WO2022002243A1

WO2022002243A1 - Imidazopyrimidine derivative, preparation method therefor and medical use thereof

Info

Publication number: WO2022002243A1
Application number: PCT/CN2021/104227
Authority: WO
Inventors: 李心; 陈阳; 蔡国栋; 贺峰; 陶维康
Original assignee: 江苏恒瑞医药股份有限公司; 上海恒瑞医药有限公司
Priority date: 2020-07-02
Filing date: 2021-07-02
Publication date: 2022-01-06
Also published as: TW202214642A; CN115867552A

Abstract

The present disclosure relates to an imidazopyrimidine derivative, a preparation method therefor, and the medical use thereof. In particular, the present disclosure relates to an imidazopyrimidine derivative as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the derivative, and the use thereof as a therapeutic agent, particularly the use thereof as an ATR kinase inhibitor and the use thereof in the preparation of a drug for treating and/or preventing hyperproliferative diseases.

Description

咪唑并嘧啶类衍生物、其制备方法及其在医药上的应用Imidazopyrimidine derivatives, their preparation method and their application in medicine

技术领域technical field

本公开属于医药领域，涉及一种通式(I)所示的咪唑并嘧啶类衍生物、其制备方法、含有该衍生物的药物组合物以及其作为治疗剂的用途，特别是作为ATR激酶抑制剂的用途和用于制备治疗和预防过度增殖性疾病的药物中的用途。The present disclosure belongs to the field of medicine, and relates to an imidazopyrimidine derivative represented by 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.

背景技术Background technique

无论是正常细胞还是肿瘤细胞中，每天都会出现成千上万次DNA的损伤。这使得DNA损伤修复在维持基因组的稳定性和细胞存活方面起到至关重要的作用。相比较于正常细胞，肿瘤细胞承受了更大的复制压力，携带更多的内源性DNA损伤，并且经常出现一个或多个DNA损伤修复通路的缺失。这使得肿瘤细胞的存活更加依赖于DNA损伤修复的顺利进行。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.

同源重组修复是DNA双链断裂的主要修复方式，以未受损的姐妹染色单体的同源序列作为其修复的模板复制受损处的DNA序列，精确修复DNA。这种修复方式主要发生在细胞的G2期和S期。ATR是同源重组修复通路中的关键酶，属于PIKK家族。当ATR/ATRIP复合物与覆盖了复制蛋白A(RPA)的受损DNA结合后，ATR被激活并通过磷酸化下游蛋白Chk1和SMARCAL等，调节细胞周期各个检查点，引起细胞周期阻滞，保证受损DNA的稳定性，提高dNTP浓度，促使DNA损伤得以修复。细胞周期S期中出现的DNA损伤修复主要由ATR通路完成，说明ATR对于保证细胞增殖非常重要。对于临床肿瘤样品的分析结果表明在多种肿瘤组织中，例如胃癌、肝癌、结直肠癌、卵巢癌、胰腺癌等，均观察到ATR表达水平升高。并且在卵巢癌、胰腺癌病人中，高水平的ATR往往伴随着较低的存活率。由此可见ATR是一个重要的肿瘤治疗的靶标。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 a key enzyme in the homologous 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, causing cell cycle arrest and ensuring The stability of damaged DNA increases the concentration of dNTPs and promotes 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.

现已公开的ATR抑制剂的专利申请包括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.

发明内容SUMMARY OF THE INVENTION

本公开的目的在于提供一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：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 its In the form of a mixture, or a pharmaceutically acceptable salt thereof:

其中：in:

R ⁰选自氢原子、烷基、卤代烷基、羟烷基、氰基和环烷基烷基； R ^{0 is} selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group and a cycloalkylalkyl group;

R ¹和R ²相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、杂环基氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R ¹ and R ^{2 are the} same or different, each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkoxy, heterocyclyloxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano , amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, alkoxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from one of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl or more substituents;

R ³选自氢原子、卤素、烷基、烯基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R ³ is selected from hydrogen, halo, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxy Substituted with one or more substituents of alkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁴相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R ^{4 are the} same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocycle wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy , substituted with one or more substituents in haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁵选自烷基、卤代烷基、羟烷基和环烷基烷基； R ^{5 is} selected from alkyl, haloalkyl, hydroxyalkyl and cycloalkylalkyl;

n为0、1、2或3。n is 0, 1, 2 or 3.

在本公开的一些实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(I-a)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is the compound represented by the general formula (Ia) or its tautomer, meso, racemate, enantiomer, Diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

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

在本公开的一些实施方案中，所述的通式(I)或(I-a)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ²为杂芳基，所述的杂芳基任选地被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基和环烷基中的一个或多个取代基所取代。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, 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, hydroxyalkyl, cyano, amino, nitro and cycloalkyl substituted with one or more substituents.

在本公开的一些实施方案中，所述的通式(I)或(I-a)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ²为五元杂芳基，所述的五元杂芳基任选地被选自卤素、C _1-6烷基、C _1-6烷氧基和卤代C _1-6烷基中的一个或多个取代基所取代。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, 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 alkane is substituted with one or more substituents of _{C 1-6} alkoxy group, C 1-6 alkoxy group and halogenated C _{1-6 alkyl group.}

在本公开的一些实施方案中，所述的通式(I)或(I-a)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ²选自吡唑基、咪唑基、吡咯基和***基，优选为吡唑基，所述的吡唑基、咪唑基、吡咯基和***基任选地被选自卤素、C _1-6烷基和卤代C _1-6烷基中的一个或多个取代基所取代。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^{2 is} selected from pyrazolyl, imidazolyl, pyrrolyl and triazolyl, preferably pyrazolyl, said pyrazolyl , imidazolyl, pyrrolyl and triazolyl are optionally substituted with one or more substituents _{selected from halogen, C 1-6} alkyl and haloC _{1-6 alkyl.}

在本公开的一些实施方案中，所述的通式(I)或(I-a)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ²为

优选为

R ^2a选自氢原子、C _1-6烷基和卤代C _1-6烷基；优选地，R ^2a为甲基或乙基。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, non- enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² is

preferably

R ^{2a is} selected from hydrogen atoms, C _1-6 alkyl groups and halogenated C _1-6 alkyl groups; preferably, R ^2a is methyl or ethyl.

在本公开的一些实施方案中，所述的通式(I)或(I-a)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ³为杂芳基，所述的杂芳基任选地被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基和环烷基中的一个或多个取代基所取代。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, 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, hydroxyalkyl, cyano, amino, nitro and cycloalkyl substituted with one or more substituents.

在本公开的一些实施方案中，所述的通式(I)或(I-a)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ³为五元杂芳基，所述的五元杂芳基任选地被选自卤素、C _1-6烷基、C _1-6烷氧基和卤代C _1-6烷基中的一个或多个取代基所取代。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, non- An enantiomer, 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 alkane is substituted with one or more substituents of _{C 1-6} alkoxy group, C 1-6 alkoxy group and halogenated C _{1-6 alkyl group.}

在本公开的一些实施方案中，所述的通式(I)或(I-a)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式或其可药用的盐，其中R ³选自吡唑基、咪唑基、吡咯基和***基，优选为吡唑基，所述的吡唑基、咪唑基、吡咯基和***基任选地被选自卤素、C _1-6烷基和卤代C _1-6烷基中的一个或多个取代基所取代。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, non- Enantiomer, or its mixture form or its pharmaceutically acceptable salt, wherein R ^{3 is} selected from pyrazolyl, imidazolyl, pyrrolyl and triazolyl, preferably pyrazolyl, said pyrazolyl, imidazolyl, pyrrolyl and triazolyl optionally substituted selected from halogen, C _1-6 alkyl and halogenated C _1-6 alkyl group with one or more substituents.

在本公开的一些实施方案中，所述的通式(I)或(I-a)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ³为

优选为

R ^3a选自氢原子、C _1-6烷基和卤代C _1-6烷基；优选地，R ^3a为氢原子。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, non- enantiomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, 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.

在本公开的一些实施方案中，所述的通式(I)或(I-a)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：In some embodiments of the present disclosure, the compound represented by the general formula (I) or (Ia) or its tautomer, meso, racemate, enantiomer, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (II) or tautomers, mesomers, racemates, enantiomers thereof Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

其中：in:

R ⁶相同或不同，各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基； R ^{6 are the} same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁷相同或不同，各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基； R ^{7 are the} same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

p和q相同或不同，各自独立地选自0、1、2或3；p and q are the same or different, each independently selected from 0, 1, 2 or 3;

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

在本公开的一些实施方案中，所述的通式(I)、(I-a)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ⁰选自氢原子、烷基、卤代烷基、羟烷基和氰基；优选地，R ⁰选自氢原子、C _1-6烷基、C _1-6卤代烷基、C _1-6羟烷基和氰基；更优选为氢原子或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 isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{0 is} selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group and a cyano group; preferably, R ^{0 is} selected 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.

在本公开的一些实施方案中，所述的通式(I)、(I-a)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ¹选自氢原子、卤素、烷基、烷氧基、杂环基氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基和环烷基；其中所述的烷基、烷氧基、杂环基氧基和环烷基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基中的一个或多个取代基所取代； 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 isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{1 is} selected from a hydrogen atom, halogen, alkyl, alkoxy, heterocyclyloxy, haloalkyl, haloalkane oxy, hydroxy, hydroxyalkyl, cyano, amino and cycloalkyl; wherein said 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, amino, and nitro;

优选地，R ¹选自氢原子、卤素、C _1-6烷基和卤代C _1-6烷基； Preferably, R ^{1 is} selected from hydrogen atom, halogen, C _1-6 alkyl and halogenated C _1-6 alkyl;

更优选地，R ¹为氢原子。 More preferably, R ¹ is a hydrogen atom.

在本公开的一些实施方案中，所述的通式(I)、(I-a)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ⁴相同或不同，各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基和环烷基；其中所述的烷基、烷氧基和环烷基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基和硝基中的一个或多个取代基所取代； In some embodiments of the present disclosure, the compound represented by the general formula (I), (Ia) or (II) or its tautomer, meso, racemate, enantiomer isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^{4 are the} same or different, each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino and cycloalkyl; wherein said alkyl, alkoxy and cycloalkyl are each independently optionally selected from halogen, alkyl, alkoxy, Substituted with one or more substituents of haloalkyl, hydroxy, hydroxyalkyl, cyano, amino and nitro;

优选地，R ⁴选自氢原子、卤素、C _1-6烷基和卤代C _1-6烷基； Preferably, R ^{4 is} selected from hydrogen atom, halogen, C _1-6 alkyl and halogenated C _1-6 alkyl;

更优选地，R ⁴为氢原子。 More preferably, R ⁴ is a hydrogen atom.

在本公开的一些实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ⁵为烷基或卤代烷基；优选为C _1-6烷基；更优选为甲基。 In some embodiments of the present disclosure, the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer in the form of a compound, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is alkyl or haloalkyl; preferably C _1-6 alkyl; more preferably methyl.

在本公开的一些实施方案中，所述的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ⁶相同或不同，各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基和硝基；优选地，R ⁶相同或不同，各自独立地选自氢原子、卤素、C _1-6烷基和卤代C _1-6烷基；进一步优选为C _1-6烷基；更优选为甲基。 In some embodiments of the present disclosure, the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{6 are the} same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano , amino and nitro; preferably, R ^{6 is the} same or different, each independently selected from hydrogen atom, halogen, C _1-6 alkyl and halogenated C _1-6 alkyl; more preferably C _1-6 alkyl ; more preferably methyl.

在本公开的一些实施方案中，所述的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ⁷相同或不同，各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基和硝基；优选地，R ⁷相同或不同，各自独立地选自氢原子、卤素、C _1-6烷基和卤代C _1-6烷基；更优选为氢原子。 In some embodiments of the present disclosure, the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer form, 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 , amino and nitro; preferably, R ^{7 is the} same or different, each independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group and a halogenated C _1-6 alkyl group; more preferably a hydrogen atom.

在本公开的一些实施方案中，所述的通式(I)、(I-a)或(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中n为0或1，优选为1。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 isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1, preferably 1.

在本公开的一些实施方案中，所述的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中p为1。In some embodiments of the present disclosure, the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein p is 1.

在本公开的一些实施方案中，所述的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中q为0或1，优选为1。In some embodiments of the present disclosure, the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1, preferably 1.

在本公开的一些实施方案中，所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ⁰选自氢原子、C _1-6烷基、C _1-6卤代烷基、C _1-6羟烷基和氰基；R ¹选自氢原子、卤素、C _1-6烷基和卤代C _1-6烷基；R ²为五元杂芳基，所述的五元杂芳基任选地被选自卤素、C _1-6烷基、C _1-6烷氧基和卤代C _1-6烷基中的一个或多个取代基所取代；R ³为五元杂芳基，所述的五元杂芳基任选地被选自卤素、C _1-6烷基、C _1-6烷氧基和卤代C _1-6烷基中的一个或多个取代基所取代；R ⁴为氢原子；R ⁵为C _1-6烷基；n为0或1。在本公开的一些实施方案中，所述的通式(I-a)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ⁰选自氢原子、C _1-6烷基、C _1-6卤代烷基、C _1-6羟烷基和氰基；R ¹选自氢原子、卤素、C _1-6烷基和卤代C _1-6烷基；R ²为

R ^2a选自氢原子、C _1-6烷基和卤代C _1-6烷基；R ³为

R ^3a选自氢原子、C _1-6烷基和卤代C _1-6烷基；R ⁴为氢原子；n为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 form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{0 is} selected 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; R ¹ is selected from hydrogen atom, halogen, C _1-6 alkyl group and halogenated C _1-6 alkyl group; R ² is a five-membered heteroaryl group, and the five-membered heteroaryl group is optionally selected from halogen, C _{1 -6} alkyl, C _1-6 alkoxy and one or more substituents in _{halogenated C 1-6} ^{alkyl; R 3} is a five-membered heteroaryl, and the five-membered heteroaryl can be any optionally substituted by one or more substituents selected from halogen, C _1-6 alkyl, C _1-6 alkoxy and halogenated 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, and diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^{0 is} selected 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; R ¹ Selected from hydrogen atom, halogen, C _1-6 alkyl and halogenated C _1-6 alkyl; R ² is

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

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

在本公开的一些实施方案中，所述的通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ⁰为氢原子或C _1-6烷基；R ¹选自氢原子、卤素、C _1-6烷基和卤代C _1-6烷基；R ⁴为氢原子；R ⁶相同或不同，各自独立地选自氢原子、卤素、C _1-6烷基和卤代C _1-6烷基；R ⁷相同或不同，各自独立地选自氢原子、卤素、C _1-6烷基和卤代C _1-6烷基；n为0或1；p为1；q为1。 In some embodiments of the present disclosure, the compound represented by the general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ is hydrogen atom or C _1-6 alkyl; R ^{1 is} selected from hydrogen atom, halogen, C _1-6 alkyl and halogenated 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 halogenated C _1-6 alkyl; R ^{7 is the} same or different, each independently is selected from hydrogen atom, halogen, C _1-6 alkyl and halogenated C _1-6 alkyl; n is 0 or 1; p is 1; q is 1.

表A本公开的典型化合物包括但不限于：Table A Typical compounds of the present disclosure include, but are not limited to:

或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐。or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

本公开的另一方面涉及通式(IA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，Another aspect of the present disclosure pertains to compounds of general formula (IA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof,

其中：in:

X为氢原子或卤素；优选为卤素；更优选为Br；X is a hydrogen atom or halogen; preferably halogen; more preferably Br;

n为0、1、2或3。n is 0, 1, 2 or 3.

本公开的另一方面涉及通式(I-aA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，Another aspect of the present disclosure pertains to a compound of formula (I-aA) or a tautomer, meso, racemate, enantiomer, diastereomer, or tautomer, meso, racemate, or in the form of a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中：in:

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

本公开的另一方面涉及通式(IIA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，Another aspect of the present disclosure pertains to compounds of general formula (IIA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof form, or a pharmaceutically acceptable salt thereof,

其中：in:

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

本公开的典型中间体化合物包括但不限于：Typical intermediate compounds of the present disclosure include, but are not limited to:

本公开的另一方面涉及一种制备通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

通式(IA)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐和通式(IB)化合物发生偶联反应，得到通式(I)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，A compound of general formula (IA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Coupling reaction with the compound of general formula (IB) to obtain the compound of general formula (I) or its tautomer, meso, racemate, enantiomer and diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中：in:

X为卤素；优选为Br；X is halogen; preferably Br;

Y为

Y is

R为氢原子或烷基；R is a hydrogen atom or an alkyl group;

R ⁰、R ¹、R ²、R ³、R ⁴、R ⁵和n如通式(I)中所定义。 R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are as defined in general formula (I).

本公开的另一方面涉及一种制备通式(I-a)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (Ia) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

通式(I-aA)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐和通式(IB)化合物发生偶联反应，得到通式(I-a)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，Compounds of general formula (I-aA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable A coupling reaction occurs between the salt of and the compound of the general formula (IB) to obtain the compound of the general formula (Ia) or its tautomer, meso, racemate, enantiomer, diastereomer form, or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中：in:

X为卤素；优选为Br；X is halogen; preferably Br;

Y为

Y is

R为氢原子或烷基；R is a hydrogen atom or an alkyl group;

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

本公开的另一方面涉及一种制备通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：Another aspect of the present disclosure relates to the preparation of a compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

通式(IIA)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐和通式(IIB)化合物发生偶联反应，得到通式(II)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，A compound of general formula (IIA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Coupling reaction with the compound of general formula (IIB) to obtain the compound of general formula (II) or its tautomer, meso, racemate, enantiomer and diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中：in:

X为卤素；优选为Br；X is halogen; preferably Br;

Y为

Y is

R为氢原子或烷基；R is a hydrogen atom or an alkyl group;

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

本公开的另一方面涉及一种药物组合物，所述药物组合物含有本公开通式(I)、(I-a)、(II)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound represented by the general formula (I), (Ia), (II) or Table A of the present disclosure, or a tautomer, internal Racemates, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

本公开进一步涉及通式(I)、(I-a)、(II)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或者包含其的药物组合物在制备用于抑制ATR激酶的药物中的用途。The present disclosure further relates to compounds of general formula (I), (Ia), (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.

本公开进一步涉及通式(I)、(I-a)、(II)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或者包含其的药物组合物在制备用于治疗或预防过度增殖性疾病的药物中的用途。The present disclosure further relates to compounds of general formula (I), (Ia), (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 a hyperproliferative disease.

本公开进一步涉及通式(I)、(I-a)、(II)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或者包含其的药物组合物在制备用于治疗或预防肿瘤的药物中的用途。The present disclosure further relates to compounds represented by general formula (I), (Ia), (II) or Table A, or tautomers, mesomers, racemates, enantiomers, unpaired isomers thereof 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 or preventing tumors.

本公开进一步涉及通式(I)、(I-a)、(II)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或者包含其的药物组合物在制备***的药物中的用途。The present disclosure further relates to compounds of general formula (I), (Ia), (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.

本公开还涉及一种抑制ATR激酶的方法，其包括给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变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，或包含其的药物组合物。The present disclosure also relates to a method of inhibiting ATR kinase, comprising administering to a patient in need thereof an inhibitory effective amount of a compound of general formula (I), (Ia), (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.

本公开还涉及一种治疗或预防过度增殖性疾病的方法，其包括给予有需要的患者治疗或预防有效量的通式(I)、(I-a)、(II)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，或包含其的药物组合物。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), (Ia), (II) or Table A or Its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same .

本公开还涉及一种治疗或预防肿瘤的方法，其包括给予有需要的患者治疗或预防有效量的通式(I)、(I-a)、(II)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，或包含其的药物组合物。The present disclosure also relates to a method of 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), (Ia), (II) or Table A or its interconversion Isomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

本公开进一步涉及一种通式(I)、(I-a)、(II)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或包含其的药物组合物，其用作药物。The present disclosure further relates to a compound represented by the general formula (I), (Ia), (II) or Table A or its tautomer, meso, racemate, enantiomer, A diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

本公开还涉及通式(I)、(I-a)、(II)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或包含其的药物组合物，其用作ATR激酶抑制剂。The present disclosure also relates to compounds of general formula (I), (Ia), (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 as an ATR kinase inhibitor.

本公开还涉及通式(I)、(I-a)、(II)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或包含其的药物组合物，其用于治疗或预防过度增殖性疾病。The present disclosure also relates to compounds of general formula (I), (Ia), (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 or prevention of a hyperproliferative disease.

本公开进一步涉及通式(I)、(I-a)、(II)或表A所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或包含其的药物组合物，其用于***。The present disclosure further relates to compounds of general formula (I), (Ia), (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.

本公开中所述的肿瘤优选自黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、乳腺癌、***、卵巢癌、***癌、皮肤癌、神经母细胞瘤、神经胶质瘤、肉瘤、骨癌、子宫内膜癌、头颈肿瘤、多发性骨髓瘤、B-细胞淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、膀胱癌和胆囊癌。The tumor described in the present disclosure is preferably 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, nerve cancer Blastoma, 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.

可将活性化合物制成适合于通过任何适当途径给药的形式，通过常规方法使用一种或多种药学上可接受的载体来配制本公开的组合物。因此，本公开的活性化合物可以配制成用于口服给药、注射(例如静脉内、肌肉内或皮下)给药、吸入或吹入给药的各种剂型。本公开的化合物可以配制成例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓剂、锭剂或糖浆等剂型。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. The compounds of the present disclosure can be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injectable solutions, dispersible powders or granules, suppositories, lozenges or syrups.

作为一般性指导，本公开活性化合物优选是以单位剂量的方式，或者是以患者可以以单剂自我给药的方式。本公开化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、粉末剂、颗粒剂、锭剂、栓剂、再生粉末或液体制剂。合适的单位剂量可以是0.1～1000mg。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. A unit dose of a compound or composition of the present disclosure can be expressed as a tablet, capsule, cachet, vial, powder, granule, lozenge, suppository, reconstituted powder, or liquid formulation. A suitable unit dose may be 0.1 to 1000 mg.

本公开的药物组合物除活性化合物外，可含有一种或多种辅料，所述辅料选自以下成分：填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同，组合物可含有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 excipients selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait. Depending on the method of administration, the composition may contain from 0.1 to 99% by weight of active compound.

片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。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与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。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.

水混悬液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此类赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。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.

油混悬液可通过使活性成分悬浮于植物油或矿物油配制而成。油混悬液可含有增稠剂。可加入甜味剂和矫味剂以提供可口的制剂。可通过加入抗氧化剂保存这些组合物。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.

本公开的药物组合物也可以是水包油乳剂的形式。油相可以是植物油、或矿物油、或其混合物。适宜的乳化剂可以是天然产生的磷脂，乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。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.

本公开的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳，可通过局部大量注射将注射液或微乳注入患者的血流中。或者，最好按可保持本公开化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。这种装置的实例是Deltec CADD-PLUS.TM.5400型静脉注射泵。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 IV pump.

本公开的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用任何调和固定油。此外，脂肪酸也可以制备注射剂。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.

可按用于直肠给药的栓剂形式给予本公开化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。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 which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

可通过加入水来制备水混悬的可分散粉末和颗粒给予本公开化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐剂混合来制备这些药物组合物。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.

如本领域技术人员所熟知的，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用具体化合物的活性、疾病的严重性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、***的速率、药物的组合等；另外，最佳的治疗方式如治疗的模式、化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。As is well known to those skilled in the art, the dosage of a drug to be 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 health of the patient condition, behavior of the patient, diet of the patient, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the optimal mode of treatment such as mode of treatment, daily dose of compound or pharmaceutically acceptable salt Species can be verified against conventional treatment protocols.

术语说明Glossary

除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, terms used in the specification and claims have the following meanings.

术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子的烷基，更优选为含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、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，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、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，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自H原子、D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。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-dimethyl pentyl, 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 Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Alkylhexyl, 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, sec-butyl base, 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-dimethylpropyl butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl base, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from H atoms, D atoms, halogens, alkyl groups , alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heterocycle One or more substituents in an aryl group.

术语“亚烷基”指饱和的直链或支链脂肪族烃基，其为从母体烷的相同碳原子或两个不同的碳原子上除去两个氢原子所衍生的残基，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子，更优选含有1至6个碳原子的亚烷基。亚烷基的非限制性实例包括但不限于亚甲基(-CH ₂-)、1,1-亚乙基(-CH(CH ₃)-)、1,2-亚乙基(-CH ₂CH ₂)-、1,1-亚丙基(-CH(CH ₂CH ₃)-)、1,2-亚丙基(-CH ₂CH(CH ₃)-)、1,3-亚丙基(-CH ₂CH ₂CH ₂-)、1,4-亚丁基(-CH ₂CH ₂CH ₂CH ₂-)等。亚烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自烷基、烯基、炔基、烷氧基、卤代烷氧基、环烷基氧基、杂环基氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基和氧代基中的一个或多个取代基。 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) carbon atoms, More preferred are alkylene groups containing 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH ₂ -), 1,1- ethylene _{(-CH (CH 3) -)} , 1,2- ethylene (-CH ₂ CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3-propylene (-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, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl , one or more substituents of heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and oxo.

术语“烯基”指分子中含有至少一个碳碳双键的烷基化合物，其中烷基的定义如上所述。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。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, haloalkyl groups, haloalkoxy groups one or more of the substituents in a radical, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl .

术语“炔基”指分子中含有至少一个碳碳三键的烷基化合物，其中烷基的定义如上所述。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自氢原子、烷基、烷氧基、卤素、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基。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, haloalkyl groups, haloalkoxy groups one or more of the substituents in a radical, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl .

术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，优选包含3至8个碳原子(例如3、4、5、6、7和8个)，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。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 3 to 8 carbon atoms 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.

术语“螺环烷基”指5至20元，单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group having one carbon atom (called a spiro atom) shared between the monocyclic rings, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

术语“稠环烷基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more rings. Multiple double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent 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:

术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：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 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

所述环烷基环包括如上所述的环烷基(包括单环、螺环、稠环和桥环)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括

等等；优选为

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

etc.; preferably

环烷基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。Cycloalkyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyls, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents in .

术语“烷氧基”指-O-(烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自H原子、 D原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基。The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from H atoms, D atoms, halogen, alkyl, alkoxy , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

术语“杂环基”指饱和或部分不饱和单环或多环环状取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个(例如1、2、3和4个)是杂原子；更优选包含3至8个环原子(例如3、4、5、6、7和8个)，其中1-3是杂原子(例如1、2和3个)；更优选包含3至6个环原子，其中1-3个是杂原子；最优选包含5或6个环原子，其中1-3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、四氢吡喃基、1,2.3.6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, The sulfur may optionally be oxo (ie, to form a sulfoxide or sulfone), but does not include ring moieties of -OO-, -OS- or -SS-, 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 1-3 are heteroatoms (eg 1, 2 and 3); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, 1-3 of them are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2.3.6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, Homopiperazinyl etc. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.

术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：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 heterocyclic groups selected from nitrogen, oxygen and sulfur. atom, the sulfur may optionally be oxo (ie to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the rings, spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group. Non-limiting examples of spiroheterocyclyl include:

术语“稠杂环基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：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 of the rings may contain one or more Double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may be optionally oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclyl groups include:

术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：The term "bridged heterocyclyl" refers to a 5- to 14-membered, polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds in which one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (ie, to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (eg 7, 8, 9 or 10 yuan). 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:

所述杂环基环包括如上所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：The heterocyclyl ring includes a heterocyclyl group (including monocyclic, spiroheterocycle, fused heterocycle and bridged heterocycle) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the The rings to which the structure is attached are heterocyclyl, non-limiting examples of which include:

等。

Wait.

杂环基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。Heterocyclyl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents in .

术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括如上所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：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 membered , such as phenyl and naphthyl. The aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring 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，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。Aryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkoxy groups , haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents.

术语“杂芳基”指包含1至4个(例如1、2、3和4个)杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元(例如5、6、7、8、9或10元)，更优选为5元或6元，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、哒嗪基、咪唑基、吡唑基、***基、四唑基等。所述杂芳基环包括如上述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：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 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkane pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include :

杂芳基可以是取代的或非取代的，当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自氢原子、卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、环烷基氧基、杂环基氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基、杂芳基中的一个或多个取代基。Heteroaryl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, alkanes Oxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl one or more substituents in .

上述环烷基、杂环基、芳基和杂芳基包括从母体环原子上除去一个氢原子所衍生的残基，或从母体的相同或两个不同的环原子上除去两个氢原子所衍生的残基，即“二价环烷基”、“二价杂环基”、“亚芳基”和“亚杂芳基”。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. Derived residues, namely "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

术语“氨基保护基”是为了使分子其它部位进行反应时氨基保持不变，用易于脱去的基团对氨基进行保护。非限制性实施例包含(三甲基硅)乙氧基甲基、四氢吡喃基、叔丁氧羰基、乙酰基、苄基、烯丙基和对甲氧苄基等。这些基团可任选地被选自卤素、烷氧基或硝基中的1-3个取代基所取代。术语“羟基保护基”是本领域已知的适当的用于羟基保护的基团，参见文献(“Protective Groups in Organic Synthesis”，5 ^Th Ed.T.W.Greene&P.G.M.Wuts)中的羟基保护基团。作为示例，优选地，所述的羟基保护基可以是(C _1-10烷基或芳基) ₃硅烷基，例如：三乙基硅基、三异丙基硅基、叔丁基二甲基硅基、叔丁基二苯基硅基等；可以是C _1-10烷基或取代烷基，优选烷氧基取代的烷基或芳基取代的烷基，更优选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，最优选C _1-4烷氧基取代的C _1-4烷基，例如：甲基、叔丁基、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)酰基，例如：甲酰基、乙酰基、苯甲酰基、对硝基苯甲酰基等；可以是(C _1-6烷基或C _6-10芳基)磺酰基；也可以是(C _1-6烷氧基或C _6-10芳基氧基)羰基。 The term "amino protecting group" is used to protect the amino group with a group that is easy to remove in order to keep the amino group unchanged when the other part of the molecule is reacted. Non-limiting examples include (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1-3 substituents selected from halogen, alkoxy or nitro. The term "hydroxyl protecting group" is a suitable group for hydroxyl protection known in the art, see the 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 Silyl, 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 with C _1-6 alkyl, most preferably C _1-4 alkoxy substituted C _1-4 alkyl, for example: methyl, t-butyl, benzyl , methoxymethyl (MOM), ethoxyethyl; can be (C _1-10 alkyl or aryl) acyl, such as: formyl, acetyl, benzoyl, p-nitrobenzoyl, etc. ; may be (C _1-6 alkyl or C _6-10 aryl) sulfonyl; may also be (C _1-6 alkoxy or C _6-10 aryloxy) carbonyl.

术语“环烷基氧基”指环烷基-O-，其中环烷基如上所定义。The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.

术语“杂环基氧基”指杂环基-O-，其中杂环基如上所定义。The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

术语“芳基氧基”指芳基-O-，其中芳基如上所定义。The term "aryloxy" refers to aryl-O-, wherein aryl is as defined above.

术语“杂芳基氧基”指杂芳基-O-，其中杂芳基如上所定义。The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

术语“烷硫基”指烷基-S-，其中烷基如上所定义。The term "alkylthio" refers to alkyl-S-, wherein alkyl is as defined above.

术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

术语“氘代烷基”指烷基被一个或多个氘原子取代，其中烷基如上所定义。The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如上所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.

术语“羟基”指-OH。The term "hydroxy" refers to -OH.

术语“巯基”指-SH。The term "thiol" refers to -SH.

术语“氨基”指-NH ₂。 The term "amino" means -NH _2.

术语“氰基”指-CN。The term "cyano" refers to -CN.

术语“硝基”指-NO ₂。 The term "nitro" refers to -NO _2.

术语“氧代基”或“氧代”指“＝O”。The term "oxo" or "oxo" refers to "=O".

术语“羰基”指C＝O。The term "carbonyl" refers to C=O.

术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.

术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基、环烷基如上所定义。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.

本公开的化合物还可包含其同位素衍生物。术语“同位素衍生物”指结构不同仅在于存在一种或多种同位素富集原子的化合物。例如，具有本公开的结构，除了用“氘”或“氚”代替氢，或者用 ¹⁸F-氟标记( ¹⁸F同位素)代替氟，或者用 ¹¹C-、 ¹³C-、或者 ¹⁴C-富集的碳( ¹¹C-、 ¹³C-、或者 ¹⁴C-碳标记； ¹¹C-、 ¹³C-、或 ¹⁴C-同位素)代替碳原子的化合物在本公开的范围内。这样的化合物可用作例如生物学测定中的分析工具或探针，或者可以用作疾病的体内诊断成像示踪剂，或者作为药效学、药动学或受体研究的示踪剂。本公开还包括各种氘化形式的化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的化合物。在制备氘代形式的化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。氘代物通常可以保留与未氘代的化合物相当的活性，并且当氘代在某些特定位点时可以取得更好的代谢稳定性，从而获得某些治疗优势。 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, the present disclosure having the structure, except that "deuterium" or "tritium" in place of a hydrogen, fluorine or instead of fluorine-labeled with ¹⁸ F- ⁽¹⁸ F isotope), or with ¹¹ C- ¹³ C-, ¹⁴ C- or rich, Compounds in which a set of 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 this 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. Those skilled in the art can refer to the relevant literature to synthesize deuterated forms of the compounds. Commercially available deuterated starting materials can be used in preparing deuterated forms of the compounds, or they can be synthesized using conventional 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.

“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团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 instances where it does not. 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”指基团中的一个或多个氢原子，优选为1～5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。本领域技术人员能够在不付出过多努力的情况下(通过实验或理论)确定可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms in a group, preferably 1 to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted by the corresponding number of substituents. A person skilled in the art can determine possible or impossible substitutions (either experimentally or theoretically) without undue effort. For example, amino or hydroxyl groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (eg, olefinic) bonds.

“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。"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.

“可药用的盐”是指本公开化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备盐。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。"Pharmaceutically acceptable salts" refers to salts of the compounds of the present disclosure that are safe and effective when used in mammals, and that possess the desired biological activity. The salts can be prepared separately during the final isolation and purification of the compounds, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

针对药物或药理学活性剂而言，术语“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。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, depends on the age and general condition of the recipient, and also depends on the specific active substance, and the appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.

本文所用的术语“溶剂化物”是指本公开的化合物与一种或多种，优选地为1-3种，无论是有机的还是无机的溶剂分子的物理结合。该物理结合包括氢键。在某些情况下，例如，当在结晶固体的晶格中掺入一种或多种，优选1-3种溶剂分子时，溶剂化物将被分离。示例性的溶剂化物包括但不限于水合物、乙醇化物、甲醇化物和异丙醇化物。溶剂化方法是本领域公知的。The term "solvate" as used herein refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. This physical bond includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated in 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.

“前药”是指可以在生理条件下，例如通过在血液中水解，在体内转化以产生活性原药化合物。"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.

本文所用的术语“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。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，单数形式的“一个”、“一种”和“该”包括复数引用，反之亦然，除非上下文另外明确指出。As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

当将术语“约”应用于如pH、浓度、温度等的参数时，表明该参数可以变化±10％，并且有时更优选地在±5％之内。如本领域技术人员将理解的，当参数不是关键的时，通常仅出于说明目的给出数字，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 is sometimes more preferably within ±5%. As those skilled in the art will appreciate, when parameters are not critical, numbers are generally given for illustrative purposes only, and not limitations.

本公开化合物的合成方法Synthetic methods of compounds of the present disclosure

为了完成本公开的目的，本公开采用如下技术方案：In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

方案一Option One

本公开通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的制备方法，包括以下步骤：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 The preparation method of medicinal salt, comprises the following steps:

通式(IA)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐和通式(IB)化合物在催化剂存在下，在碱性条件下发生偶联反应，得到通式(I)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，A compound of general formula (IA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Coupling reaction occurs with the compound of general formula (IB) in the presence of a catalyst 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为卤素；优选为Br；X is halogen; preferably Br;

Y为

Y is

R为氢原子或烷基；R is a hydrogen atom or an alkyl group;

方案二Option II

通式(I-aA)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐和通式(IB)化合物在催化剂存在下，在碱性条件下发生偶联反应，得到通式(I-a)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，Compounds of general formula (I-aA) or tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable In the presence of a catalyst, the salt of the compound and the compound of the general formula (IB) undergo a coupling reaction under basic conditions to obtain the compound of the general formula (Ia) or its tautomer, meso, racemate, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

其中：in:

X为卤素；优选为Br；X is halogen; preferably Br;

Y为

Y is

R为氢原子或烷基；R is a hydrogen atom or an alkyl group;

方案三third solution

本公开通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的制备方法，包括以下步骤：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 The preparation method of medicinal salt, comprises the following steps:

通式(IIA)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐和通式(IIB)化合物在催化剂存在下，在碱性条件下发生偶联反应，得到通式(II)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，A compound of general formula (IIA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Coupling reaction occurs with the compound of general formula (IIB) in the presence of a catalyst under basic conditions 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为卤素；优选为Br；X is halogen; preferably Br;

Y为

Y is

R为氢原子或烷基；R is a hydrogen atom or an alkyl group;

以上合成方案中提供碱性条件的试剂包括有机碱和无机碱类，所述的有机碱类包括但不限于三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、叔丁醇钠、叔丁醇钾和正丁醇钠，所述的无机碱类包括但不限于氢化钠、磷酸钾、碳酸钠、碳酸钾、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂，优选为碳酸钠或无水碳酸钠。The reagents that provide alkaline conditions in the above synthesis scheme include organic bases and inorganic bases, and the organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamine Lithium propylamide, lithium bistrimethylsilylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and sodium n-butoxide, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate , potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide, preferably sodium carbonate or anhydrous sodium carbonate.

以上合成方案中所述的催化剂包括但不限于钯/碳、四三苯基膦钯、二氯化钯、醋酸钯、双(二亚芐基丙酮)钯、氯(2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基)[2-(2'-氨基-1,1'-联苯)]钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、1,1’-双(二苄基磷)二氯二茂铁钯或三(二亚苄基丙酮)二钯，优选为[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物。The catalysts described in the above synthetic schemes include but are 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 dichloro Methane complex.

上述反应优选在溶剂中进行，所用溶剂包括但不限于：乙二醇二甲醚、醋酸、甲醇、乙醇、正丁醇、甲苯、四氢呋喃、二氯甲烷、石油醚、乙酸乙酯、正己烷、二甲基亚砜、1,4-二氧六环、水或N,N-二甲基甲酰胺。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, Dimethyl sulfoxide, 1,4-dioxane, water or N,N-dimethylformamide.

具体实施方式detailed description

以下结合实施例进一步描述本公开，但这些实施例并非限制着本公开的范围。The present disclosure is further described below in conjunction with the examples, but these examples do not limit the scope of the present disclosure.

实施例Example

化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 ^-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400或Bruker AVANCE NEO 500M核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d ₆)、氘代氯仿(CDCl ₃)、氘代甲醇(CD ₃OD)，内标为四甲基硅烷(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的测定用Agilent 1200/1290 DAD-6110/6120 Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120 Quadrupole MS)；waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)；THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。Agilent 1200/1290 DAD-6110/6120 Quadrupole MS LC/MS was used for MS determination (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).

高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色谱仪。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分析测定使用Agilent 1260 DAD高效液相色谱仪。Chiral HPLC analysis was determined using an Agilent 1260 DAD high performance liquid chromatograph.

高效液相制备色谱法使用Waters 2545-2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson GX-281制备型色谱仪。High performance liquid preparative chromatography used Waters 2545-2767, Waters 2767-SQ Detector2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

手性制备色谱法使用Shimadzu LC-20AP制备型色谱仪。Chiral preparative chromatography used a Shimadzu LC-20AP preparative chromatograph.

CombiFlash快速制备仪使用Combiflash Rf200(TELEDYNE ISCO)。The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～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 ~ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ~0.5mm.

硅胶柱层析色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

激酶平均抑制率及IC ₅₀值的测定用NovoStar酶标仪(德国BMG公司)。 The average inhibition rate and IC ₅₀ value of kinases were measured with NovoStar microplate reader (BMG, Germany).

本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG、Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。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 chemical companies.

实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。There is no special description in the examples, and the reactions can all be carried out in an argon atmosphere or a nitrogen atmosphere.

氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。Argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

氢气氛是指反应瓶连接一个约1L容积的氢气气球。Hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。The pressure hydrogenation reaction uses Parr 3916EKX hydrogenation apparatus and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.

氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.

微波反应使用CEM Discover-S 908860型微波反应器。The microwave reaction used a CEM Discover-S 908860 microwave reactor.

实施例中无特殊说明，溶液是指水溶液。There is no special description in the examples, and the solution refers to an aqueous solution.

实施例中无特殊说明，反应的温度为室温，为20℃～30℃。There is no special description in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.

实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析色谱法的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。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 chromatography and the developing solvent system of the thin layer chromatography adopted for purifying the compound include: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethyl ether can also be added Basic or acidic reagents such as amines and acetic acid are used for adjustment.

实施例1Example 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)***啉1(R)-3-Methyl-4-(6-methyl-2-(1-methyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)imidazo[ 1,5-a]pyrimidin-4-yl)morpholine 1

第一步first step

N-((4,6-二氧代-1,4,5,6-四氢嘧啶-2-基)甲基)乙酰胺1cN-((4,6-Dioxo-1,4,5,6-tetrahydropyrimidin-2-yl)methyl)acetamide 1c

在氩气氛下，将丙二酰胺1a(8.6g，84.2mmol，上海毕得)、乙酰基甘氨酸乙酯1b(12.9g，88.87mmol)、甲醇钠(11.2g，207.3mmol)加入甲醇(150mL)中，回流14小时，冷却至室温，过滤，滤液减压浓缩，得到标题产物1c(12g)，产品不经纯化直接用于下一步反应。Under argon atmosphere, malonamide 1a (8.6 g, 84.2 mmol, Shanghai Bide), ethyl acetylglycine ester 1b (12.9 g, 88.87 mmol), sodium methoxide (11.2 g, 207.3 mmol) were added to methanol (150 mL) , refluxed for 14 hours, cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 1c (12 g), which was directly 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1d2,4-Dichloro-6-methylimidazo[1,5-a]pyrimidine 1d

将粗品化合物1c(12g，65.5mmol)溶于甲苯(50mL)，加入三氯氧磷(36mL，393.1mmol)，缓慢加入N,N-二异丙基乙胺(33mL，196.5mmol)，90℃反应2小时。反应液冷却至室温，减压浓缩，加二氯甲烷(500mL)搅拌0.5小时，过滤，滤液减压浓缩，得到标题产物1d(8g)，产品不经纯化直接用于下一步反应。The crude compound 1c (12 g, 65.5 mmol) was dissolved in toluene (50 mL), phosphorus oxychloride (36 mL, 393.1 mmol) was added, and N,N-diisopropylethylamine (33 mL, 196.5 mmol) was added slowly, at 90° C. React for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, added dichloromethane (500 mL), 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***啉1f(R)-4-(2-Chloro-6-methylimidazo[1,5-a]pyrimidin-4-yl)-3-methylmorpholine 1f

将粗品化合物1d(8g,39.59mmol)溶于80mL乙腈中，加入N,N-二异丙基乙胺(232.12mmol，39mL)和(R)-3-甲基***啉(1e)(8g，79.0mmol，上海毕得)，75℃反应4小时。反应液冷却至室温，减压浓缩，加水(150mL)萃取，乙酸乙酯萃取(80mL×2)，用硅胶柱层析色谱法以洗脱剂体系C纯化得到标题化合物1f(500mg，收率：4.7％)。The 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)***啉1g(R)-3-Methyl-4-(6-methyl-2-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-4-yl)morphine Phosphine 1g

将化合物1f(40mg，0.15mmol)、1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-1H-吡唑(56mg，0.44mmol，上海毕得)溶于4mL二氧六环和水(v:v＝3:1)的混合溶液中，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(19mg，0.022mmol)和无水碳酸钠(60mg，0.56mmol)，升温至100℃反应2小时。冷却至室温，反应液过滤，滤液减压浓缩，所得残余物用硅胶柱层析色谱法以洗脱剂体系C纯化，得到标题化合物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. 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 1 g (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***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

将化合物1g(40mg，0.13mmol)溶于5mL无水四氢呋喃中，降温至-78℃，加入N-溴代丁二酰亚胺(23mg，0.13mmol)，搅拌10分钟。反应液升至室温，加入3mL饱和碳酸氢钠溶液，乙酸乙酯萃取(10mL×3)，合并有机相，减压浓缩，得到粗品标题产物1h(40mg，收率：79.2％)，产物不经纯化直接用于下步反应。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%), which was untreated. Purification was used directly in the next reaction.

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

第六步Step 6

将粗品化合物1h(40mg，0.102mmol)溶于4mL二氧六环和水(v:v＝3:1)的混合溶液中，加入(1H-吡唑-3-基)硼酸1i(23mg，0.204mmol，上海毕得)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(17mg，0.02mmol)和无水碳酸钠(27mg，0.26mmol)，升温至90℃搅拌2小时。冷却至室温，反应液过滤，减压浓缩，所得粗品用高效液相制备色谱法(Waters 2545-2767，洗脱体系：碳酸氢铵、乙腈、水)纯化，得到标题产物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°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 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,CDCl ₃):δ7.77(s,1H),7.57(s,1H),6.89(s,1H),6.71(s,1H),6.49(s,1H),4.43(s,3H),4.01(d,2H),3.93(s,1H),3.44-3.40(m,2H),3.23(d,1H),3.00(s,3H),2.95-2.92(m,1H),1.25(d,3H)。 ¹ H NMR (400MHz, 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).

实施例2Example 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***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-((4,6-二氧代-1,4,5,6-四氢嘧啶-2-基)甲基)丙酰胺2bN-((4,6-Dioxo-1,4,5,6-tetrahydropyrimidin-2-yl)methyl)propanamide 2b

在氩气氛下，将化合物1a(5g，48.9mmol，上海毕得)、化合物2a(8.5g，53.4mmol，采用专利申请“WO2015095788”中说明书第76页的中间体3公开的方法制备而得)、甲醇钠(6.6g，122.16mmol)加入甲醇(25mL)中，回流3小时，冷却至室温，过滤，滤液减压浓缩，得到标题产物2b(9.6g)，产品不经纯化直接用于下一步反应。Under 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 specification 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 in the next step without purification. 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2c2,4-Dichloro-6-ethylimidazo[1,5-a]pyrimidine 2c

将粗品化合物2b(9.6g，48.6mmol)溶于甲苯(80mL)，加入三氯氧磷(27mL，292.1mmol)，缓慢加入N,N-二异丙基乙胺(33mL，194.7mmol)，90℃反应3小时。反应液减压浓缩，加二氯甲烷(500mL)搅拌0.5小时，过滤，滤液减压浓缩，得到标题产物2c(10g)，产品不经纯化直接用于下一步反应。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 added slowly, 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***啉2d(R)-4-(2-Chloro-6-ethylimidazo[1,5-a]pyrimidin-4-yl)-3-methylmorpholine 2d

将粗品化合物2c(10g，46.3mmol)溶于80mL乙腈中，加入N,N-二异丙基乙胺(185.12mmol，32mL)和化合物1e(23g，227.4mmol)，75℃反应1小时。反应液冷却至室温，减压浓缩，加水(150mL)萃取，乙酸乙酯萃取(80mL×2)，用硅胶柱层析色谱法以洗脱剂体系C纯化得到标题化合物2d(1.3g，收率：10％)。The 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), and purified by silica gel column chromatography with eluent system C to obtain the title compound 2d (1.3 g, yield : 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***啉2e(R)-4-(6-Ethyl-2-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-4-yl)-3-methylmorphine phenoline 2e

将化合物2d(300mg，1.07mmol)、1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-1H-吡唑(555mg，2.67mmol，上海毕得)溶于6mL二氧六环和水(v:v＝5:1)的混合溶液中，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(135mg，0.16mmol)和无水碳酸钠(339mg，3.19mmol)，100℃反应2小时。冷却至室温，反应液过滤，滤液减压浓缩，所得残余物用硅胶柱层析色谱法以洗脱剂体系A纯化，得到标题化合物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***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

将化合物2e(300mg，919.13μmol)溶于10mL无水四氢呋喃中，降温至-78℃，加入N-溴代丁二酰亚胺(114mg，640.51μmol)，搅拌10分钟。反应液升至室温，加入3mL饱和碳酸氢钠溶液，乙酸乙酯萃取(10mL×3)，合并有机相，减压浓缩，得到粗品标题化合物2f(240mg)，产物不经纯化直接用于下步反应。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 in the next step without purification. reaction.

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

第六步Step 6

在氩气氛下，将粗品化合物2f(370mg，912.9μmol)溶于10mL 1,4-二氧六环和2mL水中，依次加入化合物1i(204mg，1.82mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(116mg，137μmol)和碳酸钠(193mg，1.82mmol)，在90℃搅拌4小时。反应液冷却至室温，通过硅藻土过滤，将滤液减压浓缩，粗品用高效液相制备色谱法(Waters 2545-2767，洗脱体系：碳酸氢铵、乙腈、水)纯化，得到标题化合物2(98mg，收率：27.3％)。Under an 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(bis(bis(bis(bis(bis(bis(bis(di(bis(di(bis(di(bis)))”) Phenylphosphine)ferrocene]dichloropalladium dichloromethane complex (116 mg, 137 μmol) and sodium carbonate (193 mg, 1.82 mmol) were 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,CD ₃OD):δ7.65(s,1H),7.56(d,1H),7.09-6.97(m,1H),6.90(d,2H),4.39(d,3H),4.10-3.73(m,4H),3.62-3.37(m,4H),2.95(ddd,1H),1.44(t,3H),1.13-1.02(m,3H)。 1H NMR (500MHz, CD ₃ OD): 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).

实施例3Example 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***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***啉3b(R)-4-(2-(1-Ethyl-1H-pyrazol-5-yl)-6-methylimidazo[1,5-a]pyrimidin-4-yl)-3-methylmorphine phenoline 3b

将化合物1f(100mg,0.37mmol)和1-乙基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-1H-吡唑(3a)(166mg，0.75mmol，上海毕得)溶于4mL二氧六环和水(v:v＝3:1)的混合溶液中，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(47mg，0.055mmol)和无水碳酸钠(119mg，1.12mmol)，100℃反应2小时。冷却至室温，反应液过滤，滤液减压浓缩，所得残余物用硅胶柱层析色谱法以洗脱剂体系A纯化，得到标题化合物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***啉3c(R)-4-(8-Bromo-2-(1-ethyl-1H-pyrazol-5-yl)-6-methylpyrazolo[1,5-a]pyrimidin-4-yl)- 3-Methylmorpholine 3c

将化合物3b(100mg，0.3mmol)溶于2mL无水四氢呋喃中，降温至-78℃，加入N-溴代丁二酰亚胺(27mg，0.15mmol)，搅拌20分钟。反应液升至室温，加入3mL饱和碳酸氢钠溶液，乙酸乙酯萃取(10mL×3)，合并有机相，减压浓缩，得到粗品标题化合物3c(100mg，收率：80％)，产物不经纯化直接用于下步反应。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 Purification was used directly in the next reaction.

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

第三步third step

将化合物3c(100mg，0.247mmol)溶于4mL二氧六环和水(v:v＝3:1)的混合溶液中，加入化合物1i(55mg，0.491mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(31mg，0.04mmol)和无水碳酸钠(78mg，0.74mmol)，在90℃搅拌2小时。冷却至室温，反应液过滤，减压浓缩，所得残余物用高效液相制备色谱法(Waters 2545-2767，洗脱体系：碳酸氢铵、乙腈、水)纯化，得到化合物3(30mg，收率：30.9％)。Compound 3c (100 mg, 0.247 mmol) was dissolved in 4 mL of a mixed solution of dioxane and water (v:v=3:1), and compound 1i (55 mg, 0.491 mmol), [1,1'-bis( Diphenylphosphine)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 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,CD ₃OD):δ7.85-7.45(m,2H),7.03(s,1H),6.95-6.43(m,2H),4.91(d,2H),4.20-3.56(m,4H),3.55-3.33(m,2H),3.01(s,4H),1.50(t,3H),1.05(d,3H)。 ¹ H NMR (500MHz, 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).

实施例4Example 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)***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

2,4-二羟基咪唑并[1,5-a]嘧啶-8-羧酸甲酯4b2,4-Dihydroxyimidazo[1,5-a]pyrimidine-8-carboxylate methyl ester 4b

在氩气氛下，将丙二酸二甲酯(700mg，5.3mmol)、5-氨基-1H-咪唑-4-羧酸甲酯(4a)(500mg，3.5mmol，上海瀚鸿)、碳酸铯(2.3g，7.08mmol)加入N,N-二甲基甲酰胺(15mL)中，110℃搅拌15小时。反应液冷却至室温，过滤，滤液减压浓缩，得到标题产物4b(1.2g)，产品不经纯化直接用于下一步反应。Under an argon atmosphere, dimethyl malonate (700 mg, 5.3 mmol), methyl 5-amino-1H-imidazole-4-carboxylate (4a) (500 mg, 3.5 mmol, Shanghai Hanhong), cesium carbonate ( 2.3 g, 7.08 mmol) 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4c2,4-Dichloroimidazo[1,5-a]pyrimidine-8-carboxylate methyl ester 4c

将粗品化合物4b(1.0g，4.78mmol)溶于甲苯(20mL)，加入三氯氧磷(3mL，35.1mmol)，100℃反应2小时。反应液冷却至室温，减压浓缩，加二氯甲烷(500mL)搅拌0.5小时，过滤，滤液减压浓缩，得到标题产物4c(3.2g)，产品不经纯化直接用于下一步反应。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***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

将粗品化合物4c(1.0g，1.6mmol)溶于20mL乙腈中，加入N,N-二异丙基乙胺(1.05g，8.0mmol)和化合物1e(822mg，8mmol)，75℃反应4小时。反应液冷却至室温，减压浓缩，加水(50mL)萃取，乙酸乙酯萃取(50mL×2)，用硅胶柱层析色谱法以洗脱剂体系C纯化，得到标题化合物4d(120mg)，产率：23.7％。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 reacted at 75° C. for 4 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, extracted with water (50 mL), extracted with ethyl acetate (50 mL×2), and purified by silica gel column chromatography with eluent system C to obtain the title compound 4d (120 mg) as the product Rate: 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***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

将化合物4d(100mg，0.39mmol)和1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊-2-基)-1H-吡唑(160mg，0.772mmol)溶于4mL二氧六环和水(v:v＝3:1)的混合溶液中，加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(49mg，0.06mmol)和无水碳酸钠(122mg，1.15mmol)，升温至100℃反应2小时。冷却至室温，反应液过滤，滤液减压浓缩，所得残余物用硅胶柱层析色谱法以洗脱剂体系C纯化，得到标题化合物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***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

将化合物4e(120mg，0.336mmol)溶于4mL甲醇和水(v:v＝3:1)的混合溶液中，加入氢氧化锂一水合物(70mg，1.68mmol)，搅拌15小时。反应液减压浓缩，加水5mL稀释，1N盐酸调节至pH＝5，乙酸乙酯萃取(10mL×3)，合并有机相，减压浓缩，得到粗品标题产物4f(60mg，收率：52.1％)，产物不经纯化直接用于下步反应。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 1N 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***啉4g(R)-4-(8-Bromo-2-(1-methyl-1H-pyrazol-5-yl)imidazo[1,5-a]pyrimidin-4-yl)-3-methylmorpholine 4g

将粗品化合物4f(60mg，0.175mmol)溶于4mL N,N-二甲基甲酰胺中，降温至-78℃，加入无水碳酸氢钠(30mg，0.35mmol)和N-溴代丁二酰亚胺(35mg，0.184mmol)，搅拌10分钟。反应液升至室温，加入10mL饱和碳酸氢钠溶液，乙酸乙酯萃取(10mL×3)，合并有机相，减压浓缩，得到粗品标题产物4g(30mg，收率：45.4％)，产物不经纯化直接用于下步反应。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-bromosuccinyl 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 (30 mg, yield: 45.4%) of the crude title product, which was not purified by Purification was used directly in the next reaction.

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

第七步Step 7

将粗品化合物4g(30mg，0.079mmol)溶于4mL二氧六环和水(v:v＝3:1)的混合溶液中，加入化合物1i(27mg，0.238mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(10mg，0.02mmol)和无水碳酸钠(27mg，0.26mmol)，升温至90℃搅拌2小时。冷却至室温，反应液过滤，减压浓缩，所得粗品用高效液相制备色谱法(Waters 2545-2767，洗脱体系：碳酸氢铵、乙腈、水)纯化，得到标题产物4(5mg，收率：17.2％)。The crude compound 4g (30mg, 0.079mmol) was dissolved in 4mL of a mixed solution 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), the temperature was raised 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,CDCl ₃):δ7.75(s,1H),7.52(s,1H),7.13(s,2H),7.02(s,1H),6.90(s,1H),4.23(s,3H),4.03(d,2H),3.95(s,1H),3.66-3.64(m,2H),3.53(d,1H),3.39(d,1H),1.33(d,3H)。 ¹ H NMR (400MHz, 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).

测试例：Test case:

生物学评价Biological evaluation

测试例1、本公开化合物对ATR酶的抑制活性Test Example 1. Inhibitory activity of compounds of the present disclosure on ATR enzyme

以下方法用来测定本公开化合物对ATR酶的抑制活性。The following methods were used to determine the inhibitory activity of compounds of the present disclosure on ATR enzymes.

实验方法简述如下：The experimental method is briefly described as follows:

一、实验材料及仪器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标签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、标记铕穴状化合物抗磷酸化P53蛋白抗体(cisbio，61P08KAE)5. Anti-phosphorylated P53 protein antibody labeled with europium cryptate (cisbio, 61P08KAE)

6、链接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、酶标仪(BMG，PHERAsta)10. Microplate reader (BMG, PHERAsta)

二、实验步骤2. Experimental steps

将1nM ATR酶、50nM P53蛋白、7.435μM ATP和不同浓度(首浓度1μM，3倍梯度稀释11个浓度)的本公开化合物混合，室温孵育2小时，然后加入终止液(12.5mM HEPES，250mM EDTA)混匀，再加入0.42ng/孔的标记铕穴状化合物抗磷酸化P53蛋白抗体和25ng/孔的链接d2的抗GST抗体。室温孵育过夜后用PHERAstar检测620nm和665nm荧光信号。数据使用GraphPad软件处理。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 present disclosure were mixed, incubated at room temperature for 2 hours, and then a stop solution (12.5 mM HEPES, 250 mM EDTA) was added. ) 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.

三、实验数据3. Experimental data

本公开化合物对ATR酶的抑制活性可通过以上的试验进行测定。设定未加ATR酶的空白实验孔为100％抑制，通过公式100×[1-(化合物信号–背景信号)/(DMSO孔信号–背景信号)]计算化合物的抑制率。测得的IC ₅₀值和最大抑制率见下表1。 The inhibitory activity of the compounds of the present disclosure on ATR enzyme can be determined by the above assay. 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)]. IC ₅₀ values measured and the maximum inhibition rate in Table 1 below.

表1本公开化合物对ATR酶抑制的IC ₅₀ Table 1 discloses compounds of the IC ₅₀ of enzyme inhibition ATR

实施例编号Example number	IC ₅₀/nM IC ₅₀ / nM	最大抑制率(％)Maximum inhibition rate (%)
11	88	9999
22	33	100100
33	1313	9999
44	101101	9696

结论：本公开化合物对ATR酶的抑制活性好。Conclusion: The disclosed compounds have good inhibitory activity on ATR enzyme.

测试例2、本公开化合物对ATR酶的选择性测试Test Example 2. Selectivity test of compounds of the present disclosure to ATR enzyme

以下方法分别测定了本公开化合物对ATM酶、DNA-PK酶和PI3K酶的抑制活性，用以说明本公开化合物对ATR酶具有选择性。The following methods were used to measure the inhibitory activities of the disclosed compounds on ATM enzyme, DNA-PK enzyme and PI3K enzyme, respectively, to demonstrate that the disclosed compounds have selectivity to ATR enzyme.

(一)本公开化合物对ATM酶的抑制作用(1) Inhibitory effect of the disclosed compound on ATM enzyme

一、实验材料及仪器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)

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

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、酶标仪(BMG，PHERAsta)10. Microplate reader (BMG, PHERAsta)

二、实验步骤2. Experimental steps

将1nM ATM酶、30nM P53蛋白、11μM ATP以及不同浓度(首浓度10μM， 3倍梯度稀释11个浓度)的本公开化合物混合，室温孵育2小时，然后加入终止液(12.5mM HEPES，250mM EDTA)混匀，再加入0.42ng/孔的标记铕穴状化合物抗磷酸化P53蛋白抗体和25ng/孔的链接d2的抗GST抗体。室温孵育过夜后用PHERAstar检测620nm和665nm荧光信号。数据使用GraphPad软件处理。本公开化合物对ATM酶的抑制IC ₅₀值见下表2。 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 were mixed, incubated at room temperature for 2 hours, and then a stop solution (12.5 mM HEPES, 250 mM EDTA) was added. Mix well, and then add 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 present disclosure compound to inhibit the enzyme ATM IC ₅₀ values of Table 2 below.

(二)本公开化合物对DNA-PK酶的抑制作用(2) Inhibitory effect of the disclosed compound on DNA-PK enzyme

一、实验材料及仪器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)

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

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、酶标仪(BMG，PHERAsta)10. Microplate reader (BMG, PHERAsta)

二、实验步骤2. Experimental steps

将0.02nM DNA-PK酶、50nM P53蛋白、7.3μM ATP以及不同浓度(首浓度10μM，3倍梯度稀释11个浓度)的本公开化合物混合，室温孵育1小时，然后加入终止液(12.5mM HEPES，250mM EDTA)混匀，再加入0.42ng/孔的标记铕穴状化合物抗磷酸化P53蛋白抗体和25ng/孔的链接d2的抗GST抗体。室温孵育过夜后用PHERAstar检测620nm和665nm荧光信号。数据使用GraphPad软件处理。本公开化合物对DNA-PK酶的抑制IC ₅₀值见下表2。 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 present disclosure were mixed, incubated at room temperature for 1 hour, and then a stop solution (12.5mM HEPES) was added. , 250mM EDTA) and mix, 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 present disclosure of the compound to inhibit DNA-PK enzyme IC ₅₀ values in Table 2 below.

(三)本公开化合物对PI3K酶的抑制作用(3) Inhibitory effect of the disclosed compound on PI3K enzyme

一、实验材料及仪器1. Experimental materials and instruments

1、PIK3CA/PIK3R1(p110alpha/p85alpha)激酶(Invitrogen，PV4788)1. PIK3CA/PIK3R1 (p110alpha/p85alpha) 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)(北京天恩泽生物技术有限公司，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、氯化镁六水合物(Sigma，M2393)6. Magnesium chloride hexahydrate (Sigma, M2393)

7、氯化钠(国药集团化学试剂有限公司，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激酶试验试剂盒(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、酶标仪(BMG，PHERAstar)13. Microplate reader (BMG, PHERAstar)

二、实验步骤2. Experimental steps

PIK3CA/PIK3R1(p110alpha/p85alpha)激酶终浓度为0.625nM，与不同浓度(首浓度10μM，3倍梯度稀释10个浓度)的本发明化合物混合，室温孵育30分钟，再加入PIP2:PS Lipid底物(终浓度50μM)和1x ATP(终浓度50μM)，混合，37℃孵育30分钟，然后加入检测试剂ADP-Glo(Promega，V9102)混匀，室温孵育40分钟后，加入ADP-Glo ^TM激酶试验试剂盒(Promega，V9102)的检测试剂，室温孵育40分钟。用PHERAstar检测荧光信号，数据使用GraphPad软件处理。本公开化合物对PI3K酶的抑制IC ₅₀值见下表2。 The final concentration of PIK3CA/PIK3R1 (p110alpha/p85alpha) kinase was 0.625nM, mixed with the compounds of the present invention at different concentrations (the initial concentration of 10 μM, 10 concentrations of 3-fold gradient dilution), 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 at 37°C for 30 minutes, then add detection reagent ADP-Glo (Promega, V9102) and mix well, incubate at room temperature for 40 minutes, add ADP-Glo ^TM kinase assay The detection reagents of the kit (Promega, V9102) were incubated at room temperature for 40 minutes. Fluorescence signals were detected with PHERAstar and data were processed using GraphPad software. The present disclosure of the compounds to inhibit PI3K enzymes IC ₅₀ values in Table 2 below.

表2本公开化合物对ATM酶、DNA-PK酶和PI3K酶的抑制的IC ₅₀值 TABLE 2 Compound _IC50 value for the disclosure enzyme ATM, DNA-PK inhibition of PI3K enzymes and an IC

结论：本公开化合物对ATM酶、DNA-PK酶和PI3K酶的抑制活性弱，对比测试例1和2可以看出本公开化合物对ATR酶具有选择性。Conclusion: The compounds of the present disclosure have weak inhibitory activities on ATM enzyme, DNA-PK enzyme and PI3K enzyme. Comparing Test Examples 1 and 2, it can be seen that the compounds of the present disclosure have selectivity for ATR enzyme.

测试例3、LoVo细胞增殖实验Test example 3, LoVo cell proliferation experiment

以下方法通过检测细胞内ATP含量，根据IC ₅₀大小评价本公开化合物对LoVo细胞增殖的抑制效果。 The following method evaluates the inhibitory effect of the compounds of the present disclosure on the proliferation of LoVo cells by detecting the intracellular ATP content according to the IC _{50 size.}

一、实验材料及仪器1. Experimental materials and instruments

1、LoVo，人结肠癌肿瘤细胞(南京科佰，CBP60032)1. LoVo, human 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培养基(Gibco，21127030)3. F-12K medium (Gibco, 21127030)

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

5、96孔细胞培养板(corning，3903)5. 96-well cell culture plate (corning, 3903)

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

7、酶标仪(BMG，PHERAsta)7. Microplate reader (BMG, PHERAsta)

8、细胞计数仪(上海睿钰生物科技有限公司，IC1000)8. Cell counter (Shanghai Ruiyu Biotechnology Co., Ltd., IC1000)

二、实验步骤2. Experimental steps

LoVo细胞培养在含10％FBS的F-12K培养基中，一周传代2～3次，传代比例1:3或1:5。传代时，用胰酶消化细胞后转至离心管中，1200rpm离心3分钟，弃去上清培养基残液，加入新鲜培养基重悬细胞。在96孔细胞培养板中加入90μL的细胞悬液，密度为3.88×10 ⁴细胞/ml，96孔板***只加入100μL的完全培养基。将培养板在培养箱培养24小时(37℃，5％CO ₂)。 LoVo cells were cultured in F-12K medium containing 10% FBS, passaged 2-3 times a week, and the passage ratio was 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.

将待测化合物用DMSO稀释成2mM，并以3倍依次稀释成10个浓度，并设置空白孔(无细胞无化合物)和对照孔(有细胞无化合物)。取配制成梯度浓度的待测化合物溶液5μL加入到95μL新鲜培养基中配制成含化合物的培养基溶液。再向培养板中加入10μL上述含药物的培养基溶液。将培养板在培养箱孵育3天(37℃，5％CO ₂)。在96孔细胞培养板中，每孔加入50μL CellTiter-Glo试剂，室温避光放置5-10分钟，在PHERAstar中读取化学发光信号值，数据使用GraphPad软件处理。 The compounds to be tested were diluted with DMSO to 2 mM, and diluted 3-fold successively to 10 concentrations, and blank wells (without cells without compound) and control wells (with cells without compound) 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 for 3 days in an incubator _{(37 ℃, 5% CO 2} ). 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、实验数据3. Experimental data

本公开化合物对LoVo细胞增殖的抑制活性可通过以上的试验进行测定。设定空白孔为100％抑制，通过公式100×[1-(化合物信号–空白孔信号)/(对照孔孔信号–空白孔信号)]计算化合物的抑制率。测得的IC ₅₀值和最大抑制率见下表3。 The inhibitory activity of the compounds of the present disclosure on LoVo cell proliferation can be determined by the above assay. 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)]. IC ₅₀ values measured and the maximum inhibition rate in Table 3 below.

表3本公开化合物对LoVo细胞增殖抑制的IC ₅₀ Table 3 discloses compounds on cell proliferation of LoVo IC ₅₀

实施例编号Example number	IC ₅₀/nM IC ₅₀ / nM	最大抑制率(％)Maximum inhibition rate (%)
11	4747	8484
22	9.49.4	9595
33	4040	9494

结论：本公开化合物对LoVo细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.

药代动力学评价Pharmacokinetic evaluation

测试例4、本公开化合物的药代动力学测试Test Example 4. Pharmacokinetic testing of the disclosed compounds

1、摘要1. Abstract

以裸鼠为受试动物，应用LC/MS/MS法测定了裸鼠灌胃给予实施例1化合物后不同时刻血浆中的药物浓度。研究本公开化合物在裸鼠体内的药代动力学行为，评价其药代动力学特征。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. The pharmacokinetic behavior of the disclosed compounds in nude mice was studied, and their pharmacokinetic characteristics were evaluated.

2、试验方案2. Test plan

2.1试验样品2.1 Test samples

实施例1化合物。Compound of Example 1.

2.2试验动物2.2 Experimental animals

健康成年裸鼠9只，雌性，购自维通利华实验动物有限公司。Nine healthy adult nude mice, female, were purchased from Weitong Lihua Laboratory Animal Co., Ltd.

2.3样品配制2.3 Sample preparation

称取一定量实施例1化合物，加入预定体积的PEG400(最终体积比15％，南京威尔化工有限公司)，加入搅拌子超声搅拌至样品全部溶解，再加入一定体积(终体积比85％)的已经配制好的1％HPMC K100LV溶液(HPMC K100LV粉剂购自美国DOW公司，1％HPMC K100LV溶液为公司内部配制)，将实施例1化合物配制成浓度为0.5mg/mL的给药溶液。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 DOW company in the United States, and 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给药2.4 Administration

裸鼠禁食过夜后灌胃给药，给药剂量均为10mg/kg，给药体积均为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

裸鼠灌胃给予实施例1化合物，于给药后0.25、0.5、1.0、2.0、4.0、6.0、8.0、11.0、24.0小时采血0.1mL，置于EDTA-K2抗凝试管中，4℃、10000转/分钟离心1分钟，1小时内分离血浆，于-20℃保存待测，采血至离心过程在冰浴条件下操作。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.

测定不同浓度的药物灌胃给药后裸鼠血浆中的待测化合物含量：取给药后各时刻的裸鼠血浆25μL，加入内标溶液(100ng/mL喜树碱)50μL，乙腈200μL，涡旋混合5分钟，离心10分钟(4000转/分钟)，血浆样品取上清液0.1μL进行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、药代动力学参数结果4. Pharmacokinetic parameter results

本公开化合物的药代动力学参数如下表4所示。The pharmacokinetic parameters of the compounds of the present disclosure are shown in Table 4 below.

表4本公开化合物的药代动力学参数Table 4 Pharmacokinetic parameters of the disclosed compounds

结论：本公开化合物的药代吸收良好，具有明显的药代动力学优势。Conclusion: The disclosed compounds have good pharmacokinetic absorption and obvious pharmacokinetic advantages.

Claims

一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：A compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its Medicinal salt:

其中：in:

R ⁰选自氢原子、烷基、卤代烷基、羟烷基、氰基和环烷基烷基； R ^{0 is} selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group and a cycloalkylalkyl group;

R ¹和R ²相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、杂环基氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R ¹ and R ^{2 are the} same or different, each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkoxy, heterocyclyloxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano , amino, cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein said alkyl, alkoxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from one of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl or more substituents;

R ³选自氢原子、卤素、烷基、烯基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R ³ is selected from hydrogen, halo, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocyclyl, aryl and heteroaryl wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxy Substituted with one or more substituents of alkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁴相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R ^{4 are the} same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocycle wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy , substituted with one or more substituents in haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁵选自烷基、卤代烷基、羟烷基和环烷基烷基； R ^{5 is} selected from alkyl, haloalkyl, hydroxyalkyl and cycloalkylalkyl;

n为0、1、2或3。n is 0, 1, 2 or 3.
根据权利要求1中所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ²为五元杂芳基，所述的五元杂芳基任选地被选自卤素、C _1-6烷基、C _1-6烷氧基和卤代C _1-6烷基中的一个或多个取代基所取代。 The compound represented by the general formula (I) according to claim 1 or its tautomer, meso, racemate, enantiomer, diastereomer, or its In the form of a mixture, 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 substituted with one or more substituents in the halogenated C _{1-6 alkyl group.}
根据权利要求1或2中所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ³为五元杂芳基，所述的五元杂芳基任选地被选自卤素、C _1-6烷基、C _1-6烷氧基和卤代C _1-6烷基中的一个或多个取代基所取代。 The compound represented by the general formula (I) according to claim 1 or 2 or its tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ is a five-membered heteroaryl, and the five-membered heteroaryl is optionally selected from halogen, C _1-6 alkyl, C _1-6 substituted with one or more substituents of alkoxy and haloC _{1-6 alkyl.}
根据权利要求1至3中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其为通式(II)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐：The compound represented by the general formula (I) according to any one of claims 1 to 3 or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or its mixture form, or its pharmaceutically acceptable salt, which is the compound represented by general formula (II) or its tautomer, meso, racemate, enantiomer , a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

其中：in:

R ⁶相同或不同，各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基； R ^{6 are the} same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁷相同或不同，各自独立地选自氢原子、卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基； R ^{7 are the} same or different, each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

p和q相同或不同，各自独立地选自0、1、2或3；p and q are the same or different, each independently selected from 0, 1, 2 or 3;

R ⁰、R ¹、R ⁴和n如权利要求1中所定义。 R ⁰ , R ¹ , R ⁴ and n are as defined in claim 1 .
根据权利要求1至4中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ⁰为氢原子或C _1-6烷基。 The compound represented by the general formula (I) according to any one of claims 1 to 4 or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁰ is a hydrogen atom or a C _1-6 alkyl group.
根据权利要求1至5中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ¹为氢原子。 The compound represented by the general formula (I) according to any one of claims 1 to 5 or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom.
根据权利要求1至6中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ⁴为氢原子。 The compound represented by the general formula (I) according to any one of claims 1 to 6 or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom.
根据权利要求1至3、5至7中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ⁵为甲基。 The compound represented by the general formula (I) according to any one of claims 1 to 3, 5 to 7 or its tautomer, meso, racemate, enantiomer, diastereomers thereof, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is methyl.
根据权利要求4至8中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ⁶为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 Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is C _1-6 alkyl.
根据权利要求4至9中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其中R ⁷为氢原子。 The compound represented by the general formula (I) according to any one of claims 4 to 9 or its tautomer, meso, racemate, enantiomer, diastereomer A struct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is a hydrogen atom.
根据权利要求1至10中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其选自以下任一化合物：The compound represented by the general formula (I) according to any one of claims 1 to 10 or its tautomer, meso, racemate, enantiomer, diastereomer Construct, or a mixture thereof, or a pharmaceutically acceptable salt thereof, selected from any of the following compounds:
一种通式(IA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，A compound represented by the general formula (IA) or its tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its medicinal salt,

其中：in:

X为氢原子或卤素；优选为卤素；更优选为Br；X is a hydrogen atom or halogen; preferably halogen; more preferably Br;

R ⁰选自氢原子、烷基、卤代烷基、羟烷基、氰基和环烷基烷基； R ^{0 is} selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cyano group and a cycloalkylalkyl group;

R ¹和R ²相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、杂环基氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、杂环基氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； 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 said alkyl, alkoxy, heterocyclyloxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from one of halogen, alkyl, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl or more substituents;

R ⁴相同或不同，各自独立地选自氢原子、卤素、烷基、烯基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、环烷基、杂环基、芳基和杂芳基；其中所述的烷基、烷氧基、环烷基、杂环基、芳基和杂芳基各自独立地任选被选自卤素、烷基、烷氧基、卤代烷基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代； R ^{4 are the} same or different, each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkoxy, haloalkyl, haloalkoxy, hydroxy, hydroxyalkyl, cyano, amino, cycloalkyl, heterocycle wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from halogen, alkyl, alkoxy , substituted with one or more substituents in haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁵选自烷基、卤代烷基、羟烷基和环烷基烷基； R ^{5 is} selected from alkyl, haloalkyl, hydroxyalkyl and cycloalkylalkyl;

n为0、1、2或3。n is 0, 1, 2 or 3.
根据权利要求12所述的通式(IA)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，其选自以下任一化合物：The compound represented by the general formula (IA) according to claim 12 or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof form, or a pharmaceutically acceptable salt thereof, selected from any of the following compounds:
一种制备根据权利要求1所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐的方法，该方法包括：A kind of preparation of the compound shown in the general formula (I) according to claim 1 or its tautomer, meso, racemate, enantiomer, diastereomer, or a method of a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

通式(IA)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐和通式(IB)化合物发生偶联反应，得到通式(I)的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，A compound of general formula (IA) or a tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof Coupling reaction with the compound of general formula (IB) to obtain the compound of general formula (I) or its tautomer, meso, racemate, enantiomer and diastereomer , or a mixture thereof, or a pharmaceutically acceptable salt thereof,

其中：in:

X为卤素；X is halogen;

Y为
Y is

R为氢原子或烷基；R is a hydrogen atom or an alkyl group;

R ⁰、R ¹、R ²、R ³、R ⁴、R ⁵和n如权利要求1中所定义。 R ⁰ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ and n are as defined in claim 1 .
一种药物组合物，所述药物组合物含有根据权利要求1至11中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition, the pharmaceutical composition contains the compound shown in the general formula (I) according to any one of claims 1 to 11 or its tautomer, meso, racem isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
根据权利要求1至11中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求15所述的药物组合物在制备用于抑制ATR激酶的药物中的用途。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 isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15, in the manufacture of a medicament for inhibiting ATR kinase.
根据权利要求1至11中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求15所述的药物组合物在制备用于治疗或预防过度增殖性疾病的药物中的用途。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 isomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15, in the manufacture of a medicament for the treatment or prevention of a hyperproliferative disease.
根据权利要求1至11中任一项所述的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐或根据权利要求15所述的药物组合物在制备用于治疗或预防肿瘤的药物中的用途。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 isomer, 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.
根据权利要求18所述的用途，其中所述的肿瘤选自黑色素瘤、脑瘤、食管癌、胃癌、肝癌、胰腺癌、结肠直肠癌、肺癌、肾癌、乳腺癌、***、卵巢癌、***癌、皮肤癌、神经母细胞瘤、神经胶质瘤、肉瘤、骨癌、子宫内膜癌、头颈肿瘤、多发性骨髓瘤、B-细胞淋巴瘤、真性红细胞增多症、白血病、甲状腺肿瘤、膀胱癌和胆囊癌。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 tumor, multiple myeloma, B-cell lymphoma, polycythemia vera, leukemia, thyroid tumor, Bladder and gallbladder cancer.