IC ₅₀ value.

實驗方法簡述如下： The experimental method is briefly described as follows:

一、實驗材料及儀器 1. Experimental materials and instruments

1、LoVo，細入結腸癌腫瘤細胞(南京科佰，CBP60032) 1. LoVo, penetrates into colon cancer tumor cells (Nanjing Kebai, CBP60032)

2、胎牛血清(GIBCO，10091-148) 2. Fetal bovine serum (GIBCO, 10091-148)

3、F-12K培養基(Gibco，21127030) 3. F-12K medium (Gibco, 21127030)

4、CellTite-Glo試劑(Promega，G7573) 4. CellTite-Glo reagent (Promega, G7573)

5、96孔細胞培養板(corning，3903) 5. 96-well cell culture plate (corning, 3903)

6、胰酶(invitrogen，25200-072) 6. Pancreatin (invitrogen, 25200-072)

7、酶標儀(BMG，PHERAsta) 7. Microplate reader (BMG, PHERAsta)

8、細胞計數儀(上海睿鈺生物科技有限公司，IC1000) 8. Cell counter (Shanghai Ruiyu Biotechnology Co., Ltd., IC1000)

二、實驗步驟 2. Experimental steps

LoVo細胞培養在含10%FBS的F-12K培養基中，一週傳代2至3次，傳代比例1：3或1：5。傳代時，用胰酶消化細胞後轉至離心管中，1200rpm離心3分鐘，棄去上清培養基殘液，加入新鮮培養基重新懸浮細胞。在96孔細胞培養板中加入90μL的細胞懸液，密度為3.88×10⁴細胞/ml，96孔板外圍只加入100μL的完全培養基。將培養板在培養箱培養24小時(37℃，5% CO₂)。 LoVo cells were cultured in F-12K medium containing 10% FBS and passaged 2 to 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 residue was discarded, and fresh medium was added to resuspend the cells. 90 μL of cell suspension was added to the 96-well cell culture plate at a density of 3.88×10 ⁴ cells/ml, and only 100 μL of complete medium was added to the periphery of the 96-well plate. The plates were incubated in an incubator (37°C, 5% CO ₂ ) for 24 hours.

將待測化合物用DMSO稀釋成2mM，並以3倍依次稀釋成10個濃度，並設置空白孔(無細胞無化合物)和對照孔(有細胞無化合物)。 取配製成梯度濃度的待測化合物溶液5μL加入到95μL新鮮培養基中配製成含化合物的培養基溶液。再向培養板中加入10μL上述含藥物的培養基溶液。將培養板在培養箱孵育3天(37℃，5% CO₂)。在96孔細胞培養板中，每孔加入50μL CellTiter-Glo試劑，室溫避光放置5-10分鐘，在PHERAstar中讀取化學發光信號值，數據使用GraphPad軟件處理。 The compounds to be tested were diluted with DMSO to 2 mM, and diluted 3-fold to 10 concentrations in turn, and blank wells (without cells and without compounds) and control wells (with cells and without compounds) were set. 5 μL of the solution of the compound to be tested prepared in a gradient concentration was added to 95 μL of fresh medium to prepare a compound-containing medium solution. 10 μL of the above drug-containing medium solution was added to the culture plate. The plates were incubated in an incubator (37°C, 5% CO ₂ ) for 3 days. In a 96-well cell culture plate, add 50 μL of CellTiter-Glo reagent to each well, place at room temperature for 5-10 minutes in the dark, read the chemiluminescence signal value in PHERAstar, and use GraphPad software to process the data.

三、實驗數據 3. Experimental data

本揭露化合物對LoVo細胞增殖的抑制活性可藉由以上的試驗進行測定。設定空白孔為100%抑制，藉由公式100×[1-(化合物信號-空白孔信號)/(對照孔孔信號-空白孔信號)]計算化合物的抑制率。測得的IC₅₀值和最大抑制率見下表3。 The inhibitory activity of the compounds of the present disclosure on the proliferation of LoVo cells can be determined by the above test. The blank well was set as 100% inhibition, and the inhibition rate of the compound was calculated by the formula 100×[1-(compound signal-blank well signal)/(control well well signal-blank well signal)]. Measured _IC50 values and maximal inhibition are shown in Table 3 below.

表3 本揭露化合物對LoVo細胞增殖抑制的IC₅₀

Table 3 IC ₅₀ of the compounds of the present disclosure for inhibiting the proliferation of LoVo cells

結論：本揭露化合物對LoVo細胞增殖有良好的抑制活性。 Conclusion: The disclosed compounds have good inhibitory activity on the proliferation of LoVo cells.

藥物代謝動力學評價 Pharmacokinetic evaluation

測試例4、本揭露化合物的藥物代謝動力學測試 Test Example 4. Pharmacokinetic testing of the compounds of the present disclosure

1、摘要 1. Abstract

以裸鼠為受試動物，應用LC/MS/MS法測定了裸鼠灌胃給予實施例1化合物後不同時刻血漿中的藥物濃度。研究本揭露化合物在裸鼠體內的藥物代謝動力學行為，評價其藥物代謝動力學特徵。 Taking nude mice as test animals, the drug concentration in plasma at different times after the compound of Example 1 was administered by gavage to nude mice was determined by LC/MS/MS method. To study the pharmacokinetic behavior of the disclosed compounds in nude mice, and to evaluate their pharmacokinetic characteristics.

2、試驗方案 2. Test plan

2.1 試驗樣品 2.1 Test samples

實施例1化合物。 Compound of Example 1.

2.2 試驗動物 2.2 Experimental animals

健康成年裸鼠9隻，雌性，購自維通利華實驗動物有限公司。 Nine healthy adult nude mice, female, were purchased from Weitong Lihua Laboratory Animal Co., Ltd.

2.3 樣品配製 2.3 Sample preparation

稱取一定量實施例1化合物，加入預定體積的PEG400(最終體積比15%，南京威爾化工有限公司)，加入攪拌子超聲攪拌至樣品全部溶解，再加入一定體積(終體積比85%)的已經配製好的1% HPMC K100LV溶液(HPMC K100LV粉劑購自美國DOW公司，1% HPMC K100LV溶液為公司內部配製)，將實施例1化合物配製成濃度為0.5mg/mL的給藥溶液。 Weigh a certain amount of the compound of Example 1, add a predetermined volume of PEG400 (final volume ratio 15%, Nanjing Well Chemical Co., Ltd.), add a stirrer ultrasonically and stir until the sample is completely dissolved, then add a certain volume (final volume ratio 85%) The prepared 1% HPMC K100LV solution (HPMC K100LV powder was purchased from US DOW company, 1% HPMC K100LV solution was prepared in-house), the compound of Example 1 was prepared into a dosing solution with a concentration of 0.5 mg/mL.

2.4 給藥 2.4 Administration

裸鼠禁食過夜後灌胃給藥，給藥劑量均為10mg/kg，給藥體積均為0.2mL/10g。 Nude mice were fasted overnight and then intragastrically administered. The dosage was 10 mg/kg, and the administration volume was 0.2 mL/10 g.

3、操作 3. Operation

裸鼠灌胃給予實施例1化合物，於給藥後0.25、0.5、1.0、2.0、4.0、6.0、8.0、11.0、24.0小時採血0.1mL，置於EDTA-K2抗凝試管中，4℃、10000轉/分鐘離心1分鐘，1小時內分離血漿，於-20℃保存待測，採血至離心過程在冰浴條件下操作。 Nude mice were given the compound of Example 1 by gavage, and 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 placed in an EDTA-K2 anticoagulation test tube at 4°C, 10000 Centrifuge at rpm for 1 minute, separate plasma within 1 hour, store at -20°C for testing, and operate under ice bath conditions until blood is collected until the centrifugation process.

測定不同濃度的藥物灌胃給藥後裸鼠血漿中的待測化合物含量：取給藥後各時刻的裸鼠血漿25μL，加入內標溶液(100ng/mL喜樹鹼)50μL，乙腈200μL，渦旋混合5分鐘，離心10分鐘(4000轉/分鐘)，血漿樣品取上清液0.1μL進行LC/MS/MS分析。 Determination of the content of the test compound in the plasma of nude mice after oral administration of different concentrations of drugs: take 25 μL of nude mouse plasma at each time after administration, add 50 μL of internal standard solution (100 ng/mL camptothecin), 200 μL of acetonitrile, and vortex. Spin and mix for 5 minutes, centrifuge for 10 minutes (4000 rpm), and take 0.1 μL of the supernatant from the plasma sample for LC/MS/MS analysis.

4、藥物代謝動力學參數結果 4. Results of pharmacokinetic parameters

本揭露化合物的藥物代謝動力學參數如下表4所示。 The pharmacokinetic parameters of the compounds of the present disclosure are shown in Table 4 below.

表4 本揭露化合物的藥物代謝動力學參數

Table 4 Pharmacokinetic parameters of the disclosed compounds

結論：本揭露化合物的藥代吸收良好，具有明顯的藥物代謝動力學優勢。 Conclusion: The disclosed compounds have good pharmacokinetic absorption and obvious pharmacokinetic advantages.

Claims (19)

一種通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽： A compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable of salt:

其中， in, R⁰選自氫原子、烷基、鹵烷基、羥烷基、氰基和環烷基烷基； R ⁰ is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group and a cycloalkylalkyl group; R¹和R²相同或不同，各自獨立地選自氫原子、鹵素、烷基、烯基、烷氧基、雜環基氧基、鹵烷基、鹵烷氧基、羥基、羥烷基、氰基、胺基、環烷基、雜環基、芳基和雜芳基；其中，該烷基、烷氧基、雜環基氧基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要被選自鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R ¹ and R ² are the same or different, each independently selected from hydrogen atom, 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 selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl substituted by one or more substituents in the base; R³選自氫原子、鹵素、烷基、烯基、烷氧基、鹵烷基、鹵烷氧基、羥基、羥烷基、氰基、胺基、環烷基、雜環基、芳基和雜芳基；其中，該烷基、烷氧基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要被選自鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； ^R is selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, substituted with one or more substituents of hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R⁴相同或不同，各自獨立地選自氫原子、鹵素、烷基、烯基、烷氧基、鹵烷基、鹵烷氧基、羥基、羥烷基、氰基、胺基、環烷基、雜環基、芳基和雜芳基；其中，該烷基、烷氧基、環烷基、雜環基、芳基和雜芳基各自獨 立地視需要被選自鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R ⁴ are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl , heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkane substituted with one or more substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R⁵選自烷基、鹵烷基、羥烷基和環烷基烷基； R ⁵ is selected from alkyl, haloalkyl, hydroxyalkyl and cycloalkylalkyl; n為0、1、2或3。 n is 0, 1, 2 or 3. 如請求項1所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R²為五員雜芳基，該五員雜芳基視需要地被選自鹵素、C_1-6烷基、C_1-6烷氧基和鹵C_1-6烷基中的一個或多個取代基所取代。 The compound represented by the general formula (I) according to claim 1 or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof, wherein R ² is a five-membered heteroaryl group optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy and halogen substituted with one or more substituents in the C _1-6 alkyl group. 如請求項1或2所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R³為五員雜芳基，該五員雜芳基視需要地被選自鹵素、C_1-6烷基、C_1-6烷氧基和鹵C_1-6烷基中的一個或多個取代基所取代。 The compound represented by the general formula (I) according to claim 1 or 2 or its tautomer, meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, or a pharmaceutically acceptable salt thereof, wherein R ³ is a five-membered heteroaryl group optionally selected from halogen, C _1-6 alkyl, C _1-6 alkoxy and one or more substituents in the halogen C _1-6 alkyl group. 如請求項1至3中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其為通式(II)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽： The compound represented by the general formula (I) according to any one of claims 1 to 3 or its tautomer, meso, racemate, enantiomer, and diastereomer isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

其中， in, R⁶相同或不同，各自獨立地選自氫原子、鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基； R ⁶ are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R⁷相同或不同，各自獨立地選自氫原子、鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基； R ⁷ are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; p和q相同或不同，各自獨立地選自0、1、2或3； p and q are the same or different, each independently selected from 0, 1, 2 or 3; R⁰、R¹、R⁴和n如請求項1中所定義。 R ⁰ , R ¹ , R ⁴ and n are as defined in claim 1 . 如請求項1至4中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R⁰為氫原子或C_1-6烷基。 The compound represented by general formula (I) according to any one of claims 1 to 4 or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ is a hydrogen atom or a C _1-6 alkyl group. 如請求項1至5中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R¹為氫原子。 The compound represented by the general formula (I) according to any one of claims 1 to 5 or its tautomer, meso, racemate, enantiomer, and diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom. 如請求項1至6中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R⁴為氫原子。 The compound represented by the general formula (I) according to any one of claims 1 to 6 or its tautomer, meso, racemate, enantiomer, and diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom. 如請求項1至3、5至7中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R⁵為甲基。 The compound represented by the general formula (I) according to any one of claims 1 to 3 and 5 to 7 or its tautomer, meso, racemate, enantiomer, non- An enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is methyl. 如請求項4至8中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R⁶為C_1-6烷基。 The compound represented by the general formula (I) according to any one of claims 4 to 8 or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is a C _1-6 alkyl group. 如請求項4至9中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其中，R⁷為氫原子。 The compound represented by the general formula (I) according to any one of claims 4 to 9 or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is a hydrogen atom. 如請求項1至10中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其選自以下任一化合物： The compound represented by the general formula (I) according to any one of claims 1 to 10 or its tautomer, meso, racemate, enantiomer, diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, selected from any of the following compounds:

一種通式(IA)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， A compound represented by general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable of salt,

其中， in, X為氫原子或鹵素；較佳為鹵素；更佳為Br； X is hydrogen atom or halogen; preferably halogen; more preferably Br; R⁰選自氫原子、烷基、鹵烷基、羥烷基、氰基和環烷基烷基； R ⁰ is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group and a cycloalkylalkyl group; R¹和R²相同或不同，各自獨立地選自氫原子、鹵素、烷基、烯基、烷氧基、雜環基氧基、鹵烷基、鹵烷氧基、羥基、羥烷基、氰基、胺基、環烷基、雜環基、芳基和雜芳基；其中，該烷基、烷氧基、雜環基氧基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要被選自鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R ¹ and R ² are the same or different, each independently selected from hydrogen atom, 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 selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl substituted by one or more substituents in the base; R⁴相同或不同，各自獨立地選自氫原子、鹵素、烷基、烯基、烷氧基、鹵烷基、鹵烷氧基、羥基、羥烷基、氰基、胺基、環烷基、雜環基、芳基和 雜芳基；其中，該烷基、烷氧基、環烷基、雜環基、芳基和雜芳基各自獨立地視需要被選自鹵素、烷基、烷氧基、鹵烷基、羥基、羥烷基、氰基、胺基、硝基、環烷基、雜環基、芳基和雜芳基中的一個或多個取代基所取代； R ⁴ are the same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl , heterocyclyl, aryl and heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkane substituted with one or more substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl; R⁵選自烷基、鹵烷基、羥烷基和環烷基烷基； R ⁵ is selected from alkyl, haloalkyl, hydroxyalkyl and cycloalkylalkyl; n為0、1、2或3。 n is 0, 1, 2 or 3. 如請求項12所述的通式(IA)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，其選自以下任一化合物： The compound represented by the general formula (IA) according to claim 12 or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof , or a pharmaceutically acceptable salt thereof selected from any of the following compounds:

一種製備如請求項1所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽的方法，該方法包括： A kind of preparation of the compound represented by the general formula (I) as described in claim 1 or its tautomer, meso, racemate, enantiomer, diastereomer, or its A method in the form of a mixture, or a pharmaceutically acceptable salt thereof, comprising:

通式(IA)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽和通式(IB)化合物 發生偶聯反應，得到通式(I)的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽， A compound of general formula (IA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and Compounds of general formula (IB) A coupling reaction occurs to obtain a compound of general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or its medicinal salt, 其中， in, X為鹵素； X is halogen; Y為

或

； Y is

or

; R為氫原子或烷基； R is a hydrogen atom or an alkyl group; R⁰、R¹、R²、R³、R⁴、R⁵和n如請求項1所定義。 R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are as defined in claim 1 . 一種醫藥組成物，該醫藥組成物含有如請求項1至11中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽，以及一種或多種藥學上可接受的載體、稀釋劑或賦形劑。 A pharmaceutical composition containing a compound represented by the general formula (I) as described in any one of claims 1 to 11 or a tautomer, meso, racemate, para Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. 如請求項1至11中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽或如請求項15所述的醫藥組成物在製備用於抑制ATR激酶的藥物中的用途。 The compound represented by the general formula (I) according to any one of claims 1 to 11 or its tautomer, meso, racemate, enantiomer, diastereomer Use of the compound, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15 in the preparation of a medicament for inhibiting ATR kinase. 如請求項1至11中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽或如請求項15所述的醫藥組成物在製備用於治療或預防過度增殖性疾病的藥物中的用途。 The compound represented by the general formula (I) according to any one of claims 1 to 11 or its tautomer, meso, racemate, enantiomer, diastereomer Use of a compound, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 15 in the manufacture of a medicament for the treatment or prevention of a hyperproliferative disease. 如請求項1至11中任一項所述的通式(I)所示的化合物或其互變異構體、內消旋體、外消旋體、對映異構體、非對映異構體、或其混合物形式、或其可藥用的鹽或如請求項15所述的醫藥組成物在製備用於治療或預防腫瘤的藥物中的用途。 The compound represented by the general formula (I) according to any one of claims 1 to 11 or its tautomer, meso, racemate, enantiomer, diastereomer Use of the compound, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15 in the preparation of a medicament for treating or preventing tumors. 如請求項18所述的用途，其中，該腫瘤選自黑色素瘤、腦瘤、食管癌、胃癌、肝癌、胰腺癌、結腸直腸癌、肺癌、腎癌、乳腺癌、子宮頸癌、卵巢癌、***癌、皮膚癌、神經母細胞瘤、神經膠質瘤、肉瘤、骨癌、子宮內膜癌、頭頸腫瘤、多發性骨髓瘤、B-細胞淋巴瘤、真性紅細胞增多症、白血病、甲狀腺腫瘤、膀胱癌和膽囊癌。 The use according to claim 18, wherein the tumor is selected from the group consisting of 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 tumors, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor, bladder cancer and gallbladder cancer.