WO2019214399A1

WO2019214399A1 - Benzo- seven-membered heterocyclic compound, preparation method therefor, pharmaceutical composition thereof, and application thereof

Info

Publication number: WO2019214399A1
Application number: PCT/CN2019/082610
Authority: WO
Inventors: 朱久香; 胡永韩; 蔡冬梅; 董加强; 王铁林
Original assignee: 罗欣药业(上海)有限公司; 山东罗欣药业集团股份有限公司
Priority date: 2018-05-10
Filing date: 2019-04-15
Publication date: 2019-11-14
Also published as: CN111819181A

Abstract

Disclosed are a benzo- seven-membered heterocyclic compound represented by formula I, and a tautomer, a solvate, a pharmaceutically-acceptable salt or a prodrug thereof. The benzo- seven-membered heterocyclic compound of the present invention has good cell activity and metabolic stability, and therefor can become an effective drug for treating tumors.

Description

苯并七元杂环类化合物、其制备方法、药物组合物及应用Benzo seven-membered heterocyclic compound, preparation method thereof, pharmaceutical composition and application thereof

本申请要求申请日为2018年5月10日的中国专利申请CN201810445018.0的优先权。本申请引用上述中国专利申请的全文。The present application claims priority to Chinese Patent Application No. CN201810445018.0, filed on May 10, 2018. This application cites the entire text of the above-mentioned Chinese patent application.

技术领域Technical field

本发明涉及一种苯并七元杂环的类化合物、其制备方法、药物组合物及应用。The present invention relates to a benzo seven-membered heterocyclic compound, a process for the preparation thereof, a pharmaceutical composition and use thereof.

背景技术Background technique

肿瘤是近年来全球范围内导致人类死亡的主要原因之一。肿瘤总体治愈率低且复发率高，因此***具有重要的价值。Tumors are one of the leading causes of human death worldwide in recent years. The overall cure rate of tumors is low and the recurrence rate is high, so the treatment of tumors has important value.

表观遗传调控的异常是导致肿瘤发生的重要因素之一。表观遗传是指基于非基因序列改变所致基因表达水平的变化，包括DNA甲基化、组蛋白修饰、染色体重塑和非编码RNA调控等，主要通过对基因转录或翻译过程的调控，影响其功能和特性。组蛋白是染色质的核心，参与转录后修饰，主要包括乙酰化、甲基化、磷酸化和泛素化。Abnormal epigenetic regulation is one of the important factors leading to tumorigenesis. Epigenetics refers to changes in gene expression levels based on non-gene sequence changes, including DNA methylation, histone modification, chromosomal remodeling, and non-coding RNA regulation, primarily through regulation of gene transcription or translation processes. Its functions and features. Histones are the core of chromatin and are involved in post-transcriptional modifications, including acetylation, methylation, phosphorylation, and ubiquitination.

溴结构域是进化上高度保守的蛋白，溴结构域和乙酰化蛋白的结合通常较弱(K _D值在较低的微摩尔到毫摩尔量级)，这也增加了找到潜在的抑制剂的可能性。对溴结构域家族成药性的评估显示，BET(溴结构域和额外C-末端结构域)亚家族得分很高，这一点已被目前已经找到的一些具有不同骨架结构的小分子抑制剂所证实。 Bromo domain is evolutionarily highly conserved proteins, and acetylated binding domain protein bromo generally weak (K _D values in the low micromolar to mmole scale), which also increases the potential inhibitor found possibility. Evaluation of the medicinal properties of the bromodomain family revealed that the BET (bromodomain and extra C-terminal domain) subfamily scores are high, as evidenced by some small molecule inhibitors with different skeletal structures that have been identified so far. .

因此，抑制溴结构域与乙酰化蛋白结合的这些化合物预示着治疗一系列炎症和癌症的新颖方法。到目前为止，学术界和工业界的研究组找到了不同化学类型的BET抑制剂，并且有些已经进入临床测试阶段。目前公开了一系列BET抑制剂的专利申请，其中包括WO2011054553、WO2011054845、WO2013097052、WO2013185284、WO2014139324、WO2014164771、WO2015100282、WO2015075665、WO2015080707、WO2015164480、WO2015195862、WO2016050821等。Thus, these compounds that inhibit the binding of the bromodomain to the acetylated protein are indicative of novel methods of treating a range of inflammations and cancers. So far, academic and industrial research groups have found BET inhibitors of different chemical types, and some have entered the clinical testing phase. A series of patent applications for BET inhibitors are disclosed, including WO2011054553, WO2011054845, WO2013097052, WO2013185284, WO2014139324, WO2014164771, WO2015100282, WO2015075665, WO2015080707, WO2015164480, WO2015195862, WO2016050821, and the like.

其中，艾伯维(Abbive)公司开发的溴结构域抑制剂ABBV-075在急性髓系白血病(AML)、多发性骨髓瘤(MM)和实体肿瘤的治疗中极具开发前景，目前正处于一期临床试验阶段。Tensha Therapeutics公司致力于小分子表观遗传蛋白BET抑制剂的开发，其首个候选药物Tensha-010正在开展两项Ib期研究。另外，Constellation制药公司开发的CPI-0610、葛兰素史克(GSK)公司开发的GSK-525762、默克(Merck)基团开发的MK-8628也均已进入临床I/II期。Among them, ABBV-075, a bromine domain inhibitor developed by Abbive, has great development prospects in the treatment of acute myeloid leukemia (AML), multiple myeloma (MM) and solid tumors. Phase of clinical trials. Tensha Therapeutics is working on the development of small molecule epigenetic protein BET inhibitors, and its first drug candidate, Tensha-010, is conducting two Phase Ib studies. In addition, CPI-0610 developed by Constellation Pharmaceuticals, GSK-525762 developed by GlaxoSmithKline (GSK), and MK-8628 developed by Merck Group have also entered clinical stage I/II.

现阶段，更多可用于治疗涉及到溴结构域功能包括BET结构域功能的疾病和适应症的新型溴结构域抑制剂亟待开发。At this stage, more novel bromodomain inhibitors that can be used to treat diseases and indications involving bromodomain function, including BET domain function, are in need of development.

发明内容Summary of the invention

本发明所要解决的技术问题在于开发更多新型溴结构域抑制剂，从而为涉及到溴结构域功能包括BET结构域功能的疾病和适应症提供更多治疗方法，因而提供了一系列与现有技术完全不同的具有溴结构域抑制作用的苯并七元杂环类化合物。本发明的苯并七元杂环类化合物具有较好的细胞活性和代谢稳定性，因此可以成为***的有效药物。The technical problem to be solved by the present invention is to develop more novel bromodomain inhibitors, thereby providing more therapeutic methods for diseases and indications involving bromodomain function including BET domain function, thus providing a series of existing and existing A completely different benzoheptene heterocyclic compound with bromine domain inhibition. The benzo seven-membered heterocyclic compound of the present invention has good cell activity and metabolic stability, and thus can be an effective drug for treating tumors.

本发明通过下述技术方案来解决上述技术问题。The present invention solves the above technical problems by the following technical solutions.

本发明提供了一种如式I所示的苯并七元杂环类化合物、其互变异构体、其溶剂化物、其药学上可接受的盐(例如甲酸盐，又例如一甲酸盐)或其前药：The present invention provides a benzo seven-membered heterocyclic compound of the formula I, a tautomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof (for example, a formate, for example, a formic acid) Salt) or its prodrugs:

其中，Z为CH或N；Where Z is CH or N;

X为N、NH或C(＝O)；Y为C、CH或N；

代表Y和X为单键或双键相连； X is N, NH or C(=O); Y is C, CH or N;

Representing Y and X as single or double bonds;

R ¹为-H、C ₁-C ₅的烷基(例如C ₁-C ₃的烷基，又例如甲基、乙基、正丙基或异丙基，还例如甲基、乙基或异丙基)、C ₃-C ₇环烷基(例如环丙基)、被一个或多个(例如2个、3个或4个)R ⁰取代的C ₁-C ₅的烷基(当存在多个R ⁰时，所述的R ⁰相同或不同；所述的“C ₁-C ₅的烷基”例如甲基或乙基；所述的“被一个R ⁰取代的C ₁-C ₅的烷基”例如2-羟基乙基、或甲氧基甲基)、或-(CH ₂)n ₀C(＝O)N(R ^R1)(R ^R2)；(当R ¹不为氢、且Z为CH时，Z中的碳原子为手性碳原子；所述的手性碳原子的构型可为R型、S型或它们的混合物) R ¹ is -H, C ₁ -C ₅ alkyl (for example C ₁ -C ₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl, also for example methyl, ethyl or iso) Propyl), C ₃ -C ₇ cycloalkyl (eg cyclopropyl), C ₁ -C ₅ alkyl substituted by one or more (eg 2, 3 or 4) R ⁰ (when present When R ⁰ is a plurality of R ⁰ , the R ^{0 is the} same or different; the “C ₁ -C ₅ alkyl group” is, for example, a methyl group or an ethyl group; and the “C ₁ -C ₅ substituted by a R ⁰ . An alkyl group such as 2-hydroxyethyl or methoxymethyl, or -(CH ₂ ) n ₀ C(=O)N(R ^R1 )(R ^R2 ); (when R ^{1 is} not hydrogen, And when Z is CH, the carbon atom in Z is a chiral carbon atom; the configuration of the chiral carbon atom may be R type, S type or a mixture thereof)

R ⁰为C ₁-C ₅的烷氧基(例如C ₁-C ₃的烷氧基，再例如甲氧基)或-OH； R ⁰ is a C ₁ -C ₅ alkoxy group (for example, a C ₁ -C ₃ alkoxy group, such as a methoxy group) or -OH;

n ₀为0或1(例如1)； n ₀ is 0 or 1 (for example 1);

R ^R1和R ^R2独立地为-H或C ₁-C ₅的烷基(例如C ₁-C ₃的烷基，又例如甲基、乙基、正丙基或异丙基，还例如甲基、乙基或异丙基)； R ^R1 and R ^{R2 are} independently -H or C ₁ -C ₅ alkyl (for example C ₁ -C ₃ alkyl, again such as methyl, ethyl, n-propyl or isopropyl, also for example methyl , ethyl or isopropyl);

Q为“被一个或多个(例如2个、3个或4个)R ^Q1取代的苯基”{当存在多个R ^Q1时，所述的R ^Q1相同或不同；当存在1个R ^Q1时，所述的R ^Q1可独立地连在所述的苯基的邻位、间位或对位；当存在2个R ^Q1时，所述的R ^Q1可连在所述的苯基的邻位和对位、或者、间位和对位；当存在3个R ^Q1时，所述的R ^Q1可连在所述的苯基的邻位、邻位和对位；[所述的“被一个或多个R ^Q1取代的苯基”例如4-氟苯基、2-甲基-4氟苯基、2-三氟甲基-4氟苯基、2，6二氯苯基、2，5二氯苯基、2，3二氯苯基、2-环丙基-4氟-苯基、2-氯苯基、2，6二氯-4氟苯基、2,4,6-三氟苯基、4-羟基苯基、3-羟基-4-氟苯基、4-甲氧基苯基、4-氯苯基、4-氰基苯基、3-氯苯基、3-氟苯基、4-氰基苯基、2,4-二氟苯基、2,4-二氯苯基、2-氟-4-氯苯基、2-氯-4-氟-5-甲氧基苯基、3-甲氧基-4-氟苯基、3-甲氧基-4-氯苯基、4-甲氧基-3-氟苯基、2-甲氧基-4-氟苯基、2-氯-4-氟苯基、或2-氟-4-氰基苯]}、或者为“被一个或多个(例如2个、3个或4个)R ^Q2取代的5-6元杂芳基”，所述的5-6元杂芳基中的杂原子为N和/或O，其个数为1-3个；{当存在多个R ^Q2时，所述的R ^Q2相同或不同；所述的“5-6元杂芳基”例如吡啶基或嘧啶基，优选吡啶基；[所述“被一个或多个(例如2个、3个或4个)R ^Q2取代的5-6元杂芳基”例如

]}； Q is "phenyl substituted by one or more (for example, 2, 3 or 4) R ^Q1 " {when there are a plurality of R ^Q1 , the R ^{Q1 is the} same or different; when there is 1 R ^Q1 When said R ^Q1 may be independently attached to the ortho, meta or para position of said phenyl; when 2 R ^Q1 is present, said R ^Q1 may be attached to said phenyl ortho Bit and alignment, or, meta and para; when there are 3 R ^Q1 , the R ^Q1 may be attached to the ortho, ortho and para positions of the phenyl group; One or more R ^Q1 substituted phenyl" such as 4-fluorophenyl, 2-methyl-4fluorophenyl, 2-trifluoromethyl-4fluorophenyl, 2,6 dichlorophenyl, 2, 5 dichlorophenyl, 2,3 dichlorophenyl, 2-cyclopropyl-4fluoro-phenyl, 2-chlorophenyl, 2,6-dichloro-4-fluorophenyl, 2,4,6-three Fluorophenyl, 4-hydroxyphenyl, 3-hydroxy-4-fluorophenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-cyanophenyl, 3-chlorophenyl, 3-fluoro Phenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluoro-5-methoxy Phenylphenyl, 3-methoxy-4-fluorophenyl, 3-methoxy-4-chlorophenyl, 4-methoxy-3-fluorophenyl, 2-methoxy-4-fluorophenyl, 2-chloro-4-fluorophenyl, or 2-fluoro-4-cyanobenzene]}, or "by one or more (eg, 2, 3 Or 4) R ^Q2 substituted 5-6 membered heteroaryl", wherein the hetero atom in the 5-6 membered heteroaryl group is N and/or O, the number of which is 1-3; When R ^Q2 is plural, said R ^{Q2 is the} same or different; said "5-6 membered heteroaryl" such as pyridyl or pyrimidinyl, preferably pyridyl; [the" is by one or more (for example 2 , 3 or 4) R ^Q2 substituted 5-6 membered heteroaryl"

]};

所述R ^Q1和R ^Q2独立地为-H、卤素、卤代或未取代的C ₁-C ₅的烷基[所述的“C ₁-C ₅的烷基”例如C ₁-C ₃的烷基，又例如甲基、乙基、正丙基或异丙基；所述的“卤代”时卤素的个数为1个或多个(例如2个、3个或4个)；当有多个卤素时，所述的卤素相同或不同]、C ₃-C ₇环烷基(例如环丙基)、或、C ₁-C ₅的烷氧基(例如C ₁-C ₃的烷氧基，又例如甲氧基、乙氧基、正丙氧基或异丙氧基，还例如甲氧基)； The R ^Q1 and R ^{Q2 are} independently -H, halogen, halogenated or unsubstituted C ₁ -C ₅ alkyl [the "C ₁ -C ₅ alkyl group" such as C ₁ -C ₃ An alkyl group, such as methyl, ethyl, n-propyl or isopropyl; the number of halogens in the "halogenated" is one or more (for example, 2, 3 or 4); When there are a plurality of halogens, the halogens are the same or different], a C ₃ -C ₇ cycloalkyl group (for example, a cyclopropyl group), or a C ₁ -C ₅ alkoxy group (for example, a C ₁ -C ₃ alkane) An oxy group, such as methoxy, ethoxy, n-propoxy or isopropoxy, for example also methoxy);

n为0、1或2；当n为1时，至少一个R位于Y的对位或间位；n is 0, 1, or 2; when n is 1, at least one R is located at the para or meta position of Y;

R独立地为卤素(例如氟、氯或溴，再例如氟或氯)、羟基取代的C ₁-C ₅的烷基{所述的“C ₁-C ₅的烷基”例如C ₁-C ₃的烷基，又例如甲基、乙基、正丙基或异丙基；[所述羟基取代的C ₁-C ₅的烷基例如

较佳地为

]}、-N(R ^2e)(CH ₂)n ^β2-S(＝O) ₂(R ²ⁱ)(例如

)、-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)(例如-N(R ^2k)S(＝O) ₂(R ^2d)，又例如

)、-(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)(例如-S(＝O) ₂N(R ^2f)(R ^2g)或-CH ₂-S(＝O) ₂N(R ^2f)(R ^2g)；[所述的-S(＝O) ₂N(R ^2f)(R ^2g)例如-S(＝O) ₂N(R ^2g)H，又例如；所述-S(＝O) ₂N(R ^2f)(R ^2g)例如

)]、-S(＝O)(R ²ⁱ)(例如

)或-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)[所述的C ₁-C ₆的烷基例如C ₁-C ₃的烷基，又例如甲基、乙基、正丙基或异丙基，还例如甲基；(所述的“-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)”例如-(CH ₂)n ^β2-S(＝O) ₂(R ²ⁱ)、n ^β2为1、2、3或4，又例如-CH ₂-S(＝O) ₂(R ²ⁱ)，还例如

]； R is independently halogen (e.g., fluorine, chlorine or bromine, again such as fluorine or chlorine), hydroxy-substituted C ₁ -C ₅ alkyl {the above-mentioned "C ₁ -C ₅ alkyl" such as C ₁ -C An alkyl group of ₃ , for example, a methyl group, an ethyl group, a n-propyl group or an isopropyl group; [the hydroxy-substituted C ₁ -C ₅ alkyl group, for example

Preferably

]}, -N(R ^2e )(CH ₂ )n ^β2 -S(=O) ₂ (R ²ⁱ ) (for example

), -(CH ₂ )n ^β2 N(R ^2k )S(=O) ₂ (R ^2d ) (for example, -N(R ^2k )S(=O) ₂ (R ^2d ), for example

), -(CH ₂ )n ^β2 -S(=O) ₂ N(R ^2f )(R ^2g ) (for example -S(=O) ₂ N(R ^2f )(R ^2g ) or -CH ₂ -S( =O) ₂ N(R ^2f )(R ^2g ); [the -S(=O) ₂ N(R ^2f )(R ^2g ) such as -S(=O) ₂ N(R ^2g )H, For example; the -S(=O) ₂ N(R ^2f )(R ^2g )

)], -S(=O)(R ²ⁱ ) (for example

Or -C ₁ -C ₆ alkyl-S(=O) ₂ (R ²ⁱ ) [the C ₁ -C ₆ alkyl group such as a C ₁ -C ₃ alkyl group, such as methyl, B a group, n-propyl or isopropyl, also for example a methyl group; (the "-C ₁ -C ₆ alkyl-S(=O) ₂ (R ²ⁱ )" such as -(CH ₂ )n ^β2 - S(=O) ₂ (R ²ⁱ ), n ^β2 is 1, ^2, 3 or 4, again for example -CH ₂ -S(=O) ₂ (R ²ⁱ ), also for example

];

所述n ^β2独立地为0、1或2(例如0或1)； The n ^{β2 is} independently 0, 1 or 2 (eg 0 or 1);

所述R ^2d、R ^2e、R ^2f、R ^2g、R ²ⁱ和R ^2k各自独立地为-H、C ₁-C ₆的烷基(例如C ₁-C ₃的烷基，再例如甲基、乙基或异丙基)、被1个或多个(例如2个或3个)卤素(例如氟或氯)取代C ₁-C ₆的烷基(当为多个卤素取代时，所述卤素相同或不同)、或3-7元环烷基(例如环丙基)； The R ^2d , R ^2e , R ^2f , R ^2g , R ²ⁱ and R ^2k are each independently -H, a C ₁ -C ₆ alkyl group (for example, a C ₁ -C ₃ alkyl group, such as a methyl group, Ethyl or isopropyl), substituted by one or more (for example, 2 or 3) halogens (for example, fluorine or chlorine) with a C ₁ -C ₆ alkyl group (when substituted with a plurality of halogens, the halogen The same or different), or a 3-7 membered cycloalkyl group (such as cyclopropyl);

[例如-N(CH ₂)n ^β2(R ^2e)S(＝O) ₂(R ²ⁱ)中的R ^2e为3-7元环烷基；R ²ⁱ为C ₁-C ₆的烷基(例如乙基)； [For example _{^{-N (CH 2) n β2 (}} R 2e) S (= O) 2 (R 2i) is R ^2e is a 3-7 membered cycloalkyl; R ²ⁱ is a C ₁ -C ₆ alkyl (e.g. Ethyl);

例如所述-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)中R ^2k为-H；R ^2d为C ₁-C ₆的烷基(例如C ₁-C ₃的烷基，再例如甲基或乙基)； For example, in the -(CH ₂ )n ^β2 N(R ^2k )S(=O) ₂ (R ^2d ), R ^2k is -H; and R ^2d is a C ₁ -C ₆ alkyl group (for example, C ₁ -C ₃ Alkyl, such as methyl or ethyl);

例如所述-(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)中R ^2f为氢；R ^2g为-H或C ₁-C ₆的烷基(例如乙基) For example, wherein -(CH ₂ )n ^β2 -S(=O) ₂ N(R ^2f )(R ^2g ) wherein R ^2f is hydrogen; R ^2g is -H or C ₁ -C ₆ alkyl (eg ethyl )

例如所述-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)中R ²ⁱ为C ₁-C ₆的烷基、卤素取代的C ₁-C ₆的烷基(例如-CF ₃)、或3-7元环烷基]； For example, in the -C ₁ -C ₆ alkyl-S(=O) ₂ (R ²ⁱ ), R ²ⁱ is a C ₁ -C ₆ alkyl group, a halogen-substituted C ₁ -C ₆ alkyl group (for example - CF ₃ ), or 3-7 membered cycloalkyl];

或者，当n为2、且两个R相邻时，相邻的两个R与它们连接的原子共同形成含1个或多个(例如2个或3个)杂原子(例如N、O或S)或者砜基的5-6元杂环烃基{所述杂原子为多个时，所述杂原子相同或不同(例如一个N原子，一个S原子；再例如当含有一个S原子和一个N原子时，所述S原子和N原子相邻；所述5-6元杂环烃基例如

}； Alternatively, when n is 2 and two Rs are adjacent, the adjacent two Rs together with the atoms to which they are attached form one or more (eg, two or three) heteroatoms (eg, N, O, or S) or a 5-6 membered heterocyclic hydrocarbon group of a sulfone group. When the hetero atom is plural, the hetero atom is the same or different (for example, an N atom, an S atom; and, for example, when it contains an S atom and a N In the case of an atom, the S atom and the N atom are adjacent; the 5-6 membered heterocycloalkyl group, for example

};

W为CH或N；W is CH or N;

R ²为氢、-NR ^2-1R ^2-2或-C(＝O)NR ^2-3R ^2-4； R ² is hydrogen, -NR ^2-1 R ^2-2 or -C(=O)NR ^2-3 R ^2-4 ;

R ^2-1、R ^2-2、R ^2-3和R ^2-4各自独立地为氢、C ₁-C ₅的烷基(例如C ₁-C ₃的烷基，又例如甲基、乙基、正丙基或异丙基)或C ₃-C ₆环烷基(例如环丙基)； R ^2-1 , R ^2-2 , R ^2-3 and R ^2-4 are each independently hydrogen, C ₁ -C ₅ alkyl (for example, C ₁ -C ₃ alkyl, for example methyl, B Base, n-propyl or isopropyl) or C ₃ -C ₆ cycloalkyl (eg cyclopropyl);

但所述式I所示的苯并七元杂环类化合物不为以下化合物：However, the benzoheptacyclic heterocyclic compound represented by the formula I is not the following compound:

6-(4-氟苯基)-2-甲基-9-(甲基砜甲基)-5-氧代2,4,5,6-四氢苯并[b]吡咯并[3,4-d]吖庚因-3-腈；6-(4-Fluorophenyl)-2-methyl-9-(methylsulfonemethyl)-5-oxo 2,4,5,6-tetrahydrobenzo[b]pyrrolo[3,4 -d] 吖gyne-3-nitrile;

6-(4-氟苯基)-2-甲基-9-(甲基砜甲基)-5-氧代2,4,5,6-四氢苯并[b]吡咯并[3,4-d]吖庚因-3-羧酰胺；6-(4-Fluorophenyl)-2-methyl-9-(methylsulfonemethyl)-5-oxo 2,4,5,6-tetrahydrobenzo[b]pyrrolo[3,4 -d] anthraquinone-3-carboxamide;

6-(4-氟苯基)-2-甲基-9-(甲基砜甲基)-2,4,5,6-四氢苯并[b]吡咯并[3,4-d]吖庚因-3-腈；6-(4-Fluorophenyl)-2-methyl-9-(methylsulfonemethyl)-2,4,5,6-tetrahydrobenzo[b]pyrrolo[3,4-d]indole Gyne-3-nitrile;

6-(4-氟苯基)-2-甲基-9-(甲基砜甲基)-2,4,5,6-四氢苯并[b]吡咯并[3,4-d]吖庚因-3-羧酰胺；6-(4-Fluorophenyl)-2-methyl-9-(methylsulfonemethyl)-2,4,5,6-tetrahydrobenzo[b]pyrrolo[3,4-d]indole Gyne-3-carboxamide;

9-氟-6-(4-氟苯基)-2-甲基-2,4,5,6-四氢吡啶并[2,3-b]吡咯并[3,4-d]吖庚因-3-羧酰胺；9-fluoro-6-(4-fluorophenyl)-2-methyl-2,4,5,6-tetrahydropyrido[2,3-b]pyrrolo[3,4-d]azepine -3-carboxamide;

7-(4-氟苯基)-2-甲基-10-(甲基砜甲基)-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮；7-(4-Fluorophenyl)-2-methyl-10-(methylsulfonemethyl)-2H-benzo[c]pyrido[3,4-e]azepine-3(5H)- ketone;

7-(4-氟苯基)-2-甲基-10-(甲基砜甲基)-6,7-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮甲酸盐；7-(4-Fluorophenyl)-2-methyl-10-(methylsulfonemethyl)-6,7-dihydro-2H-benzo[c]pyrido[3,4-e]aza Zhuo-3(5H)-ketoformate;

7-(4-氟苯基)-2-甲基-10-(甲基砜甲基)-6,7-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮；7-(4-Fluorophenyl)-2-methyl-10-(methylsulfonemethyl)-6,7-dihydro-2H-benzo[c]pyrido[3,4-e]aza Zhuo-3(5H)-one;

7-(4-氟苯基)-2-甲基-10-(乙基砜甲基)-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮；7-(4-Fluorophenyl)-2-methyl-10-(ethylsulfonemethyl)-2H-benzo[c]pyrido[3,4-e]azepine-3(5H)- ketone;

7-(4-氯苯基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；7-(4-chlorophenyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyrido[3,4-e]azepin-3-one;

7-(4-氯苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；7-(4-Chlorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyrido[3,4-e] Azaoxa-3-one;

7-(2,4-二氟苯基)-2-甲基-10-(乙基砜甲基)-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮；7-(2,4-Difluorophenyl)-2-methyl-10-(ethylsulfonemethyl)-2H-benzo[c]pyrido[3,4-e]azepine-3 ( 5H)-ketone;

7-(4-氯-2-氟苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；7-(4-Chloro-2-fluorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridin[3, 4-e]azepin-3-one;

(S)-2-(7-(4-氟苯基)-2-甲基-10-(甲基砜甲基)-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺；(S)-2-(7-(4-fluorophenyl)-2-methyl-10-(methylsulfonylmethyl)-3-oxo-3,5-dihydro-2H-benzo[c Pyridine[3,4-e]azepin-5-yl)acetamide;

(S)-N-乙基-2-(7-(4-氟苯基)-2-甲基-10-(甲基砜甲基)-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺；(S)-N-ethyl-2-(7-(4-fluorophenyl)-2-methyl-10-(methylsulfonemethyl)-3-oxo-3,5-dihydro-2H -benzo[c]pyrido[3,4-e]azepin-5-yl)acetamide;

(S)-2-(7-(4-氯苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)-N-乙基乙酰胺；(S)-2-(7-(4-chlorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e] Azaoxa-5-yl)-N-ethylacetamide;

(S)-2-(7-(4-氯苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)-乙酰胺；(S)-2-(7-(4-chlorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e] Aza-pyridyl-5-yl)-acetamide;

(S)-2-(7-(4-氯苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)-N-异丙基乙酰胺；(S)-2-(7-(4-chlorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e] Aza-pyridyl-5-yl)-N-isopropylacetamide;

N-(7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；N-(7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e]azepine- 10-based) ethanesulfonamide;

7-(4-氟苯基)-10-甲氧基-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；7-(4-Fluorophenyl)-10-methoxy-2-methyl-2,5-dihydro-3H-benzo[c]pyrido[3,4-e]azepine-3- ketone;

7-(4-氟苯基)-9-甲氧基-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；7-(4-Fluorophenyl)-9-methoxy-2-methyl-2,5-dihydro-3H-benzo[c]pyrido[3,4-e]azepine-3- ketone;

(S)-N-乙基-2-(7-(4-氟苯基)-10-甲氧基-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4- e]氮杂卓-5-基)乙酰胺；(S)-N-ethyl-2-(7-(4-fluorophenyl)-10-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[ c] pyrido[3,4-e]azepine-5-yl)acetamide;

10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-2,5-二氢-3H-二吡啶并[2,3-c:3',4'-e]氮杂卓-3-酮；10-((Ethyl sulfonyl)methyl)-7-(4-fluorophenyl)-2-methyl-2,5-dihydro-3H-dipyrido[2,3-c:3',4 '-e】azepine-3-one;

(S)-N-乙基-2-(7-(4-氟苯基)-9-甲氧基-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺；(S)-N-ethyl-2-(7-(4-fluorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[ c] pyrido[3,4-e]azepin-5-yl)acetamide;

N-(7-(4-氯苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；N-(7-(4-chlorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e]azepine- 10-based) ethanesulfonamide;

(S)-7-(4-氯苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-7-(4-chlorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyrido[3,4-e]azepine-3 -ketone;

(S)-10-((乙基砜)甲基)-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridine [3,4-e]azepin-3-one;

(R)-10-((乙基砜)甲基)-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(R)-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridine [3,4-e]azepin-3-one;

7-(4-氯苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-二吡啶并[3,4-c:3',4'-e]氮杂卓-3-酮；7-(4-Chlorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-dipyrido[3,4-c:3',4 '-e】azepine-3-one;

7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridin[3, 4-e]azepin-3-one;

(S)-2-(7-(4-氯苯基)-2-甲基-3-氧代-3,5-二氢-2H-二吡啶并[2,3-c:3',4'-e]氮杂卓-5-基)乙酰胺；(S)-2-(7-(4-chlorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-dipyrido[2,3-c:3',4 '-e>azepine-5-yl)acetamide;

(S)-2-(7-(4-氯苯基)-2-甲基-3-氧代-3,5-二氢-2H-二吡啶并[2,3-c:3',4'-e]氮杂卓-5-基)-N-乙基乙酰胺；(S)-2-(7-(4-chlorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-dipyrido[2,3-c:3',4 '-e>azepine-5-yl)-N-ethylacetamide;

N-(9-氯-7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；N-(9-chloro-7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e] Aza-indene-10-yl)ethanesulfonamide;

(S)-2-(7-(4-氯苯基)-9-氟-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)-N-乙基乙酰胺；(S)-2-(7-(4-chlorophenyl)-9-fluoro-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridin[3, 4-e]azepine-5-yl)-N-ethylacetamide;

(S)-N-乙基-2-(8-氟-7-(4-氟苯基)-9-甲氧基-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺；(S)-N-ethyl-2-(8-fluoro-7-(4-fluorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H -benzo[c]pyrido[3,4-e]azepin-5-yl)acetamide;

(S)-N-乙基-2-(10-氟-7-(4-氟苯基)-9-甲氧基-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺；(S)-N-ethyl-2-(10-fluoro-7-(4-fluorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H -benzo[c]pyrido[3,4-e]azepin-5-yl)acetamide;

(S)-10-((乙基砜)甲基)-7-(4-氯苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-chlorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridine [3,4-e]azepin-3-one;

(S)-5-乙基-10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e] 氮杂卓-3-酮；(S)-5-ethyl-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-2-methyl-2,5-dihydro-3H-benzo[c] Pyrido[3,4-e]azepin-3-one;

9-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；9-((Ethyl sulfonyl)methyl)-7-(4-fluorophenyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyrido[3,4-e] Azaoxa-3-one;

(R)-10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-5-(三氟甲基)-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(R)-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-2-methyl-5-(trifluoromethyl)-2,5-dihydro-3H-benzene And [c] pyrido[3,4-e]azepin-3-one;

10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基螺[苯并[c]吡啶并[3,4-e]氮杂卓-5,1'-环丙烷]-3(2H)-酮；10-((Ethyl sulfonyl)methyl)-7-(4-fluorophenyl)-2-methylspiro[benzo[c]pyrido[3,4-e]azepine-5,1' -cyclopropane]-3(2H)-one;

(S)-5-环丙基-10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-5-cyclopropyl-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-2-methyl-2,5-dihydro-3H-benzo[c Pyridine[3,4-e]azepin-3-one;

(S)-7-(4-氟苯基)-2,5-二甲基-10-((三氟甲基砜)甲基)-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-7-(4-fluorophenyl)-2,5-dimethyl-10-((trifluoromethylsulfone)methyl)-2,5-dihydro-3H-benzo[c] Pyrido[3,4-e]azepin-3-one;

(S)-10-((异丙基砜)甲基)-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((isopropylsulfone)methyl)-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridine And [3,4-e]azepin-3-one;

(S)-7-(4-氟苯基)-2,5-二甲基-10-((环丙基砜)甲基)-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-7-(4-fluorophenyl)-2,5-dimethyl-10-((cyclopropylsulfone)methyl)-2,5-dihydro-3H-benzo[c]pyridine And [3,4-e]azepin-3-one;

(S)-7-(2,4-二氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-7-(2,4-difluorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c Pyridine[3,4-e]azepin-3-one;

(S)-5-乙基-10-((乙基砜)甲基)-7-(4-氯苯基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-5-ethyl-10-((ethylsulfone)methyl)-7-(4-chlorophenyl)-2-methyl-2,5-dihydro-3H-benzo[c] Pyrido[3,4-e]azepin-3-one;

(5S)-10-((乙基亚砜)甲基)-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(5S)-10-((ethyl sulfoxide)methyl)-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridine And [3,4-e]azepin-3-one;

(S)-N-(7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；(S)-N-(7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4 -e]azepine-10-yl)ethanesulfonamide;

(S)-N-(7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)甲氨基磺酰胺；(S)-N-(7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4 -e]azepine-10-yl)methylaminosulfonamide;

(S)-1-乙基-3-(7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)脲；(S)-1-ethyl-3-(7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine And [3,4-e]azepine-10-yl)urea;

(S)-N-乙基-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-磺酰胺；(S)-N-ethyl-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridin[3 , 4-e]azepine-10-sulfonamide;

(S)-10-((乙基砜)甲基)-7-(4-甲氧基苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-methoxyphenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c] Pyrido[3,4-e]azepin-3-one;

(S)-10-((乙基砜)甲基)-7-(4-羟基苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e] 氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-hydroxyphenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridine [3,4-e] azerazin-3-one;

(S)-10-((乙基砜)甲基)-7-(4-氟-3-甲氧基苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-fluoro-3-methoxyphenyl)-2,5-dimethyl-2,5-dihydro-3H-benzene And [c] pyrido[3,4-e]azepin-3-one;

(S)-10-((乙基砜)甲基)-7-(4-氟-3-羟基苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-fluoro-3-hydroxyphenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[ c] pyrido[3,4-e]azepin-3-one;

(S)-N-(9-氟-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；(S)-N-(9-fluoro-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)ethanesulfonamide;

(S)-N-乙基-2-(10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺；(S)-N-ethyl-2-(10-((ethylsulfonyl)methyl)-7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro -2H-benzo[c]pyrido[3,4-e]azepin-5-yl)acetamide;

(S)-2-(10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酸；(S)-2-(10-((ethylsulfonyl)methyl)-7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo [c] Pyrido[3,4-e]azepine-5-yl)acetic acid;

(S)-2-(10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺；(S)-2-(10-((ethylsulfonyl)methyl)-7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo [c] Pyrido[3,4-e]azepin-5-yl)acetamide;

(S)-10-((乙基砜)甲基)-7-(4-氟苯基)-9-甲氧基-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-9-methoxy-2,5-dimethyl-2,5-dihydro-3H-benzene And [c] pyrido[3,4-e]azepin-3-one;

(S)-10-((乙基砜)甲基)-7-(4-氟苯基)-9-羟基-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-9-hydroxy-2,5-dimethyl-2,5-dihydro-3H-benzo[ c] pyrido[3,4-e]azepin-3-one;

(S)-N-(9-氯-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙基磺酰胺；(S)-N-(9-chloro-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)ethylsulfonamide;

(S)-7-(4-氟苯基)-2,5-二甲基-10-((甲基砜)甲基)-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-7-(4-fluorophenyl)-2,5-dimethyl-10-((methylsulfone)methyl)-2,5-dihydro-3H-benzo[c]pyridine [3,4-e]azepin-3-one;

(S)-10-((乙基砜)甲基)-7-(4-氟苯基)-5-异丙基-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-5-isopropyl-2-methyl-2,5-dihydro-3H-benzo[c Pyridine[3,4-e]azepin-3-one;

(S)-N-(7-(4-氯苯基)-9-氟-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；(S)-N-(7-(4-chlorophenyl)-9-fluoro-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)ethanesulfonamide;

(S)-N-(9-氯-5-乙基-7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；(S)-N-(9-chloro-5-ethyl-7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c] Pyrido[3,4-e]azepin-10-yl)ethanesulfonamide;

(S)-N-(5-乙基-9-氟-7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；(S)-N-(5-ethyl-9-fluoro-7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c] Pyrido[3,4-e]azepin-10-yl)ethanesulfonamide;

(S)-N-(9-氯-7-(4-氯苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；(S)-N-(9-chloro-7-(4-chlorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)ethanesulfonamide;

(S)-10-氨基-9-氯-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-amino-9-chloro-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridin[3,4 -e]azepine-3-one;

(S)-10-氨基-9-氟-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-amino-9-fluoro-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridin[3,4 -e]azepine-3-one;

(S)-(7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)甲磺酰胺；(S)-(7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e Azapine-10-yl)methanesulfonamide;

(S)-1-(7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)-N-甲基甲磺酰胺；(S)-1-(7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4 -e]azepine-10-yl)-N-methylmethanesulfonamide;

(S)-1-(7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10基)-N,N-二甲基甲磺酰胺；(S)-1-(7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4 -e]azepine-10-)-N,N-dimethylmethanesulfonamide;

(S)-N-(9-氟-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)甲磺酰胺；(S)-N-(9-fluoro-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)methanesulfonamide;

(S)-4-(10-((乙基砜)甲基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡唑并[3,4-e]氮杂卓-7-基)苯甲腈；(S)-4-(10-((ethylsulfonyl)methyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrazolo[ 3,4-e]azepine-7-yl)benzonitrile;

(S)-N-(9-氯-5-环丙基-7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；(S)-N-(9-chloro-5-cyclopropyl-7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c Pyridine[3,4-e]azepin-10-yl)ethanesulfonamide;

10-((乙基砜)甲基)-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[e]吡啶并[4,3-c][1,2]二氮杂卓-3-酮；10-((Ethyl sulfonyl)methyl)-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[e]pyrido[4,3 -c][1,2]diazepine-3-one;

(S)-N-(9-氯-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)甲磺酰胺；(S)-N-(9-chloro-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)methanesulfonamide;

(S)-N-(9-氯-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)环丙基磺酰胺；(S)-N-(9-chloro-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)cyclopropylsulfonamide;

10-((乙基砜)甲基)-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]哒嗪并[3,4-e]氮杂卓-3-酮；10-((Ethyl sulfonyl)methyl)-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridazine[3, 4-e]azepin-3-one;

10-((乙基砜)甲基)-7-(4-氟苯基)-5-(甲氧基甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；10-((Ethyl sulfonyl)methyl)-7-(4-fluorophenyl)-5-(methoxymethyl)-2-methyl-2,5-dihydro-3H-benzo[c Pyridine[3,4-e]azepin-3-one;

(S)-N-(9-氟-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)丙酰胺；(S)-N-(9-fluoro-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)propionamide;

(S)-N-(5-环丙基-9-氟-7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；(S)-N-(5-cyclopropyl-9-fluoro-7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c Pyridine[3,4-e]azepin-10-yl)ethanesulfonamide;

(S)-10-((乙基砜)甲基)-9-氟-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e] 氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-9-fluoro-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[ c] pyrido[3,4-e]azepin-3-one;

(S)-9-氯-10-((乙基砜)甲基)-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-9-chloro-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[ c] pyrido[3,4-e]azepin-3-one;

(S)-10-((乙基砜)甲基)-7-(4-氟-2-甲氧基苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-fluoro-2-methoxyphenyl)-2,5-dimethyl-2,5-dihydro-3H-benzene And [c] pyrido[3,4-e]azepin-3-one;

(S)-10-((乙基砜)甲基)-7-(4-氟苯基)-5-(2-羟乙基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-5-(2-hydroxyethyl)-2-methyl-2,5-dihydro-3H- Benzo[c]pyrido[3,4-e]azepin-3-one;

10-((乙基砜)甲基)-7-(4-氟-3-甲氧基苯基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；10-((Ethyl sulfonyl)methyl)-7-(4-fluoro-3-methoxyphenyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridin[ 3,4-e]azepin-3-one;

(S)-2-(7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)-N-甲基丙烷-2-磺酰胺；(S)-2-(7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4 -e]azepine-10-yl)-N-methylpropane-2-sulfonamide;

1-((S)-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)-N-甲基乙烷-1-磺酰胺；1-((S)-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4 -e]azepine-10-yl)-N-methylethane-1-sulfonamide;

N-(9-氟-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[e]吡啶并[4,3-c][1,2]二氮杂卓-10-基)乙磺酰胺；N-(9-fluoro-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[e]pyrido[4,3 -c][1,2]diazepine-10-yl)ethanesulfonamide;

7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[e]吡啶并[4,3-c][1,2]二氮杂卓-3-酮；7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[e]pyridine [4,3-c][1,2]diazepine-3-one;

10-((乙基砜)甲基)-7-(4-氟苯基)-9-甲氧基-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；10-((Ethyl sulfonyl)methyl)-7-(4-fluorophenyl)-9-methoxy-2-methyl-2,5-dihydro-3H-benzo[c]pyridin[ 3,4-e]azepin-3-one;

N-(9-氟-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢吡啶-2H-苯并[c]哒嗪并[3,4-e]氮杂卓-10-基)乙磺酰胺；N-(9-fluoro-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydropyridine-2H-benzo[c]pyridazine[3 , 4-e]azepine-10-yl)ethanesulfonamide;

7-(2-氯-4-氟-5-甲氧基苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；7-(2-Chloro-4-fluoro-5-methoxyphenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c Pyridine[3,4-e]azepin-3-one;

7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]哒嗪并[3,4-e]氮杂卓-3-酮；7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridazine And [3,4-e]azepin-3-one;

7-(2-氯-4-氟苯基)-2-甲基-10-((甲基砜)甲基)-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；7-(2-Chloro-4-fluorophenyl)-2-methyl-10-((methylsulfone)methyl)-2,5-dihydro-3H-benzo[c]pyridin[3, 4-e]azepin-3-one;

1-(7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[e]吡啶并[4,3-c][1,2]二氮杂卓-10-基)-N-甲基甲磺酰胺；1-(7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[e]pyrido[4,3-c][ 1,2]diazepine-10-yl)-N-methylmethanesulfonamide;

10-((乙基砜)甲基)-7-(4-氟-3-甲氧基苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]哒嗪并[3,4-e]氮杂卓-3-酮；10-((Ethyl sulfonyl)methyl)-7-(4-fluoro-3-methoxyphenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c] Pyridazine[3,4-e]azepin-3-one;

(S)-7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-7-(2-chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[ c] pyrido[3,4-e]azepin-3-one;

(S)-7-(2-氯-4-氟-5-甲氧基苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-7-(2-chloro-4-fluoro-5-methoxyphenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro -3H-benzo[c]pyrido[3,4-e]azepin-3-one;

(S)-1-(7-(4-氟-3-甲氧基苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)-N-甲基甲磺酰胺；(S)-1-(7-(4-fluoro-3-methoxyphenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c] Pyrido[3,4-e]azepin-10-yl)-N-methylmethanesulfonamide;

(S)-10-((乙基砜)甲基)-7-(3-氟-4-甲氧基苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(3-fluoro-4-methoxyphenyl)-2,5-dimethyl-2,5-dihydro-3H-benzene And [c] pyrido[3,4-e]azepin-3-one;

(S)-10-((乙基砜)甲基)-2,5-二甲基-7-(吡啶-4-基)-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮。(S)-10-((ethylsulfone)methyl)-2,5-dimethyl-7-(pyridin-4-yl)-2,5-dihydro-3H-benzo[c]pyridine [3,4-e]azepin-3-one.

其中，R ^R1和R ^R2可均为氢。 Wherein R ^R1 and R ^R2 may both be hydrogen.

其中，所述

可为

Wherein said

Can be

其中，所述的“被一个或多个R ^Q1取代的苯基”可为4-氟苯基、2-甲基-4氟苯基、2-三氟甲基-4氟苯基、2，6二氯苯基、2，5二氯苯基、2，3二氯苯基、2-环丙基-4氟氯苯基、2-氯苯基、2，6二氯-4氟苯基、2,4,6-三氟苯基、2,4-二氯苯基、3-甲氧基-4-氯苯基或2-氯-4-氟苯基。 Wherein the "phenyl group substituted by one or more R ^Q1 " may be 4-fluorophenyl, 2-methyl-4fluorophenyl, 2-trifluoromethyl-4fluorophenyl, 2, 6 dichlorophenyl, 2,5 dichlorophenyl, 2,3 dichlorophenyl, 2-cyclopropyl-4fluorochlorophenyl, 2-chlorophenyl, 2,6 dichloro-4 fluorophenyl 2,4,6-Trifluorophenyl, 2,4-dichlorophenyl, 3-methoxy-4-chlorophenyl or 2-chloro-4-fluorophenyl.

其中，当所述的R ^Q1连在所述的苯基的邻位时，所述R ^Q1可为卤素、卤代或未取代的C ₁-C ₅的烷基、C ₃-C ₇环烷基或C ₁-C ₅的烷氧基；例如苯基的2位为卤素、卤代或未取代的C ₁-C ₅的烷基或C ₃-C ₇环烷基；例如苯基的6位为卤素或C ₁-C ₅的烷氧基。 Wherein, when said R ^{Q1 is} attached to the ortho position of said phenyl group, said R ^Q1 may be halogen, halogenated or unsubstituted C ₁ -C ₅ alkyl group, C ₃ -C ₇ cycloalkane Or a C ₁ -C ₅ alkoxy group; for example, the 2-position of the phenyl group is a halogen, a halogenated or unsubstituted C ₁ -C ₅ alkyl group or a C ₃ -C ₇ cycloalkyl group; for example, a phenyl group 6 The position is a halogen or a C ₁ -C ₅ alkoxy group.

其中，当所述的R ^Q1连在所述的苯基的间位时，所述R ^Q1可为卤素或C ₁-C ₅的烷氧基；例如苯基的3位为卤素；例如苯基的5位为卤素或C ₁-C ₅的烷氧基。 Wherein, when R ^{Q1 is} attached to the meta position of the phenyl group, the R ^Q1 may be a halogen or a C ₁ -C ₅ alkoxy group; for example, the 3-position of the phenyl group is a halogen; for example, a phenyl group; The 5 position is a halogen or a C ₁ -C ₅ alkoxy group.

其中，当所述的R ^Q1连在所述的苯基的对位时，所述R ^Q1可为卤素或C ₁-C ₅的烷氧基。 Wherein, when R ^{Q1 is} attached to the para position of the phenyl group, the R ^Q1 may be a halogen or a C ₁ -C ₅ alkoxy group.

其中，所述n可为1或2。Wherein, the n may be 1 or 2.

其中，所述R ²可为氢。 Wherein R ² may be hydrogen.

其中，所述R可为“-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)”，例如-(CH ₂)n ^β2-S(＝O) ₂(R ²ⁱ)、n ^β2为1、2、3或4，又例如-CH ₂-S(＝O) ₂(R ²ⁱ)，还例如

Wherein R may be "-C ₁ -C ₆ alkyl-S(=O) ₂ (R ²ⁱ )", for example -(CH ₂ )n ^β2 -S(=O) ₂ (R ²ⁱ ), n ^β2 is 1, 2, 3 or 4, again for example -CH ₂ -S(=O) ₂ (R ²ⁱ ), also for example

其中，所述R可为-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)(例如-N(R ^2k)S(＝O) ₂(R ^2d)，又例如

或-N(CH ₂)n ^β2(R ^2e)S(＝O) ₂(R ²ⁱ)(例如

)。 Wherein R may be -(CH ₂ )n ^β2 N(R ^2k )S(=O) ₂ (R ^2d ) (for example, -N(R ^2k )S(=O) ₂ (R ^2d ), for example,

Or -N(CH ₂ )n ^β2 (R ^2e )S(=O) ₂ (R ²ⁱ ) (for example

).

其中，所述R可为-CH ₂-S(＝O) ₂N(R ^2f)(R ^2g)，例如

Wherein R can be -CH ₂ -S(=O) ₂ N(R ^2f )(R ^2g ), for example

其中，所述R可为羟基取代的C ₁-C ₅的烷基(所述的“C ₁-C ₅的烷基”例如C ₁-C ₃的烷基，又例如甲基、乙基、正丙基或异丙基；所述羟基取代的C ₁-C ₅的烷基例如

较佳地为

)。 Wherein R may be a hydroxy-substituted C ₁ -C ₅ alkyl group (the "C ₁ -C ₅ alkyl group" such as a C ₁ -C ₃ alkyl group, for example, a methyl group, an ethyl group, N-propyl or isopropyl; the hydroxy-substituted C ₁ -C ₅ alkyl group

Preferably

).

其中，所述n为1或2；至少一个R位于所述的Y的对位；Wherein n is 1 or 2; at least one R is located at the opposite of the Y;

其中，所述R可为卤素、羟基取代的C ₁-C ₅的烷基、-N(CH ₂)n ^β2(R ^2e)S(＝O) ₂(R ²ⁱ)、-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)、-(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)、-(CR ^2xR ^2y)-S(＝O) ₂N(R ^2f)(R ^2g)、-(CH ₂)n ^β2-S(＝O)(R ²ⁱ)或-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)。 Wherein R can be halogen, hydroxy-substituted C ₁ -C ₅ alkyl, -N(CH ₂ )n ^β2 (R ^2e )S(=O) ₂ (R ²ⁱ ), -(CH ₂ )n ^{^{β2 N (R 2k) S (}} = O) 2 (R 2d), - (CH 2) n β2 -S (= O) 2 N (R 2f) (R 2g), - (CR 2x R 2y) -S (=O) ₂ N(R ^2f )(R ^2g ), -(CH ₂ )n ^β2 -S(=O)(R ²ⁱ ) or -C ₁ -C ₆ alkyl-S(=O) ₂ ( R ²ⁱ ).

其中，所述n为1，R可位于所述的Y的对位或间位(又例如对位)。Wherein, n is 1, and R may be located in the para or meta position of the Y (also, for example, in the para position).

其中，所述n为2，一个R可位于所述Y的对位，另一个R可位于所述Y的间位(例如一个R位于所述Y的对位，另一个R位于所述Y的间位)。Wherein n is 2, one R may be in the alignment of the Y, and the other R may be in the meta position of the Y (eg, one R is in the alignment of the Y and the other R is in the Y Interdigit).

本发明一实施方式中，所述n为1，R为卤素、羟基取代的C ₁-C ₅的烷基、-N(CH ₂)n ^β2(R ^2e)S(＝O) ₂(R ²ⁱ)、-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)、-(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)、-S(＝O) ₂N(R ^2f)(R ^2g)、-CH ₂-S(＝O) ₂N(R ^2f)(R ^2g)、-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)或相邻的两个R与其相邻的C形成含1个或多个杂原子的5-6元杂环烃基。 In one embodiment of the present invention, the n is 1, R is a halogen, a hydroxy-substituted C ₁ -C ₅ alkyl group, -N(CH ₂ )n ^β2 (R ^2e )S(=O) ₂ (R ²ⁱ ), -(CH ₂ )n ^β2 N(R ^2k )S(=O) ₂ (R ^2d ), -(CH ₂ )n ^β2 -S(=O) ₂ N(R ^2f )(R ^2g ), - S(=O) ₂ N(R ^2f )(R ^2g ), -CH ₂ -S(=O) ₂ N(R ^2f )(R ^2g ), -C ₁ -C ₆ alkyl-S(=O ₂ (R ²ⁱ ) or an adjacent two R and its adjacent C form a 5-6 membered heterocycloalkyl group having one or more hetero atoms.

本发明一实施方式中，所述n为2，一个R为羟基取代的C ₁-C ₅的烷基、-N(CH ₂)n ^β2(R ^2e)S(＝O) ₂(R ²ⁱ)、-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)、-(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)、-S(＝O) ₂N(R ^2f)(R ^2g)、-CH ₂-S(＝O) ₂N(R ^2f)(R ^2g)或-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)；另一个R为卤素。 In one embodiment of the present invention, the n is 2, one R is a hydroxy-substituted C ₁ -C ₅ alkyl group, -N(CH ₂ )n ^β2 (R ^2e )S(=O) ₂ (R ²ⁱ ) , -(CH ₂ )n ^β2 N(R ^2k )S(=O) ₂ (R ^2d ), -(CH ₂ )n ^β2 -S(=O) ₂ N(R ^2f )(R ^2g ), -S (=O) ₂ N(R ^2f )(R ^2g ), -CH ₂ -S(=O) ₂ N(R ^2f )(R ^2g ) or -C ₁ -C ₆ alkyl-S(=O) ₂ (R ²ⁱ ); the other R is a halogen.

本发明另一实施例方式中，所述n＝1，R位于所述的Y的对位或间位(又例如对位)，R为卤素、羟基取代的C ₁-C ₅的烷基、-N(CH ₂)n ^β2(R ^2e)S(＝O) ₂(R ²ⁱ)、-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)、-(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)、-S(＝O) ₂N(R ^2f)(R ^2g)、-CH ₂- S(＝O) ₂N(R ^2f)(R ^2g)、-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)或相邻的两个R与其相邻的C形成含1个或多个杂原子的5-6元杂环烃基。 In another embodiment of the present invention, the n=1, R is in the para or meta position of the Y (also, for example, para), and R is a halogen, a hydroxy-substituted C ₁ -C ₅ alkyl group, -N(CH ₂ )n ^β2 (R ^2e )S(=O) ₂ (R ²ⁱ ), -(CH ₂ )n ^β2 N(R ^2k )S(=O) ₂ (R ^2d ), -(CH ₂ n ^{β 2} -S(=O) ₂ N(R ^2f )(R ^2g ), -S(=O) ₂ N(R ^2f )(R ^2g ), -CH ₂ - S(=O) ₂ N(R ^2f )(R ^2g ), -C ₁ -C ₆ alkyl-S(=O) ₂ (R ²ⁱ ) or two adjacent Rs and its adjacent C form 5 with one or more heteroatoms -6 membered heterocycloalkyl.

本发明另一实施方式中，所述n为2，一个R位于所述Y的对位，为羟基取代的C ₁-C ₅的烷基、-N(CH ₂)n ^β2(R ^2e)S(＝O) ₂(R ²ⁱ)、-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)、-(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)、-S(＝O) ₂N(R ^2f)(R ^2g)、-CH ₂-S(＝O) ₂N(R ^2f)(R ^2g)或-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)；另一个R位于所述Y的间位，为卤素。 In another embodiment of the present invention, the n is 2, and one R is in the para position of the Y, which is a hydroxy-substituted C ₁ -C ₅ alkyl group, -N(CH ₂ )n ^β2 (R ^2e )S (=O) ₂ (R ²ⁱ ), -(CH ₂ )n ^β2 N(R ^2k )S(=O) ₂ (R ^2d ), -(CH ₂ )n ^β2 -S(=O) ₂ N(R ^2f )(R ^2g ), -S(=O) ₂ N(R ^2f )(R ^2g ), -CH ₂ -S(=O) ₂ N(R ^2f )(R ^2g ) or -C ₁ -C ₆ The alkyl group -S(=O) ₂ (R ²ⁱ ); the other R is in the meta position of the Y and is a halogen.

其中，当Z为CH时，所述式I所示的苯并七元杂环类化合物可为

(例如

)或

(例如

)；当R ¹不为氢时，所述

可为

所述

可为

各取代基定义如前所述。 Wherein, when Z is CH, the benzo seven-membered heterocyclic compound represented by the formula I may be

(E.g

)or

(E.g

When R ^{1 is} not hydrogen,

Can be

Said

Can be

Each substituent is as defined above.

其中，当Z为N时，所述式I所示的苯并七元杂环类化合物可为式I-2所示的化合物：Wherein, when Z is N, the benzoheptacyclic heterocyclic compound represented by the formula I may be a compound represented by the formula I-2:

各取代基定义如前所述。

Each substituent is as defined above.

其中，式I所示的苯并七元杂环类化合物可为如下式I-3、I-4、I-5、I-6、II、III或IV所示的任一结构的化合物：Wherein the benzoheptacyclic heterocyclic compound represented by Formula I may be a compound of any of the following formulas I-3, I-4, I-5, I-6, II, III or IV:

(当R ¹不为氢时，例如

)、

(当R ¹不为氢时，例如

)、

(When R ^{1 is} not hydrogen, for example

),

(When R ^{1 is} not hydrogen, for example

),

本发明一较佳实施方式中，所述Z为N，

为

R ¹为乙基。 In a preferred embodiment of the present invention, the Z is N,

for

R ¹ is an ethyl group.

本发明一较佳实施方式中，所述Q为“被一个或多个R ^Q1取代的苯基”。 In a preferred embodiment of the invention, the Q is "phenyl substituted by one or more R ^Q1 ".

本发明一较佳实施例中，所述Z为CH，所述

为

In a preferred embodiment of the present invention, the Z is CH, the

for

在某一技术方案中，所述的化合物I中各基团的定义可如下所述(未注释的定义如前任一所述)：In a certain embodiment, the definition of each group in the compound I can be as follows (unannotated definitions are as described above):

Z为CH或N；Z is CH or N;

为

for

R ¹为-H、C ₁-C ₅的烷基(例如C ₁-C ₃的烷基，又例如甲基、乙基、正丙基或异丙基，还例如甲基、乙基或异丙基)、C ₃-C ₇环烷基(例如环丙基)、被一个或多个(例如2个、3个或4个)R ⁰取代的C ₁-C ₅的烷基(当存在多个R ⁰时，所述的R ⁰相同或不同；所述的“C ₁-C ₅的烷基”例如甲基或乙基；所述的“被一个R ⁰取代的C ₁-C ₅的烷基”例如2-羟基乙基、或甲氧基甲基)、或-(CH ₂)n ₀C(＝O)N(R ^R1)(R ^R2)； R ¹ is -H, C ₁ -C ₅ alkyl (for example C ₁ -C ₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl, also for example methyl, ethyl or iso) Propyl), C ₃ -C ₇ cycloalkyl (eg cyclopropyl), C ₁ -C ₅ alkyl substituted by one or more (eg 2, 3 or 4) R ⁰ (when present When R ⁰ is a plurality of R ⁰ , the R ^{0 is the} same or different; the “C ₁ -C ₅ alkyl group” is, for example, a methyl group or an ethyl group; and the “C ₁ -C ₅ substituted by a R ⁰ . An alkyl group such as 2-hydroxyethyl or methoxymethyl, or -(CH ₂ )n ₀ C(=O)N(R ^R1 )(R ^R2 );

(当Z为CH，R ¹不为氢时，其连接的碳原子为手性碳原子；所述的手性碳原子的构型可为R型、S型、或R型和S型的混合物) (When Z is CH and R ^{1 is} not hydrogen, the carbon atom to which it is attached is a chiral carbon atom; the configuration of the chiral carbon atom may be an R type, an S type, or a mixture of an R type and an S type; )

n ₀为0或1(例如1)； n ₀ is 0 or 1 (for example 1);

R ^R1和R ^R2各自独立地为-H或C ₁-C ₅的烷基(例如C ₁-C ₃的烷基，又例如甲基、乙基、正丙基或异丙基，还例如甲基、乙基或异丙基)； R ^R1 and R ^R2 are each independently -H or a C ₁ -C ₅ alkyl group (eg, a C ₁ -C ₃ alkyl group, such as methyl, ethyl, n-propyl or isopropyl, and also Base, ethyl or isopropyl);

R为“-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)”例如-(CH ₂)n ^β2-S(＝O) ₂(R ²ⁱ)、n ^β2为1、2、3或4，又例如-CH ₂-S(＝O) ₂(R ²ⁱ)，还例如

R is "-C ₁ -C ₆ alkyl-S(=O) ₂ (R ²ⁱ )" such as -(CH ₂ )n ^β2 -S(=O) ₂ (R ²ⁱ ), n ^β2 is 1, 2 , 3 or 4, again for example -CH ₂ -S(=O) ₂ (R ²ⁱ ), also for example

所述n ^β2为0、1或2(例如0或1)； The n ^β2 is 0, 1 or 2 (eg 0 or 1);

所述R ^2d、R ^2e、R ^2f、R ^2g、R ²ⁱ和R ^2k各自独立地为-H、C ₁-C ₆的烷基、被1个或多个(例如2个或3个)卤素(例如氟或氯)取代C ₁-C ₆的烷基(当为多个卤素取代时，所述卤素相同或不同)、或3-7元环烷基； The R ^2d , R ^2e , R ^2f , R ^2g , R ²ⁱ and R ^2k are each independently -H, C ₁ -C ₆ alkyl, 1 or more (for example 2 or 3) halogen Substituting (for example, fluorine or chlorine) a C ₁ -C ₆ alkyl group (when substituted for a plurality of halogens, the same or different halogens), or a 3-7 membered cycloalkyl group;

n为0、1或2；当n为1或2时，至少一个R位于Y的对位或间位；n is 0, 1, or 2; when n is 1 or 2, at least one R is located at the para or meta position of Y;

Q为“被一个或多个(例如2个、3个或4个)R ^Q1取代的苯基”{当存在多个R ^Q1时，所述的R ^Q1相同或不同；所述的R ^Q1可独立地连在所述的苯基的邻位、间位或对位；当存在2个R ^Q1时，所述的R ^Q1可连在所述的苯基的邻位和对位、或者、间位和对位；当存在3个R ^Q1时，所述的R ^Q1可连在所述的苯基的邻位、邻位和对位；(所述的“被一个或多个R ^Q1取代的苯基”例如4-氟苯基、2-甲基-4氟苯基、2-三氟甲基-4氟苯基、2，6二氯苯基、2，5二氯苯基、2，3二氯苯基、2-环丙基-4氟苯基、2-氯苯基、2，6二氯-4氟苯基、2,4,6-三氟苯基、4-羟基苯基、3-羟基-4-氟苯基、4-甲氧基苯基、4-氯苯基、4-氰基苯基、3-氯苯基、3-氟苯基、4-氰基苯基、2,4-二氟苯基、2,4-二氯苯基、2-氟-4-氯苯基、 2-氯-4-氟-5-甲氧基苯基、3-甲氧基-4-氟苯基、3-甲氧基-4-氯苯基、4-甲氧基-3-氟苯基、2-甲氧基-4-氟苯基、2-氯-4-氟苯基、或2-氟-4-氰基苯)}、或者“被一个或多个(例如2个、3个或4个)R ^Q2取代的5-6元杂芳基”{当存在多个R ^Q2时，所述的R ^Q2相同或不同；所述的5-6元杂芳基中的杂原子为N和/或O，其个数为1-3个；(所述的“5-6元杂芳基”例如吡啶基或嘧啶基，优选吡啶基；(所述“被一个或多个(例如2个、3个或4个)R ^Q2取代的5-6元杂芳基”例如

)}； Q is "phenyl substituted by one or more (for example, 2, 3 or 4) R ^Q1 " {when a plurality of R ^Q1 are present, the R ^{Q1 is the} same or different; the R ^Q1 may be Independently attached to the ortho, meta or para position of the phenyl group; when two R ^Q1 are present, the R ^Q1 may be attached to the ortho and para positions of the phenyl group, or Bit and para position; when there are 3 R ^Q1 , the R ^Q1 may be attached to the ortho, ortho and para positions of the phenyl group; (the said "replaced by one or more R ^Q1 Phenyl" such as 4-fluorophenyl, 2-methyl-4fluorophenyl, 2-trifluoromethyl-4fluorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 2, 3 dichlorophenyl, 2-cyclopropyl-4fluorophenyl, 2-chlorophenyl, 2,6-dichloro-4-fluorophenyl, 2,4,6-trifluorophenyl, 4-hydroxyphenyl , 3-hydroxy-4-fluorophenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-cyanophenyl, 3-chlorophenyl, 3-fluorophenyl, 4-cyanophenyl , 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluoro-5-methoxyphenyl, 3-methoxy 4-fluorophenyl, 3-methoxy-4-chlorophenyl, 4-methoxy-3-fluorophenyl, 2-methoxy-4-fluorophenyl , 2-chloro-4-fluorophenyl, or 2-fluoro-4-cyanobenzene), or "5-6" substituted by one or more (eg, 2, 3 or 4) R ^Q2 "heteroaryl" {when a plurality of R ^Q2 are present, the R ^{Q2 is the} same or different; the hetero atom in the 5-6 membered heteroaryl is N and/or O, the number of which is 1-3 (the "5-6 membered heteroaryl" such as pyridyl or pyrimidinyl, preferably pyridyl; (the "substituted by one or more (eg, 2, 3 or 4) R ^Q2 5-6 membered heteroaryl" for example

)};

所述R ^Q1和R ^Q2各自独立地为-H、卤素、卤代或未取代的C ₁-C ₅的烷基(所述的“C ₁-C ₅的烷基”例如C ₁-C ₃的烷基，又例如甲基、乙基、正丙基或异丙基；所述的“卤代”时卤素的个数为1个或多个[例如2个、3个或4个]；当有多个卤素时，所述的卤素相同或不同；)、C ₃-C ₇环烷基(例如环丙基)、或C ₁-C ₅的烷氧基(例如C ₁-C ₃的烷氧基，又例如甲氧基、乙氧基、正丙氧基或异丙氧基，还例如甲氧基) The R ^Q1 and R ^Q2 are each independently -H, halogen, halogenated or unsubstituted C ₁ -C ₅ alkyl (the "C ₁ -C ₅ alkyl" such as C ₁ -C ₃ An alkyl group, such as methyl, ethyl, n-propyl or isopropyl; the number of halogens in the "halogenated" is one or more [eg 2, 3 or 4]; When there are a plurality of halogens, the halogens are the same or different;), a C ₃ -C ₇ cycloalkyl group (for example, a cyclopropyl group), or a C ₁ -C ₅ alkoxy group (for example, a C ₁ -C ₃ group) Alkoxy, for example methoxy, ethoxy, n-propoxy or isopropoxy, also for example methoxy)

W为CH或N；W is CH or N;

R ^2-1、R ^2-2、R ^2-3和R ^2-4各自独立地为氢、C ₁-C ₅的烷基(例如C ₁-C ₃的烷基，又例如甲基、乙基、正丙基或异丙基)或C ₃-C ₆环烷基(例如环丙基)。 R ^2-1 , R ^2-2 , R ^2-3 and R ^2-4 are each independently hydrogen, C ₁ -C ₅ alkyl (for example, C ₁ -C ₃ alkyl, for example methyl, B Base, n-propyl or isopropyl) or C ₃ -C ₆ cycloalkyl (eg cyclopropyl).

Z为CH或N；Z is CH or N;

为

for

n ₀为0或1(例如1)； n ₀ is 0 or 1 (for example 1);

R为-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)(例如-N(R ^2k)S(＝O) ₂(R ^2d)，又例如、

)或-N(CH ₂)n ^β2(R ^2e)S(＝O) ₂(R ²ⁱ)(例如

R is -(CH ₂ )n ^β2 N(R ^2k )S(=O) ₂ (R ^2d ) (for example, -N(R ^2k )S(=O) ₂ (R ^2d ), for another example,

Or -N(CH ₂ )n ^β2 (R ^2e )S(=O) ₂ (R ²ⁱ ) (for example

所述n ^β2为0、1或2(例如0或1)； The n ^β2 is 0, 1 or 2 (eg 0 or 1);

Q为“被一个或多个(例如2个、3个或4个)R ^Q1取代的苯基”{当存在多个R ^Q1时，所述的R ^Q1相同或不同；所述的R ^Q1可独立地连在所述的苯基的邻位、间位或对位；当存在2个R ^Q1时，所述的R ^Q1可连在所述的苯基的邻位和对位、或者、间位和对位；当存在3个R ^Q1时，所述的R ^Q1可连在所述的苯基的邻位、邻位和对位；(所述的“被一个或多个R ^Q1取代的苯基”例如4-氟苯基、2-甲基-4氟苯基、2-三氟甲基-4氟苯基、2，6二氯苯基、2，5二氯苯基、2，3二氯苯基、2-环丙基-4氟苯基、2-氯苯基、2，6二氯-4氟苯基、2,4,6-三氟苯基、4-羟基苯基、3-羟基-4-氟苯基、4-甲氧基苯基、4-氯苯基、4-氰基苯基、3-氯苯基、3-氟苯基、4-氰基苯基、2,4-二氟苯基、2,4-二氯苯基、2-氟-4-氯苯基、2-氯-4-氟-5-甲氧基苯基、3-甲氧基-4-氟苯基、3-甲氧基-4-氯苯基、4-甲氧基-3-氟苯基、2-甲氧基-4-氟苯基、2-氯-4-氟苯基、或2-氟-4-氰基苯)}、或者“被一个或多个(例如2个、3个或4个)R ^Q2取代的5-6元杂芳基”{当存在多个R ^Q2时，所述的R ^Q2相同或不同；所述的5-6元杂芳基中的杂原子为N和/或O，其个数为1-3个；(所述的“5-6元杂芳基”例如吡啶基或嘧啶基，优选吡啶基；(所述“被一个或多个(例如2个、3个或4个)R ^Q2取代的5-6元杂芳基”例如

)}； Q is "phenyl substituted by one or more (for example, 2, 3 or 4) R ^Q1 " {when a plurality of R ^Q1 are present, the R ^{Q1 is the} same or different; the R ^Q1 may be Independently attached to the ortho, meta or para position of the phenyl group; when two R ^Q1 are present, the R ^Q1 may be attached to the ortho and para positions of the phenyl group, or Bit and para position; when there are 3 R ^Q1 , the R ^Q1 may be attached to the ortho, ortho and para positions of the phenyl group; (the said "replaced by one or more R ^Q1 Phenyl" such as 4-fluorophenyl, 2-methyl-4fluorophenyl, 2-trifluoromethyl-4fluorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 2, 3 dichlorophenyl, 2-cyclopropyl-4fluorophenyl, 2-chlorophenyl, 2,6-dichloro-4-fluorophenyl, 2,4,6-trifluorophenyl, 4-hydroxyphenyl , 3-hydroxy-4-fluorophenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-cyanophenyl, 3-chlorophenyl, 3-fluorophenyl, 4-cyanophenyl , 2,4-difluorophenyl, 2,4-dichlorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluoro-5-methoxyphenyl, 3-methoxy 4-fluorophenyl, 3-methoxy-4-chlorophenyl, 4-methoxy-3-fluorophenyl, 2-methoxy-4-fluorophenyl 2-chloro-4-fluorophenyl, or 2-fluoro-4-cyanophenyl)}, or "substituted with one or more (e.g. 2, 3 or 4) R ^Q2 is a substituted 5-6 membered heteroaryl "Aryl" {when a plurality of R ^Q2 are present, the R ^{Q2 is the} same or different; the hetero atom in the 5-6 membered heteroaryl is N and/or O, and the number thereof is 1-3 (the "5-6 membered heteroaryl" such as pyridyl or pyrimidinyl, preferably pyridyl; (the "5" substituted by one or more (eg, 2, 3 or 4) R ^Q2 -6-membered heteroaryl" for example

)};

W为CH或N；W is CH or N;

Z为CH或N；Z is CH or N;

为

for

n ₀为0或1(例如1)； n ₀ is 0 or 1 (for example 1);

R为-CH ₂-S(＝O) ₂N(R ^2f)(R ^2g)例如

R is -CH ₂ -S(=O) ₂ N(R ^2f )(R ^2g ), for example

所述n ^β2为0、1或2(例如0或1)； The n ^β2 is 0, 1 or 2 (eg 0 or 1);

Q为“被一个或多个(例如2个、3个或4个)R ^Q1取代的苯基”{当存在多个R ^Q1 时，所述的R ^Q1相同或不同；所述的R ^Q1可独立地连在所述的苯基的邻位、间位或对位；当存在2个R ^Q1时，所述的R ^Q1可连在所述的苯基的邻位和对位、或者、间位和对位；当存在3个R ^Q1时，所述的R ^Q1可连在所述的苯基的邻位、邻位和对位；(所述的“被一个或多个R ^Q1取代的苯基”例如4-氟苯基、2-甲基-4氟苯基、2-三氟甲基-4氟苯基、2，6二氯苯基、2，5二氯苯基、2，3二氯苯基、2-环丙基-4氟苯基、2-氯苯基、2，6二氯-4氟苯基、2,4,6-三氟苯基、4-羟基苯基、3-羟基-4-氟苯基、4-甲氧基苯基、4-氯苯基、4-氰基苯基、3-氯苯基、3-氟苯基、4-氰基苯基、2,4-二氟苯基、2,4-二氯苯基、2-氟-4-氯苯基、2-氯-4-氟-5-甲氧基苯基、3-甲氧基-4-氟苯基、3-甲氧基-4-氯苯基、4-甲氧基-3-氟苯基、2-甲氧基-4-氟苯基、2-氯-4-氟苯基、或2-氟-4-氰基苯)}、或者“被一个或多个(例如2个、3个或4个)R ^Q2取代的5-6元杂芳基”{当存在多个R ^Q2时，所述的R ^Q2相同或不同；所述的5-6元杂芳基中的杂原子为N和/或O，其个数为1-3个；(所述的“5-6元杂芳基”例如吡啶基或嘧啶基，优选吡啶基；(所述“被一个或多个(例如2个、3个或4个)R ^Q2取代的5-6元杂芳基”例如

)};

W为CH或N；W is CH or N;

Z为CH或N；Z is CH or N;

为

for

R ¹为-H、C ₁-C ₅的烷基(例如C ₁-C ₃的烷基，又例如甲基、乙基、正丙基或异丙基，还例如甲基、乙基或异丙基)、C ₃-C ₇环烷基(例如环丙基)、被一个或多个(例如2个、 3个或4个)R ⁰取代的C ₁-C ₅的烷基(当存在多个R ⁰时，所述的R ⁰相同或不同；所述的“C ₁-C ₅的烷基”例如甲基或乙基；所述的“被一个R ⁰取代的C ₁-C ₅的烷基”例如2-羟基乙基、或甲氧基甲基)、或-(CH ₂)n ₀C(＝O)N(R ^R1)(R ^R2)； R ¹ is -H, C ₁ -C ₅ alkyl (for example C ₁ -C ₃ alkyl, for example methyl, ethyl, n-propyl or isopropyl, also for example methyl, ethyl or iso) Propyl), C ₃ -C ₇ cycloalkyl (eg cyclopropyl), C ₁ -C ₅ alkyl substituted by one or more (eg 2, 3 or 4) R ⁰ (when present When R ⁰ is a plurality of R ⁰ , the R ^{0 is the} same or different; the “C ₁ -C ₅ alkyl group” is, for example, a methyl group or an ethyl group; and the “C ₁ -C ₅ substituted by a R ⁰ . An alkyl group such as 2-hydroxyethyl or methoxymethyl, or -(CH ₂ )n ₀ C(=O)N(R ^R1 )(R ^R2 );

n ₀为0或1(例如1)； n ₀ is 0 or 1 (for example 1);

R为-S(＝O) ₂N(R ^2f)(R ^2g)例如-S(＝O) ₂N(R ^2g)H，又例如

R is -S(=O) ₂ N(R ^2f )(R ^2g ) such as -S(=O) ₂ N(R ^2g )H, for example

所述n ^β2为0、1或2(例如0或1)； The n ^β2 is 0, 1 or 2 (eg 0 or 1);

Q为“被一个或多个(例如2个、3个或4个)R ^Q1取代的苯基”{当存在多个R ^Q1时，所述的R ^Q1相同或不同；所述的R ^Q1可独立地连在所述的苯基的邻位、间位或对位；当存在2个R ^Q1时，所述的R ^Q1可连在所述的苯基的邻位和对位、或者、间位和对位；当存在3个R ^Q1时，所述的R ^Q1可连在所述的苯基的邻位、邻位和对位；(所述的“被一个或多个R ^Q1取代的苯基”例如4-氟苯基、2-甲基-4氟苯基、2-三氟甲基-4氟苯基、2，6二氯苯基、2，5二氯苯基、2，3二氯苯基、2-环丙基-4氟苯基、2-氯苯基、2，6二氯-4氟苯基、2,4,6-三氟苯基、4-羟基苯基、3-羟基-4-氟苯基、4-甲氧基苯基、4-氯苯基、4-氰基苯基、3-氯苯基、3-氟苯基、4-氰基苯基、2,4-二氟苯基、2,4-二氯苯基、2-氟-4-氯苯基、2-氯-4-氟-5-甲氧基苯基、3-甲氧基-4-氟苯基、3-甲氧基-4-氯苯基、4-甲氧基-3-氟苯基、2-甲氧基-4-氟苯基、2-氯-4-氟苯基、或2-氟-4-氰基苯)}、或者“被一个或多个(例如2个、3个或4个)R ^Q2取代的5-6元杂芳基”{当存在多个R ^Q2时，所述的R ^Q2相同或不同；所述的5-6元杂芳基中的杂原子为N和/或O，其个数为1-3个；(所述的“5-6元杂芳基”例如吡啶基或嘧啶基，优选吡啶基；(所述“被一个或多个(例如2个、3个或4 个)R ^Q2取代的5-6元杂芳基”例如

)};

W为CH或N；W is CH or N;

Z为CH或N；Z is CH or N;

为

for

n ₀为0或1(例如1)； n ₀ is 0 or 1 (for example 1);

R为羟基取代的C ₁-C ₅的烷基(所述的“C ₁-C ₅的烷基”例如C ₁-C ₃的烷基，又例如甲基、乙基、正丙基或异丙基；所述羟基取代的C ₁-C ₅的烷基例如

较佳地为

)； R is a hydroxy-substituted C ₁ -C ₅ alkyl group (the "C ₁ -C ₅ alkyl group" such as a C ₁ -C ₃ alkyl group, such as methyl, ethyl, n-propyl or iso a propyl group; the hydroxy-substituted C ₁ -C ₅ alkyl group

Preferably

);

所述n ^β2为0、1或2(例如0或1)； The n ^β2 is 0, 1 or 2 (eg 0 or 1);

)};

W为CH或N；W is CH or N;

在某一技术方案中，所述的化合物I所示的中各基团的定义可如下所述(未注释的定义如前任一所述)：In a certain embodiment, the definition of each group represented by the compound I can be as follows (unannotated definition as described above):

Z为CH；Z is CH;

W为CH或N；W is CH or N;

Z为CH；Z is CH;

Q选自

4-氟苯基、2-甲基-4氟苯基、2-三氟甲基-4氟苯基、2，6二氯苯基、2，5二氯苯基、2，3二氯苯基、2-环丙基-4氟苯基、2-氯苯基、2，6二氯-4氟苯基、2,4,6-三氟苯基、4-羟基苯基、3-羟基-4-氟苯基、4-甲氧基苯基、4-氯苯基、4-氰基苯基、3-氯苯基、3-氟苯基、4-氰基苯基、2,4-二氟苯基、2,4-二氯苯基、2-氟-4-氯苯基、2-氯-4-氟-5-甲氧基苯基、3-甲氧基-4-氟苯基、3-甲氧基-4-氯苯基、4-甲氧基-3-氟苯基、2-甲氧基-4-氟苯基、2-氯-4-氟苯基、或2-氟-4-氰基苯。 Q is selected from

4-fluorophenyl, 2-methyl-4fluorophenyl, 2-trifluoromethyl-4fluorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 2,3 dichlorobenzene Base, 2-cyclopropyl-4fluorophenyl, 2-chlorophenyl, 2,6-dichloro-4-fluorophenyl, 2,4,6-trifluorophenyl, 4-hydroxyphenyl, 3-hydroxyl 4-fluorophenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-cyanophenyl, 3-chlorophenyl, 3-fluorophenyl, 4-cyanophenyl, 2,4 -difluorophenyl, 2,4-dichlorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluoro-5-methoxyphenyl, 3-methoxy-4-fluoro Phenyl, 3-methoxy-4-chlorophenyl, 4-methoxy-3-fluorophenyl, 2-methoxy-4-fluorophenyl, 2-chloro-4-fluorophenyl, or 2-fluoro-4-cyanobenzene.

Z为CH；Z is CH;

Q选自

4-氟苯基、2-甲基-4氟苯基、2-三氟甲基-4氟苯基、2，6二氯苯基、2，5二氯苯基、2，3二氯苯基、2-环丙基-4氟氯苯基、2-氯苯基、2，6二氯-4氟苯基、2,4,6-三氟苯基、2,4-二氯苯基、3-甲氧基-4-氯苯基或2-氯-4-氟苯基。 Q is selected from

4-fluorophenyl, 2-methyl-4fluorophenyl, 2-trifluoromethyl-4fluorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 2,3 dichlorobenzene Base, 2-cyclopropyl-4fluorochlorophenyl, 2-chlorophenyl, 2,6-dichloro-4-fluorophenyl, 2,4,6-trifluorophenyl, 2,4-dichlorophenyl , 3-methoxy-4-chlorophenyl or 2-chloro-4-fluorophenyl.

所述Z为CH；The Z is CH;

所述R ¹不为氢，所述式I所示的化合物为

The R ^{1 is} not hydrogen, and the compound represented by the formula I is

所述Q为“被一个或多个R ^Q1取代的苯基”。 The Q is "phenyl substituted by one or more R ^Q1 ".

所述Z为N；The Z is N;

所述

为

Said

for

所述R ¹为乙基。 The R ¹ is an ethyl group.

所述Z为CH；The Z is CH;

所述R ¹不为氢，所述式I所示的化合物为

The R ^{1 is} not hydrogen, and the compound represented by the formula I is

所述

为

Said

for

所述Z为CH；The Z is CH;

所述R ¹不为氢，所述式I所示的化合物为

The R ^{1 is} not hydrogen, and the compound represented by the formula I is

所述

为

Said

for

所述式I所示的含七元环的化合物可选自如下所示任一结构的化合物：The seven-membered ring-containing compound of Formula I may be selected from compounds of any of the structures shown below:

其中，所述化合物4097-P1和4097-P2在下述条件下的保留时间分别为2.39min和 3.47min；Wherein the retention times of the compounds 4097-P1 and 4097-P2 under the following conditions were 2.39 min and 3.47 min, respectively;

SFC中，色谱柱为OZ柱，规格为20*250mm，粒径10um；流动相为超临界CO ₂/MEOH(0.2％甲醇胺)＝45/55；流速:80g/min。 In the SFC, the column is an OZ column with a size of 20*250 mm and a particle size of 10 μm; the mobile phase is supercritical CO _{2 /} MEOH (0.2% methanolamine) = 45/55; and the flow rate is 80 g/min.

本发明还提供了一种如式(II)所示的苯并七元杂环类化合物的制备方法，其包含下述步骤：将如式(II-1)所示的中间体化合物与Q’进行Ullmann偶联反应，即可；The present invention also provides a process for preparing a benzo seven-membered heterocyclic compound represented by formula (II), which comprises the steps of: intermediate compound represented by formula (II-1) with Q' Performing a Ullmann coupling reaction;

其中，所述的各取代基均如前所述，Q’为结构片段Q反应位点上相应的卤化物。Wherein each of the substituents is as described above, and Q' is the corresponding halide on the reaction site of the structural fragment Q.

所述的Ullmann偶联反应可采用本领域此类反应的常规反应条件和参数进行。本发明优选在溶剂中，在钯催化剂和碱的存在下进行反应；或辅以微波辐射促进也可。The Ullmann coupling reaction can be carried out using conventional reaction conditions and parameters of such reactions in the art. The present invention preferably carries out the reaction in the presence of a palladium catalyst and a base in a solvent; or it may be promoted by microwave irradiation.

其中，所述的溶剂为本领域进行Ullmann偶联反应的常规溶剂，包括但不限于1,4-二氧六环、乙腈、水或其混合物。Wherein, the solvent is a conventional solvent for performing Ullmann coupling reaction in the art, including but not limited to 1,4-dioxane, acetonitrile, water or a mixture thereof.

所述的Ullmann偶联反应的反应温度为本领域进行此类反应的常规温度，如80℃-110℃。The reaction temperature of the Ullmann coupling reaction is a conventional temperature at which the reaction is carried out in the art, such as from 80 ° C to 110 ° C.

所述的铜催化剂为本领域进行Ullmann偶联反应的常规催化剂，其包括但不限于碘化亚铜。The copper catalysts are conventional catalysts for Ullmann coupling reactions in the art including, but not limited to, cuprous iodide.

所述的铜催化剂还可与本领域进行Ullmann偶联反应的常规配体进行配位后再进行催化。所述的配体包括但不限于N1,N2-二甲基乙烷-1,2-二胺。The copper catalyst can also be catalyzed by coordination with conventional ligands in the art for Ullmann coupling reactions. The ligands include, but are not limited to, N1,N2-dimethylethane-1,2-diamine.

所述的碱为本领域进行Suzuki偶联反应的常规催化剂，其包括但不限于钠、钾和铯的碳酸盐或磷酸盐。The bases are conventional catalysts for Suzuki coupling reactions in the art including, but not limited to, carbonates or phosphates of sodium, potassium and rubidium.

所述的化合物II的制备方法，还可包括下述步骤：将如式(II-2)所示的中间体化合物进行环合反应得到所述式II-1所示化合物，即可；The preparation method of the compound II may further include the following steps: subjecting the intermediate compound represented by the formula (II-2) to a cyclization reaction to obtain the compound of the formula II-1;

各取代基均如前所述。Each substituent is as previously described.

所述的化合物II的制备方法，还可包括下述步骤：将如式(II-3)所示的中间体化合物与如式(II-4)所示的中间体化合物进行Suzuki偶联反应，得到所述式II-2所示化合物即可；The method for preparing the compound II may further comprise the steps of: subjecting an intermediate compound represented by the formula (II-3) to an intermediate compound represented by the formula (II-4), and performing a Suzuki coupling reaction, The compound of the formula II-2 can be obtained;

本发明还提供了一种如式III所示的含七元环的化合物的制备方法，其包含下述步骤：将如式III-1所示的中间体化合物进行环合反应，即可；The present invention also provides a method for preparing a seven-membered ring-containing compound represented by Formula III, which comprises the steps of: subjecting an intermediate compound represented by Formula III-1 to a cyclization reaction;

其中，所述的各取代基均如前所述。Wherein each of the substituents is as described above.

其中，所述的环合反应可采用本领域中进行环合反应的常规反应条件和参数，本发明中优选在二氯甲烷中和在室温下通过三氟乙酸处理进行。Wherein, the cyclization reaction can employ conventional reaction conditions and parameters for performing a cyclization reaction in the art, and is preferably carried out by treatment with trifluoroacetic acid in dichloromethane and at room temperature in the present invention.

所述的如式III所示的含七元环的化合物的制备方法，其进一步还包含下述步骤：方法一：将如式III-2所示的中间体化合物与如式III-3所示的中间体化合物进行Suzuki偶联反应,得到所述式III-1所示化合物，即可；The method for preparing a seven-membered ring-containing compound as shown in Formula III, further comprising the following steps: Method 1: the intermediate compound represented by Formula III-2 is as shown in Formula III-3 The intermediate compound is subjected to a Suzuki coupling reaction to obtain the compound of the formula III-1;

所述的Suzuki偶联反应可采用本领域此类反应的常规反应条件和参数进行。本发明优选在溶剂中，在钯催化剂和碱的存在下进行反应；或辅以微波辐射促进也可；The Suzuki coupling reaction can be carried out using conventional reaction conditions and parameters of such reactions in the art. The present invention preferably carries out the reaction in the presence of a palladium catalyst and a base in a solvent; or it may be promoted by microwave irradiation;

其中，所述的溶剂为本领域进行Suzuki偶联反应的常规溶剂，包括但不限于1,4-二氧六环、乙腈、水或其混合物。Wherein, the solvent is a conventional solvent for performing Suzuki coupling reaction in the art, including but not limited to 1,4-dioxane, acetonitrile, water or a mixture thereof.

所述的Suzuki偶联反应的反应温度为本领域进行此类反应的常规温度，如80℃-110℃。The reaction temperature of the Suzuki coupling reaction is a conventional temperature at which the reaction is carried out in the art, such as from 80 °C to 110 °C.

所述的钯催化剂为本领域进行Suzuki偶联反应的常规催化剂，其包括但不限于四三苯基膦钯、三(二亚苄基丙酮)钯(0)、或[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)。The palladium catalyst is a conventional catalyst for performing Suzuki coupling reaction in the art, including but not limited to tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)palladium(0), or [1,1'-double (Diphenylphosphino)ferrocene]dichloropalladium (II).

所述的钯催化剂还可与本领域进行Suzuki偶联反应的常规配体进行配位后再进行催化。所述的配体包括但不限于2-二环己基膦-2',4',6'-三异丙基-1,1'-联苯(XPhos)。The palladium catalyst can also be catalyzed by coordination with conventional ligands which are subjected to Suzuki coupling reactions in the art. Such ligands include, but are not limited to, 2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl (XPhos).

本发明中，基于Suzuki偶联反应的反应机理，上述反应中的反应物如式III-3所示的中间体化合物还可以其硼酸或其他硼酸酯衍生物代替。In the present invention, based on the reaction mechanism of the Suzuki coupling reaction, the reactant in the above reaction may be replaced by a boronic acid or other boronic acid ester derivative as the intermediate compound represented by the formula III-3.

所述的化合物III的制备方法，还可包括下述步骤：将如式(III-4)所示的中间体化合物与如式(III-5)所示的中间体化合物进行Suzuki偶联反应，得到所述式III-1所示化合物，即可；The preparation method of the compound III may further include the following steps: subjecting an intermediate compound represented by the formula (III-4) to an intermediate compound represented by the formula (III-5), and performing a Suzuki coupling reaction, Obtaining the compound of the formula III-1, that is,

本发明还提供了一种如式IV所示的含七元环的化合物的制备方法，其包含下述步骤：将如式IV-1所示的中间体化合物进行环合反应，即可；The present invention also provides a method for preparing a seven-membered ring-containing compound represented by Formula IV, which comprises the steps of: subjecting an intermediate compound represented by Formula IV-1 to a cyclization reaction;

其中，所述的环合反应可采用本领域中进行环合反应的常规反应条件和参数，本发明中优选在乙醇中(含碳酸钾)加热回流进行。Wherein, the cyclization reaction can employ conventional reaction conditions and parameters for performing a cyclization reaction in the art, and in the present invention, it is preferred to carry out heating under reflux in ethanol (including potassium carbonate).

所述的如式IV所示的含七元环的化合物的制备方法，还可进一步还包含下述步骤：将如式III-2所示的中间体化合物与如式IV-2所示的中间体化合物进行Suzuki偶联反应,得到所述式IV-1所示化合物，即可；The method for preparing a seven-membered ring-containing compound as shown in Formula IV may further comprise the step of: intermediate the compound represented by Formula III-2 with the intermediate of Formula IV-2 The compound is subjected to a Suzuki coupling reaction to obtain the compound of the formula IV-1;

所述的各取代基均如前所述。Each of the substituents described above is as described above.

所述的Suzuki偶联反应可采用本领域此类反应的常规反应条件和参数进行。The Suzuki coupling reaction can be carried out using conventional reaction conditions and parameters of such reactions in the art.

所述的Suzuki偶联反应的反应温度可为本领域进行此类反应的常规温度，如80℃-110℃。The reaction temperature of the Suzuki coupling reaction can be a conventional temperature for conducting such a reaction in the art, such as from 80 °C to 110 °C.

本发明优选在溶剂中，在钯催化剂和碱的存在下进行反应；或辅以微波辐射促进也可。The present invention preferably carries out the reaction in the presence of a palladium catalyst and a base in a solvent; or it may be promoted by microwave irradiation.

其中，所述的溶剂为本领域进行Suzuki偶联反应的常规溶剂，例如包括但不限于1,4-二氧六环、乙腈、水或其混合物。Wherein, the solvent is a conventional solvent for performing a Suzuki coupling reaction in the art, and includes, for example, but not limited to, 1,4-dioxane, acetonitrile, water or a mixture thereof.

其中，所述的钯催化剂可为本领域进行Suzuki偶联反应的常规催化剂，其包括但不限于四三苯基膦钯、三(二亚苄基丙酮)钯(0)、或[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)。Wherein, the palladium catalyst can be a conventional catalyst for performing Suzuki coupling reaction in the art, including but not limited to tetrakistriphenylphosphine palladium, tris(dibenzylideneacetone)palladium(0), or [1,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II).

其中，所述的钯催化剂还可与本领域进行Suzuki偶联反应的常规配体进行配位后再进行催化，例如所述的配体包括但不限于2-二环己基膦-2',4',6'-三异丙基-1,1'-联苯(XPhos)。Wherein, the palladium catalyst can also be catalyzed by coordination with a conventional ligand which is subjected to a Suzuki coupling reaction in the art, for example, the ligand includes but is not limited to 2-dicyclohexylphosphine-2', 4 ',6'-Triisopropyl-1,1'-biphenyl (XPhos).

其中，所述的碱为本领域进行Suzuki偶联反应的常规催化剂，其包括但不限于钠、钾和铯的碳酸盐或磷酸盐。Wherein the base is a conventional catalyst for the Suzuki coupling reaction in the art, including but not limited to carbonates or phosphates of sodium, potassium and rubidium.

本发明中，基于Suzuki偶联反应的反应机理，上述反应中的反应物如式IV-2所示的中间体化合物还可以其硼酸或其他硼酸酯衍生物代替。In the present invention, based on the reaction mechanism of the Suzuki coupling reaction, the reactant in the above reaction may be replaced by a boronic acid or other boronic acid ester derivative as the intermediate compound represented by the formula IV-2.

所述的化合物IV的制备方法，还可包括下述步骤：将如式(IV-3)所示的中间体化合物与如式(IV-4)所示的中间体化合物进行Suzuki偶联反应，得到所述式IV-1所示化合物，即可；The method for preparing the compound IV may further comprise the steps of: subjecting an intermediate compound represented by the formula (IV-3) to an intermediate compound represented by the formula (IV-4), and performing a Suzuki coupling reaction. Obtaining the compound of the formula IV-1, that is,

本发明还进一步提供了如上所述的化合物II-1、II-2、II-3、II-4、III-1、III-2、III-3、III-4、III-5、IV-1、IV-2、IV-3或IV-4。The present invention still further provides the compounds II-1, II-2, II-3, II-4, III-1, III-2, III-3, III-4, III-5, IV-1 as described above. , IV-2, IV-3 or IV-4.

本发明还提供了所述的如式I所示的苯并氮杂环类化合物、其互变异构体、光学异构体、溶剂化物、其药学上可接受的盐或其前药在制备溴结构域抑制剂中的应用。The present invention also provides the above-described benzazepine heterocyclic compound represented by Formula I, a tautomer thereof, an optical isomer, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof. Application in bromine domain inhibitors.

本发明还提供了所述的如式I所示的苯并氮杂环类化合物、其互变异构体、光学异构体、溶剂化物、其药学上可接受的盐或其前药在制备治疗和/预防需要调节溴结构域与乙酰化蛋白的结合能力来治疗和/或预防的疾病的药物中的应用。The present invention also provides the above-described benzazepine heterocyclic compound represented by Formula I, a tautomer thereof, an optical isomer, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof. Therapeutic and/or prophylactic applications of drugs that require modulation of the binding capacity of a bromodomain to an acetylated protein for the treatment and/or prevention of a disease.

所述的需要调节溴结构域与乙酰化蛋白的结合能力来治疗和/或预防的疾病优选包括：听神经瘤、急性白血病、急性淋巴细胞性白血病、急性髓细胞性白血病(单核细胞性、成髓细胞性、腺癌、血管肉瘤、星形细胞瘤、髓单核细胞性和早幼粒细胞性)、急性t-细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌、支气管癌、***、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞性白血病、慢性髓细胞性(粒细胞性)白血病、慢性骨髓性白血病、结肠癌、结肠直肠癌、颅咽管瘤、囊腺癌、弥漫性大B- 细胞淋巴瘤、不良增生性变化(dysproliferativechanges)(发育不良和化生)、胚胎癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食管癌、***受体阳性乳腺癌、原发性血小板增多症、尤因氏肉瘤、纤维肉瘤、滤泡性淋巴瘤、生殖细胞睾丸癌、神经胶质瘤、成胶质细胞瘤、神经胶质肉瘤、重链病、血管母细胞瘤、肝癌、肝细胞癌、激素不敏感性***癌、平滑肌肉瘤、白血病、脂肪肉瘤、肺癌、***内皮肉瘤(lymphagioendotheliosarcoma)、***肉瘤、淋巴母细胞白血病、淋巴瘤(霍奇金和非霍奇金)、膀胱、乳腺、结肠、肺、卵巢、胰腺、***、皮肤和子宫的恶性肿瘤和过度增生障碍、T-细胞或B-细胞源淋巴恶性肿瘤、白血病、淋巴瘤、髓样癌、髓母细胞瘤、黑色素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、骨髓性白血病、骨髓瘤、粘液肉瘤、神经母细胞瘤、NUT中线癌(NMC)、非小细胞肺癌、少突神经胶质瘤、口腔癌、骨原性肉瘤、卵巢癌、胰腺癌、***状腺癌、***状癌、松果体瘤、真性红细胞增多症、***癌、直肠癌、肾细胞癌、成视网膜细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、***瘤、皮肤癌、小细胞肺癌、实体瘤(癌和肉瘤)、小细胞肺癌、胃癌、鳞状细胞癌、滑膜瘤、汗腺瘤、甲状腺癌、原发性巨球蛋白血症、睾丸肿瘤、子宫癌和肾母细胞瘤等。The diseases which require modulation of the binding ability of the bromodomain to the acetylated protein for treatment and/or prevention preferably include: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocyte, Myeloid, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, Bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharynx Tumor, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasia and metaplasia), embryonal cancer, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, Erythemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocytosis, Ewing's sarcoma, fibrosarcoma, follicular lymphoma, germ cell testis Pill cancer, glioma, glioblastoma, glial sarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer , lymphatic endothelial sarcoma (lymphagioendotheliosarcoma), lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin and non-Hodgkin), bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus Tumor and hyperproliferative disorders, T-cell or B-cell-derived lymphoid malignancies, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia , myeloma, mucinous sarcoma, neuroblastoma, NUT midline cancer (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, Papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland cancer, spermatogonium Tumor, skin cancer, small cell lung cancer, solid tumor (cancer and sarcoma), small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial tumor, sweat adenoma, thyroid cancer, primary macroglobulinemia, testicular tumor , uterine cancer and nephroblastoma.

本发明还提供了所述的如式I所示的苯并氮杂环类化合物、其互变异构体、光学异构体、溶剂化物、其药学上可接受的盐或其前药在制备治疗和/预防肿瘤的药物中的应用。The present invention also provides the above-described benzazepine heterocyclic compound represented by Formula I, a tautomer thereof, an optical isomer, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof. Application in the treatment and prevention of tumors.

所述的肿瘤优选包括：听神经瘤、急性白血病、急性淋巴细胞性白血病、急性髓细胞性白血病(单核细胞性、成髓细胞性、腺癌、血管肉瘤、星形细胞瘤、髓单核细胞性和早幼粒细胞性)、急性t-细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌、支气管癌、***、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞性白血病、慢性髓细胞性(粒细胞性)白血病、慢性骨髓性白血病、结肠癌、结肠直肠癌、颅咽管瘤、囊腺癌、弥漫性大B-细胞淋巴瘤、不良增生性变化(dysproliferativechanges)(发育不良和化生)、胚胎癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食管癌、***受体阳性乳腺癌、原发性血小板增多症、尤因氏肉瘤、纤维肉瘤、滤泡性淋巴瘤、生殖细胞睾丸癌、神经胶质瘤、成胶质细胞瘤、神经胶质肉瘤、重链病、血管母细胞瘤、肝癌、肝细胞癌、激素不敏感性***癌、平滑肌肉瘤、白血病、脂肪肉瘤、肺癌、***内皮肉瘤(lymphagioendotheliosarcoma)、***肉瘤、淋巴母细胞白血病、淋巴瘤(霍奇金和非霍奇金)、膀胱、乳腺、结肠、肺、卵巢、胰腺、***、皮肤和子宫的恶性肿瘤和过度增生障碍、T-细胞或B-细胞源淋巴恶性肿瘤、白血病、淋巴瘤、髓样癌、髓母细胞瘤、黑色素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、骨髓性白血病、骨髓瘤、粘液肉瘤、神经母细胞瘤、NUT中线癌(NMC)、非小细胞肺癌、少突神经胶质瘤、口腔癌、骨原性肉瘤、卵巢癌、胰腺癌、***状腺癌、***状癌、松果体瘤、真性红细胞增多症、***癌、直肠癌、肾细胞癌、成视网膜细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、***瘤、皮肤癌、小细胞肺癌、实体瘤(癌和肉瘤)、小细胞肺癌、胃癌、鳞状细胞癌、滑膜瘤、汗腺瘤、甲状腺癌、原发性巨球蛋白血症、睾丸肿瘤、子宫癌和肾母细胞瘤等。The tumor preferably includes: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic cells) And promyelocytic), acute t-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, Chronic lymphocytic leukemia, chronic myeloid (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, poor proliferative Dysprofiferative changes (dysplasia and metaplasia), embryonic cancer, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, primary thrombocytosis Disease, Ein's sarcoma, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, glial sarcoma, heavy chain disease, Tumor cell tumor, liver cancer, hepatocellular carcinoma, hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma (lymphagioendotheliosarcoma), lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodge Malignant tumors and hyperproliferative disorders of the bladder, breast, colon, lung, ovary, pancreas, prostate, skin and uterus, T-cell or B-cell-derived lymphoid malignancies, leukemia, lymphoma, Medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline cancer (NMC), non-small cell lung cancer , oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma , retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland cancer, seminoma, skin cancer, small cell lung cancer, solid tumor (cancer and sarcoma), small cell lung cancer , gastric cancer, squamous cell carcinoma, synovial tumor, sweat adenoma, thyroid cancer, primary macroglobulinemia, testicular tumor, uterine cancer and nephroblastoma.

本发明还进一步提供了所述的如式I所示的含七元环的化合物、其互变异构体、光学异构体、溶剂化物、其药学上可接受的盐或其前药在制备用于治疗和/或预防肺部疾病、炎性疾病或自身免疫疾病的药物中的应用。The present invention still further provides the seven-membered ring-containing compound, the tautomer, the optical isomer, the solvate thereof, the pharmaceutically acceptable salt thereof or the prodrug thereof as described in Formula I. Use in medicines for the treatment and/or prevention of pulmonary diseases, inflammatory diseases or autoimmune diseases.

所述的肺部疾病、炎性疾病或自身免疫疾病优选包括：艾迪生病、急性痛风、强直性脊柱炎、哮喘、动脉粥样硬化、白塞病、大疱性皮肤病、慢性阻塞性肺病(COPD)、克罗恩病、皮炎、湿疹、巨细胞性动脉炎、肾小球性肾炎、肝炎、下垂体炎、炎性肠病、川崎病、狼疮性肾炎、多发性硬化、心肌炎、肌炎、肾炎、器官移植排斥、骨关节炎、胰腺炎、心包炎、结节性多动脉炎、局限性肺炎、原发性胆汁性肝硬化、银屑病、银屑病性关节炎、类风湿性关节炎、巩膜炎、硬化性胆管炎、脓毒症、***性红斑狼疮、高安氏动脉炎、中毒性休克、甲状腺炎、I型糖尿病、溃疡性结肠炎、葡萄膜炎、白癜风、脉管炎和韦格纳肉芽肿等。The pulmonary disease, inflammatory disease or autoimmune disease preferably includes: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, Behcet's disease, bullous skin disease, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypopituitaritis, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, muscle Inflammation, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, nodular polyarteritis, localized pneumonia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid Arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, high-angstrom arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculature Inflammation and Wegener's granuloma.

本发明还提供了一种药物组合物，其包含所述的如式I所示的苯并氮杂环类化合物、其互变异构体、光学异构体、溶剂化物、其药学上可接受的盐或其前药，和至少一种药用辅料。所述的如式I所示的含七元环的化合物、其互变异构体、光学异构体、溶剂化物、其药学上可接受的盐或其前药在药物组合物中的质量百分比为0.1％-99.9％，所述的质量百分比是指所述的如式I所示的苯丙氮杂环类化合物、其互变异构体、光学异构体、水合物、溶剂化物、其药学上可接受的盐或其前药占药物组合物总质量的百分比。所述的如式I所示的含七元环的化合物、其互变异构体、光学异构体、溶剂化物、其药学上可接受的盐或其前药与所述的药用辅料的质量分数之和为100％。所述的药用辅料的选择因施用途径和作用特点而异，通常是填充剂、稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、乳化剂或助悬剂。The present invention also provides a pharmaceutical composition comprising the benzazepine heterocyclic compound of the formula I, a tautomer thereof, an optical isomer, a solvate thereof, which is pharmaceutically acceptable Salt or its prodrug, and at least one pharmaceutical excipient. Percentage by mass of the seven-membered ring-containing compound, tautomer, optical isomer, solvate, pharmaceutically acceptable salt thereof or prodrug thereof as shown in Formula I in the pharmaceutical composition 0.1% to 99.9%, the mass percentage referred to as the phenylpropanoid heterocyclic compound represented by Formula I, a tautomer thereof, an optical isomer, a hydrate, a solvate thereof, and the like. A pharmaceutically acceptable salt or a prodrug thereof as a percentage of the total mass of the pharmaceutical composition. The seven-membered ring-containing compound, the tautomer, the optical isomer, the solvate thereof, the pharmaceutically acceptable salt thereof or the prodrug thereof, and the pharmaceutically acceptable excipient as described in Formula I The sum of the quality scores is 100%. The choice of the pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, and is usually a filler, a diluent, a binder, a wetting agent, a disintegrating agent, a lubricant, an emulsifier or a suspending agent.

本发明还提供了所述的药物组合物在制备溴结构域抑制剂中的应用。The invention also provides the use of the pharmaceutical composition for the preparation of a bromodomain inhibitor.

本发明还提供了所述的药物组合物在制备治疗和/预防需要调节溴结构域与乙酰化蛋白的结合能力来治疗和/或预防的疾病的药物中的应用。The present invention also provides the use of the pharmaceutical composition for the preparation of a medicament for treating and preventing a disease requiring modulation of the binding ability of a bromodomain to an acetylated protein for treatment and/or prevention.

所述的需要调节溴结构域与乙酰化蛋白的结合能力来治疗和/或预防的疾病如前所述。The diseases which require modulation of the binding ability of the bromodomain to the acetylated protein for treatment and/or prevention are as described above.

本发明还提供了一种治疗个体疾病或疾病状态的方法，所述的方法包括给予需要其的个体治疗有效量的如式I所示的含七元环的化合物、其互变异构体、光学异构体、水合物、溶剂化物、其药学上可接受的盐或其前药，其中所述的疾病或疾病状态选自如前所述的需要调节溴结构域与乙酰化蛋白的结合能力来治疗和/或预防的疾病、肺部疾病、炎性疾病或自身免疫疾病(其定义均如上所述)。The invention also provides a method of treating a disease or condition in an individual, the method comprising administering to the individual in need thereof a therapeutically effective amount of a seven-membered ring-containing compound, a tautomer thereof, of the formula I, An optical isomer, hydrate, solvate, pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein the disease or condition is selected from the group consisting of the ability to modulate the binding of a bromodomain to an acetylated protein as previously described. The disease to be treated and/or prevented, the lung disease, the inflammatory disease or the autoimmune disease (the definitions are as described above).

在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。The above preferred conditions can be arbitrarily combined without departing from the ordinary knowledge in the art, that is, preferred embodiments of the present invention.

除非另有说明，在本发明说明书和权利要求书中出现的以下术语具有下述含义：Unless otherwise stated, the following terms appearing in the specification and claims of the present invention have the following meanings:

术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base. When a relatively acidic functional group is contained in the compound of the present invention, a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When a relatively basic functional group is contained in the compound of the present invention, an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; and salts of amino acids (such as arginine, etc.) And salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the invention contain both basic and acidic functional groups which can be converted to any base or acid addition salt.

优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。Preferably, the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound. The parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.

本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。As used herein, a "pharmaceutically acceptable salt" is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids. Conventional non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturaldehyde, propionic acid, salicylic acid, stearic acid, acrylic acid, succinic acid, sulfamic acid, p-aminobenzenesulfonic acid, sulfuric acid, tannin, Tartaric acid and p-toluenesulfonic acid.

本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid. Generally, a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.

除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。In addition to the form of the salt, the compounds provided herein also exist in the form of prodrugs. Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention. Furthermore, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.

本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.

术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams & Wilkins(2005)，该文献的内容通过引用的方式并入本文。The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on the vector, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the disclosure of which is incorporated herein by reference.

术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。The term "excipient" generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.

针对药物或药理学活性剂而言，术语“有效量”或“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。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。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。The term "effective amount" or "therapeutically effective amount" with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect. For oral dosage forms in the present invention, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.

本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.

本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention. Additional asymmetric carbon atoms may be present in the substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are included within the scope of the invention.

本文中消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120.1985年,62:114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。Graphical representations of racemates, ambiscalemic and scalemic or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. 1985, 62: 114-120. The absolute configuration of a stereocenter is indicated by a wedge key and a dashed key unless otherwise stated. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the invention.

本发明涉及的化学通式可以表现出互变异构、结构异构和立体异构现象。本发明包括其任意互变或结构或立体异构形式及其混合物，他们的能力不限于任何一种异构或其混合物的形式。The chemical formulae of the present invention may exhibit tautomerism, structural isomerism, and stereoisomerism. The invention includes any interconversion or structural or stereoisomeric forms thereof, and mixtures thereof, the ability of which is not limited to any one or a mixture thereof.

可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的分步结晶法或色谱法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。The optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer. Alternatively, when a molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a salt of a diastereomer is formed with a suitable optically active acid or base, followed by stepping as is known in the art. The diastereomeric resolution is carried out by crystallization or chromatography, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of an amino group from an amine). Formate).

本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( ³H)，碘-125( ¹²⁵I)或C-14( ¹⁴C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, radiolabeled compounds can be used, such as tritium ⁽³ H), iodine -125 ⁽¹²⁵ I) or ^C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.

除非另有规定，术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为酮基(即＝O或氧代)时，意味着两个氢原子被取代。酮取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。Unless otherwise specified, the term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and after substitution The compound is stable. When the substituent is a keto group (ie, =0 or oxo), it means that two hydrogen atoms are substituted. Ketone substitution does not occur on the aryl group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.

除非另有规定，当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。当一个基团被多个R取代、且所有的R均为H时，其表示未被取代的基团。Unless otherwise specified, when any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. When a group is substituted by a plurality of R and all of R are H, it represents an unsubstituted group.

当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.

本发明中，当采用类似“R ¹-R ²-R ³-”的形式对取代基的类型和范围进行定义时，其表示如“R ¹-R ²-R ³-”所示的取代基整体上是以R ³与所述的化合物母体直接成键，并且其中的如R ¹、R ²、R ³所示的取代基彼此之间通过化学键依次键合；另外如“R ¹-R ²-R ³-”所示的取代基还可以通过文字描述来进行定义，如本发明中所述的“R ¹-R ²-R ³-”与“被R ¹取代的R ²-R ³-”，其含义是一致的。 In the present invention, when the type and range of the substituent are defined in a form similar to "R ¹ -R ² -R ³ -", it means a substituent as shown by "R ¹ -R ² -R ³ -" In general, R ^{3 is} directly bonded to the parent of the compound, and the substituents represented by R ¹ , R ² , and R ³ are sequentially bonded to each other by a chemical bond; otherwise, as “R ¹ —R ² -R ³ - "shown substituents may be defined by the character described, the present invention as described in ^{^{^{the" R 1 -R 2 -R 3 -}}} "and" is substituted by R ¹ R ² -R ³ - ", the meaning is the same.

除非另有规定，当一个基团或者取代基的键可以交叉连接到一个环上的两个原子时，这种基团或者取代基可以与这个环上的任意原子相键合。当所列举的基团或者取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时，这种基团或者取代基可以通过其任何原子相键合。基团或者取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。Unless otherwise specified, when a group or a bond of a substituent may be cross-linked to two atoms on a ring, such a group or substituent may be bonded to any atom on the ring. When the recited group or substituent does not indicate which atom is attached to a compound included in the chemical structural formula, but not specifically mentioned, such a group or substituent may be bonded through any of its atoms. Combinations of groups or substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的、单元或多元不饱和的，可以是单取代、二取代或多取代的，可以包括二价或多价原子团，具有指定数量的碳原子(如C ₁-C ₁₀表示1至10个碳)。所述烃基包括脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烷基”表示直链的或支链或环状的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烷基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2，4-戊二烯基、3-(1，4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。 Unless otherwise specified, the term "hydrocarbyl" or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic. The hydrocarbon radical or a combination thereof may be fully saturated, unitary or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may include divalent or polyvalent radicals having a specified number of carbon atoms (eg, C1 ₎ -C ₁₀ represents 1 to 10 carbons). The hydrocarbon group includes an aliphatic hydrocarbon group including an chain hydrocarbon group and a cyclic hydrocarbon group, and includes, but not limited to, an alkyl group, an alkenyl group, and an alkynyl group, and the aromatic hydrocarbon group includes, but not limited to, a 6-12 member aromatic hydrocarbon group. For example, benzene, naphthalene, and the like. In some embodiments, the term "alkyl" refers to a straight or branched or cyclic group of atoms or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals. Examples of saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl). A homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl. The unsaturated alkyl group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and Structure.

除非另有规定，所述杂烃基、杂环基、烃杂基、环杂基、杂烃基杂基、杂环基杂基是指特定基团上含有杂原子或杂原子团，杂原子或杂原子团包括但不限于N、NH、被取代或者被保护的NH、O、S、S(＝O)、S(＝O) ₂、C(＝O)、C(＝O)O，对于环系而言，杂原子或杂原子团可以位于环系之内或环系之外(比如环丙基砜基、环丙基酰基)，其中，所谓杂烃基、杂环基是通过碳原子与分子其余部分相连接，即杂原子可以位于该基团的任何位置(除该基团附着于分子其余部分的位置之外)；所谓烃杂基、环杂基是通过杂原子与分子其余部分相连接，即杂原子位于该基团附着于分子其余部分的位置上；所谓杂烃基杂基、杂环基杂基是通过杂原子与分子其余部分相连接，其中杂原子可以位于该基团的任何位置(包括该基团附着于分子其余部分的位置)。 Unless otherwise specified, the heteroalkyl, heterocyclyl, hydrocarbyl, cyclohetero, heteroalkylhetero, heterocyclylhetero group means a hetero atom or a hetero atom group, a hetero atom or a hetero atom group on a specific group. Including but not limited to N, NH, substituted or protected NH, O, S, S(=O), S(=O) ₂ , C(=O), C(=O)O, for the ring system The hetero atom or hetero atom group may be located within the ring system or outside the ring system (such as cyclopropyl sulfone group, cyclopropyl acyl group), wherein the so-called heterohydrocarbyl group and heterocyclic group are through the carbon atom and the rest of the molecule. Linking, that is, a hetero atom can be located anywhere in the group (except where the group is attached to the rest of the molecule); the so-called hydrocarbon heterocycle, cyclohetero is attached to the rest of the molecule through a heteroatom, ie, The atom is located at a position where the group is attached to the rest of the molecule; the so-called heterohydroalkyl heterocyclyl, heterocyclylhetero is attached to the remainder of the molecule through a heteroatom, wherein the heteroatom can be located anywhere in the group (including the The group is attached to the rest of the molecule).

除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子B、O、N和S可以位于杂烃基的任何内部位置(除该烃基附着于分子其余部分的位置之外)。实例包括但不限于-CH ₂-CH ₂-O-CH ₃、-CH ₂-CH ₂-NH-CH ₃、-CH ₂-CH ₂-N(CH ₃)-CH ₃、-CH ₂-S-CH ₂-CH ₃、-CH ₂-CH ₂、-S(O)-CH ₃、-CH ₂-CH ₂-S(O) ₂-CH ₃、-CH＝CH-O-CH ₃、-CH ₂-CH＝N-OCH ₃和–CH＝CH-N(CH ₃)-CH ₃。至多两个杂原子可以是连续的，例如-CH ₂-NH-OCH ₃。 Unless otherwise specified, the term "heterohydrocarbyl" or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom. In some embodiments, the term "heterohydrocarbyl" or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and the like), by itself or in combination with another term, means a stable straight chain. A hydrocarbon group of a chain or a combination thereof having a number of carbon atoms and at least one hetero atom. In a typical embodiment, the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized. The heteroatoms B, O, N and S may be located at any internal position of the heterohydrocarbyl group (except where the hydrocarbyl group is attached to the rest of the molecule). Examples include, but are not limited to, -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -NH-CH ₃ , -CH ₂ -CH ₂ -N(CH ₃ )-CH ₃ , -CH ₂ -S -CH ₂ -CH ₃ , -CH ₂ -CH ₂ , -S(O)-CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH=CH-O-CH ₃ ,- CH ₂ -CH=N-OCH ₃ and -CH=CH-N(CH ₃ )-CH ₃ . Up to two heteroatoms may be consecutive, for example, -CH ₂ -NH-OCH _3.

除非另有规定，术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部分的那些烷基基团。Unless otherwise specified, the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) are customary and are meant to be attached to the molecule through an oxygen, amino or sulfur atom, respectively. The rest of those alkyl groups.

除非另有规定，术语“环烃基”、“杂环烃基”、“环烃杂基”或者其下位概念(比如芳基、杂芳基、芳杂基、环烷基、杂环烷基、环烷杂基、环烯基、杂环烯基、环烯杂基、环炔基、杂环炔基、环炔杂基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”或“烃杂基”。环烷基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。Unless otherwise specified, the terms "cycloalkyl", "heterocycloalkyl", "cyclohetero" or subordinates thereof (such as aryl, heteroaryl, aryl, cycloalkyl, heterocycloalkyl, ring) Alkyl, cycloalkenyl, heterocycloalkenyl, cycloalkenyl, cycloalkynyl, heterocycloalkynyl, cycloalkynyl, and the like, by themselves or in combination with other terms, respectively denote a cyclized "hydrocarbyl group", Heterohydrocarbyl" or "hydrocarbyl". Examples of cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Non-limiting examples of heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.

除非另有规定，术语“卤代”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C ₁-C ₄)烷基”意在包括但不仅限于三氟甲基、2，2，2-三氟乙基、4-氯丁基和3-溴丙基等等。 Unless otherwise specified, the term "halo" or "halogen", by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom. Further, the term "haloalkyl" is intended to include both monohaloalkyl and polyhaloalkyl. For example, the term "halo(C ₁ -C ₄ )alkyl" is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.

除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代、二取代或多取代的，它可以是单环或多环(优选1至3个环)，它们稠合在一起或共价连接。术语“杂芳基”、“芳杂基”、“杂芳环”、“芳杂环”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，该基团为双环时，一个环可为苯基、另一个换可为含杂原子的环烃基。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。在一个示范性实例中，碳原子可任选地被氧化。杂芳基可通过杂原子连接到分子的其余部分，也可通过碳原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-噁唑基、4-噁唑基、2-苯基-4-噁唑基、5-噁唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。Unless otherwise specified, the term "aryl" denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, which may be monocyclic or polycyclic (preferably 1 to 3 rings), They are fused together or covalently linked. The terms "heteroaryl", "arylhetero", "heteroaryl ring", "aromatic heterocycle" refer to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, when the group is bicyclic, one ring may be a phenyl group and the other may be a hetero atom-containing cyclic hydrocarbon group. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized. In an illustrative example, the carbon atom can be optionally oxidized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom or to the remainder of the molecule through a carbon atom. Non-limiting examples of aryl or heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, indolyl, 2-benzimidazolyl, 5-indenyl, 1-isoquinolyl, 5-isoquinolinyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolinyl. The substituents of any of the above aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.

除非另有规定，为简便起见，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。Unless otherwise specified, for ease of use, aryl groups, when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen. Those alkyl groups substituted by an atom, such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.

除非另有规定，“环”表示被取代或未被取代的环烷基、被取代或未被取代的杂环烷基、被取代或未被取代的芳基或被取代或未被取代的杂芳基。所谓的环包括稠环。环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子。除非另有规定，该环任选地包含1-3个杂原子。因此，“5-7元环”包括例如苯基吡啶和哌啶基；另一方面，术语“5-7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。Unless otherwise specified, "ring" means substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted hetero Aryl. The so-called ring includes a fused ring. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5-7 membered ring" means 5-7 atoms arranged around. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms. Thus, "5-7 membered ring" includes, for example, phenylpyridine and piperidinyl; on the other hand, the term "5-7 membered heterocycloalkyl ring" includes pyridyl and piperidinyl, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, each of which "ring" independently conforms to the above definition.

除非另有规定，本文所用术语“杂原子”包括碳(C)和氢(H)以外的原子，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)和硼(B)等。The term "hetero atom" as used herein, unless otherwise specified, includes atoms other than carbon (C) and hydrogen (H), including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), antimony ( Ge), aluminum (Al) and boron (B).

除非另有规定，术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。Unless otherwise specified, the term "leaving group" refers to a functional group or atom that can be substituted by another functional group or atom by a substitution reaction (eg, an affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.

除非另有规定，术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。Unless otherwise specified, the term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like. The term "hydroxy protecting group" refers to a protecting group suitable for use in preventing hydroxy side reactions. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.

除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基。C _1-6烷氧基包括C ₁、C ₂、C ₃、C ₄、C ₅和C ₆的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。“环烷基”包括饱和环基，如环丙基、环丁基或环戊基。3-7环烷基包括C ₃、C ₄、C ₅、C ₆和C ₇环烷基。“链烯基”包括直链或支链构型的烃链，其中该链上任何的稳定位点上存在一个或多个碳-碳双键，例如乙烯基和丙烯基。 Unless otherwise specified, examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. "Alkoxy" represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge. The C _1-6 alkoxy group includes a C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy. "Cycloalkyl" includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl. The 3-7 cycloalkyl group includes C ₃ , C ₄ , C ₅ , C ₆ and C ₇ cycloalkyl groups. "Alkenyl" includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.

除非另有规定，术语“卤素”或“卤素”是指氟、氯、溴和碘。Unless otherwise specified, the term "halogen" or "halogen" refers to fluoro, chloro, bromo and iodo.

除非另有规定，术语“杂环”或“杂环基”意指稳定的单环或双环或双环杂环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。Unless otherwise specified, the term "heterocycle" or "heterocyclyl" means a stable monocyclic or bicyclic or bicyclic heterocyclic ring which may be saturated, partially unsaturated or unsaturated (aromatic), which A carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocyclic rings may be fused to a phenyl ring to form a bicyclic ring.

除非另有规定，杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并***基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、isatino基、异苯并呋喃基、吡喃、异吲哚基、异二氢吲哚基、异吲哚基、吲哚基、异喹啉基、异噻唑基、异噁唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、异噁唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并噁唑、吡啶并咪唑、吡啶并噻唑、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、吡唑基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩基、噻吩并噁唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基和呫吨基。还包括稠环和螺环化合物。Unless otherwise specified, examples of heterocyclic compounds include, but are not limited to, acridinyl, anthracycline, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazole , benzoxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH -carbazolyl, porphyrinyl, chromanyl, chromene, porphyrinyldecahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuran[2 ,3-b]tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl, indanyl, mesoindolyl, anthracene , 3H-fluorenyl, isatino, isobenzofuranyl, pyran, isodecyl, isoindoline, isodecyl, fluorenyl, isoquinolyl, isothiazolyl, Isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4- Oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, Oxazolyl, hydroxymethyl, pyrimidinyl, phenanthryl, phenanthroline, phenazine, phenothiazine, benzoxanthyl, phenoloxazinyl, pyridazinyl, piperazinyl, piperidinyl , piperidinone, 4-piperidinone, piperonyl, pteridinyl, fluorenyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridine Oxazole, pyridoimidazole, pyridylthiazole, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, pyrazolyl, quinazolinyl, quinolyl, 4H-quina Azinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2, 3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiazide, thiazolyl, isothiazolyl Thienyl, thienyl, thienooxazolyl, thienothiazolyl, thienoimidazolyl, thienyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1 , 2,5-triazolyl, 1,3,4-triazolyl and xanthene. Also included are fused ring and spiro compounds.

除非另有规定，本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。Unless otherwise specified, the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthesis methods, and techniques of the art. Preferred embodiments are well known to those skilled in the art, and preferred embodiments include, but are not limited to, embodiments of the invention.

除非另有规定，对于每个单个步骤最佳的反应条件和反应时间可以根据所采用的具体反应物和所用的反应物中存在的取代基而变化。除非另有说明，溶剂、温度和其它反应条件可以由本领域技术人员容易地选择。具体方法提供在合成实施例部分。反应可以以常规的方式进行后处理，例如通过从残余物中除去溶剂并根据本领域已知的方法学进一步纯化，所述方法学例如，但不限于，结晶、蒸馏、萃取、研制和色谱。除非另有说明，所述原料和试剂可商购获得或可以由本领域技术人员使用化学文献中描述的方法由可商购获得的材料制备。Unless otherwise specified, the optimum reaction conditions and reaction times for each individual step may vary depending on the particular reactant employed and the substituents present in the reactants employed. Solvents, temperatures and other reaction conditions can be readily selected by one skilled in the art, unless otherwise indicated. Specific methods are provided in the Synthesis Examples section. The reaction can be post-treated in a conventional manner, for example by removing the solvent from the residue and further purifying according to methods known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise indicated, the starting materials and reagents are either commercially available or can be prepared from the commercially available materials by those skilled in the art using methods described in the chemical literature.

除非另有规定，常规实验，包括反应条件、试剂和合成路线顺序的适当操作，与反应条件不能相容的任何化学官能团的保护，和在该方法的反应顺序中在适当的点的脱保护都包括在本发明的范围内。合适的保护基团和使用这些合适的保护基团用于保护和脱保护不同取代基的方法，是本领域技术人员熟知的，其实例可见于T.Greene和P.Wuts,Protecting Groups in Organic Synthesis(3rd ed.),John Wiley & Sons,NY(1999)，其通过引用方式以其整体并入本文。本发明化合物的合成可以通过类似于在上文中描述的合成反应路线和具体实施例中所述方法来完成。Unless otherwise specified, routine experimentation, including appropriate conditions for reaction conditions, reagents and synthetic route sequences, protection of any chemical functional groups that are incompatible with the reaction conditions, and deprotection at appropriate points in the reaction sequence of the process are It is included in the scope of the invention. Suitable protecting groups and methods for protecting and deprotecting different substituents using these suitable protecting groups are well known to those skilled in the art, examples of which can be found in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis. (3rd ed.), John Wiley & Sons, NY (1999), which is incorporated herein in its entirety by reference. The synthesis of the compounds of the invention can be accomplished by methods analogous to those described above in the synthetic reaction schemes and in the specific examples.

除非另有规定，原料如果不能商购，可通过选自标准有机化学技术，类似于合成已知的、结构类似的化合物的技术，或类似于上述反应路线或在合成实施例部分中所述的方法来制备。Unless otherwise specified, starting materials, if not commercially available, may be selected from techniques selected from standard organic chemistry techniques, similar to techniques for synthesizing known, structurally similar compounds, or similar to those described above in the Reaction Schemes section or in the Synthesis Examples section. Method to prepare.

除非另有规定，当需要化合物的旋光形式时，它可以通过进行本文所述的方法之一使用光学活性的原料(例如通过不对称诱导合适的反应步骤来制备)来获得，或通过使用标准方法(如色谱分离、重结晶或酶拆分)拆分化合物或中间体的立体异构体混合物来获得。Unless otherwise specified, when an optically active form of the compound is desired, it can be obtained by performing an optically active starting material (e.g., by asymmetrically inducing a suitable reaction step) in one of the methods described herein, or by using standard methods. Obtained as a mixture of stereoisomers of a compound or an intermediate, such as by chromatographic separation, recrystallization or enzymatic resolution.

除非另有规定，当需要化合物的纯几何异构体时，它可以通过进行上述方法之一，使用纯几何异构体作为原料，或通过使用标准方法，如色谱分离来拆分化合物或中间体的几何异构体的混合物来制备。Unless otherwise specified, when a pure geometric isomer of a compound is desired, it can be resolved by one of the methods described above, using pure geometric isomers as starting materials, or by resolution using standard methods such as chromatographic separation. A mixture of geometric isomers is prepared.

除非另有规定，本发明所用试剂和原料均市售可得。Unless otherwise specified, the reagents and starting materials used in the present invention are commercially available.

除非另有规定，本发明采用下述缩略词：aq代表水；HATU代表O-7-氮杂苯并***-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH ₃代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc ₂O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl ₂代表氯化亚砜；CS ₂代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu ₄NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点。 Unless otherwise specified, the invention employs the following abbreviations: aq for water; HATU for O-7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea Hexafluorophosphate; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, etc. CDI stands for carbonyl diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; CBz stands for benzyloxycarbonyl, an amine protecting group; BOC stands for t-butylcarbonyl is an amine protecting group; HOAc stands for acetic acid; NaCNBH ₃ stands for cyanide Sodium borohydride; rt stands for room temperature; O/N stands for overnight; THF stands for tetrahydrofuran; Boc ₂ O stands for di-tert-butyldicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; SOCl ₂ Represents thionyl chloride; CS ₂ represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS represents 1-chloropyrrolidine-2,5-dione; n-Bu ₄ N F represents tetrabutylammonium fluoride; iPrOH represents 2-propanol; mp represents a melting point.

除非另有规定，本发明的化合物经手工或者

软件命名，市售化合物采用供应商目录名称。 Unless otherwise specified, the compounds of the invention are either by hand or

Software naming, commercially available compounds using the supplier catalog name.

本发明的积极进步效果在于：本发明的含氮大环类化合物可有效地结合BET家族BRD4、BRD3、BRD2和BRDT的溴结构域，以调控下游基因c-myc和其相关靶基因的转录，进而调节下游的信号通路，发挥特定作用，包括治疗疾病如炎性疾病、癌症和AIDS；其中部分化合物具有很高的活性，并且具有较好的细胞活性和代谢稳定性，因此可以成为***的有效药物。The positive progress of the present invention is that the nitrogen-containing macrocyclic compound of the present invention can effectively bind to the bromine domains of the BET family BRD4, BRD3, BRD2 and BRDT to regulate the transcription of the downstream gene c-myc and its related target genes. In turn, it regulates the downstream signaling pathway and plays a specific role, including the treatment of diseases such as inflammatory diseases, cancer and AIDS; some of the compounds have high activity, and have good cell activity and metabolic stability, so they can be used to treat tumors. Effective drugs.

具体实施方式detailed description

下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。The invention is further illustrated by the following examples, which are not intended to limit the invention. The experimental methods in the following examples which do not specify the specific conditions are selected according to conventional methods and conditions, or according to the product specifications.

实施例Example

4106：10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-2,5-二氢-3H-苯并[c]哒嗪并[3,4-e]氮杂卓-3-酮4106: 10-((Ethyl sulfonyl)methyl)-7-(4-fluorophenyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridazine[3,4 -e]azepine-3-one

步骤1：2-((3,6-二氯哒嗪-4-基)甲基)异吲哚-1,3-二酮Step 1: 2-((3,6-Dichloropyridazin-4-yl)methyl)isoindole-1,3-dione

在70℃下，向3,6-二氯哒嗪(10g,67mmol)，2-(1,3-二氧代异吲哚-2-基)乙酸(24.5g,114mmol)，硝酸银(1.1g,6.7mmol)和三氟乙酸(1.54g,13.4mmol)的水溶液(100mL)中缓慢加入过硫酸铵(27g,120mmol)的水溶液(100mL)，得到的混合物在70℃下搅拌过夜。反应液冷却至室温，用乙酸乙酯(200mL)稀释，氢氧化铵中和(pH＝9.0)。有机相用无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/1(体积比，)，得标题化合物2-((3,6-二氯哒嗪-4-基)甲基)异吲哚-1,3-二酮(1.2g,5％)，为白色固体。To 3,6-dichloropyridazine (10 g, 67 mmol), 2-(1,3-dioxoisoindol-2-yl)acetic acid (24.5 g, 114 mmol) at 70 ° C, silver nitrate (1.1 An aqueous solution (100 mL) of ammonium persulfate (27 g, 120 mmol) was slowly added to an aqueous solution (100 mL) of trifluoroacetic acid (1.54 g, 13.4 mmol), and the mixture was stirred at 70 ° C overnight. The reaction solution was cooled to room temperature, diluted with ethyl acetate (200 mL), and then evaporated. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (EtOAc/EtOAc (EtOAc:EtOAc) Indole-1,3-dione (1.2 g, 5%) was obtained as a white solid.

LCMS(ESI)[M+H] ⁺＝308.0. LCMS (ESI) [M+H] ⁺ = 308.0.

步骤2：2-((3-氯-6-羟基哒嗪-4-基)甲基)异吲哚-1,3-二酮Step 2: 2-((3-Chloro-6-hydroxypyridazin-4-yl)methyl)isoindole-1,3-dione

将2-((3,6-二氯哒嗪-4-基)甲基)异吲哚-1,3-二酮(1.2g,3.9mmol)溶于乙酸(20mL)中，加热至100℃搅拌过夜。反应液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/1(体积比))，得标题化合物2-((3-氯-6-羟基哒嗪-4-基)甲基)异吲哚-1,3-二酮(500mg,44％)，为白色固体。LCMS(ESI)[M+H] ⁺＝290.1. 2-((3,6-Dichloropyridazin-4-yl)methyl)isoindole-1,3-dione (1.2 g, 3.9 mmol) was dissolved in acetic acid (20 mL) and heated to 100 ° C Stir overnight. The reaction mixture was concentrated, and the residue was purified (jjjjjjjjjj Methyl)isoindole-1,3-dione (500 mg, 44%) was obtained as a white solid. LCMS (ESI) [M+H] ⁺ = 290.1.

步骤3：2-((3-氯-1-甲基-6-氧代-1,6-二氢哒嗪-4-基)甲基)异吲哚-1,3-二酮Step 3: 2-((3-Chloro-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)methyl)isoindole-1,3-dione

将2-((3-氯-6-羟基哒嗪-4-基)甲基)异吲哚-1,3-二酮(500mg,1.7mmol)，碘甲烷(250mg,1.7mmol)和碳酸铯(1.7g,5.2mmol)混合于N,N-二甲基甲酰胺(10mL)中，在室温下搅拌过夜。反应液中加入水和乙酸乙酯(20mL)，分离有机相。有机相用无水硫酸钠干燥，过滤并浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/1(体积比))，得标题化合物2-((3-氯-1-甲基-6-氧代-1,6-二氢哒嗪-4-基)甲基)异吲哚-1,3-二酮(300mg,58％)，为白色固体。LCMS(ESI)[M+H] ⁺＝304.0. 2-((3-Chloro-6-hydroxypyridazin-4-yl)methyl)isoindole-1,3-dione (500 mg, 1.7 mmol), iodomethane (250 mg, 1.7 mmol) and cesium carbonate (1.7 g, 5.2 mmol) was added in EtOAc (EtOAc) Water and ethyl acetate (20 mL) were added to the mixture and the organic layer was separated. The organic phase was dried over anhydrous sodium sulfate (MgSO4) Methyl-6-oxo-1,6-dihydropyridazin-4-yl)methyl)isoindole-1,3-dione (300 mg, 58%) as a white solid. LCMS (ESI) [M+H] ⁺ = 304.0.

步骤4：5-(氨甲基)-6-氯-2-甲基哒嗪-3(2H)-酮Step 4: 5-(Aminomethyl)-6-chloro-2-methylpyridazine-3(2H)-one

将2-((3-氯-1-甲基-6-氧代-1,6-二氢哒嗪-4-基)甲基)异吲哚-1,3-二酮(300mg,1mmol)和水合肼(2.4mL,12mmol)溶于乙醇(20mL)中，在室温下搅拌过夜。反应液浓缩，得标题化合物5-(氨甲基)-6-氯-2-甲基哒嗪-3(2H)-酮粗品(147mg)，为黄色油状物，不经纯化直接用于下一步反应。LCMS(ESI)[M+H] ⁺＝174.0. 2-((3-Chloro-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)methyl)isoindole-1,3-dione (300 mg, 1 mmol) The hydrazine hydrate (2.4 mL, 12 mmol) was dissolved in ethanol (20 mL) and stirred at room temperature overnight. The reaction mixture was concentrated to give purified crystal crystal crystal crystal crystal crystal crystal reaction. LCMS (ESI) [M+H] ⁺ = 174.0.

步骤5：(3-氯-1-甲基-6-氧代-1,6-二氢哒嗪-4-基)甲基氨基甲酸叔丁酯Step 5: (3-Chloro-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)methylcarbamic acid tert-butyl ester

将5-(氨甲基)-6-氯-2-甲基哒嗪-3(2H)-酮(150mg,0.87mmol)，二碳酸二叔丁酯(378mg,1.73mmol)和三乙胺(264mg,2.61mmol)溶于二氯甲烷(5mL)中，在室温下搅拌过夜。反应液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝2/1)，得标题化合物(3-氯-1-甲基-6-氧代-1,6-二氢哒嗪-4-基)甲基氨基甲酸叔丁酯(150mg,两步产率63％)，为白色固体。LCMS(ESI)[M+H] ⁺＝274.0. 5-(Aminomethyl)-6-chloro-2-methylpyridazin-3(2H)-one (150 mg, 0.87 mmol), di-tert-butyl dicarbonate (378 mg, 1.73 mmol) and triethylamine ( 264 mg, 2.61 mmol) was dissolved in dichloromethane (5 mL). The reaction mixture was concentrated, and the residue was crystalljjjjjjjjjjjjjjjjj tert-Butyl 4-pyridyl-4-methylcarbamate (150 mg, 63% yield in two steps) as a white solid. LCMS (ESI) [M+H] ⁺ =274.0.

步骤6：(3-(5-((乙基砜)甲基)-2-(4-氟苯甲酰基)苯基)-1-甲基-6-氧代-1,6-二氢哒嗪-4-基)甲基氨基甲酸叔丁酯Step 6: (3-(5-((Ethyl sulfonyl)methyl)-2-(4-fluorobenzoyl)phenyl)-1-methyl-6-oxo-1,6-dihydroindole Tert-butyl ester of pyrazin-4-yl)methylcarbamate

将(3-氯-1-甲基-6-氧代-1,6-二氢哒嗪-4-基)甲基氨基甲酸叔丁酯(90mg,0.33mmol)，(4-((乙基砜)甲基)-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)(4-氟苯基)甲酮(142mg,0.33mmol)，三(二亚苄基丙酮)二钯(30mg,0.033mmol)，2-双环己基膦-2',4',6'-三异丙基联苯(16mg,0.033mmol)和磷酸钾(140mg,0.66mmol)混合于1,4-二氧六环(5mL)和水(1滴)中，在氮气保护下加热至100℃搅拌过夜。反应液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/2(体积比))，得标题化合物(3-(5-((乙基砜)甲基)-2-(4-氟苯甲酰基)苯基)-1-甲基-6-氧代-1,6-二氢哒嗪-4-基)甲基氨基甲酸叔丁酯(25mg,14％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝544.0. tert-Butyl (3-chloro-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)methylcarbamate (90 mg, 0.33 mmol), (4-((ethyl) Sulfone)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(4-fluorophenyl)methanone 142 mg, 0.33 mmol), tris(dibenzylideneacetone)dipalladium (30 mg, 0.033 mmol), 2-biscyclohexylphosphine-2',4',6'-triisopropylbiphenyl (16 mg, 0.033 mmol) It was mixed with potassium phosphate (140 mg, 0.66 mmol) in 1,4-dioxane (5 mL) and water (1 drop), and heated to 100 ° C under nitrogen atmosphere and stirred overnight. The reaction mixture was concentrated, and the residue was purified (jjjjjjjjj (4-Fluorobenzoyl)phenyl)-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)methylcarbamic acid tert-butyl ester (25 mg, 14%) Yellow oil. LCMS (ESI) [M+H] ⁺ = 544.0.

步骤7：10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-2,5-二氢-3H-苯并[c]哒嗪并[3,4-e]氮杂卓-3-酮Step 7: 10-((Ethyl sulfonyl)methyl)-7-(4-fluorophenyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridazine[3, 4-e]azazo-3-one

将(3-(5-((乙基砜)甲基)-2-(4-氟苯甲酰基)苯基)-1-甲基-6-氧代-1,6-二氢哒嗪-4-基)甲基氨基甲酸叔丁酯(25mg,0.05mmol)和三氟乙酸(1mL)溶于二氯甲烷(4mL)中，在室温下搅拌过夜。反应液浓缩，残余物用制备-HPLC分离纯化，得标题化合物10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-2,5-二氢-3H-苯并[c]哒嗪并[3,4-e]氮杂卓-3-酮(11mg,58％)，为白色固体。LCMS(ESI)[M+H] ⁺＝426.1，纯度100％(UV 214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.12(s,1H),7.72(m,1H),7.58(m,2H),7.42(d,J＝7.6Hz,1H),7.22(m,2H),7.07(s,1H),4.88(m,1H),4.65(s,2H),4.21(m,1H),3.91(s,3H),3.27(q,J＝7.6Hz,2H),1.44 (t,J＝7.6Hz,3H). (3-(5-((ethylsulfonyl)methyl)-2-(4-fluorobenzoyl)phenyl)-1-methyl-6-oxo-1,6-dihydropyridazine- Tetrabutyl 4-methyl)methylcarbamate (25 mg, 0.05 mmol) and trifluoroacetic acid (1 mL) were dissolved in dichloromethane (4 mL) and stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was crystallijjjjjjjjjjjjjjj 3H-Benzo[c]pyridazino[3,4-e]azepin-3-one (11 mg, 58%) as a white solid. LCMS (ESI) [M + H ] + = 426.1, purity ^{100 (UV 214nm)%; 1} H NMR (400MHz, CD 3 OD) δ8.12 (s, 1H), 7.72 (m, 1H), 7.58 (m , 2H), 7.42 (d, J = 7.6 Hz, 1H), 7.22 (m, 2H), 7.07 (s, 1H), 4.88 (m, 1H), 4.65 (s, 2H), 4.21 (m, 1H) , 3.91 (s, 3H), 3.27 (q, J = 7.6 Hz, 2H), 1.44 (t, J = 7.6 Hz, 3H).

4107：(S)-7-(2-氯-4-氟苯基)-5-环丙基-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮4107: (S)-7-(2-Chloro-4-fluorophenyl)-5-cyclopropyl-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro- 3H-benzo[c]pyrido[3,4-e]azepin-3-one

步骤1：(S)-N-((S)-环丙基(5-(5-((乙基砜)甲基)-2-(4-氟苯甲酰基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)-2-甲基丙烷-2-亚磺酰胺Step 1: (S)-N-((S)-cyclopropyl(5-(5-((ethylsulfonyl)methyl)-2-(4-fluorobenzoyl)phenyl)-1-yl) 5-oxo-1,2-dihydropyridin-4-yl)methyl)-2-methylpropane-2-sulfinamide

将(2-溴-5-氯-4-((乙基砜)甲基)苯基)(2-氯-4-氟苯基)甲酮(80mg,0.18mmol)，(S)-N-((S)-环丙基(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基)-2-甲基丙烷-2-亚磺酰胺(108mg,0.26mmol)，磷酸钾(113mg,0.53mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(15mg,0.02mmol)混合于1,4-二氧六环(5mL)和水(0.5mL)中，在氮气保护下加热至95℃搅拌1小时。向反应液中加入乙酸乙酯(10mL)和水(10mL)，分离有机相。有机相用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。残余物用制备-TLC分离纯化(乙酸乙酯/甲醇＝25/1(体积比))，得标题化合物(S)-N-((S)-环丙基(5-(5-((乙基砜)甲基)-2-(4-氟苯甲酰基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)-2-甲基丙烷-2-亚磺酰胺(50mg,45％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝621.0. (2-Bromo-5-chloro-4-((ethylsulfonyl)methyl)phenyl)(2-chloro-4-fluorophenyl)methanone (80 mg, 0.18 mmol), (S)-N- ((S)-cyclopropyl (1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2-dihydropyridin-4-yl)methyl)-2-methylpropane-2-sulfenamide (108 mg, 0.26 mmol), potassium phosphate (113 mg, 0.53 mmol) and [1,1'- Bis(diphenylphosphino)ferrocene]palladium(II) chloride (15 mg, 0.02 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) under nitrogen Heat to 95 ° C and stir for 1 hour. Ethyl acetate (10 mL) and water (10 mL) were added to the mixture and the organic phase was separated. The organic phase was washed with water and brine, dried over anhydrous The residue was purified by preparative-TLC (ethyl acetate/methanol=25/1 (vol.)) to give the title compound (S)-N-((S)-cyclopropyl (5-(5-((B) Sulfone)methyl)-2-(4-fluorobenzoyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)-2-methyl Propane-2-sulfinamide (50 mg, 45%) as a yellow oil. LCMS (ESI) [M+H] ⁺ = 621.0.

步骤2：(S)-7-(2-氯-4-氟苯基)-5-环丙基-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮Step 2: (S)-7-(2-Chloro-4-fluorophenyl)-5-cyclopropyl-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro -3H-benzo[c]pyrido[3,4-e]azepin-3-one

向(S)-N-((S)-环丙基(5-(5-((乙基砜)甲基)-2-(4-氟苯甲酰基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)-2-甲基丙烷-2-亚磺酰胺(50mg,0.08mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌1小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物(S)-7-(2-氯-4-氟苯基)-5-环丙基-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(28.7mg,72％)，为白色固体。LCMS(ESI)[M+H] ⁺＝500.1，纯度100％(UV 214nm)； To (S)-N-((S)-cyclopropyl(5-(5-((ethylsulfonyl)methyl)-2-(4-fluorobenzoyl)phenyl)-1-methyl- Addition of trifluoroethane to a solution of 2-oxo-1,2-dihydropyridin-4-yl)methyl)-2-methylpropane-2-sulfenamide (50 mg, 0.08 mmol) in dichloromethane (4 mL) Acetic acid (1 mL). The reaction solution was stirred at room temperature for 1 hour and concentrated. The residue was purified by preparative-HPLC to give the title compound (S)-7-(2-chloro-4-fluorophenyl)-5-cyclopropyl-10-((ethylsulfonyl)methyl)-2- Methyl-2,5-dihydro-3H-benzo[c]pyrido[3,4-e]azepin-3-one (28.7 mg, 72%) as a white solid. LCMS (ESI) [M+H] ⁺ = 500.1, mp.

¹H NMR(400MHz,DMSO-d ₆)δ8.05(s,1H),7.69(s,1H),7.53-7.51(m,1H),7.44-7.36(m,2H),7.35-7.30(m,1H),7.06-7.04(d,J＝8.0Hz,2H),4.62-4.49(q,J＝13.6Hz,2H),3.54(s,3H),3.53-3.52(d,J＝4.8Hz,2H),3.11-3.06(q,J＝7.6Hz,2H),1.53(s,1H),1.24-1.20(t,J＝14.8Hz,3H),0.72-0.71(d,J＝3.2Hz,2H),0.58-0.50(m,2H),0.34-0.33(t,J＝5.2Hz,1H). ^{1 H NMR (400MHz, DMSO-} d 6) δ8.05 (s, 1H), 7.69 (s, 1H), 7.53-7.51 (m, 1H), 7.44-7.36 (m, 2H), 7.35-7.30 (m , 1H), 7.06-7.04 (d, J = 8.0 Hz, 2H), 4.62-4.49 (q, J = 13.6 Hz, 2H), 3.54 (s, 3H), 3.53-3.52 (d, J = 4.8 Hz, 2H), 3.11-3.06 (q, J = 7.6 Hz, 2H), 1.53 (s, 1H), 1.24-1.20 (t, J = 14.8 Hz, 3H), 0.72-0.71 (d, J = 3.2 Hz, 2H ), 0.58-0.50 (m, 2H), 0.34-0.33 (t, J = 5.2 Hz, 1H).

4108：(S)-7-(4-氟苯基)-2,5-二甲基-5,9,10,12-四氢-[1,2]噻嗪并[5',4':4,5]苯并[1,2-c]吡啶并[3,4-e]氮杂卓-3(2H)-酮11,11-二氧化物4108: (S)-7-(4-Fluorophenyl)-2,5-dimethyl-5,9,10,12-tetrahydro-[1,2]thiazino[5',4': 4,5]benzo[1,2-c]pyrido[3,4-e]azepine-3(2H)-one 11,11-dioxide

步骤1：(7-溴-2,2-二氧化-3,4-二氢-1H-苯并[d][1,2]噻嗪-6-基)(4-氟苯基)甲酮Step 1: (7-Bromo-2,2-dioxy-3,4-dihydro-1H-benzo[d][1,2]thiazin-6-yl)(4-fluorophenyl)methanone

将(3-溴-4-(4-氟苯甲酰基)苯基)甲磺酰胺(170mg,0.46mmol)，三氟甲磺酸酐(130mg, 0.46mmol)和多聚甲醛(0.46mg,42mmol)溶于三氟甲磺酸(2mL)中，在室温下搅拌4小时。反应液用水淬灭(30mL)，然后用乙酸乙酯萃取(30mL*2)。有机相用水和饱和食盐水洗涤，无水硫酸钠干燥并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝3/2(体积比)，得标题化合物(7-溴-2,2-二氧化-3,4-二氢-1H-苯并[d][1,2]噻嗪-6-基)(4-氟苯基)甲酮(28mg,16％)，为白色固体。LCMS(ESI)[M+H] ⁺＝384.0. (3-Bromo-4-(4-fluorobenzoyl)phenyl)methanesulfonamide (170 mg, 0.46 mmol), trifluoromethanesulfonic anhydride (130 mg, 0.46 mmol) and paraformaldehyde (0.46 mg, 42 mmol) Dissolved in trifluoromethanesulfonic acid (2 mL) and stirred at room temperature for 4 hours. The reaction was quenched with water (30 mL)EtOAc. The organic phase was washed with water and a brine The residue was purified by flash chromatography (EtOAc/EtOAc (EtOAc:EtOAc) [d][1,2]thiazin-6-yl)(4-fluorophenyl)methanone (28 mg, 16%) as a white solid. LCMS (ESI) [M+H] ⁺ = 384.0.

步骤2：(S)-N-((S)-1-(5-(6-(4-氟苯甲酰基)-2,2-二氧化-3,4-二氢-1H-苯并[d][1,2]噻嗪-7-基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺Step 2: (S)-N-((S)-1-(5-(6-(4-fluorobenzoyl)-2,2-dioxy-3,4-dihydro-1H-benzo[ d][1,2]thiazin-7-yl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-arylene Sulfonamide

将(7-溴-2,2-二氧化-3,4-二氢-1H-苯并[d][1,2]噻嗪-6-基)(4-氟苯基)甲酮(28mg,0.073mmol)，2-甲基-N-((S)-1-(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)乙基)丙烷-2-亚磺酰胺(33mg,0.085mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(6mg,0.007mmol)和碳酸钾(26mg,0.18mmol)混合于1,4-二氧六环(2mL)和水(0.2mL)中，在氮气保护下加热至90℃搅拌2小时。反应液中加入水和乙酸乙酯，分离有机相。有机相用无水硫酸钠干燥，浓缩得标题化合物(S)-N-((S)-1-(5-(6-(4-氟苯甲酰基)-2,2-二氧化-3,4-二氢-1H-苯并[d][1,2]噻嗪-7-基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺粗品，为黑色油状物。LCMS(ESI)[M+H] ⁺＝560.2. (7-Bromo-2,2-dioxy-3,4-dihydro-1H-benzo[d][1,2]thiazin-6-yl)(4-fluorophenyl)methanone (28 mg , 0.073 mmol), 2-methyl-N-((S)-1-(1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl)ethyl)propane-2-sulfenamide (33 mg, 0.085 mmol), [1,1'-bis (two Phenylphosphino)ferrocene]palladium(II) chloride (6 mg, 0.007 mmol) and potassium carbonate (26 mg, 0.18 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) The mixture was heated to 90 ° C under nitrogen for 2 hours. Water and ethyl acetate were added to the reaction mixture, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate (MgSO4) 4-Dihydro-1H-benzo[d][1,2]thiazin-7-yl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl) Crude -2-methylpropane-2-sulfinamide as a black oil. LCMS (ESI) [M+H] ⁺ = 560.2.

步骤3：(S)-7-(4-氟苯基)-2,5-二甲基-5,9,10,12-四氢-[1,2]噻嗪并[5',4':4,5]苯并[1,2-c]吡啶并[3,4-e]氮杂卓-3(2H)-酮11,11-二氧化物Step 3: (S)-7-(4-Fluorophenyl)-2,5-dimethyl-5,9,10,12-tetrahydro-[1,2]thiazino[5',4' :4,5]Benzo[1,2-c]pyrido[3,4-e]azepine-3(2H)-one 11,11-dioxide

将(S)-N-((S)-1-(5-(6-(4-氟苯甲酰基)-2,2-二氧化-3,4-二氢-1H-苯并[d][1,2]噻嗪-7-基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(粗品)溶于三氟乙酸/二氯甲烷(2mL/3mL)中，在室温下搅拌16小时。反应液浓缩，残余物用制备-HPLC分离纯化，得标题化合物(S)-7-(4-氟苯基)-2,5-二甲基-5,9,10,12-四氢-[1,2]噻嗪并[5',4':4,5]苯并[1,2-c]吡啶并[3,4-e]氮杂卓-3(2H)-酮11,11-二氧化物(16.6mg,两步产率52％)，为白色固体。LCMS(ESI)[M+H] ⁺＝437.9，纯度100％(UV 214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.07(s,1H),7.51-7.47(m,3H),7.18-7.12(m,2H),6.63(s,1H),4.55-4.53(m,4H),4.11(q,1H),3.66(s,3H),1.77(d,3H). (S)-N-((S)-1-(5-(6-(4-fluorobenzoyl)-2,2-dioxy-3,4-dihydro-1H-benzo[d] [1,2]thiazin-7-yl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (Rough) was dissolved in trifluoroacetic acid / dichloromethane (2 mL / 3 mL) and stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the residue was crystallijjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1,2]thiazino[5',4':4,5]benzo[1,2-c]pyrido[3,4-e]azepine-3(2H)-one 11,11- Dioxide (16.6 mg, 52% in two steps) was obtained as a white solid. LCMS (ESI) [M + H ] + = 437.9, purity ^{100 (UV 214nm)%; 1} H NMR (400MHz, CD 3 OD) δ8.07 (s, 1H), 7.51-7.47 (m, 3H), 7.18 -7.12 (m, 2H), 6.63 (s, 1H), 4.55-4.53 (m, 4H), 4.11 (q, 1H), 3.66 (s, 3H), 1.77 (d, 3H).

4109：7-(2-氯-4-氟苯基)-10-((环丙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮4109: 7-(2-Chloro-4-fluorophenyl)-10-((cyclopropylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridine [3,4-e]azazo-3-one

步骤1：(2-溴-4-((环丙基砜)甲基)苯基)(2-氯-4-氟苯基)甲酮Step 1: (2-Bromo-4-((cyclopropylsulfone)methyl)phenyl)(2-chloro-4-fluorophenyl)methanone

将(2-溴-4-(溴甲基)苯基)(2-氯-4-氟苯基)甲酮(400mg,1.0mmol)和环丙烷磺酸钠盐(230mg,2.0mmol)溶于二甲基亚砜(10mL)中，在室温下搅拌1小时。向反应液中加入乙酸乙酯(10mL)和水(20mL)，分离有机相。有机相用饱和食盐水洗涤(10mL*3)，无水硫酸钠干燥，过滤并浓缩，得标题化合物(2-溴-4-((环丙基砜)甲基)苯基)(2-氯-4-氟苯基)甲酮(270mg,62％)，为白色固体。LCMS(ESI)[M+H] ⁺＝430.9. (2-Bromo-4-(bromomethyl)phenyl)(2-chloro-4-fluorophenyl)methanone (400 mg, 1.0 mmol) and sodium cyclopropane sulfonate (230 mg, 2.0 mmol) were dissolved. The mixture was stirred at room temperature for 1 hour in dimethyl sulfoxide (10 mL). Ethyl acetate (10 mL) and water (20 mL) were added to the mixture and the organic phase was separated. The organic phase was washed with EtOAc (EtOAc m. 4-fluorophenyl)methanone (270 mg, 62%) as a white solid. LCMS (ESI) [M+H] ⁺ =430.9.

步骤2：((5-(2-(2-氯-4-氟苯甲酰基)-5-((环丙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯Step 2: ((5-(2-(2-Chloro-4-fluorobenzoyl)-5-((cyclopropylsulfone)methyl)phenyl)-1-methyl-2-oxo-1 ,2-dihydropyridin-4-yl)methyl)carbamic acid tert-butyl ester

将((1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(96mg,0.27mmol)，(2-溴-4-((环丙基砜)甲基)苯基)(2-氯-4-氟苯基)甲酮(78mg,0.18mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(20mg,0.027mmol)和磷酸钾(115mg,0.54mmol)混合于1,4-二氧六环(2mL)和水(0.2mL)中，在氮气保护下加热至90℃搅拌2小时。反应液过滤，滤液浓缩。残余物用快速色谱法分离纯化(乙酸乙酯/甲醇＝15/1(体积比))，得标题化合物((5-(2-(2-氯-4-氟苯甲酰基)-5-((环丙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(75mg,71％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝589.0. ((1-Methyl-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-di Hydrogen pyridin-4-yl)methyl)carbamic acid tert-butyl ester (96 mg, 0.27 mmol), (2-bromo-4-((cyclopropylsulfonyl)methyl)phenyl) (2-chloro-4-fluoro) Phenyl)methanone (78 mg, 0.18 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (20 mg, 0.027 mmol) and potassium phosphate (115 mg, 0.54) Methyl) was mixed with 1,4-dioxane (2 mL) and water (0.2 mL) and heated to 90 ° C under nitrogen for 2 hours. The reaction solution was filtered and the filtrate was concentrated. The residue was purified by EtOAc EtOAc EtOAc (HHHHHHHH (cyclopropyl sulfone)methyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)carbamic acid tert-butyl ester (75 mg, 71%) It is a yellow oil. LCMS (ESI) [M+H] ⁺ = 589.0.

步骤3：7-(2-氯-4-氟苯基)-10-((环丙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮Step 3: 7-(2-Chloro-4-fluorophenyl)-10-((cyclopropylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridine And [3,4-e]azepin-3-one

向((5-(2-(2-氯-4-氟苯甲酰基)-5-((环丙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(75mg,0.127mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌5小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物7-(2-氯-4-氟苯基)-10-((环丙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(24.4mg,41％)，为白色固体。LCMS(ESI)[M+H] ⁺＝471.1，purity 100％(UV 214nm)； ¹H NMR(400MHz,DMSO-d ₆)δ8.06(s,1H),7.72(s,1H),7.62-7.58(m,1H),7.44-7.31(m,3H),7.04(d,J＝8.0Hz,1H),6.52(s,1H),4.76(d,J＝10.4Hz,1H),4.69-4.55(m,2H),3.94 (d,J＝10.0Hz,1H),3.54(s,3H),2.67-2.62(m,1H),0.97-0.77(m,4H). To ((5-(2-(2-chloro-4-fluorobenzoyl)-5-((cyclopropylsulfone)methyl)phenyl)-1-methyl-2-oxo-1,2 To a solution of tert-butyl dihydropyridin-4-yl)methyl)carbamate (75 mg, 0.127 mmol) in dichloromethane (4 mL) The reaction solution was stirred at room temperature for 5 hours and concentrated. The residue was purified by preparative-HPLC to give the title compound 7-(2-chloro-4-fluorophenyl)-10-((cyclopropylsulfone)methyl)-2-methyl-2,5-dihydro -3H-Benzo[c]pyrido[3,4-e]azepin-3-one (24.4 mg, 41%) as a white solid. LCMS (ESI) [M + H ] + = 471.1, purity 100 (UV 214nm)%; 1 H NMR (400MHz, DMSO-d 6) δ8.06 (s, 1H), 7.72 (s, 1H), 7.62- 7.58(m,1H),7.44-7.31(m,3H),7.04(d,J=8.0Hz,1H),6.52(s,1H),4.76(d,J=10.4Hz,1H),4.69-4.55 (m, 2H), 3.94 (d, J = 10.0 Hz, 1H), 3.54 (s, 3H), 2.67-2.62 (m, 1H), 0.97-0.77 (m, 4H).

4110：(S)-1-(7-(2-氯-4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)-N-甲基甲磺酰胺4110: (S)-1-(7-(2-chloro-4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c] Pyrido[3,4-e]azepin-10-yl)-N-methylmethanesulfonamide

步骤1：(3-溴-4-(2-氯-4-氟苯甲酰基)苯基)甲磺酰胺Step 1: (3-Bromo-4-(2-chloro-4-fluorobenzoyl)phenyl)methanesulfonamide

将(2-溴-4-(溴甲基)苯基)(2-氯-4-氟苯基)甲酮(820mg,2.02mmol)和3-甲氧基-3-氧代丙烷亚磺酸钠(388mg,2.43mmol)混合于二甲基亚砜(5mL)中，在室温下搅拌0.5小时。然后加入1,8-二氮杂环[5,4,0]十一烯-7(369mg,2.43mmol)并在室温下搅拌1小时。向上述反应液中加入乙酸钠(767mg,9.3mmol)和羟胺-O-磺酸(1140mg,10.18mmol)的水(5mL)溶液，得到的混合物在室温下搅拌20小时。反应液用乙酸乙酯(80mL)稀释,水和饱和食盐水洗涤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/1(体积比))，得标题化合物(3-溴-4-(2-氯-4-氟苯甲酰基)苯基)甲磺酰胺(300mg,37％)，为无色油状物。LCMS(ESI)[M+H] ⁺＝406.0. (2-Bromo-4-(bromomethyl)phenyl)(2-chloro-4-fluorophenyl)methanone (820 mg, 2.02 mmol) and 3-methoxy-3-oxopropanesulfinic acid Sodium (388 mg, 2.43 mmol) was mixed in dimethyl sulfoxide (5 mL) and stirred at room temperature for 0.5 hr. Then, 1,8-diazacyclo[5,4,0]undecene-7 (369 mg, 2.43 mmol) was added and stirred at room temperature for 1 hour. A solution of sodium acetate (767 mg, 9.3 mmol) and hydroxylamine-O-sulfonic acid (1140 mg, 10.18 mmol) in water (5 mL) was added to the mixture, and the mixture was stirred at room temperature for 20 hr. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc (EtOAc/EtOAc (EtOAc) Methanesulfonamide (300 mg, 37%) was obtained as a colorless oil. LCMS (ESI) [M+H] ⁺ = 406.0.

步骤2：((3-溴-4-(2-氯-4-氟苯甲酰基)苯基)磺酰基)氨基甲酸叔丁酯Step 2: ((3-Bromo-4-(2-chloro-4-fluorobenzoyl)phenyl)sulfonyl)carbamic acid tert-butyl ester

将(3-溴-4-(2-氯-4-氟苯甲酰基)苯基)甲磺酰胺(300mg,0.74mmol)，二碳酸二叔丁酯(322mg,1.48mmol)，4-二甲氨基吡啶(10mg,0.08mmol)和三乙胺(224mg,2.22mmol)溶于二氯甲烷(5mL)中，在氮气保护下于室温搅拌18小时。反应液用乙酸乙酯(90mL)稀释，用水和饱和食盐水洗涤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝10/1(体积比)，得标题化合物((3-溴-4-(2-氯-4-氟苯甲酰基)苯基)磺酰基)氨基甲酸叔丁酯(90mg,24％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝451.0. (3-Bromo-4-(2-chloro-4-fluorobenzoyl)phenyl)methanesulfonamide (300 mg, 0.74 mmol), di-tert-butyl dicarbonate (322 mg, 1.48 mmol), 4-dimethyl Aminopyridine (10 mg, 0.08 mmol) and triethylamine (224 mg, 2.22 mmol) were dissolved in dichloromethane (5 mL). The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc (EtOAc (EtOAc) sulfonyl) carbamate (90mg, 24%), as a yellow oil .LCMS (ESI) [M + H ] + = 451.0.

步骤3：((3-溴-4-(2-氯-4-氟苯甲酰基)苯甲基)磺酰基)(甲基)氨基甲酸叔丁酯Step 3: ((3-Bromo-4-(2-chloro-4-fluorobenzoyl)benzyl)sulfonyl)(methyl)carbamic acid tert-butyl ester

将((3-溴-4-(2-氯-4-氟苯甲酰基)苯甲基)磺酰基)氨基甲酸叔丁酯(90mg,0.18mmol)，碘甲烷(20.11mg,0.142mmol)和碳酸钾(25mg,0.18mmol)混合于N,N-二甲基甲酰胺(5mL)，在室温下搅拌18小时。反应液用乙酸乙酯(30mL)稀释，用水和饱和食盐水洗涤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝2/1(体积比))，得标题化合物((3-溴-4-(2-氯-4-氟苯甲酰基)苯甲基)磺酰基)(甲基)氨基甲酸叔丁酯(67mg,73％)。LCMS(ESI)[M+H] ⁺＝537.0. ((3-Bromo-4-(2-chloro-4-fluorobenzoyl)benzyl)sulfonyl)carbamic acid tert-butyl ester (90 mg, 0.18 mmol), iodomethane (20.11 mg, 0.142 mmol) Potassium carbonate (25 mg, 0.18 mmol) was mixed with N,N-dimethylformamide (5 mL) and stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc (EtOAc) The residue was purified by EtOAc (EtOAc/EtOAc (EtOAc:EtOAc) Tert-butyl (meth)sulfonyl)(methyl)carbamate (67 mg, 73%). LCMS (ESI) [M+H] ⁺ = 537.0.

步骤4：((3-(4-((S)-1-(((S)-叔丁基亚磺酰胺)氨基)乙基)-1-甲基-6-氧代-1,6-二氢吡啶-3-基)-4-(2-氯-4-氟苯甲酰基)苯甲基)磺酰基)(甲基)氨基甲酸叔丁酯Step 4: ((3-(4-((S)-1-((S)-tert-butylsulfenamide)amino)ethyl)-1-methyl-6-oxo-1,6- Dihydropyridin-3-yl)-4-(2-chloro-4-fluorobenzoyl)benzyl)sulfonyl)(methyl)carbamic acid tert-butyl ester

将((3-溴-4-(2-氯-4-氟苯甲酰基)苯甲基)磺酰基)(甲基)氨基甲酸叔丁酯(35mg,0.067mmol)，(S)-2-甲基-N-((S)-1-(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)乙基)丙烷-2-亚磺酰胺(40mg,0.10mmol)，磷酸钾(43mg,0.20mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(10mg,0.01mmol)混合于1,4-二氧六环(5mL)和水(0.5mL)中，在氮气保护下加热到95℃搅拌1小时。向反应液中加入乙酸乙酯(10mL)和水(10mL)，分离有机相。有机相用水和饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。残余物用制备-TLC分离纯化(乙酸乙酯/甲醇＝25/1(体积比))，得标题化合物((3-(4-((S)-1-(((S)-叔丁基亚磺酰胺)氨基)乙基)-1-甲基-6-氧代-1,6-二氢吡啶-3-基)-4-(2-氯-4-氟苯甲酰基)苯甲基)磺酰基)(甲基)氨基甲酸叔丁酯(20mg,43％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝696.0. ((3-Bromo-4-(2-chloro-4-fluorobenzoyl)benzyl)sulfonyl)(methyl)carbamic acid tert-butyl ester (35 mg, 0.067 mmol), (S)-2- Methyl-N-((S)-1-(1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1,2-dihydropyridin-4-yl)ethyl)propane-2-sulfinamide (40 mg, 0.10 mmol), potassium phosphate (43 mg, 0.20 mmol) and [1,1'- double (Diphenylphosphino)ferrocene]palladium(II) chloride (10 mg, 0.01 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL), heated under nitrogen Stir at 95 ° C for 1 hour. Ethyl acetate (10 mL) and water (10 mL) were added to the mixture and the organic phase was separated. The organic phase was washed with water and brine, dried over anhydrous The residue was purified by EtOAc-EtOAc (EtOAc (MeOH) Sulfonamide)amino)ethyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(2-chloro-4-fluorobenzoyl)benzyl tert-Butyl sulfonyl)(methyl)carbamate (20 mg, 43%) as a yellow oil. LCMS (ESI) [M+H] ⁺ = 696.0.

步骤5：(S)-1-(7-(2-氯-4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)-N-甲基甲磺酰胺Step 5: (S)-1-(7-(2-chloro-4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c Pyridine[3,4-e]azepin-10-yl)-N-methylmethanesulfonamide

向((3-(4-((S)-1-(((S)-叔丁基亚磺酰基)氨基)乙基)-1-甲基-6-氧代-1,6-二氢吡啶-3-基)-4-(2-氯-4-氟苯甲酰基)苯甲基)磺酰基)(甲基)氨基甲酸叔丁酯(20mg,0.028mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌12小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物(S)-1-(7-(2-氯-4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)-N-甲基甲磺酰胺(9.6mg,72％)，为白色固体。 LCMS(ESI)[M+H] ⁺＝474.1，纯度100％(UV 214nm)； ¹H NMR(400MHz,DMSO-d ₆)δ8.08(s,1H),7.65(s,1H),7.58-7.54(m,1H),7.43-7.30(m,3H),7.06-7.00(m,2H),6.42(s,1H),4.49-4.36(dd,J＝14Hz,2H),4.01-3.99(d,J＝5.6Hz,1H),3.53(s,3H),2.57-2.56(d,J＝4.8Hz,3H),1.65-1.63(d,J＝6.4Hz,3H). To ((3-(4-((S)-1-((S)-tert-butylsulfinyl)amino)ethyl)-1-methyl-6-oxo-1,6-dihydro Pyridin-3-yl)-4-(2-chloro-4-fluorobenzoyl)benzylsulfonyl)(methyl)carbamic acid tert-butyl ester (20 mg, 0.028 mmol) in dichloromethane (4 mL) Trifluoroacetic acid (1 mL) was added to the solution. The reaction solution was stirred at room temperature for 12 hours and concentrated. The residue was purified by preparative-HPLC to give the title compound (S)-1-(7-(2-chloro-4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5- Dihydro-2H-benzo[c]pyrido[3,4-e]azepin-10-yl)-N-methylmethanesulfonamide (9.6 mg, 72%) as a white solid. LCMS (ESI) [M + H ] + = 474.1, purity ^{100 (UV 214nm)%; 1} H NMR (400MHz, DMSO-d 6) δ8.08 (s, 1H), 7.65 (s, 1H), 7.58- 7.54 (m, 1H), 7.43-7.30 (m, 3H), 7.06-7.00 (m, 2H), 6.42 (s, 1H), 4.49-4.36 (dd, J = 14 Hz, 2H), 4.01-3.99 (d , J = 5.6 Hz, 1H), 3.53 (s, 3H), 2.57-2.56 (d, J = 4.8 Hz, 3H), 1.65-1.63 (d, J = 6.4 Hz, 3H).

4111：7-(2,4-二氯苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮4111:7-(2,4-Dichlorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridin[3 , 4-e]azazo-3-one

步骤1：(2-溴-4-甲基苯基)(2,4-二氯苯基)甲醇Step 1: (2-Bromo-4-methylphenyl)(2,4-dichlorophenyl)methanol

在氮气保护下，向1-溴-2,4-二氯苯(450mg,2.0mmol)的四氢呋喃(5mL)溶液中加入异丙基氯化镁溶液(1.0mL,2.0mmol)，反应液在室温下搅拌0.5小时得格氏试剂。在0℃下，向2-溴-4-甲基苯甲醛(0.4g,2.0mmol)的四氢呋喃(5mL)溶液中缓慢滴加上述格氏试剂，得到的混合物在室温下搅拌4小时。反应液用饱和氯化铵水溶液淬灭，然后用乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝5/1(体积比))，得标题化合物(2-溴-4-甲基苯基)(2,4-二氯苯基)甲醇(0.31g,45％)，为无色油状物。LCMS(ESI)[M-H ₂O+H] ⁺＝326.9. Add isopropylmagnesium chloride solution (1.0 mL, 2.0 mmol) to a solution of 1-bromo-2,4-dichlorobenzene (450 mg, 2.0 mmol) in tetrahydrofuran (5 mL). Grignard reagent was obtained in 0.5 hours. The above Grignard reagent was slowly added dropwise to a solution of 2-bromo-4-methylbenzaldehyde (0.4 g, 2.0 mmol) in tetrahydrofuran (5 mL) at 0 ° C, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was quenched with saturated aq. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by EtOAc (EtOAc/EtOAc (EtOAc) Methanol (0.31 g, 45%) was obtained as a colorless oil. LCMS (ESI) [MH ₂ O + H] ⁺ = 326.9.

步骤2：(2-溴-4-甲基苯基)(2,4-二氯苯基)甲酮Step 2: (2-Bromo-4-methylphenyl)(2,4-dichlorophenyl)methanone

将(2-溴-4-甲基苯基)(2,4-二氯苯基)甲醇(5.3g,15.4mmol)和Dess-Martin试剂(7.2g,17.0mmol)混合于二氯甲烷(100mL)中，在室温下搅拌2小时。蒸除溶剂，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝5/1(体积比))，得标题化合物(2-溴-4-甲基苯基)(2,4-二氯苯基)甲酮(4.0g,76％)，为无色油状物。LCMS(ESI)[M+H] ⁺＝343.0. (2-Bromo-4-methylphenyl)(2,4-dichlorophenyl)methanol (5.3 g, 15.4 mmol) and Dess-Martin reagent (7.2 g, 17.0 mmol) were mixed in dichloromethane (100 mL) In the mixture, it was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was purified (jjjjjjjjjj Chlorophenyl)methanone (4.0 g, 76%) as a colorless oil. LCMS (ESI) [M+H] ⁺ = 343.0.

步骤3：(2-溴-4-(二溴甲基)苯基)(2,4-二氯苯基)甲酮Step 3: (2-Bromo-4-(dibromomethyl)phenyl)(2,4-dichlorophenyl)methanone

将N-溴代丁二酰亚胺(4.2g,23.4mmol)，偶氮二异丁腈(50mg,0.3mmol)和(2-溴-4-甲基苯基)(2,4-二氯苯基)甲酮(4.0g,11.7mmol)溶于四氯化碳(50mL)中，加热至90℃搅拌12小时。反应液浓缩，得标题化合物(2-溴-4-(二溴甲基)苯基)(2,4-二氯苯基)甲酮，不经纯化直接用于下一步反应。N-bromosuccinimide (4.2 g, 23.4 mmol), azobisisobutyronitrile (50 mg, 0.3 mmol) and (2-bromo-4-methylphenyl) (2,4-dichloro) Phenyl)methanone (4.0 g, 11.7 mmol) was dissolved in carbon tetrachloride (50 mL) and heated to 90 ° C for 12 hours. The reaction mixture was concentrated to give the title compound (2-bromo-4-(dibromomethyl)phenyl) (2,4-dichlorophenyl)methanone.

步骤4：(2-溴-4-(溴甲基)苯基)(2,4-二氯苯基)甲酮Step 4: (2-Bromo-4-(bromomethyl)phenyl)(2,4-dichlorophenyl)methanone

向(2-溴-4-(二溴甲基)苯基)(2,4-二氯苯基)甲酮(5.83g,11.7mmol)的二氯甲烷(50mL)溶液中加入磷酸二乙酯(3.42g,23.4mmol)和二异丙基乙胺(3.02g,23.4mmol)。反应液在室温下搅拌4小时并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝10/1(体积比))，得标题化合物(2-溴-4-(溴甲基)苯基)(2,4-二氯苯基)甲酮(4.0g,两步产率81％)，为无色油状物。LCMS(ESI)：无离子流。To a solution of (2-bromo-4-(dibromomethyl)phenyl)(2,4-dichlorophenyl)methanone (5.83 g, 11.7 mmol) in dichloromethane (50 mL) (3.42 g, 23.4 mmol) and diisopropylethylamine (3.02 g, 23.4 mmol). The reaction solution was stirred at room temperature for 4 hours and concentrated. The residue was purified by flash chromatography (EtOAc /EtOAcEtOAcEtOAc Phenyl)methanone (4.0 g, 81% yield in two steps) as a colorless oil. LCMS (ESI): no ion stream.

步骤5：(2-溴-4-((乙基砜)甲基)苯基)(2,4-二氯苯基)甲酮Step 5: (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(2,4-dichlorophenyl)methanone

向2-溴-4-(溴甲基)苯基)(2,4-二氯苯基)甲酮(0.42g,1.0mmol)的N,N-二甲基甲酰胺(3mL)溶液中加入乙烷亚磺酸钠(232mg,2.0mmol)。反应液加热至65℃搅拌1小时。向反应液中加入乙酸乙酯(20mL)和水(50mL)，分离有机相。有机相用饱和食盐水洗涤(50mL*3)，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/1(体积比))，得标题化合物(2-溴-4-((乙基砜)甲基)苯基)(2,4-二氯苯基)甲酮(380mg,88％)。LCMS(ESI)[M+H] ⁺＝435.0. Add to a solution of 2-bromo-4-(bromomethyl)phenyl)(2,4-dichlorophenyl)methanone (0.42 g, 1.0 mmol) in N,N-dimethylformamide (3 mL) Sodium ethanesulfinate (232 mg, 2.0 mmol). The reaction solution was heated to 65 ° C and stirred for 1 hour. Ethyl acetate (20 mL) and water (50 mL) were added to the mixture and the organic phase was separated. The organic phase was washed with brine (50 mL*3) The residue was purified by EtOAc (EtOAc/EtOAc (EtOAc) 4-Dichlorophenyl)methanone (380 mg, 88%). LCMS (ESI) [M+H] ⁺ =435.0.

步骤6：((5-(2-(2,4-二氯苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯Step 6: ((5-(2-(2,4-Dichlorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl-2-oxo-1,2 -dihydropyridin-4-yl)methyl)carbamic acid tert-butyl ester

将(2-溴-4-((乙基砜)甲基)苯基)(2,4-二氯苯基)甲酮(130mg,0.3mmol)，((1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(110mg,0.3mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(20mg,0.026mmol)和磷酸钾(84mg,0.6mmol)混合于1,4-二氧六环(4mL)和水(0.4mL)中，在氮气保护下加热至90℃搅拌3小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/甲醇＝10/1(体积比))，得标题化合物((5-(2-(2,4-二氯苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(70mg,39％)，为白色固体。LCMS(ESI)：无离子流。(2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(2,4-dichlorophenyl)methanone (130 mg, 0.3 mmol), ((1-methyl-2-oxo) -5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl)methyl)carbamic acid tert-Butyl ester (110 mg, 0.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (20 mg, 0.026 mmol) and potassium phosphate (84 mg, 0.6 mmol) It was mixed with 1,4-dioxane (4 mL) and water (0.4 mL), and heated to 90 ° C under nitrogen atmosphere and stirred for 3 hours. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjj Acyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)carbamic acid tert-butyl ester (70 mg , 39%), as a white solid. LCMS (ESI): no ion stream.

步骤7：7-(2,4-二氯苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮Step 7: 7-(2,4-Dichlorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridin[ 3,4-e]azepin-3-one

向((5-(2-(2,4-二氯苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(70mg,0.12mmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(3mL)。反应液在室温下搅拌2小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物7-(2,4-二氯苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(5.9mg,10％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝425.1，纯度100％(UV 214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.16(s,1H),7.79(s,1H),7.59(d,J＝8.0Hz,1H),7.51-7.48(m,3H),7.18(d,J＝8.0Hz,1H),6.66(s,1H),4.79(d,J＝10.4Hz,1H),4.57(s,2H),4.16(d,J＝10.4Hz,1H),3.71(s,3H),3.13(q,J＝7.2Hz,2H),1.39(t,J＝7.6Hz,3H). To ((5-(2-(2,4-dichlorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl-2-oxo-1,2-di To a solution of tert-butyl hydropyridine-4-yl)methyl)carbamate (70 mg, 0.12 mmol) in dichloromethane (2 mL) The reaction solution was stirred at room temperature for 2 hr and concentrated. The residue was purified by preparative-HPLC to give the title compound 7-(2,4-dichlorophenyl)-10-((ethylsulfonyl)methyl)-2-methyl-2,5-dihydro-3H -Benzo[c]pyrido[3,4-e]azepin-3-one (5.9 mg, 10%) as a yellow solid. LCMS (ESI) [M + H ] + = 425.1, purity ^{100% (UV 214nm); 1} H NMR (400MHz, CD 3 OD) δ8.16 (s, 1H), 7.79 (s, 1H), 7.59 (d , J = 8.0 Hz, 1H), 7.51-7.48 (m, 3H), 7.18 (d, J = 8.0 Hz, 1H), 6.66 (s, 1H), 4.79 (d, J = 10.4 Hz, 1H), 4.57 (s, 2H), 4.16 (d, J = 10.4 Hz, 1H), 3.71 (s, 3H), 3.13 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.6 Hz, 3H).

4113：(S)-7-(2,4-二氯苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮4113: (S)-7-(2,4-Dichlorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H-benzo [c]pyrido[3,4-e]azepin-3-one

步骤1：N-((S)-1-(5-(2-(2,4-二氯苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺Step 1: N-((S)-1-(5-(2-(2,4-Dichlorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl- 2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide

将(2-溴-4-((乙基砜)甲基)苯基)(2,4-二氯苯基)甲酮(86mg,0.2mmol)，(S)-2-甲基-N-((S)-1-(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)乙基)丙烷-2-亚磺酰胺(76mg,0.2mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(15mg,0.02mmol)和磷酸钾(55mg,0.4mmol)混合于1,4-二氧六环(4mL)和水(0.4mL)中，在氮气保护下加热至90℃搅拌3小时。反应液过滤，滤液浓缩。残余物用快速色谱法分离纯化(乙酸乙酯/甲醇＝10/1(体积比))，得标题化合物N-((S)-1-(5-(2-(2,4-二氯苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(78mg,64％)，为白色固体。LCMS(ESI)[M+H] ⁺＝611.0. (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(2,4-dichlorophenyl)methanone (86 mg, 0.2 mmol), (S)-2-methyl-N- ((S)-1-(1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,2-dihydropyridin-4-yl)ethyl)propane-2-sulfinamide (76 mg, 0.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium (II) (15 mg, 0.02 mmol) and potassium phosphate (55 mg, 0.4 mmol) were mixed in 1,4-dioxane (4 mL) and water (0.4 mL) and heated to 90 ° C under a nitrogen atmosphere. hour. The reaction solution was filtered and the filtrate was concentrated. The residue was purified by flash chromatography (ethyl acetate / EtOAc (MeOH): Formyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane 2- sulfinamide (78 mg, 64%) as a white solid. LCMS (ESI) [M+H] ⁺ = 611.0.

步骤2：(S)-7-(2,4-二氯苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮Step 2: (S)-7-(2,4-Dichlorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H-benzene And [c]pyrido[3,4-e]azepin-3-one

向N-((S)-1-(5-(2-(2,4-二氯苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰氨基(78mg,0.13mmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(3mL)，反应液在室温下搅拌2小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物(S)-7-(2,4-二氯苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(30mg,47％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝489.1，纯度100％(UV 214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.13(s,1H),7.79(s,1H),7.59(d,J＝8.0Hz,1H),7.52-7.49(m,3H),7.20(d,J＝8.0Hz,1H),6.66(s,1H),4.58(s,2H),4.25(d,J＝6.8 Hz,1H),3.71(s,3H),3.13(q,J＝7.2Hz,2H),1.78(d,J＝6.4Hz,3H),1.39(t,J＝7.6Hz,3H). To N-((S)-1-(5-(2-(2,4-dichlorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl-2- Addition of trifluoroacetic acid to a solution of oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinylamino (78 mg, 0.13 mmol) in dichloromethane (2 mL) (3 mL), the reaction mixture was stirred at room temperature for 2 hr and concentrated. The residue was purified by preparative-HPLC to give the title compound (S)-7-(2,4-dichlorophenyl)-10-((ethylsulfonyl)methyl)-2,5-dimethyl-2 ,5-Dihydro-3H-benzo[c]pyrido[3,4-e]azepin-3-one (30 mg, 47%) as a yellow solid. LCMS (ESI) [M + H ] + = 489.1, purity ^{100% (UV 214nm); 1} H NMR (400MHz, CD 3 OD) δ8.13 (s, 1H), 7.79 (s, 1H), 7.59 (d , J=8.0Hz, 1H), 7.52-7.49(m, 3H), 7.20 (d, J=8.0Hz, 1H), 6.66(s,1H), 4.58(s,2H), 4.25(d,J= 6.8 Hz, 1H), 3.71 (s, 3H), 3.13 (q, J = 7.2 Hz, 2H), 1.78 (d, J = 6.4 Hz, 3H), 1.39 (t, J = 7.6 Hz, 3H).

4114：(S)-7-(2-氯-4-氟苯基)-5-乙基-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮4114: (S)-7-(2-Chloro-4-fluorophenyl)-5-ethyl-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H -benzo[c]pyrido[3,4-e]azepin-3-one

步骤1：(S)-N-(1-(5-(2-(2-氯-4-氟苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)丙基)-2-甲基丙烷-2-亚磺酰胺Step 1: (S)-N-(1-(5-(2-(2-chloro-4-fluorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl) -2-oxo-1,2-dihydropyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide

将(2-溴-5-氯-4-((乙基砜)甲基)苯基)(2-氯-4-氟苯基)甲酮(106mg,0.25mmol)，(S)-2-甲基-N-((S)-1-(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)丙基)丙烷-2-亚磺酰胺(250mg,0.63mmol)，磷酸钾(160mg,0.75mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(20mg,0.03mmol)混合于1,4-二氧六环(5mL)和水(0.5mL)中，在氮气保护下加热至95℃搅拌1小时。反应液过滤，滤液浓缩，残余物用制备-TLC分离纯化(乙酸乙酯/甲醇＝25/1(体积比))，得标题化合物(S)-N-(1-(5-(2-(2-氯-4-氟苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)丙基)-2-甲基丙烷-2-亚磺酰胺(60mg,39％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝609.0. (2-Bromo-5-chloro-4-((ethylsulfonyl)methyl)phenyl)(2-chloro-4-fluorophenyl)methanone (106 mg, 0.25 mmol), (S)-2- Methyl-N-((S)-1-(1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1,2-dihydropyridin-4-yl)propyl)propane-2-sulfinamide (250 mg, 0.63 mmol), potassium phosphate (160 mg, 0.75 mmol) and [1,1'-double (Diphenylphosphino)ferrocene]palladium(II) chloride (20 mg, 0.03 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL), heated under nitrogen Stir at 95 ° C for 1 hour. The reaction mixture was filtered, and the filtrate was evaporated.jjjjjjjjjjjjjjjjjjjj 2-Chloro-4-fluorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)propane 2-methylpropane-2-sulfinamide (60 mg, 39%) as a yellow oil. LCMS (ESI) [M+H] ⁺ = 609.0.

步骤2：(S)-7-(2-氯-4-氟苯基)-5-乙基-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮Step 2: (S)-7-(2-Chloro-4-fluorophenyl)-5-ethyl-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro- 3H-benzo[c]pyrido[3,4-e]azepin-3-one

向(S)-N-((S)-1-(5-(2-(2-氯-4-氟苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)丙基)-2-甲基丙烷-2-亚磺酰胺(60mg,0.09mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌1小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物(S)-7-(2-氯-4-氟苯基)-5-乙基-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(31.2mg,65％)，为白色固体。LCMS(ESI)[M+H] ⁺＝487.1，纯度100％(UV 214nm)； ¹H NMR(400MHz,DMSO-d ₆)δ8.06(s,1H),7.70(s,1H),7.53-7.50(m,1H),7.45-7.40(m,2H),7.35-7.31(m,1H),7.09-7.07(d,J＝7.6Hz,1H),6.39(s,1H),4.63-4.50(dd,J＝13.2Hz,2H),3.67-3.64(q,J＝3.2Hz,1H),3.40(s,3H),3.13-3.07(q,J＝7.2Hz,2H),2.21-2.14(m,2H),1.23-1.20(t,J＝12.0Hz,3H),1.03-1.00(t,J＝6.8Hz,3H). To (S)-N-((S)-1-(5-(2-(2-chloro-4-fluorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1- Methyl-2-oxo-1,2-dihydropyridin-4-yl)propyl)-2-methylpropane-2-sulfinamide (60 mg, 0.09 mmol) in dichloromethane (4 mL) Trifluoroacetic acid (1 mL) was added. The reaction solution was stirred at room temperature for 1 hour and concentrated. The residue was purified by preparative-HPLC to give the title compound (S)-7-(2-chloro-4-fluorophenyl)-5-ethyl-10-((ethylsulfonyl)methyl)-2- Base-2,5-dihydro-3H-benzo[c]pyrido[3,4-e]azepin-3-one (31.2 mg, 65%) as a white solid. LCMS (ESI) [M + H ] + = 487.1, purity ^{100 (UV 214nm)%; 1} H NMR (400MHz, DMSO-d 6) δ8.06 (s, 1H), 7.70 (s, 1H), 7.53- 7.50 (m, 1H), 7.45-7.40 (m, 2H), 7.35-7.31 (m, 1H), 7.09-7.07 (d, J = 7.6 Hz, 1H), 6.39 (s, 1H), 4.63-4.50 ( Dd, J = 13.2 Hz, 2H), 3.67-3.64 (q, J = 3.2 Hz, 1H), 3.40 (s, 3H), 3.13 - 3.07 (q, J = 7.2 Hz, 2H), 2.21-2.14 (m , 2H), 1.23-1.20 (t, J = 12.0 Hz, 3H), 1.03-1.00 (t, J = 6.8 Hz, 3H).

4115：1-(7-(2-氯-4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)-N-甲基甲磺酰胺4115: 1-(7-(2-Chloro-4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4- e] azepine-10-yl)-N-methylmethanesulfonamide

步骤1：((3-(4-(((叔丁氧羰基)氨基)甲基)-1-甲基-6-氧代-1,6-二氢吡啶-3-基)-4-(2-氯-4-氟苯甲酰基)苯甲基)磺酰基)(甲基)氨基甲酸叔丁酯Step 1: ((3-(4-((tert-Butoxycarbonyl))amino)methyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-( 2-Chloro-4-fluorobenzoyl)benzyl)sulfonyl)(methyl)carbamic acid tert-butyl ester

将((3-溴-4-(2-氯-4-氟苯甲酰基)苯甲基)磺酰基)(甲基)氨基甲酸叔丁酯(35mg,0.067mmol)，((1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(36.7mg,0.10mmol)，碳酸钾(28mg,0.20mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(10mg,0.01mmol)混合于1,4-二氧六环(5mL)和水(0.5mL)中，在氮气保护下加热至95℃搅拌1小时。反应液过滤，滤液浓缩，残余物用制备-TLC分离纯化(乙酸乙酯/甲醇＝25/1(体积比))，得标题化合物((3-(4-(((叔丁氧羰基)氨基)甲基)-1-甲基-6-氧代-1,6-二氢吡啶-3-基)-4-(2-氯-4-氟苯甲酰基)苯甲基)磺酰基)(甲基)氨基甲酸叔丁酯(20mg,44％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝678.0. tert-Butyl ((3-bromo-4-(2-chloro-4-fluorobenzoyl)phenyl)sulfonyl)(methyl)carbamate (35 mg, 0.067 mmol), ((1-methyl) -2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl) tert-Butyl methyl)carbamate (36.7 mg, 0.10 mmol), potassium carbonate (28 mg, 0.20 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (10 mg, 0.01 mmol) was mixed with 1,4-dioxane (5 mL) and water (0.5 mL), and heated to 95 ° C under a nitrogen atmosphere for 1 hour. The reaction mixture was filtered, and the filtrate was evaporated.jjjjjjjjjjjjjjjjjj )methyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(2-chloro-4-fluorobenzoyl)benzyl)sulfonyl) tert-Butyl methylcarbamate (20 mg, 44%) was obtained as a yellow oil. LCMS (ESI) [M+H] ⁺ = 678.0.

步骤2：1-(7-(2-氯-4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)-N-甲基甲磺酰胺Step 2: 1-(7-(2-Chloro-4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridin[3,4 -e]azepine-10-yl)-N-methylmethanesulfonamide

向((3-(4-(((叔丁氧羰基)氨基)甲基)-1-甲基-6-氧代-1,6-二氢吡啶-3-基)-4-(2-氯-4-氟苯甲酰基)苯甲基)磺酰基)(甲基)氨基甲酸叔丁酯(20mg,0.029mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌12小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物1-(7-(2-氯-4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)-N-甲基甲磺酰胺(1.2mg,9％)，为白色固体。LCMS(ESI)[M+H] ⁺＝460.1； ¹H NMR(400MHz,CD ₃OD)δ8.15(s,1H),7.76(s,1H),7.63-7.59(m,1H),7.50-7.48(d,J＝7.6Hz,1H),7.26-7.22(m,2H),7.17-7.15(d,J＝8.8Hz,1H),6.65(s,1H),4.79-4.47(d,J＝ 10.4Hz,1H),4.49(s,2H),4.13-4.12(d,J＝2.4Hz,1H),3.70(s,3H),2.71-2.70(d,J＝5.2Hz,3H). To ((3-(4-((tert-Butoxycarbonyl))amino)methyl)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-(2- To a solution of chloro-4-fluorobenzoyl)benzyl)sulfonyl)(methyl)carbamic acid tert-butyl ester (20 mg, 0.029 mmol) in dichloromethane (4 mL) The reaction solution was stirred at room temperature for 12 hours and concentrated. The residue was purified by preparative-HPLC to give the title compound 1-(7-(2-chloro-4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzene. [c] Pyrido[3,4-e]azepin-10-yl)-N-methylmethanesulfonamide (1.2 mg, 9%) as a white solid. LCMS (ESI) [M + H ] + = 460.1; 1 H NMR (400MHz, CD 3 OD) δ8.15 (s, 1H), 7.76 (s, 1H), 7.63-7.59 (m, 1H), 7.50- 7.48 (d, J = 7.6 Hz, 1H), 7.26 - 7.22 (m, 2H), 7.17 - 7.15 (d, J = 8.8 Hz, 1H), 6.65 (s, 1H), 4.79 - 4.47 (d, J = 10.4 Hz, 1H), 4.49 (s, 2H), 4.13-4.12 (d, J = 2.4 Hz, 1H), 3.70 (s, 3H), 2.71-2.70 (d, J = 5.2 Hz, 3H).

4116:(S)-7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-5-(2-羟基乙基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮4116: (S)-7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-5-(2-hydroxyethyl)-2-methyl-2H-benzene And [c]pyrido[3,4-e]azepine-3(5H)-one

步骤1:(S)-N-((S)-1-(5-溴-1-甲基-2-氧代-1,2-二氢吡啶-4-基)-3-(叔丁基二甲基硅氧基)丙基)-2-甲基丙烷-2-亚磺酰胺Step 1: (S)-N-((S)-1-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-3-(tert-butyl) Dimethylsiloxy)propyl)-2-methylpropane-2-sulfinamide

在冰浴冷却下，向(S)-N-((S)-1-(5-溴-1-甲基-2-氧代-1,2-二氢吡啶-4-基)-3-羟丙基)-2-甲基丙烷-2-亚磺酰胺(60mg,0.17mmol),三乙胺(34mg,0.34mmol)的二氯甲烷(5mL)溶液中慢慢加入叔丁基二甲基氯硅烷(38mg,0.26mmol)。反应液在室温下搅拌过夜。向反应液中加入二氯甲烷(20mL)和水(15mL)，分离有机相。有机相用饱和食盐水洗涤(50mL*3)，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/1(体积比))，得标题化合物(S)-N-((S)-1-(5-溴-1-甲基-2-氧代-1,2-二氢吡啶-4-基)-3-(叔丁基二甲基硅氧基)丙基)-2-甲基丙烷-2-亚磺酰胺(20mg,25％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝479.0。 To (S)-N-((S)-1-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-3- under cooling in an ice bath Hydroxypropyl)-2-methylpropane-2-sulfinamide (60 mg, 0.17 mmol), triethylamine (34 mg, 0.34 mmol) in dichloromethane (5 mL) Chlorosilane (38 mg, 0.26 mmol). The reaction was stirred at room temperature overnight. Dichloromethane (20 mL) and water (15 mL) were added to the mixture and the organic layer was separated. The organic phase was washed with brine (50 mL*3) The residue was purified by flash chromatography (EtOAc/EtOAc/EtOAc (EtOAc) -2-oxo-1,2-dihydropyridin-4-yl)-3-(tert-butyldimethylsilyloxy)propyl)-2-methylpropane-2-sulfinamide (20 mg, 25%), a yellow oil. LCMS (ESI) [M + H ] + = 479.0.

步骤2:(S)-N-((S)-3-(叔丁基二甲基硅氧基)-1-(5-(2-(2-氯-4-氟苯甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)丙基)-2-2-甲基丙烷-2-亚磺酰胺Step 2: (S)-N-((S)-3-(tert-Butyldimethylsilyloxy)-1-(5-(2-(2-chloro-4-fluorobenzoyl)-5) -(ethylsulfonemethyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)propyl)-2-2-methylpropane-2-sulfin Amide

将(S)-N-((S)-1-(5-溴-1-甲基-2-氧代-1,2-二氢吡啶-4-基)-3-(叔丁基二甲基硅氧基)丙基)-2-甲基丙烷-2-亚磺酰胺(20mg,0.043mmol),(2-氯-4-氟苯基)(4-(乙基砜甲基)-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)甲酮(20mg.0.043mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(3mg,0.0043mmol)和磷酸钾(27mg,0.13mmol)混合于1,4-二氧六环(5mL)及水(2滴)中，反应液在氮气保护下加热至90℃搅拌1小时。向反应液中加入水(15mL)和乙酸乙酯(25mL)，分离有机相，用无水硫酸钠干燥，过滤并浓缩。残余物用薄层色谱法分离纯化(二氯甲烷/甲醇＝10/1(体积比))，得标题化合物(S)-N-((S)-3-(叔丁基二甲基硅氧基)-1-(5-(2-(2-氯-4-氟苯甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)丙基)-2-2-甲基丙烷-2-亚磺酰胺(8mg,13％)，为灰色固体。LCMS(ESI)[M+H] ⁺＝739.3。 (S)-N-((S)-1-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-3-(tert-butyl dimethyl) Silyloxy)propyl)-2-methylpropane-2-sulfinamide (20 mg, 0.043 mmol), (2-chloro-4-fluorophenyl) (4-(ethylsulfonylmethyl)-2 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (20 mg.0.043 mmol), [1,1'-bis ( Diphenylphosphino)ferrocene]palladium(II) chloride (3 mg, 0.0043 mmol) and potassium phosphate (27 mg, 0.13 mmol) in 1,4-dioxane (5 mL) and water (2 drops) In the reaction, the reaction solution was heated to 90 ° C under nitrogen for 1 hour. Water (15 mL) and ethyl acetate (25 mL) were evaporated. The residue was purified by chromatography (dichloromethane / methanol = 10/1 (vol.)) to give the title compound (S)-N-((S)-3-(tert-butyldimethylsiloxane) 1-(5-(2-(2-chloro-4-fluorobenzoyl)-5-(ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1,2 -Dihydropyridin-4-yl)propyl)-2-2-methylpropane-2-sulfinamide (8 mg, 13%) as a grey solid. LCMS (ESI) [M + H ] + = 739.3.

步骤3:(S)-7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-5-(2-羟基乙基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮Step 3: (S)-7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-5-(2-hydroxyethyl)-2-methyl-2H- Benzo[c]pyrido[3,4-e]azepine-3(5H)-one

将(S)-N-((S)-3-(叔丁基二甲基硅氧基)-1-(5-(2-(2-氯-4-氟苯甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)丙基)-2-2-甲基丙烷-2-亚磺酰胺(8mg,0.011mmol)溶于二氯甲烷(4mL)和三氟乙酸(1mL)中，反应液在室温下搅拌过夜。反应液浓缩后用制备HPLC纯化，得标题化合物(S)-7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-5-(2-羟基乙基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮(0.5mg,9％)，为白色固体。LCMS(ESI) [M+H] ⁺＝503.1，纯度100％(UV 214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.11(s,1H),7.79(s,1H),7.60(m,2H),7.22(m,3H),6.62(s,1H),4.57(s,1H),4.25(t,J＝7.2Hz,1H),3.91(m,2H),3.70(s,3H),3.16(t,J＝7.6Hz,2H),2.52(m,1H),2.30(m,1H),1.41(q,J＝7.6Hz,3H)。 (S)-N-((S)-3-(tert-Butyldimethylsilyloxy)-1-(5-(2-(2-chloro-4-fluorobenzoyl)-5-() Ethyl sulfone methyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)propyl)-2-2-methylpropane-2-sulfinamide ( 8 mg, 0.011 mmol) was dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL). The reaction mixture was concentrated and purified by preparative EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2-methyl-2H-benzo[c]pyrido[3,4-e]azepine-3(5H)-one (0.5 mg, 9%) as a white solid. LCMS (ESI) [M+H] ⁺ = 503.1, purity 100% (UV 214nm); ¹ H NMR (400 MHz, CD ₃ OD) δ 8.11 (s, 1H), 7.79 (s, 1H), 7.60 (m) , 2H), 7.22 (m, 3H), 6.62 (s, 1H), 4.57 (s, 1H), 4.25 (t, J = 7.2 Hz, 1H), 3.91 (m, 2H), 3.70 (s, 3H) , 3.16 (t, J = 7.6 Hz, 2H), 2.52 (m, 1H), 2.30 (m, 1H), 1.41 (q, J = 7.6 Hz, 3H).

4117:(S)-7-(4-氯-3-甲氧基苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮4117: (S)-7-(4-Chloro-3-methoxyphenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H -benzo[c]pyrido[3,4-e]azepin-3-one

步骤1:(2-溴-4-甲苯基(4-氯-3-甲氧基苯基)甲醇Step 1: (2-Bromo-4-methylphenyl(4-chloro-3-methoxyphenyl)methanol

向圆底烧瓶中依次加入四氢呋喃(5mL)、镁屑(432mg,18mmol)、一粒碘及少量4-溴-1-氯-2-甲氧基苯(3.7g,18mmol)的四氢呋喃(20mL)溶液。电吹风加热引发反应之后慢慢滴加余下的四氢呋喃溶液。反应液回流搅拌30分钟，得到(4-氯-3-甲氧基苯基)溴化鎂的四氢呋喃溶液。在另一圆底烧瓶中将2-溴-4-甲基苯甲醛(1.8g,9mmol)的四氢呋喃(10mL)溶液冷却到0℃，然后慢慢加入前述格氏试剂。反应液在室温下搅拌4小时，向反应液中加入乙酸乙酯(20mL)和饱和氯化铵水溶液(15mL)，分离有机相。有机相用饱和食盐水洗涤(50mL*3)，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝20/1(体积比))，得(2-溴-4-甲苯基(4-氯-3-甲氧苯基)甲醇(1.1g,36％)，为黄色油状物。Tetrahydrofuran (5 mL), magnesium turnings (432 mg, 18 mmol), one iodine and a small amount of 4-bromo-1-chloro-2-methoxybenzene (3.7 g, 18 mmol) in tetrahydrofuran (20 mL) were sequentially added to a round bottom flask. Solution. After the hair dryer was heated to initiate the reaction, the remaining tetrahydrofuran solution was slowly added dropwise. The reaction solution was stirred at reflux for 30 minutes to give (4-chloro-3-methoxyphenyl)magnesium bromide in tetrahydrofuran. A solution of 2-bromo-4-methylbenzaldehyde (1.8 g, 9 mmol) in tetrahydrofuran (10 mL) was cooled to 0.degree. The reaction mixture was stirred at room temperature for 4 hours, and ethyl acetate (20 mL) and aq. The organic phase was washed with brine (50 mL*3) The residue was purified by flash chromatography (peel ether / ethyl acetate = 20/1 (vol.)) to give (2-bromo-4-tolyl(4-chloro-3-methoxyphenyl)methanol (1.1 g, 36%), as a yellow oil.

步骤2:(2-溴-4-甲苯基)(4-氯-3-甲氧苯基)甲酮Step 2: (2-Bromo-4-methylphenyl)(4-chloro-3-methoxyphenyl)methanone

向(2-溴-4-甲苯基l)(4-氯-3-甲氧苯基)甲醇(1.1g,3.2mmol)的二氯甲烷溶液(20mL)加入Dess-Martin氧化剂(2.1g,4.8mmol)，反应液在室温下搅拌2小时。反应液浓缩后残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝5/1(体积比))，得(2-溴-4-甲苯基)(4-氯-3-甲氧苯基)甲酮(1.0g,92％)，为无色油状物。To a solution of (2-bromo-4-methylphenyl)-(4-chloro-3-methoxyphenyl)methanol (1.1 g, 3.2 mmol) in dichloromethane (20 mL) (mmol), the reaction was stirred at room temperature for 2 hours. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 5 / 1 (volume ratio)) to give (2-bromo-4-methylphenyl) (4-chloro-3-methoxybenzene). Methyl ketone (1.0 g, 92%) was obtained as a colorless oil.

步骤3:(2-溴-4-(二溴甲基)苯基)(4-氯-3-甲氧基苯基)甲酮Step 3: (2-Bromo-4-(dibromomethyl)phenyl)(4-chloro-3-methoxyphenyl)methanone

将N-溴代丁二酰亚胺(1.1g,5.0mmol)、偶氮二异丁腈(15mg,0.1mmol)和(2-溴-4-甲苯基)(4-氯-3-甲氧苯基)甲酮(1.0g,2.9mmol)的四氯化碳(50mL)溶液在90℃下搅拌12小时。反应液浓缩后得(2-溴-4-(二溴甲基)苯基)(4-氯-3-甲氧苯基)甲酮，直接用于下一步反应。N-bromosuccinimide (1.1 g, 5.0 mmol), azobisisobutyronitrile (15 mg, 0.1 mmol) and (2-bromo-4-tolyl) (4-chloro-3-methoxy) A solution of phenyl)methanone (1.0 g, 2.9 mmol) in carbon tetrachloride (50 mL) was stirred at 90 ° C for 12 h. The reaction mixture was concentrated to give (2-bromo-4-(dibromomethyl)phenyl)(4-chloro-3-methoxyphenyl)methanone, which was directly used for the next reaction.

步骤4:(2-溴-4-(溴甲基)苯基)(4-氯-3-甲氧基苯基)甲酮Step 4: (2-Bromo-4-(bromomethyl)phenyl)(4-chloro-3-methoxyphenyl)methanone

向(2-溴-4-(二溴甲基)苯基)(4-氯-3-甲氧苯基)甲酮(1.0g,2.0mmol)的二氯甲烷(20mL)溶液加入亚磷酸二乙酯(0.3g,2.0mmol)、二异丙基乙胺(0.6g,4.7mmol)。反应液在室温下搅拌1小时。反应液浓缩后残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝10/1(体积比))，得(2-溴-4-(溴甲基)苯基)(4-氯-3-甲氧苯基)甲酮(0.8g,96％)，为无色油状物。To a solution of (2-bromo-4-(dibromomethyl)phenyl)(4-chloro-3-methoxyphenyl)methanone (1.0 g, 2.0 mmol) in dichloromethane (20 mL) Ethyl ester (0.3 g, 2.0 mmol), diisopropylethylamine (0.6 g, 4.7 mmol). The reaction solution was stirred at room temperature for 1 hour. After the reaction mixture was concentrated, the residue was purified by flash chromatography ( petroleum ether / ethyl acetate = 10/1 (volume ratio) to give (2-bromo-4-(bromomethyl)phenyl) (4-chloro- 3-methoxyphenyl)methanone (0.8 g, 96%) was obtained as a colorless oil.

步骤5:(2-溴-4-((乙基砜)甲基)苯基)(4-氯-3-甲氧基苯基)甲酮Step 5: (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(4-chloro-3-methoxyphenyl)methanone

将乙基亚磺酸钠(0.9g,7.0mmol)、2-溴-4-(溴甲基)苯基)(4-氯-3-甲氧苯基)甲酮(0.8g,1.76mmol)的二甲基亚砜(10mL)溶液在室温下搅拌1小时，向反应液中加入乙酸乙酯(20mL)和水(50mL)，分离有机相。有机相用饱和食盐水洗涤(50mL*3)，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/1(体积比))，得(2-溴-4-((乙基砜)甲基)苯基)(4-氯-3-甲氧苯基)甲酮(0.7g,85％)，为棕色固体。LCMS(ESI)[M+H] ⁺＝471.9. Sodium ethyl sulfinate (0.9 g, 7.0 mmol), 2-bromo-4-(bromomethyl)phenyl)(4-chloro-3-methoxyphenyl)methanone (0.8 g, 1.76 mmol) A solution of dimethyl sulfoxide (10 mL) was stirred at room temperature for 1 hour, and ethyl acetate (20 mL) and water (50 mL) were added to the mixture. The organic phase was washed with brine (50 mL*3) The residue is purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1 (volume ratio)) to give (2-bromo-4-((ethylsulfonyl)methyl)phenyl) 3-methoxyphenyl)methanone (0.7 g, 85%) was obtained as a brown solid. LCMS (ESI) [M+H] ⁺ = 471.9.

步骤6:(S)-N-(1-(5-(2-(4-氯-3-甲氧苯基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺Step 6: (S)-N-(1-(5-(2-(4-Chloro-3-methoxyphenyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl) -2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide

将(2-溴-4-((乙基砜)甲基)苯基)(4-氯-3-甲氧苯基)甲酮(100mg,0.3mmol),(S)-2-甲基-N-((S)-1-(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(133mg,0.3mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(20mg,0.026mmol)和磷酸钾(148mg,0.7mmol)混合于1,4-二氧六环(4mL)及水(0.4mL)中，反应液在氮气保护下加热至90℃搅拌1小时。反应液过滤后浓缩。残余物用快速色谱法分离纯化(乙酸乙酯/甲醇＝10/1(体积比))，得(S)-N-(1-(5-(2-(4-氯-3-甲氧苯基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(60mg,43％)，为白色固体。LCMS(ESI)[M+H] ⁺＝607.2. (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(4-chloro-3-methoxyphenyl)methanone (100 mg, 0.3 mmol), (S)-2-methyl- N-((S)-1-(1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfenamide (133 mg, 0.3 mmol), [1,1'-bis(diphenylphosphino) Ferrocene]Palladium(II) dichloride (20 mg, 0.026 mmol) and potassium phosphate (148 mg, 0.7 mmol) were mixed in 1,4-dioxane (4 mL) and water (0.4 mL). Heat to 90 ° C under nitrogen for 1 hour. The reaction solution was filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate / methanol = 10/1 (vol.)) to give (S)-N-(1-(5-(2-(4-chloro-3-methoxybenzene) 5-(-(ethylsulfonyl)methyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane- 2-sulfinamide (60 mg, 43%) as a white solid. LCMS (ESI) [M+H] ⁺ = 607.2.

步骤7:(S)-7-(4-氯-3-甲氧基苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮Step 7: (S)-7-(4-Chloro-3-methoxyphenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro- 3H-benzo[c]pyrido[3,4-e]azepin-3-one

将(S)-N-(1-(5-(2-(4-氯-3-甲氧苯基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(60mg,0.1mmol)溶于二氯甲烷(4mL)和三氟乙酸(1mL)中，反应液在室温下搅拌16小时。反应液浓缩后用制备HPLC纯化，得标题化合物(S)-7-(4-氯-3-甲氧基苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(35.2mg,73％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝485.1，纯度100％(UV 214nm)； ¹H NMR(400MHz,DMSO-d ₆)δ8.04(s,1H),7.71(s,1H),7.49-7.42(m,2H),7.35(d,J＝8.4Hz,1H),7.26(s,1H),6.80-6.82(m,1H),6.43(s,1H),4.60(dd,J ₁＝13.2Hz,J ₂＝9.2Hz,2H),3.96(q,J＝6.4Hz,1H),3.84(s,3H),3.48(s,3H),3.15(q,J＝2.8Hz,2H),1.67(d,J＝6.4Hz,3H),1.25(t,J＝7.2Hz,3H). (S)-N-(1-(5-(2-(4-Chloro-3-methoxyphenyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl-2) -oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfenamide (60 mg, 0.1 mmol) dissolved in dichloromethane (4 mL) In 1 mL), the reaction solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by preparative hp~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Base-2,5-dihydro-3H-benzo[c]pyrido[3,4-e]azepin-3-one (35.2 mg, 73%) as a yellow solid. LCMS (ESI) [M + H ] + = 485.1, purity ^{100 (UV 214nm)%; 1} H NMR (400MHz, DMSO-d 6) δ8.04 (s, 1H), 7.71 (s, 1H), 7.49- 7.42 (m, 2H), 7.35 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 6.80-6.82 (m, 1H), 6.43 (s, 1H), 4.60 (dd, J ₁ = 13.2) Hz, J ₂ = 9.2 Hz, 2H), 3.96 (q, J = 6.4 Hz, 1H), 3.84 (s, 3H), 3.48 (s, 3H), 3.15 (q, J = 2.8 Hz, 2H), 1.67 (d, J = 6.4 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H).

4118:(S)-7-(2-氯-4-氟苯基)-10-(乙基砜)-2,5-二甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮4118: (S)-7-(2-Chloro-4-fluorophenyl)-10-(ethylsulfone)-2,5-dimethyl-2H-benzo[c]pyrido[3,4- e] azepine-3(5H)-one

步骤1:2-溴-4-(乙硫基)苯甲酸甲酯Step 1: Methyl 2-bromo-4-(ethylthio)benzoate

将2-溴-4-氟苯甲酸甲酯(2.0g,8.6mmol),乙硫醇(800mg,12.9mmol)和碳酸钾(2.4g,17.2mmol)的N,N-二甲基甲酰胺(10mL)溶液在100℃下搅拌2小时，向反应液中加入乙酸乙酯(30mL)和水(30mL)，分离有机相。有机相用饱和食盐水洗涤(30mL*2)，无水硫酸钠干燥，过滤并浓缩，得2-溴-4-(乙硫基)苯甲酸甲酯粗产物(1.7g)。LCMS(ESI)[M+H] ⁺＝275.0. Methyl 2-bromo-4-fluorobenzoate (2.0 g, 8.6 mmol), ethanethiol (800 mg, 12.9 mmol) and potassium carbonate (2.4 g, 17.2 mmol) of N,N-dimethylformamide ( The solution was stirred at 100 ° C for 2 hours, and ethyl acetate (30 mL) and water (30 mL) were added to the mixture, and the organic phase was separated. The organic phase was washed with EtOAc (EtOAc m. LCMS (ESI) [M+H] ⁺ =275.0.

步骤2:2-溴-4-(乙基砜)苯甲酸甲酯Step 2: Methyl 2-bromo-4-(ethylsulfone)benzoate

向2-溴-4-(乙硫基)苯甲酸甲酯(第一步的粗产物)的二氯甲烷溶液(20mL)加入间氯过氧苯甲酸(3.7g,21.6mmol)，反应液在室温下搅拌2小时。反应液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝3/1(体积比))，得2-溴-4-(乙基砜)苯甲酸甲酯(1.5g,两步总收率53％).LCMS(ESI)[M+H] ⁺＝324.0. To a solution of methyl 2-bromo-4-(ethylthio)benzoate (the crude product of the first step) in methylene chloride (20 mL) was added m-chloroperoxybenzoic acid (3.7 g, 21.6 mmol). Stir at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified by flash chromatography (ethyl ether / ethyl acetate=3/1 (vol.)) to give methyl 2-bromo-4-(ethyl sulfone) benzoate (1.5 g, The total yield of the step was 53%). LCMS (ESI) [M+H] ⁺ = 324.0.

步骤3:2-溴-4-(乙基砜)苯甲醇Step 3: 2-Bromo-4-(ethylsulfone)benzyl alcohol

冰水浴冷却下，向2-溴-4-(乙基砜)苯甲酸甲酯(1.5g,4.88mmol)的四氢呋喃溶液(20mL)中加入二异丙基氢化铝(1.0M的甲苯溶液,15mL,15mmol)。反应液在室温下搅拌2小时后浓缩，残余物溶于乙酸乙酯(100mL)，先后用稀盐酸(2M,20mL)和碳酸钠水溶液(20mL)洗涤，无水硫酸钠干燥，过滤并浓缩后得2-溴-4-(乙基砜)苯甲醇粗产物(1.4g,100％)。LCMS(ESI)[M+NH ₄] ⁺＝296.0. To a solution of methyl 2-bromo-4-(ethylsulfonate)benzoate (1.5 g, 4.88 mmol) in tetrahydrofuran (20 mL) was added diisopropyl aluminum hydride (1.0 M in toluene, 15 mL). , 15mmol). The reaction mixture was stirred at room temperature for 2 hr then evaporated, evaporated, evaporated, evaporated, evaporated The crude product of 2-bromo-4-(ethylsulfone)benzyl alcohol (1.4 g, 100%). LCMS (ESI) [M+NH ₄ ] ⁺ = 296.0.

步骤4:2-溴-4-(乙基砜)苯甲醛Step 4: 2-Bromo-4-(ethylsulfone)benzaldehyde

向2-溴-4-(乙基砜)苯甲醇(1.4g,5.0mmol)的二氯甲烷溶液(20mL)加入Dess-Martin氧化剂(3.2g,7.5mmol)，反应液在室温下搅拌16小时。反应液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝3/1(体积比))，得2-溴-4-(乙基砜)苯甲醛(1.0g,74％)，为无色油状物。To a solution of 2-bromo-4-(ethylsulfonyl)benzyl alcohol (1.4 g, 5.0 mmol) in dichloromethane (20 mL), EtOAc (EtOAc, Et. . The reaction mixture was concentrated, and the residue was purified and purified (jjjjjjjjjjj , is a colorless oil.

步骤5:(2-溴-4-(乙基砜)苯基)(2-氯-4-氟苯基)甲醇Step 5: (2-Bromo-4-(ethylsulfone)phenyl)(2-chloro-4-fluorophenyl)methanol

向2-氯-4-氟-1-碘苯(923mg,3.6mmol)的四氢呋喃(8.8mL)溶液中滴加异丙基氯化镁(2M的四氢呋喃溶液,1.8mL,3.6mmol)。反应液在0℃下搅拌3小时。将该格式试剂加入到预先冷却至-20℃的2-溴-4-(乙基砜)苯甲醛(500mg,1.8mmol)，三甲基氯硅烷(196mg,1.8mmol)和干燥四氢呋喃(10mL)的混合液中。反应液在室温下搅拌过夜。加入氯化铵水溶液(10mL)淬灭反应，然后用乙酸乙酯(30mL*2)萃取，萃取液合并后用稀盐酸(1M,10mL)和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤并浓缩后得(2-溴-4-(乙基砜)苯基)(2-氯-4-氟苯基)甲醇粗产物，为黄色油状物。LCMS(ESI)[M+NH ₄] ⁺＝424.0. To a solution of 2-chloro-4-fluoro-1-iodobenzene (923 mg, 3.6 mmol) in tetrahydrofuran (8.8 mL), isopropylmagnesium chloride (2M in tetrahydrofuran, 1.8 mL, 3.6 mmol). The reaction solution was stirred at 0 ° C for 3 hours. The format reagent was added to 2-bromo-4-(ethylsulfone)benzaldehyde (500 mg, 1.8 mmol), trimethylchlorosilane (196 mg, 1.8 mmol) and dry tetrahydrofuran (10 mL) cooled to -20 °C. In the mixture. The reaction was stirred at room temperature overnight. The reaction was quenched with aqueous EtOAc (EtOAc) (EtOAc (EtOAc) (EtOAc) After concentration, the crude product (2-bromo-4-(ethylsulfonyl)phenyl)(2-chloro-4-fluorophenyl)methanol was obtained as a yellow oil. LCMS (ESI) [M+NH ₄ ] ⁺ = 424.0.

步骤6:(2-溴-4-(乙基砜)苯基)(2-氯-4-氟苯基)甲酮Step 6: (2-Bromo-4-(ethylsulfone)phenyl)(2-chloro-4-fluorophenyl)methanone

向(2-溴-4-(乙基砜)苯基)(2-氯-4-氟苯基)甲醇(第五步粗产物)的二氯甲烷溶液(10mL)加入Dess-Martin氧化剂(1.2g,2.7mmol)，反应液在室温下搅拌16小时。反应液浓缩后残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝3/1(体积比))，得(2-溴-4-(乙基砜)苯基)(2-氯-4-氟苯基)甲酮(700mg,两步总收率96％)，为红色油状物。LCMS(ESI)[M+NH ₄] ⁺＝422.0. To a solution of (2-bromo-4-(ethylsulfonyl)phenyl)(2-chloro-4-fluorophenyl)methanol (5th crude product) in dichloromethane (10 mL) was added Dess-Martin oxidant (1.2 g, 2.7 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1 (volume ratio)) to give (2-bromo-4-(ethylsulfonyl)phenyl) (2-chloro-) 4-fluorophenyl)methanone (700 mg, total yield of 96% in two steps) as a red oil. LCMS (ESI) [M+NH ₄ ] ⁺ = 422.0.

步骤7:(S)-N-((S)-1-(5-(2-(2-氯-4-氟苯甲酰基)-5-(乙基砜)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺Step 7: (S)-N-((S)-1-(5-(2-(2-chloro-4-fluorobenzoyl)-5-(ethylsulfone)phenyl)-1-methyl -2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide

将(2-溴-4-(乙基砜)苯基)(2-氯-4-氟苯基)甲酮(100mg,0.25mmol),(S)-2-甲基-N-((S)-1-(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(115mg,0.3mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(18mg,0.024mmol)和碳酸钾(87mg,0.63mmol)混合于1,4-二氧六环(4mL)及水(0.4mL)中，反应液在氮气保护下加热至90℃搅拌2小时。反应液过滤后浓缩得(S)-N-((S)-1-(5-(2-(2-氯-4-氟苯甲酰基)-5-(乙基砜)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺粗产物，为褐色油状物。LCMS(ESI)[M+H] ⁺＝581.2. (2-Bromo-4-(ethylsulfone)phenyl)(2-chloro-4-fluorophenyl)methanone (100 mg, 0.25 mmol), (S)-2-methyl-N-((S) )-1-(1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2 -dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (115 mg, 0.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene] Palladium(II) chloride (18 mg, 0.024 mmol) and potassium carbonate (87 mg, 0.63 mmol) were mixed in 1,4-dioxane (4 mL) and water (0.4 mL). Stir at 90 ° C for 2 hours. The reaction solution was filtered and concentrated to give (S)-N-((S)-1-(5-(2-(2-chloro-4-fluorobenzoyl)-5-(ethylsulfone)phenyl)-1 -Methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfenamide as a brown oil. LCMS (ESI) [M+H] ⁺ = 581.2.

步骤8:(S)-7-(2-氯-4-氟苯基)-10-(乙基砜)-2,5-二甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮Step 8: (S)-7-(2-Chloro-4-fluorophenyl)-10-(ethylsulfone)-2,5-dimethyl-2H-benzo[c]pyridin[3,4 -e]azepine-3(5H)-one

将步骤7所得粗产物(S)-N-((S)-1-(5-(2-(2-氯-4-氟苯甲酰基)-5-(乙基砜)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺溶于二氯甲烷(3mL)和三氟乙酸(2mL)中，反应液在室温下搅拌4小时。反应液浓缩后用制备HPLC纯化，得标题化合物(S)-7-(2-氯-4-氟苯基)-10-(乙基砜)-2,5-二甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮(49mg,两步总收率43％)，为白色固体。LCMS(ESI)[M+H] ⁺＝458.9，纯度100％(UV214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.24(s,1H),8.23(s,1H),7.93(d,J＝8.0Hz,1H),7.71(d,J＝8.4Hz,1H),7.43(d,J＝8.4Hz,1H),7.30-7.24(m,2H),6.67(s,1H),4.23(q,J＝ 6.4Hz,1H),3.71(s,3H),3.34(q,J＝7.2Hz,2H),1.79(d,J＝6.4Hz,3H),1.31(t,J＝7.2Hz,3H). The crude product obtained in Step 7 (S)-N-((S)-1-(5-(2-(2-chloro-4-fluorobenzoyl)-5-(ethylsulfone)phenyl)-1 -Methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfenamide dissolved in dichloromethane (3 mL) and trifluoroacetic acid (2 mL The reaction solution was stirred at room temperature for 4 hours. The reaction mixture was concentrated and purified by preparative EtOAc EtOAc. [c] Pyrido[3,4-e]azepine-3(5H)-one (49 mg, a two-step total yield of 43%) as a white solid. LCMS (ESI) [M + H ] + = 458.9, purity ^{100 (UV214nm)%; 1 H} NMR (400MHz, CD 3 OD) δ8.24 (s, 1H), 8.23 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.30-7.24 (m, 2H), 6.67 (s, 1H), 4.23 ( q, J = 6.4 Hz, 1H), 3.71 (s, 3H), 3.34 (q, J = 7.2 Hz, 2H), 1.79 (d, J = 6.4 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H).

4119:((S)-7-(2-氯-4-氟苯基)-N-乙基-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-磺酰胺4119: ((S)-7-(2-Chloro-4-fluorophenyl)-N-ethyl-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo [c] Pyrido[3,4-e]azepine-10-sulfonamide

步骤1:3-溴-4-((2-氯-4-氟苯基)(羟基)甲基)-N-乙基苯磺酰胺Step 1: 3-Bromo-4-((2-chloro-4-fluorophenyl)(hydroxy)methyl)-N-ethylbenzenesulfonamide

向2-氯-4-氟-1-碘苯(2.26g,8.8mmol)的四氢呋喃(4.4mL)溶液中滴加异丙基氯化镁的四氢呋喃溶液(2M,4.4mL,8.8mmol)。反应液在0℃下搅拌3小时。将该格式试剂加入到预先冷却至-20℃的3-溴-N-乙基-4-甲酰基苯磺酰胺(1.3g,4.4mmol)，三甲基氯硅烷(478mg,4.4mmol)和干燥四氢呋喃(10mL)的混合液中。反应液在室温下搅拌过夜，加入氯化铵水溶液(10mL)淬灭反应，然后用乙酸乙酯(30mL*2)萃取，萃取液合并后用稀盐酸(1M,20mL)和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤并浓缩后得3-溴-4-((2-氯-4-氟苯基)(羟基)甲基)-N-乙基苯磺酰胺粗产物，为黄色油状物。LCMS(ESI)[M+H] ⁺＝424.0 To a solution of 2-chloro-4-fluoro-1-iodobenzene (2.26 g, 8.8 mmol) in EtOAc (EtOAc) The reaction solution was stirred at 0 ° C for 3 hours. The format reagent was added to 3-bromo-N-ethyl-4-formylbenzenesulfonamide (1.3 g, 4.4 mmol), trimethylchlorosilane (478 mg, 4.4 mmol), and dried, previously cooled to -20 °C. In a mixture of tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature overnight, and then filtered and evaporated with with with with with with with with with with with with with with with with with Drying over anhydrous sodium sulfate, filtration and concentration to give the crude product of 3-bromo-4-((2-chloro-4-fluorophenyl)(hydroxy)methyl)-N-ethylbenzenesulfonamide as a yellow oil Things. LCMS (ESI) [M+H] ⁺ =424.0

步骤2:3-溴-4-(2-氯-4-氟苯甲酰基)-N-乙基苯磺酰胺Step 2: 3-Bromo-4-(2-chloro-4-fluorobenzoyl)-N-ethylbenzenesulfonamide

向3-溴-4-((2-氯-4-氟苯基)(羟基)甲基)-N-乙基苯磺酰胺(第一步的粗产物)的二氯甲烷溶液(20mL)加入Dess-Martin氧化剂(2.8g,6.6mmol)，反应液在室温下搅拌16小时。反应液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝3/1(体积比))，得3-溴-4-(2-氯-4-氟苯甲酰基)-N-乙基苯磺酰胺(520mg,两步总收率28％)，为红色油状物。LCMS(ESI)[M+H] ⁺＝438.9. Add to 3-bromo-4-((2-chloro-4-fluorophenyl)(hydroxy)methyl)-N-ethylbenzenesulfonamide (crude of the first step) in dichloromethane (20 mL) Dess-Martin oxidant (2.8 g, 6.6 mmol) was stirred at room temperature for 16 h. The reaction mixture was concentrated, and the residue was purified and purified eluting eluting eluting Ethylbenzenesulfonamide (520 mg, 28% total yield in two steps) as a red oil. LCMS (ESI) [M+H] ⁺ =438.9.

步骤3:4-(2-氯-4-氟苯基)-3-(4-((S)-1-((S)-1,1-二甲基乙基亚磺酰胺)乙基-1-甲基-6-氧代-1,6-二氢吡啶-3-基)-N-乙基苯磺酰胺Step 3: 4-(2-Chloro-4-fluorophenyl)-3-(4-((S)-1-((S)-1,1-dimethylethylsulfinamide)ethyl- 1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-N-ethylbenzenesulfonamide

将3-溴-4-(2-氯-4-氟苯甲酰基)-N-乙基苯磺酰胺(100mg,0.24mmol),(S)-2-甲基-N-((S)-1-(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(111mg,0.29mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(18mg,0.024mmol)和碳酸钾(83mg,0.6mmol)混合于1,4-二氧六环(4mL)及水(0.4mL)中，反应液在氮气保护下加热至90℃搅拌2小时。反应液过滤后浓缩。残余物用快速色谱法分离纯化(乙酸乙酯/甲醇＝10/1(体积比))，得4-(2-氯-4-氟苯基)-3-(4-((S)-1-((S)-1,1-二甲基乙基亚磺酰胺)乙基-1-甲基-6-氧代-1,6-二氢吡啶-3-基)-N-乙基苯磺酰胺(45mg,32％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝596.2. 3-Bromo-4-(2-chloro-4-fluorobenzoyl)-N-ethylbenzenesulfonamide (100 mg, 0.24 mmol), (S)-2-methyl-N-((S)- 1-(1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-di Hydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (111 mg, 0.29 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium (II) (18 mg, 0.024 mmol) and potassium carbonate (83 mg, 0.6 mmol) were mixed in 1,4-dioxane (4 mL) and water (0.4 mL), and the mixture was heated to 90 ° C under nitrogen atmosphere. Stir for 2 hours. The reaction solution was filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate / methanol = 10/1 (vol.)) to give 4-(2-chloro-4-fluorophenyl)-3-(4-((S)-1) -((S)-1,1-dimethylethylsulfinamide)ethyl-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-N-ethylbenzene sulfonamide (45mg, 32%), as a yellow solid .LCMS (ESI) [M + H ] + = 596.2.

步骤4:((S)-7-(2-氯-4-氟苯基)-N-乙基-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-磺酰胺Step 4: ((S)-7-(2-Chloro-4-fluorophenyl)-N-ethyl-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzene And [c]pyrido[3,4-e]azepine-10-sulfonamide

将4-(2-氯-4-氟苯基)-3-(4-((S)-1-((S)-1,1-二甲基乙基亚磺酰胺)乙基-1-甲基-6-氧代-1,6-二氢吡啶-3-基)-N-乙基苯磺酰胺(45mg,0.075mmol)溶于二氯甲烷(3mL)和三氟乙酸(2mL)中，反应液在室温下搅拌4小时。反应液浓缩后用制备HPLC纯化，得标题化合物((S)-7-(2-氯-4-氟苯基)-N-乙基-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-磺酰胺(14.5mg,38％)，为白色固体。LCMS(ESI)[M+H] ⁺＝474.1，纯度100％(UV 214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.16(s,1H),8.14(s,1H),7.85(d,J＝8.0Hz,1H),7.70(d,J＝8.0Hz,1H),7.36(d,J＝8.0Hz,1H),7.29-7.23(m,2H),6.67(s,1H),4.22(q,J＝6.4Hz,1H),3.71(s,3H),3.02(q,J＝7.2Hz,2H),1.79(d,J＝6.4Hz,3H),1.12(t,J＝7.2Hz,3H). 4-(2-Chloro-4-fluorophenyl)-3-(4-((S)-1-((S)-1,1-dimethylethylsulfinamide)ethyl-1- Methyl-6-oxo-1,6-dihydropyridin-3-yl)-N-ethylbenzenesulfonamide (45 mg, 0.075 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (2 mL) The reaction mixture was stirred at room temperature for 4 hr. Dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e]azepine-10-sulfonamide (14.5 mg, 38%), white LCMS (ESI) [M+H] ⁺ = 474.1, mp. 100% (UV 214nm); ¹ H NMR (400 MHz, CD ₃ OD) δ 8.16 (s, 1H), 8.14 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.29-7.23 (m, 2H), 6.67 (s, 1H) , 4.22 (q, J = 6.4 Hz, 1H), 3.71 (s, 3H), 3.02 (q, J = 7.2 Hz, 2H), 1.79 (d, J = 6.4 Hz, 3H), 1.12 (t, J = 7.2 Hz, 3H).

4120:(S)-10-((乙基砜)甲基)-7-(4-氟-2-三氟甲基苯基)-2,5-二甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮4120: (S)-10-((ethylsulfone)methyl)-7-(4-fluoro-2-trifluoromethylphenyl)-2,5-dimethyl-2H-benzo[c] Pyrido[3,4-e]azepine-3(5H)-one

步骤1:(2-溴-4-甲苯基(4-氟-2-三氟甲基苯基)甲醇Step 1: (2-Bromo-4-methylphenyl(4-fluoro-2-trifluoromethylphenyl)methanol

向1-溴-4-氟-2-三氟甲基苯(760mg,3.1mmol)的四氢呋喃(20mL)溶液中滴加异丙基氯化镁的四氢呋喃溶液(1.55mL,3.1mmol)。室温搅拌30分钟后加入2-溴-4-甲基苯甲醛(0.50g,2.5mmol)。反应液在室温下搅拌2小时，向反应液中加入乙酸乙酯(20mL)和饱和氯化铵水溶液(15mL)，分离有机相。有机相用饱和食盐水洗涤(50mL*3)，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝20/1(体积比))，得(2-溴-4-甲苯基(4-氟-2-三氟甲基苯基)甲醇(0.75g,83％)，为无色油状物。To a solution of 1-bromo-4-fluoro-2-trifluoromethylbenzene (760 mg, 3.1 mmol) in tetrahydrofuran (20 mL) EtOAc (EtOAc m. After stirring at room temperature for 30 minutes, 2-bromo-4-methylbenzaldehyde (0.50 g, 2.5 mmol) was added. The reaction mixture was stirred at room temperature for 2 hr. ethyl acetate (20 mL) and aq. The organic phase was washed with brine (50 mL*3) The residue was purified by flash chromatography (petrole ether / ethyl acetate = 20/1 (vol.)) to give (2-bromo-4-tolyl(4-fluoro-2-trifluoromethylphenyl)methanol (0.75 g, 83%) as a colorless oil.

步骤2:(2-溴-4-甲苯基)(4-氟-2-三氟甲基苯基)甲酮Step 2: (2-Bromo-4-methylphenyl)(4-fluoro-2-trifluoromethylphenyl)methanone

向(2-溴-4-甲苯基(4-氟-2-三氟甲基苯基)甲醇(725mg,2.0mmol)的二氯甲烷溶液(20mL)加入Dess-Martin氧化剂(1.0g,2.4mmol)，反应液在室温下搅拌2小时。反应液浓缩后残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝20/1(体积比))，得(2-溴-4-甲苯基)(4-氟-2-三氟甲基苯基)甲酮(480mg,67％)，为无色油状物。LCMS(ESI)[M+H] ⁺＝361.0. To a solution of (2-bromo-4-tolyl(4-fluoro-2-trifluoromethylphenyl)methanol (725 mg, 2.0 mmol) in dichloromethane (20 mL) The reaction solution was stirred at room temperature for 2 hours. After the reaction mixture was concentrated, the residue was purified by flash chromatography ( petroleum ether / ethyl acetate = 20/1 (volume ratio) to give (2-bromo-4-methylphenyl) ) (4-fluoro-2-trifluoromethylphenyl) methanone (480mg, 67%), as a colorless oil .LCMS (ESI) [M + H ] + = 361.0.

步骤3:(2-溴-4-(二溴甲基)苯基)(4-氟-2-三氟甲基苯基)甲酮Step 3: (2-Bromo-4-(dibromomethyl)phenyl)(4-fluoro-2-trifluoromethylphenyl)methanone

将N-溴代丁二酰亚胺(475mg,2.67mmol)、偶氮二异丁腈(45mg,0.3mmol)和(2-溴-4-甲苯基)(4-氟-2-三氟甲基苯基)甲酮(480mg,1.33mmol)的四氯化碳(5mL)溶液在80℃下搅拌1小时。反应液浓缩后得(2-溴-4-(二溴甲基)苯基)(4-氟-2-三氟甲基苯基)甲酮，直接用于下一步反应。N-bromosuccinimide (475 mg, 2.67 mmol), azobisisobutyronitrile (45 mg, 0.3 mmol) and (2-bromo-4-tolyl) (4-fluoro-2-trifluoromethyl) A solution of phenyl) ketone (480 mg, 1.33 mmol) in carbon tetrachloride (5 mL) was stirred at 80 ° C for 1 hour. The reaction mixture was concentrated to give (2-bromo-4-(dibromomethyl)phenyl)(4-fluoro-2-trifluoromethylphenyl)methanone, which was directly used for the next reaction.

步骤4:(2-溴-4-(溴甲基)苯基)(4-氟-2-三氟甲基苯基)甲酮Step 4: (2-Bromo-4-(bromomethyl)phenyl)(4-fluoro-2-trifluoromethylphenyl)methanone

向(2-溴-4-(二溴甲基)苯基)(4-氟-2-三氟甲基苯基)甲酮(686mg,1.33mmol)的二氯甲烷(10mL)溶液加入亚磷酸二乙酯(0.39g,2.67mmol)、二异丙基乙胺(0.52g,4.0mmol)。反应液在室温下搅拌2小时。反应液浓缩后残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝20/1(体积比))，得(2-溴-4-(溴甲基)苯基)(4-氟-2-三氟甲基苯基)甲酮(450mg,两步收率78％)，为无色油状物。LCMS(ESI)[M+NH ₄] ⁺＝456.0. To a solution of (2-bromo-4-(dibromomethyl)phenyl)(4-fluoro-2-trifluoromethylphenyl)methanone (686 mg, 1.33 mmol) in dichloromethane (10 mL) Diethyl ester (0.39 g, 2.67 mmol), diisopropylethylamine (0.52 g, 4.0 mmol). The reaction solution was stirred at room temperature for 2 hours. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 20/1 (volume ratio)) to give (2-bromo-4-(bromomethyl)phenyl) (4-fluoro-) 2-Trifluoromethylphenyl)methanone (450 mg, 78% yield in two steps) as a colorless oil. LCMS (ESI) [M+NH ₄ ] ⁺ = 456.0.

步骤5:(2-溴-4-((乙基砜)甲基)苯基)(4-氟-2-三氟甲基苯基)甲酮Step 5: (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(4-fluoro-2-trifluoromethylphenyl)methanone

将乙基亚磺酸钠(230mg,2.0mmol)、(2-溴-4-(溴甲基)苯基)(4-氟-2-三氟甲基苯基)甲酮(440mg,1.0mmol)的二甲基亚砜(5mL)溶液在65℃下搅拌2小时，向反应液中加入乙酸乙酯(30mL)和水(30mL)，分离有机相。有机相用饱和食盐水洗涤(30mL*2)，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝2/3(体积比))，得(2-溴-4-((乙基砜)甲基)苯基)(4-氟-2-三氟甲基苯基)甲酮(270mg,60％)，为棕色油状物。LCMS(ESI)[M+NH ₄] ⁺＝470.0. Sodium ethyl sulfinate (230 mg, 2.0 mmol), (2-bromo-4-(bromomethyl)phenyl)(4-fluoro-2-trifluoromethylphenyl)methanone (440 mg, 1.0 mmol) A solution of dimethyl sulfoxide (5 mL) was stirred at 65 ° C for 2 hours, and ethyl acetate (30 mL) and water (30 mL) were added to the mixture, and the organic phase was separated. The organic phase was washed with brine (30 mL*2) The residue was purified by flash chromatography (petrole ether / ethyl acetate = 2 / 3 (volume ratio)) to give (2-bromo-4-((ethylsulfonyl)methyl)phenyl) 2-Trifluoromethylphenyl)methanone (270 mg, 60%) as a brown oil. LCMS (ESI) [M+NH ₄ ] ⁺ = 470.0.

步骤6:(S)-N-(1-(5-(5-((乙基砜)甲基)-2-(4-氟-2-(三氟甲基)苯基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺Step 6: (S)-N-(1-(5-(5-((ethylsulfonyl)methyl)-2-(4-fluoro-2-(trifluoromethyl)phenyl)phenyl)-) 1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide

将(2-溴-4-((乙基砜)甲基)苯基)(4-氟-2-三氟甲基苯基)甲酮(67mg,0.15mmol),(S)-2-甲基-N-((S)-1-(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(60mg,0.15mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(20mg,0.026mmol)和碳酸钾(63mg,0.45mmol)混合于1,4-二氧六环(5mL)及水(1mL)中，反应液在氮气保护下加热至90℃搅拌1小时。反应液过滤后浓缩。残余物用快速色谱法分离纯化(二氯甲烷/甲醇＝20/1(体积比))，得(S)-N-(1-(5-(5-((乙基砜)甲基)-2-(4-氟-2-(三氟甲基)苯基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(80mg,85％)，为白色固体。LCMS(ESI)[M+H] ⁺＝629.3. (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(4-fluoro-2-trifluoromethylphenyl)methanone (67 mg, 0.15 mmol), (S)-2-A --N-((S)-1-(1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfenamide (60 mg, 0.15 mmol), [1,1'-bis(diphenylphosphine) a mixture of palladium(II) dichloride (20 mg, 0.026 mmol) and potassium carbonate (63 mg, 0.45 mmol) in 1,4-dioxane (5 mL) and water (1 mL) Heat to 90 ° C under nitrogen for 1 hour. The reaction solution was filtered and concentrated. The residue was purified by flash chromatography (dichloromethane / methanol = 20/1 (vol.)) to give (S)-N-(1-(5-(5-((ethylsulfonyl)methyl)) 2-(4-Fluoro-2-(trifluoromethyl)phenyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2- Methylpropane-2-sulfinamide (80 mg, 85%) as a white solid. LCMS (ESI) [M+H] ⁺ = 629.3.

步骤7:(S)-10-((乙基砜)甲基)-7-(4-氟-2-(三氟甲基)苯基)-2,5-二甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮Step 7: (S)-10-((Ethyl sulfonyl)methyl)-7-(4-fluoro-2-(trifluoromethyl)phenyl)-2,5-dimethyl-2H-benzo [c] Pyrido[3,4-e]azepine-3(5H)-one

将(S)-N-(1-(5-(5-((乙基砜)甲基)-2-(4-氟-2-(三氟甲基)苯基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(80mg,0.13mmol)溶于二氯甲烷(2mL)和三氟乙酸(2mL)中，反应液在室温下搅拌过夜。反应液浓缩后用制备HPLC纯化，得标题化合物(S)-10-((乙基砜)甲基)-7-(4-氟-2-(三氟甲基)苯基)-2,5-二甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮(23mg,35％)，为白色固体。LCMS(ESI)[M+H] ⁺＝507.3，purity100％(UV 214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.12(s,1H),7.79(s,1H),7.57-7.46(m,4H),7.15(d,J＝8.4Hz,1H),6.64(s,1H),4.57(s,2H),4.20(q,J＝6.4Hz,1H),3.72(s,3H),3.12(q,J＝7.6Hz,2H),1.76(d,J＝6.4Hz,3H),1.37(t,J＝7.6Hz,3H). (S)-N-(1-(5-(5-((ethylsulfonyl)methyl)-2-(4-fluoro-2-(trifluoromethyl)phenyl)phenyl)-1- Methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (80 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL) The reaction mixture was stirred at room temperature overnight in trifluoroacetic acid (2 mL). The reaction mixture was concentrated and purified with EtOAc EtOAcjjjj -Dimethyl-2H-benzo[c]pyrido[3,4-e]azepine-3(5H)-one (23 mg, 35%) as a white solid. LCMS (ESI) [M+H] ⁺ = 507.3, Purity 100% (UV 214nm); ¹ H NMR (400 MHz, CD ₃ OD) δ 8.12 (s, 1H), 7.79 (s, 1H), 7.57-7.46 ( m, 4H), 7.15 (d, J = 8.4 Hz, 1H), 6.64 (s, 1H), 4.57 (s, 2H), 4.20 (q, J = 6.4 Hz, 1H), 3.72 (s, 3H), 3.12 (q, J = 7.6 Hz, 2H), 1.76 (d, J = 6.4 Hz, 3H), 1.37 (t, J = 7.6 Hz, 3H).

4121:(S)-7-(2-氯-4-氟苯基)-10-(2-羟基丙烷-2-基)-2,5-二甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮4121: (S)-7-(2-Chloro-4-fluorophenyl)-10-(2-hydroxypropan-2-yl)-2,5-dimethyl-2H-benzo[c]pyridine [3,4-e]azepine-3(5H)-one

步骤1:3-溴-4-((2-氯-4-氟苯基)(羟基)甲基)苯甲酸甲酯Step 1: Methyl 3-bromo-4-((2-chloro-4-fluorophenyl)(hydroxy)methyl)benzoate

向2-氯-4-氟-1-碘苯(256mg,1.0mmol)的四氢呋喃(5mL)溶液中滴加异丙基氯化镁(2M的四氢呋喃溶液,0.5mL,1.0mmol)。反应液在-20℃下搅拌3小时。将该格式试剂加入到预先冷却至-20℃的3-溴-4-甲酰基苯甲酸甲酯(120mg,0.5mmol)，三甲基氯硅烷(50mg,0.46mmol)和干燥四氢呋喃(10mL)的混合液中。反应液在室温下搅拌12小时。加入氯化铵水溶液(10mL)淬灭反应，然后用乙酸乙酯(20mL*3)萃取，萃取液合并后用稀盐酸(1M,20mL)和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤并浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝10/1(体积比))，得3-溴-4-((2-氯-4-氟苯基)(羟基)甲基)苯甲酸甲酯(50mg,27％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝372.8. To a solution of 2-chloro-4-fluoro-1-iodobenzene (256 mg, 1.0 mmol) in tetrahydrofuran (5 mL), isopropylmagnesium chloride (2M in tetrahydrofuran, 0.5 mL, 1.0 mmol). The reaction solution was stirred at -20 ° C for 3 hours. The format reagent was added to methyl 3-bromo-4-formylbenzoate (120 mg, 0.5 mmol), trimethylchlorosilane (50 mg, 0.46 mmol) and dry tetrahydrofuran (10 mL), which was previously cooled to -20 °C. In the mixture. The reaction solution was stirred at room temperature for 12 hours. The reaction was quenched with aqueous EtOAc (EtOAc (EtOAc) (EtOAc (EtOAc) Concentrated and purified by flash chromatography (petroleum ether / ethyl acetate = 10/1 (volume ratio)) to give 3-bromo-4-((2-chloro-4-fluorophenyl) (hydroxy) Methyl)benzoic acid methyl ester (50 mg, 27%) was obtained as a yellow oil. LCMS (ESI) [M+H] ⁺ =372.8.

步骤2:3-溴-4-((2-氯-4-氟苯甲酰基)苯甲酸甲酯Step 2: Methyl 3-bromo-4-((2-chloro-4-fluorobenzoyl)benzoate

向3-溴-4-((2-氯-4-氟苯基)(羟基)甲基)苯甲酸甲酯(100mg,0.27mmol)的二氯甲烷溶液(101mL)加入Dess-Martin氧化剂(227mg,0.54mmol)，反应液在室温下搅拌2小时。将反应液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝10/1(体积比))，得3-溴-4-((2-氯-4-氟苯甲酰基)苯甲酸甲酯(80mg,80％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝371.0. Add Dess-Martin Oxidant (227 mg) to a solution of methyl 3-bromo-4-((2-chloro-4-fluorophenyl)(hydroxy)methyl)benzoate (100 mg, 0.27 mmol) in dichloromethane (101 mL) , 0.54 mmol), and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was purified and purified eluting eluting eluting benzoic acid methyl ester (80mg, 80%), as a yellow oil .LCMS (ESI) [M + H ] + = 371.0.

步骤3:(2-溴-4-(2-羟基丙烷-2-基)苯基)(2-氯-4-氟苯基)甲酮Step 3: (2-Bromo-4-(2-hydroxypropan-2-yl)phenyl)(2-chloro-4-fluorophenyl)methanone

向3-溴-4-((2-氯-4-氟苯甲酰基)苯甲酸甲酯(75mg,0.2mmol)的无水四氢呋喃溶液(3mL)加入甲基溴化镁(3M四氢呋喃溶液,0.4mL,1.2mmol)，反应液在室温下搅拌4小时。加入水(20mL)淬灭反应，然后用乙酸乙酯(20mL*3)萃取，萃取液合并后用食盐水(20 mL)洗涤，无水硫酸钠干燥，过滤并浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝5/1(体积比))，得(2-溴-4-(2-羟基丙烷-2-基)苯基)(2-氯-4-氟苯基)甲酮(20mg,27％)，为黄色油状物.LCMS(ESI)[M+H] ⁺＝371.0. Add methyl magnesium bromide (3M tetrahydrofuran solution, 0.4 to a solution of methyl 3-bromo-4-((2-chloro-4-fluorobenzoyl)benzoate (75 mg, 0.2 mmol) in anhydrous tetrahydrofuran (3 mL) The reaction mixture was stirred at room temperature for 4 hours. The reaction was quenched with water (20 mL) and then extracted with ethyl acetate (20mL*3). The extracts were combined and washed with brine (20 mL) The organic layer was dried over sodium sulfate, filtered and evaporated, and the residue was purified by flash chromatography ( petroleum ether / ethyl acetate = 5 / 1 (vol) ratio) to give (2-bromo-4-(2-hydroxypropane-2-) yl) phenyl) (2-chloro-4-fluorophenyl) methanone (20mg, 27%), as a yellow oil .LCMS (ESI) [M + H ] + = 371.0.

步骤4:(S)-N-((S)-1-(5-(2-(2-氯-4-氟苯基)-5-(2-羟基丙烷-2-基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺Step 4: (S)-N-((S)-1-(5-(2-(2-chloro-4-fluorophenyl)-5-(2-hydroxypropan-2-yl)phenyl)- 1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide

将(2-溴-4-(2-羟基丙烷-2-基)苯基)(2-氯-4-氟苯基)甲酮(112mg,0.3mmol),(S)-2-甲基-N-((S)-1-(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(114mg,0.3mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(22mg,0.03mmol)和磷酸钾(191mg,0.9mmol)混合于1,4-二氧六环(5mL)及水(一滴)中，反应液在氮气保护下加热至95℃搅拌1小时。反应液过滤后浓缩。残余物用快速色谱法分离纯化(乙酸乙酯/甲醇＝10/1(体积比))，得(S)-N-((S)-1-(5-(2-(2-氯-4-氟苯基)-5-(2-羟基丙烷-2-基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(40mg,24％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝547.2. (2-Bromo-4-(2-hydroxypropan-2-yl)phenyl)(2-chloro-4-fluorophenyl)methanone (112 mg, 0.3 mmol), (S)-2-methyl- N-((S)-1-(1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (114 mg, 0.3 mmol), [1,1'-bis(diphenylphosphino) Ferrocene]Palladium(II) dichloride (22 mg, 0.03 mmol) and potassium phosphate (191 mg, 0.9 mmol) were mixed in 1,4-dioxane (5 mL) and water (one drop). Heat to 95 ° C under stirring for 1 hour. The reaction solution was filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate / methanol = 10/1 (vol.)) to give (S)-N-((S)-1-(5-(2-(2-) -fluorophenyl)-5-(2-hydroxypropan-2-yl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2- Methylpropane-2-sulfinamide (40 mg, 24%) as a yellow solid. LCMS (ESI) [M+H] ⁺ = 547.2.

步骤5:(S)-7-(2-氯-4-氟苯基)-10-(2-羟基丙烷-2-基)-2,5-二甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮Step 5: (S)-7-(2-Chloro-4-fluorophenyl)-10-(2-hydroxypropan-2-yl)-2,5-dimethyl-2H-benzo[c]pyridine And [3,4-e]azepine-3(5H)-one

将(S)-N-((S)-1-(5-(2-(2-氯-4-氟苯基)-5-(2-羟基丙烷-2-基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(45mg,0.075mmol)溶于二氯甲烷(4mL)和三氟乙酸(1mL)中，反应液在室温下搅拌12小时。反应液浓缩，残余物用制备HPLC纯化，得标题化合物(S)-7-(2-氯-4-氟苯基)-10-(2-羟基丙烷-2-基)-2,5-二甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮(20mg,65％)，为白色固体。LCMS(ESI)[M+H] ⁺＝425.1，purity 100％(UV 214nm)；1H NMR(400MHz,CD ₃OD)δ8.08(s,1H),7.82(d,J＝2.0Hz,1H),7.54-2-7.56(m,2H),7.23-7.25(m,2H),7.12(d,J＝8.0Hz,1H),6.65(s,1H),4.19(q,J＝6.8Hz,1H),3.71(s,3H),1.77(d,J＝6.8Hz,3H),1.62(s,6H). (S)-N-((S)-1-(5-(2-(2-chloro-4-fluorophenyl)-5-(2-hydroxypropan-2-yl)phenyl)-1- Methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (45 mg, 0.075 mmol) was dissolved in dichloromethane (4 mL) The reaction solution was stirred at room temperature for 12 hours in trifluoroacetic acid (1 mL). The reaction mixture was concentrated and purified with m~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Methyl-2H-benzo[c]pyrido[3,4-e]azepine-3(5H)-one (20 mg, 65%) as a white solid. LCMS (ESI) [M + H ] + = 425.1, purity 100 (UV 214nm)%; 1H NMR (400MHz, CD 3 OD) δ8.08 (s, 1H), 7.82 (d, J = 2.0Hz, 1H) , 7.54-2-7.56 (m, 2H), 7.23-7.25 (m, 2H), 7.12 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 4.19 (q, J = 6.8 Hz, 1H) ), 3.71 (s, 3H), 1.77 (d, J = 6.8 Hz, 3H), 1.62 (s, 6H).

4122:10-((乙基砜)甲基)-7-(4-氟-2-甲基苯基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮4122: 10-((Ethyl sulfonyl)methyl)-7-(4-fluoro-2-methylphenyl)-2-methyl-2H-benzo[c]pyrido[3,4-e] Azazale-3(5H)-one

步骤1:(2-溴-4-甲基苯基)亚甲基双乙酸酯Step 1: (2-Bromo-4-methylphenyl)methylene diacetate

将2-溴-4-甲基苯甲醛(3.0g,15mmol)和浓硫酸(2滴)混合于乙酸酐(30mL)中，在室温下搅拌1小时。蒸除溶剂，向残余物中加入乙酸乙酯(50mL)和碳酸钠水溶液(25mL)，分离有机相。有机相用无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝2/1(体积比)),得(2-溴-4-甲基苯基)亚甲基双乙酸酯(3.0g,67％)。为黄色油状物。 ¹H NMR(400MHz,CDCl ₃)δ7.87(s,1H),7.43(d,J＝8.0Hz,2H),7.18(d,J＝8.0Hz,1H),2.34(s,3H),2.14(s,6H). 2-Bromo-4-methylbenzaldehyde (3.0 g, 15 mmol) and concentrated sulfuric acid (2 drops) were mixed with acetic acid (30 mL) and stirred at room temperature for 1 hour. The solvent was evaporated, and ethyl acetate (50 mL) and aqueous The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (peel ether / ethyl acetate = 2 / 1 (vol.)) to afford (2-bromo-4-methylphenyl) methylene diacetate (3.0 g, 67 %). It is a yellow oil. ^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.87 (s, 1H), 7.43 (d, J = 8.0Hz, 2H), 7.18 (d, J = 8.0Hz, 1H), 2.34 (s, 3H), 2.14 (s, 6H).

步骤2:(2-溴-4-溴甲基苯基)亚甲基双乙酸酯Step 2: (2-Bromo-4-bromomethylphenyl)methylene diacetate

将N-溴代丁二酰亚胺(3.6g,20.0mmol)，偶氮二异丁氰(166mg,1.0mmol)和(2-溴-4-甲基苯基)亚甲基双乙酸酯(3.0g,10.0mmol)混合于四氯化碳(25mL)中，加热至70℃搅拌16小时。反应液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/1(体积比))，得(2-溴-4-溴甲基苯基)亚甲基双乙酸酯(3.8g，95％)，为黄色油状物。LCMS(ESI)[M+NH ₄] ⁺＝398.0. N-bromosuccinimide (3.6 g, 20.0 mmol), azobisisobutyronitrile (166 mg, 1.0 mmol) and (2-bromo-4-methylphenyl)methylene diacetate (3.0 g, 10.0 mmol) was mixed with carbon tetrachloride (25 mL), and the mixture was stirred at 70 ° C for 16 hours. The reaction mixture was concentrated, and the residue was purified by flash chromatography ( petroleum ether / ethyl acetate = 1 / 1 (volume ratio) to give (2-bromo-4-bromomethylphenyl) methylene diacetate. (3.8 g, 95%) as a yellow oil. LCMS (ESI) [M+NH ₄ ] ⁺ = 398.0.

步骤3:(2-溴-4-(乙基砜)甲基)苯基)亚甲基双乙酸酯Step 3: (2-Bromo-4-(ethylsulfone)methyl)phenyl)methylene diacetate

向(2-溴-4-溴甲基苯基)亚甲基双乙酸酯(3.8g,10mmol)的二甲亚砜(5mL)溶液中加入乙烷亚磺酸钠(2.3g,20.0mmol)。反应液在室温下搅拌1小时。向反应液中加入乙酸乙酯(50mL)和水(50mL)，分离有机相。有机相用饱和食盐水洗涤(10mL x 3)，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/2(体积比))，得(2-溴-4-(乙基砜)甲基)苯基)亚甲基双乙酸酯(1.7g,43％)。LCMS(ESI)[M+NH ₄] ⁺＝410.0. To a solution of (2-bromo-4-bromomethylphenyl)methylene diacetate (3.8 g, 10 mmol) in dimethyl sulfoxide (5 mL), sodium ethanesulfinate (2.3 g, 20.0 mmol) ). The reaction solution was stirred at room temperature for 1 hour. Ethyl acetate (50 mL) and water (50 mL) were added to the mixture, and the organic phase was separated. The organic phase was washed with brine (10 mL EtOAc) The residue was purified by flash chromatography (petrole ether / ethyl acetate = 1/2 (by volume)) to give (2-bromo-4-(ethylsulfonyl)methyl)phenyl)methylenediacetic acid Ester (1.7 g, 43%). LCMS (ESI) [M+NH ₄ ] ⁺ = 410.0.

步骤4:2-溴-4-(乙基砜)甲基)苯甲醛Step 4: 2-Bromo-4-(ethylsulfone)methyl)benzaldehyde

向(2-溴-4-(乙基砜)甲基)苯基)亚甲基双乙酸酯(500mg,1.3mmol)的四氢呋喃(2.5mL)溶液中加入浓盐酸(0.5mL)。反应液在室温下搅拌12小时并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/1(体积比))，得2-溴-4-(乙基砜)甲基)苯甲醛(350mg,94％)，为白色固体。 ¹HNMR(400MHz,DMSO-d ₆)δ10.20(s,1H),7.89(t,J＝8.0Hz,1H),7.61(d,J＝8.0Hz,1H),7.30(s,1H),4.64(s,2H),3.10(q,J＝7.2Hz,2H),1.25(t,J＝7.2Hz,3H). To a solution of (2-bromo-4-(ethylsulfonyl)methyl)phenyl)methylene diacetate (500 mg, 1.3 mmol) in THF (2.5 mL) The reaction solution was stirred at room temperature for 12 hours and concentrated. The residue was purified by flash chromatography (EtOAc/EtOAc/EtOAc (EtOAc:EtOAc) White solid. ^{1 HNMR (400MHz, DMSO-d} 6) δ10.20 (s, 1H), 7.89 (t, J = 8.0Hz, 1H), 7.61 (d, J = 8.0Hz, 1H), 7.30 (s, 1H), 4.64 (s, 2H), 3.10 (q, J = 7.2 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H).

步骤5:(2-溴-4-(乙基砜甲基)苯基)(4-氟-2-甲基苯基)甲醇Step 5: (2-Bromo-4-(ethylsulfonylmethyl)phenyl)(4-fluoro-2-methylphenyl)methanol

在氮气保护下，向镁屑(24mg,1.0mmol)和一小块碘单质中加入四氢呋喃(1mL)，然后缓慢加入少量1-溴-4-氟-2-甲苯(189mg,1.0mmol)的四氢呋喃(6mL)。待反应引发后，反应液升温至60℃，并缓慢加入剩余的原料，大约用时15分钟。反应液继续回流30分钟得格氏试剂。将2-溴-4-(乙基砜)甲基)苯甲醛(150mg,0.5mmol)的四氢呋喃(2mL)溶液冷却至0℃，然后缓慢加入上述格氏试剂，得到的混合物在室温下搅拌4小时。反应液用乙酸乙酯和饱和氯化铵溶液分离。有机相用饱和食盐水洗涤，无水硫酸钠干燥并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/2(体积比))，得(2-溴-4-(乙基砜甲基)苯基)(4-氟-2-甲基苯基)甲醇(80mg,20％)，为黄色油状物。LCMS(ESI)[M-H ₂O+H] ⁺＝385.0. To a magnesia (24 mg, 1.0 mmol) and a small piece of iodine, tetrahydrofuran (1 mL) was added under a nitrogen atmosphere, and then a small amount of 1-bromo-4-fluoro-2-toluene (189 mg, 1.0 mmol) in tetrahydrofuran was slowly added. (6mL). After the reaction was initiated, the reaction solution was warmed to 60 ° C and the remaining starting material was slowly added for approximately 15 minutes. The reaction solution was refluxed for 30 minutes to obtain a Grignard reagent. A solution of 2-bromo-4-(ethylsulfonyl)methyl)benzaldehyde (150 mg, 0.5 mmol) in tetrahydrofuran (2 mL) was cooled to 0 ° C, then the above-mentioned Grignard reagent was slowly added, and the resulting mixture was stirred at room temperature 4 hour. The reaction solution was separated with ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic phase was washed with brine, dried over anhydrous sodium sulfate The residue was purified by flash chromatography (petrole ether / ethyl acetate = 1/2 (vol.)) to give (2-bromo-4-(ethyl sulfonyl)phenyl) Methylphenyl)methanol (80 mg, 20%) was obtained as a yellow oil. LCMS (ESI) [MH ₂ O + H] ⁺ = 385.0.

步骤6:(2-溴-4-(乙基砜甲基)苯基)(4-氟-2-甲基苯基)甲酮Step 6: (2-Bromo-4-(ethylsulfonylmethyl)phenyl)(4-fluoro-2-methylphenyl)methanone

将(2-溴-4-(乙基砜甲基)苯基)(4-氟-2-甲基苯基)甲醇(80mg,0.2mmol)和Dess-Martin氧化剂(85mg,0.4mmol)混合于二氯甲烷(10mL)中，在室温下搅拌12小时。将反应液过滤，滤液浓缩后得(2-溴-4-(乙基砜甲基)苯基)(4-氟-2-甲基苯基)甲酮(80mg,99％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝399.0. (2-Bromo-4-(ethylsulfonylmethyl)phenyl)(4-fluoro-2-methylphenyl)methanol (80 mg, 0.2 mmol) and Dess-Martin oxidant (85 mg, 0.4 mmol) The mixture was stirred at room temperature for 12 hours in dichloromethane (10 mL). The reaction solution was filtered, and the filtrate was evaporated to ethyldiamine (2-bromo-4-(ethylsulfonylmethyl)phenyl) (4-fluoro-2-methylphenyl)methanone (80 mg, 99%) as a yellow oil. Things. LCMS (ESI) [M+H] ⁺ = 399.0.

步骤7:(5-(5-(乙基砜甲基)-2-(4-氟-2-甲基苯甲酰基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯Step 7: (5-(5-(ethylsulfonylmethyl)-2-(4-fluoro-2-methylbenzoyl)phenyl)-1-methyl-2-oxo-1,2- Dihydropyridin-4-yl)methylcarbamic acid tert-butyl ester

将(2-溴-4-(乙基砜甲基)苯基)(4-氟-2-甲基苯基)甲酮(80mg,0.2mmol)，(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(109mg,0.3mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(15mg,0.02mmol)和磷酸钾(127mg,0.6mmol)混合于1,4-二氧六环(5mL)和水(0.2mL)中，在氮气保护下加热至90℃搅拌1小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/甲醇＝30/1)，得(5-(5-(乙基砜甲基)-2-(4-氟-2-甲基苯甲酰基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(30mg,27％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝557.2. (2-Bromo-4-(ethylsulfonylmethyl)phenyl)(4-fluoro-2-methylphenyl)methanone (80 mg, 0.2 mmol), (1-methyl-2-oxo- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl)methylcarbamic acid tert-butyl Ester (109 mg, 0.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (15 mg, 0.02 mmol) and potassium phosphate (127 mg, 0.6 mmol) were mixed in In 1,4-dioxane (5 mL) and water (0.2 mL), the mixture was heated to 90 ° C under a nitrogen atmosphere and stirred for 1 hour. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjj -Methylbenzoyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methylcarbamic acid tert-butyl ester (30 mg, 27%) as yellow oil Things. LCMS (ESI) [M+H] ⁺ = 557.2.

步骤8:10-((乙基砜)甲基)-7-(4-氟-2-甲基苯基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮Step 8: 10-((Ethyl sulfonyl)methyl)-7-(4-fluoro-2-methylphenyl)-2-methyl-2H-benzo[c]pyrido[3,4-e Azazale-3(5H)-one

向(5-(5-(乙基砜甲基)-2-(4-氟-2-甲基苯甲酰基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(30mg,0.05mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌12小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物10-((乙基砜)甲基)-7-(4-氟-2-甲基苯基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮(7.0mg,29％)，为白色固体。LCMS(ESI)[M+H] ⁺＝439.1，纯度100％(UV 214nm)； ¹HNMR(400MHz,CD ₃ ^`OD)δ8.18(s,1H),7.78(d,J＝1.60Hz,1H),7.49(m,1H),7.34(d,J＝7.6Hz,1H),7.19(d,J＝8.0Hz,1H),7.02(m,2H),6.65(s,1H),4.77(d,J＝10.8Hz,1H),4.57(s,2H),4.15(d,J＝10.8Hz,1H),3.71(s,3H),3.18(q,J＝7.2Hz,2H),1.86(s,3H),1.42(t,J＝7.2Hz,3H). To (5-(5-(ethylsulfonylmethyl)-2-(4-fluoro-2-methylbenzoyl)phenyl)-1-methyl-2-oxo-1,2-dihydro A solution of tert-butyl pyridin-4-yl)methylcarbamate (30 mg, 0.05 mmol) in dichloromethane (4 mL) The reaction solution was stirred at room temperature for 12 hours and concentrated. The residue was purified by preparative EtOAc (EtOAc-EtOAc) Pyrido[3,4-e]azepine-3(5H)-one (7.0 mg, 29%) as a white solid. LCMS (ESI) [M+H] ⁺ = 439.1, purity 100% (UV 214nm); ¹ H NMR (400 MHz, CD ₃ ^` OD) δ 8.18 (s, 1H), 7.78 (d, J = 1.60 Hz, 1H) ), 7.49 (m, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.02 (m, 2H), 6.65 (s, 1H), 4.77 (d) , J = 10.8 Hz, 1H), 4.57 (s, 2H), 4.15 (d, J = 10.8 Hz, 1H), 3.71 (s, 3H), 3.18 (q, J = 7.2 Hz, 2H), 1.86 (s , 3H), 1.42 (t, J = 7.2 Hz, 3H).

4123:(S)-7-(2,6-二氯苯基)-10-((乙基砜)甲基)-2,5-二甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮4123: (S)-7-(2,6-Dichlorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2H-benzo[c]pyridin[3 , 4-e]azepine-3(5H)-one

步骤1:(2-溴-4-甲基苯基)(2,6-二氯苯基)甲醇Step 1: (2-Bromo-4-methylphenyl)(2,6-dichlorophenyl)methanol

在氮气保护下，向2-溴-1,3-二氯苯(2.25g,5mmol)的无水四氢呋喃(10mL)溶液中加入异丙基氯化镁(2M的四氢呋喃溶液,5mL,10mmol)，反应液在-20℃下搅拌3小时得格氏试剂。在氮气保护下，向2-溴-4-甲基苯甲醛(1.0g,5.02mmol)的无水四氢呋喃(10mL)溶液中加入上述制备的格氏试剂，得到的反应液在室温下搅拌16小时。反应液用饱和氯化铵(10mL)淬灭，用乙酸乙酯萃取(20mL x 2)。有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤并浓缩，得(2-溴-4-甲基苯基)(2,6-二氯苯基)甲醇粗产品，为黄色油状物。LCMS(ESI)[M-H ₂O+H] ⁺＝329.0. To a solution of 2-bromo-1,3-dichlorobenzene (2.25 g, 5 mmol) in anhydrous tetrahydrofuran (10 mL) was added isopropyl magnesium chloride (2M in tetrahydrofuran, 5 mL, 10 mmol). The Grignard reagent was obtained by stirring at -20 ° C for 3 hours. The above-prepared Grignard reagent was added to a solution of 2-bromo-4-methylbenzaldehyde (1.0 g, 5.02 mmol) in anhydrous tetrahydrofuran (10 mL), and the obtained mixture was stirred at room temperature for 16 hours. . The reaction was quenched with EtOAc EtOAc (EtOAc) The organic phase was washed with saturated brine (20 mL) Oily. LCMS (ESI) [MH ₂ O + H] ⁺ = 329.0.

步骤2:(2-溴-4-甲基苯基)(2,6-二氯苯基)甲酮Step 2: (2-Bromo-4-methylphenyl)(2,6-dichlorophenyl)methanone

向(2-溴-4-甲基苯基)(2,6-二氯苯基)甲醇(第一步粗产物)的二氯甲烷溶液(20mL)加入Dess-Martin氧化剂(3.19g,7.53mmol)，反应液在室温下搅拌16小时。反应液浓缩后残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝20/1(体积比))，得(2-溴-4-甲基苯基)(2,6-二氯苯基)甲酮(1.3g,两步总收率75％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝344.9. To a solution of (2-bromo-4-methylphenyl)(2,6-dichlorophenyl)methanol (2,6-dichlorophenyl)methanol (m.p. The reaction solution was stirred at room temperature for 16 hours. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 20/1 (vol.)) to give (2-bromo-4-methylphenyl) (2,6-dichlorobenzene). Methyl ketone (1.3 g, 75% total yield in two steps) as a yellow oil. LCMS (ESI) [M+H] ⁺ = 344.9.

步骤3:(2-溴-4-(溴甲基)苯基)(2,6-二氯苯基)甲酮Step 3: (2-Bromo-4-(bromomethyl)phenyl)(2,6-dichlorophenyl)methanone

将N-溴代丁二酰亚胺(740mg,4.2mmol)、过氧化苯甲酰(92mg,0.48mmol)和(2-溴-4-甲基苯基)(2,6-二氯苯基)甲酮(1.3g,3.8mmol)的四氯化碳(20mL)溶液在80℃下搅拌6小时。向反应液中加入乙酸乙酯(100mL)。混合液用碳酸钠溶液(5％,40mL x 2)和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤并浓缩，得(2-溴-4-(溴甲基)苯基)(2,6-二氯苯基)甲酮粗产品(1.3g)。LCMS(ESI)[M+H] ⁺＝422.8. N-bromosuccinimide (740 mg, 4.2 mmol), benzoyl peroxide (92 mg, 0.48 mmol) and (2-bromo-4-methylphenyl) (2,6-dichlorophenyl) A solution of ketone (1.3 g, 3.8 mmol) in carbon tetrachloride (20 mL) was stirred at 80 ° C for 6 hours. Ethyl acetate (100 mL) was added to the reaction mixture. The mixture was washed with a sodium carbonate solution (5%, 40 mL), and brine (20mL), dried over anhydrous sodium sulfate, filtered and concentrated to give (2-bromo-4-(bromomethyl)phenyl) (2, 6-Dichlorophenyl)methanone crude product (1.3 g). LCMS (ESI) [M+H] ⁺ = 422.8.

步骤4:(2-溴-4-((乙基砜)甲基)苯基)(2,6-二氯苯基)甲酮Step 4: (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(2,6-dichlorophenyl)methanone

将乙基亚磺酸钠(660mg,5.7mmoL)和(2-溴-4-(溴甲基)苯基)(2,6-二氯苯基)甲酮(1.3g，步骤3粗产品)的二甲基亚砜(10mL)溶液在室温下搅拌2小时，向反应液中加入乙酸乙酯(100mL)和水(50mL)，分离有机相。有机相用饱和食盐水洗涤(50mL x 3)，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/1(体积比))，得(2-溴-4-((乙基砜)甲基)苯基)(2,6-二氯苯基)甲酮(850mg,两步总收率51％)。LCMS(ESI)[M+NH ₄] ⁺＝454.0. Sodium ethyl sulfinate (660 mg, 5.7 mmol) and (2-bromo-4-(bromomethyl)phenyl)(2,6-dichlorophenyl)methanone (1.3 g, step 3 crude product) A solution of dimethyl sulfoxide (10 mL) was stirred at room temperature for 2 hours, and ethyl acetate (100 mL) and water (50 mL) were added to the mixture, and the organic phase was separated. The organic phase was washed with brine (50 mL EtOAc) The residue is purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1 (volume ratio)) to give (2-bromo-4-((ethylsulfonyl)methyl)phenyl) (2,6- Dichlorophenyl)methanone (850 mg, total yield in two steps of 51%). LCMS (ESI) [M+NH ₄ ] ⁺ = 454.0.

步骤5:(S)-N-((S)-1-(5-(2-(2,6-二氯苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代- 1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺Step 5: (S)-N-((S)-1-(5-(2-(2,6-Dichlorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1 -methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide

将(2-溴-4-((乙基砜)甲基)苯基)(2,6-二氯苯基)甲酮(50mg,0.11mmol),(S)-2-甲基-N-((S)-1-(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(66mg,0.17mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(8mg,0.011mmol)和碳酸钾(38mg,0.28mmol)混合于1,4-二氧六环(4mL)及水(0.4mL)中，反应液在氮气保护下加热至90℃搅拌2小时。反应液过滤后浓缩。得(S)-N-((S)-1-(5-(2-(2,6-二氯苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺粗产品，为黑色油状物。LCMS(ESI)[M+H] ⁺＝611.2. (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(2,6-dichlorophenyl)methanone (50 mg, 0.11 mmol), (S)-2-methyl-N- ((S)-1-(1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (66 mg, 0.17 mmol), [1,1'-bis(diphenylphosphino)dilen Iron] palladium(II) chloride (8 mg, 0.011 mmol) and potassium carbonate (38 mg, 0.28 mmol) were mixed in 1,4-dioxane (4 mL) and water (0.4 mL). The mixture was heated to 90 ° C and stirred for 2 hours. The reaction solution was filtered and concentrated. (S)-N-((S)-1-(5-(2-(2,6-dichlorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl A crude product of benzyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfenamide as a black oil. LCMS (ESI) [M+H] ⁺ = 611.2.

步骤6:(S)-4-(1-氨基乙基)-5-(2-(2,6-二氯苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基吡啶-2(1H)-酮Step 6: (S)-4-(1-Aminoethyl)-5-(2-(2,6-dichlorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1 -methylpyridine-2(1H)-one

将(S)-N-((S)-1-(5-(2-(2,6-二氯苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰(步骤5粗产物)溶于二氯甲烷(3mL)和三氟乙酸(2mL)中，反应液在室温下搅拌16小时。将反应液浓缩，得(S)-4-(1-氨基乙基)-5-(2-(2,6-二氯苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基吡啶-2(1H)-酮粗产品，为黑色固体。LCMS(ESI)[M+H] ⁺＝507.1 (S)-N-((S)-1-(5-(2-(2,6-Dichlorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl Base-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinyl (step 5 crude product) dissolved in dichloromethane (3 mL) and three The reaction solution was stirred at room temperature for 16 hours in fluoroacetic acid (2 mL). The reaction solution was concentrated to give (S)-4-(1-aminoethyl)-5-(2-(2,6-dichlorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl a crude product of 1-methylpyridine-2(1H)-one as a black solid. LCMS (ESI) [M+H] ⁺ = 507.1

步骤7:(S)-7-(2,6-二氯苯基)-10-((乙基砜)甲基)-2,5-二甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮Step 7: (S)-7-(2,6-Dichlorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2H-benzo[c]pyridin[ 3,4-e]azepine-3(5H)-one

将(S)-4-(1-氨基乙基)-5-(2-(2,6-二氯苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基吡啶-2(1H)-酮(步骤6粗产物)溶于四氢呋喃(3mL)，加入四乙氧基钛(50mg,0.22mmol)，反应液在70℃下搅拌16小时。反应液浓缩，残余物用制备HPLC纯化，得标题化合物(S)-7-(2,6-二氯苯基)-10-((乙基砜)甲基)-2,5-二甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮(22.5mg,三步总收率40％)，为白色固体。LCMS(ESI)[M+H] ⁺＝489.0. ¹H，纯度100％(UV 214nm)； ¹HNMR(400MHz,CD ₃OD)δ8.10(s,1H),7.99(s,1H),7.63(d,J＝8.8Hz,1H),7.53(d,J＝8.0Hz,1H),7.45(d,J＝8.0Hz,1H),7.35-7.29(m,2H),6.67(s,1H),4.57(s,2H),4.33(q,J＝6.4Hz,1H),3.71(s,3H),3.16(q,J＝7.2Hz,2H),1.79(d,J＝6.4Hz,3H),1.40(t,J＝7.2Hz,3H). (S)-4-(1-Aminoethyl)-5-(2-(2,6-dichlorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl The pyridyl-2(1H)-one (the crude product of Step 6) was dissolved in tetrahydrofuran (3 mL), and then evaporated toluene (50 mg, 0.22 mmol), and the mixture was stirred at 70 ° C for 16 hours. The reaction mixture was concentrated, and purified mjjjjjjjjjjj -2H-benzo[c]pyrido[3,4-e]azepine-3(5H)-one (22.5 mg, a three-step total yield 40%) as a white solid. LCMS (ESI) [M+H] ⁺ = 489.0. ¹ H, purity 100% (UV 214nm); ¹ H NMR (400 MHz, CD ₃ OD) δ 8.10 (s, 1H), 7.99 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.35-7.29 (m, 2H), 6.67 (s, 1H) , 4.57 (s, 2H), 4.33 (q, J = 6.4 Hz, 1H), 3.71 (s, 3H), 3.16 (q, J = 7.2 Hz, 2H), 1.79 (d, J = 6.4 Hz, 3H) , 1.40 (t, J = 7.2 Hz, 3H).

4124:(S)-7-(2-环丙基-4-氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮4124: (S)-7-(2-cyclopropyl-4-fluorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H -benzo[c]pyrido[3,4-e]azepin-3-one

步骤1:(S)-7-(2-环丙基-4-氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮Step 1: (S)-7-(2-Cyclopropyl-4-fluorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro- 3H-benzo[c]pyrido[3,4-e]azepin-3-one

将(S)-7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(16mg,0.034mmol)，环丙基三氟硼酸钾(6mg,0.034mmol)，三(二亚苄基丙酮)二钯(2mg,0.034mmol)和碳酸钾(9mg,0.068mmol)混合于1,4-二氧六环(2mL)中，在氮气保护下加热至110℃搅拌3小时。反应液过滤，滤液浓缩，残余物用制备-HPLC纯化，得(S)-7-(2-环丙基-4-氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(6.1mg,38％)，为白色固体。LCMS(ESI)[M+H] ⁺＝479.2，纯度100％(UV 214nm)； ¹H NMR(400MHz,DMSO-d ₆)δ8.03(s,1H),7.68(d,J＝1.2Hz,1H),7.40(d,J＝8.0Hz,1H),7.26-7.21(m,1H),7.09-7.01(m,2H),6.76(d,J＝8.0Hz,1H),6.41(s,1H),4.56(m,2H),4.00(d,J＝6.0Hz,1H),3.53(s,3H),3.07(d,J＝7.2Hz,2H),1.63(d,J＝6.4Hz,3H),1.32-1.30(m,1H),1.23(t,J＝7.6Hz,3H),0.52-0.49(m,2H),0.39-0.36(m,2H). (S)-7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H-benzo [c] Pyrido[3,4-e]azepin-3-one (16 mg, 0.034 mmol), cyclopropyltrifluoroborate (6 mg, 0.034 mmol), tris(dibenzylideneacetone) palladium (2 mg, 0.034 mmol) and potassium carbonate (9 mg, 0.068 mmol) were mixed in 1,4-dioxane (2 mL) and heated to 110 ° C under nitrogen atmosphere for 3 hours. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 5-Dimethyl-2,5-dihydro-3H-benzo[c]pyrido[3,4-e]azepin-3-one (6.1 mg, 38%) as a white solid. LCMS (ESI) [M + H ] + = 479.2, purity ^{100 (UV 214nm)%; 1} H NMR (400MHz, DMSO-d 6) δ8.03 (s, 1H), 7.68 (d, J = 1.2Hz, 1H), 7.40 (d, J = 8.0 Hz, 1H), 7.26-7.21 (m, 1H), 7.09-7.01 (m, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.41 (s, 1H) ), 4.56 (m, 2H), 4.00 (d, J = 6.0 Hz, 1H), 3.53 (s, 3H), 3.07 (d, J = 7.2 Hz, 2H), 1.63 (d, J = 6.4 Hz, 3H) ), 1.32-1.30 (m, 1H), 1.23 (t, J = 7.6 Hz, 3H), 0.52-0.49 (m, 2H), 0.39-0.36 (m, 2H).

4125:(S)-7-(2-氯苯基)-10-((乙基砜)甲基)-2,5-二甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮4125: (S)-7-(2-Chlorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2H-benzo[c]pyridin[3,4- e] azepine-3(5H)-one

步骤1:(2-溴-4-甲基苯基)(2-氯苯基)甲醇Step 1: (2-Bromo-4-methylphenyl)(2-chlorophenyl)methanol

向1-溴-2-氯苯(1.9g,10.0mmol)的四氢呋喃(15mL)溶液中滴加异丙基氯化镁(2M的四氢呋喃溶液,5.0mL,10.0mmol)。反应液在-20℃下搅拌3小时。将该格式试剂加入到预先冷却至-20℃的2-溴-4-甲基苯甲醛(1.0g,5.0mmol)，三甲基氯硅烷(550mg,5.0mmol)和干燥四氢呋喃(35mL)的混合液中。反应液在室温下搅拌12小时。加入氯化铵水溶液(10mL)淬灭反应，然后用乙酸乙酯(20mL*3)萃取，萃取液合并后用稀盐酸(1M,20mL)和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤并浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝8/1(体积比))，得(2-溴-4-甲基苯基)(2-氯苯基)甲醇(300mg,19％)，为黄色固体.LCMS(ESI)[M+H] ⁺＝293.1. To a solution of 1-bromo-2-chlorobenzene (1.9 g, 10.0 mmol) in tetrahydrofuran (15 mL), EtOAc (EtOAc (EtOAc) The reaction solution was stirred at -20 ° C for 3 hours. The format reagent was added to a mixture of 2-bromo-4-methylbenzaldehyde (1.0 g, 5.0 mmol) previously cooled to -20 ° C, trimethylchlorosilane (550 mg, 5.0 mmol) and dry tetrahydrofuran (35 mL). In the liquid. The reaction solution was stirred at room temperature for 12 hours. The reaction was quenched with aqueous EtOAc (EtOAc (EtOAc) (EtOAc (EtOAc) The residue was concentrated and purified by flash chromatography ( petroleum ether / ethyl acetate=8/1 (volume ratio) to afford (2-bromo-4-methylphenyl)(2-chlorophenyl)methanol ( 300 mg, 19%) as a yellow solid. LCMS (ESI) [M+H] ⁺ =293.1.

步骤2:(2-溴-4-甲基苯基)(2-氯苯基)甲酮Step 2: (2-Bromo-4-methylphenyl)(2-chlorophenyl)methanone

向(2-溴-4-甲基苯基)(2-氯苯基)甲醇(300mg,0.96mmol)的二氯甲烷溶液(4mL)加入Dess-Martin氧化剂(0.61g,1.44mmol)，反应液在室温下搅拌1小时。过滤，滤液浓缩后残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝10/1(体积比))，得(2-溴-4-甲基苯基)(2-氯苯基)甲酮(160mg,54％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝309.0. Add a solution of (2-bromo-4-methylphenyl)(2-chlorophenyl)methanol (300 mg, 0.96 mmol) in dichloromethane (4 mL) Stir at room temperature for 1 hour. Filtration and concentration of the filtrate were purified by flash chromatography (petrole ether / ethyl acetate = 10/1 (volume ratio)) to give (2-bromo-4-methylphenyl) (2-chlorophenyl) Methyl ketone (160 mg, 54%) was obtained as a yellow solid. LCMS (ESI) [M+H] ⁺ = 309.0.

步骤3:(2-溴-4-(二溴甲基)苯基)(2-氯苯基)甲酮Step 3: (2-Bromo-4-(dibromomethyl)phenyl)(2-chlorophenyl)methanone

将N-溴代丁二酰亚胺(368mg,2.07mmol)、偶氮二异丁腈(17mg,0.10mmol)和(2-溴-4-甲基苯基)(2-氯苯基)甲酮(160mg,0.52mmol)的四氯化碳(20mL)溶液在80℃下搅拌12小时。反应液浓缩后得(2-溴-4-(二溴甲基)苯基)(2-氯苯基)甲酮(200mg)，为黄色固体，该固体直接用于下一步反应。LCMS(ESI)[M+H] ⁺＝468.8. N-bromosuccinimide (368 mg, 2.07 mmol), azobisisobutyronitrile (17 mg, 0.10 mmol) and (2-bromo-4-methylphenyl)(2-chlorophenyl) A solution of the ketone (160 mg, 0.52 mmol) in carbon tetrachloride (20 mL) was stirred at <RTIgt; The reaction mixture was concentrated to give (2-bromo-4-(dibromomethyl)phenyl)(2-chlorophenyl)methanone (200 mg) as a yellow solid. LCMS (ESI) [M+H] ⁺ = 468.8.

步骤4:(2-溴-4-(溴甲基)苯基)(2-氯苯基)甲酮Step 4: (2-Bromo-4-(bromomethyl)phenyl)(2-chlorophenyl)methanone

向(2-溴-4-(二溴甲基)苯基)(2-氯苯基)甲酮(200mg,0.43mmol)的二氯甲烷(15mL)溶液加入亚磷酸二乙酯(97mg,0.65mmol)、二异丙基乙胺(84mg,0.65mmol)。反应液在室温下搅拌1小时。反应液浓缩后残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝15/1(体积比))，得(2-溴-4-(溴甲基)苯基)(2-氯苯基)甲酮(200mg,两步总收率99％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝387.9. To a solution of (2-bromo-4-(dibromomethyl)phenyl)(2-chlorophenyl)methanone (200 mg, 0.43 mmol) in dichloromethane (15 mL) Methyl), diisopropylethylamine (84 mg, 0.65 mmol). The reaction solution was stirred at room temperature for 1 hour. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 15 / 1 (vol.)) to give (2-bromo-4-(bromomethyl)phenyl) (2-chlorobenzene). Methyl ketone (200 mg, total yield of 99% in two steps) was a yellow solid. LCMS (ESI) [M+H] ⁺ = 387.9.

步骤5:(2-溴-4-((乙基砜)甲基)苯基)(2-氯苯基)甲酮Step 5: (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(2-chlorophenyl)methanone

将乙基亚磺酸钠(120mg,1.03mmol)、2-溴-4-(溴甲基)苯基)(2-氯苯基)甲酮(200mg,0.51mmol)的二甲基亚砜(4mL)溶液在室温下搅拌1小时，向反应液中加入乙酸乙酯(20mL)和水(20mL)，分离有机相。有机相用饱和食盐水洗涤(10mL*3)，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝3/1(体积比))，得(2-溴-4-((乙基砜)甲基)苯基)(2-氯苯基)甲酮(180mg,87％)，为白色固体。LCMS(ESI)[M+H] ⁺＝401.0. Sodium ethyl sulfinate (120 mg, 1.03 mmol), 2-bromo-4-(bromomethyl)phenyl)(2-chlorophenyl)methanone (200 mg, 0.51 mmol) in dimethyl sulfoxide ( 4 mL) The solution was stirred at room temperature for 1 hour, and ethyl acetate (20 mL) and water (20 mL) were added to the mixture, and the organic phase was separated. The organic phase was washed with brine (10 mL*3) The residue is purified by flash chromatography (petroleum ether / ethyl acetate = 3 / 1 (volume ratio)) to give (2-bromo-4-((ethylsulfonyl)methyl)phenyl) (2-chlorobenzene) Methyl ketone (180 mg, 87%) was obtained as a white solid. LCMS (ESI) [M+H] ⁺ = 401.0.

步骤6:(S)-N-(1-(5-(2-(2-氯苯基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺Step 6: (S)-N-(1-(5-(2-(2-Chlorophenyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl-2-oxo) -1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide

将(2-溴-4-((乙基砜)甲基)苯基)(2-氯苯基)甲酮(80mg,0.20mmol),(S)-2-甲基-N-((S)-1-(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(84mg,0.22mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(15mg,0.02mmol)和磷酸钾(127mg,0.60mmol)混合于1,4-二氧六环(1mL)及水(0.05mL)中，反应液在氮气保护下加热至95℃搅拌1小时。反应液过滤后浓缩。残余物用快速色谱法分离纯化(乙酸乙酯/甲醇＝30/1(体积比))，得(S)-N-(1-(5-(2-(2-氯甲氧苯基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(60mg,52％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝577.2. (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(2-chlorophenyl)methanone (80 mg, 0.20 mmol), (S)-2-methyl-N-((S) )-1-(1-methyl-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2 -dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfenamide (84 mg, 0.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene] Palladium(II) chloride (15 mg, 0.02 mmol) and potassium phosphate (127 mg, 0.60 mmol) were mixed in 1,4-dioxane (1 mL) and water (0.05 mL). Stir at 95 ° C for 1 hour. The reaction solution was filtered and concentrated. The residue was purified by flash chromatography (ethyl acetate / methanol = 30/1 (vol.)) to give (S)-N-(1-(5-(2-(2-chloromethoxyphenyl))- 5-((Ethyl sulfonyl)methyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2- Sulfonamide (60 mg, 52%) was obtained as a yellow solid. LCMS (ESI) [M+H] ⁺ = 577.2.

步骤7:(S)-7-(2-氯苯基)-10-((乙基砜)甲基)-2,5-二甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮Step 7: (S)-7-(2-Chlorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2H-benzo[c]pyridin[3,4 -e]azepine-3(5H)-one

将(S)-N-(1-(5-(2-(2-氯苯基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙基)-2-甲基丙烷-2-亚磺酰胺(60mg,0.1mmol)溶于二氯甲烷(4mL)和三氟乙酸(1mL)中，反应液在室温下搅拌1小时。反应液浓缩,残余物用制备HPLC纯化，得标题化合物(S)-7-(2-氯苯基)-10-((乙基砜)甲基)-2,5-二甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮(25.2mg,53％)，为白色固体。LCMS(ESI):[M+H] ⁺＝455.1，纯度100％(UV 214nm)； ¹H NMR(400MHz,DMSO-d ₆)δ8.06(s,1H),7.70(s,1H),7.52-7.50(m,1H),7.46-7.44(m,2H),7.41-7.39(m,2H),7.05(d,J＝8.0Hz,1H),6.42(s,1H),4.63-4.50(m,2H),4.04-4.02(m,1H),3.54(s,3H),3.11-3.05(m,2H),1.65(d,J＝6.4Hz,3H),1.22(t,J＝7.6Hz,3H). (S)-N-(1-(5-(2-(2-Chlorophenyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl-2-oxo-1 ,2-dihydropyridin-4-yl)ethyl)-2-methylpropane-2-sulfinamide (60 mg, 0.1 mmol) dissolved in dichloromethane (4 mL) and trifluoroacetic acid (1 mL) The solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified with ethylamineamineamineamine Benzo[c]pyrido[3,4-e]azepine-3(5H)-one (25.2 mg, 53%) was obtained as a white solid. LCMS (ESI): [M+H] ⁺ = 455.1, purity 100% (UV 214nm); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (s, 1H), 7.70 (s, 1H), 7.52 -7.50 (m, 1H), 7.46-7.44 (m, 2H), 7.41-7.39 (m, 2H), 7.05 (d, J = 8.0 Hz, 1H), 6.42 (s, 1H), 4.63-4.50 (m) , 2H), 4.04-4.02 (m, 1H), 3.54 (s, 3H), 3.11-3.05 (m, 2H), 1.65 (d, J = 6.4 Hz, 3H), 1.22 (t, J = 7.6 Hz, 3H).

4126:7-(2-氯-4-氟苯基)-10-(乙基砜基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮4126: 7-(2-Chloro-4-fluorophenyl)-10-(ethylsulfonyl)-2-methyl-2H-benzo[c]pyrido[3,4-e]azepine- 3(5H)-ketone

步骤1:(5-(2-(2-氯-4-氟苯甲酰基)-5-(乙烷磺酰苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯Step 1: (5-(2-(2-Chloro-4-fluorobenzoyl)-5-(ethanesulfonylphenyl)-1-methyl-2-oxo-1,2-dihydropyridine -4-yl)methyl)carbamic acid tert-butyl ester

将(2-溴-4-乙烷磺酰苯基)(2-氯-4-氟苯基)甲酮(100mg,0.25mmol)，((1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(137mg,0.38mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(18mg,0.025mmol)和碳酸钾(87mg,0.63mmol)混合于1,4-二氧六环(4mL)和水(0.4mL)中，在氮气保护下加热至90℃搅拌2小时。反应液过滤，滤液浓缩，得(5-(2-(2-氯-4-氟苯甲酰基)-5-(乙烷磺酰苯基)-1-甲基-2-氧代-1,2二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(粗产物)，为黑色油状物。LCMS(ESI)[M+H] ⁺＝563.2. (2-Bromo-4-ethanesulfonylphenyl)(2-chloro-4-fluorophenyl)methanone (100 mg, 0.25 mmol), ((1-methyl-2-oxo-5-() Tert-butyl 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl)methyl)carbamate ( 137 mg, 0.38 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (18 mg, 0.025 mmol) and potassium carbonate (87 mg, 0.63 mmol) were mixed at 1, 4-Dioxane (4 mL) and water (0.4 mL) were heated to 90 ° C under nitrogen for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to give (5-(2-(2-chloro-4-fluorobenzoyl)-5-(ethanesulfonylphenyl)-1-methyl-2-oxo-1, tert-Butyl dihydropyridin-4-yl)methyl)carbamate (crude) as a black oil. LCMS (ESI) [M+H] ⁺ = 563.2.

步骤2:7-(2-氯-4-氟苯基)-10-(乙基砜基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮Step 2: 7-(2-Chloro-4-fluorophenyl)-10-(ethylsulfonyl)-2-methyl-2H-benzo[c]pyrido[3,4-e]azepine -3(5H)-ketone

向(5-(2-(2-氯-4-氟苯甲酰基)-5-(乙烷磺酰苯基)-1-甲基-2-氧代-1,2-2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(第一步粗产物)的二氯甲烷(3mL)溶液中加入三氟乙酸(2mL)。反应液在室温下搅拌16小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物7-(2-氯-4-氟苯基)-10-(乙基砜基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮(31.5mg,两步总收率29％)，为白色固体。LCMS(ESI)[M+H] ⁺＝445.1，纯度100％(UV 214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.29(s,1H),8.23(s,1H),7.92(d,J＝8.0Hz,1H),7.71(d,J＝8.4Hz,1H),7.42(d,J＝8.4Hz,1H),7.30-7.24(m,2H)6.67(s,1H),4.86(d,J＝10.8Hz,1H),4.18(d,J＝10.8Hz,1H),3.71(s,3H),3.39(q,J＝7.2Hz,2H),1.31(t,J＝7.2Hz,3H). To (5-(2-(2-chloro-4-fluorobenzoyl)-5-(ethanesulfonylphenyl)-1-methyl-2-oxo-1,2-2-dihydropyridine To a solution of tert-butyl 4-methyl)carbamate (the crude product of the first step) in dichloromethane (3 mL) was added trifluoroacetic acid (2mL). The reaction was stirred at room temperature for 16 hours and concentrated. The residue was purified by preparative-HPLC to give the title compound 7-(2-chloro-4-fluorophenyl)-10-(ethylsulfonyl)-2-methyl-2H-benzo[c]pyridine [ 3,4-e]azepine-3(5H)-one (31.5 mg, two-step total yield 29%) as a white solid. LCMS (ESI) [M + H ] + = 445.1, purity ^{100% (UV 214nm); 1} H NMR (400MHz, CD 3 OD) δ8.29 (s, 1H), 8.23 (s, 1H), 7.92 (d , J = 8.0 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.30-7.24 (m, 2H) 6.67 (s, 1H), 4.86 ( d, J = 10.8 Hz, 1H), 4.18 (d, J = 10.8 Hz, 1H), 3.71 (s, 3H), 3.39 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H).

4127:7-(2-氯-4-氟苯基)-N-乙基-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-磺酰胺4127: 7-(2-Chloro-4-fluorophenyl)-N-ethyl-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridin[3, 4-e]azepine-10-sulfonamide

步骤1:(5-(2-(2-氯-4-氟苯甲酰基)-5-(N-乙基磺酰氨基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯Step 1: (5-(2-(2-Chloro-4-fluorobenzoyl)-5-(N-ethylsulfonylamino)-1-methyl-2-oxo-1,2-dihydro Pyridin-4-yl)methyl)carbamic acid tert-butyl ester

将3-溴-4-(2-氯-4-氟苯甲酰基)-N-乙基苯磺酰胺(100mg,0.24mmol)，((1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(131mg,0.36mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(18mg,0.025mmol)和碳酸钾(83mg,0.6mmol)混合于1,4-二氧六环(4mL)和水(0.4mL)中，在氮气保护下加热至90℃搅拌2小时。反应液过滤，滤液浓缩，得(5-(2-(2-氯-4-氟苯甲酰基)-5-(N-乙基磺酰氨基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(粗产物)，为黑色油状物。LCMS(ESI)[M+H] ⁺＝578.1. 3-Bromo-4-(2-chloro-4-fluorobenzoyl)-N-ethylbenzenesulfonamide (100 mg, 0.24 mmol), ((1-methyl-2-oxo-5-(4) ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl)methyl)carbamic acid tert-butyl ester (131 mg , 0.36 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (18 mg, 0.025 mmol) and potassium carbonate (83 mg, 0.6 mmol) were mixed at 1,4 In a dioxane (4 mL) and water (0.4 mL), the mixture was heated to 90 ° C under a nitrogen atmosphere and stirred for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to give (5-(2-(2-chloro-4-fluorobenzoyl)-5-(N-ethylsulfonylamino)-1-methyl-2-oxo-1 ,2-Dihydropyridin-4-yl)methyl)carbamic acid tert-butyl ester (crude) as a black oil. LCMS (ESI) [M+H] ⁺ = 578.1.

步骤2:7-(2-氯-4-氟苯基)-N-乙基-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-磺酰胺Step 2: 7-(2-Chloro-4-fluorophenyl)-N-ethyl-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridin[3 ,4-e]azepine-10-sulfonamide

向(5-(2-(2-氯-4-氟苯甲酰基)-5-(N-乙基磺酰氨基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(第一步粗产物)的二氯甲烷(3mL)溶液中加入三氟乙酸(2mL)。反应液在室温下搅拌16小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物7-(2-氯-4-氟苯基)-N-乙基-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-磺酰胺(26.5mg,两步总收率24％)，为白色固体。LCMS(ESI)[M+H] ⁺＝460.0，纯度100％(UV214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.21(s,1H),8.15(s,1H),7.84(d,J＝8.0Hz,1H),7.69(d,J＝8.4Hz,1H),7.35(d,J＝8.4Hz,1H),7.30-7.24(m,2H),6.67(s,1H),4.84(d,J＝10.8Hz,1H),4.17(d,J＝10.8Hz,1H),3.71(s,3H),3.02(q,J＝7.2Hz,2H),1.12(t,J＝7.2Hz,3H). To (5-(2-(2-chloro-4-fluorobenzoyl)-5-(N-ethylsulfonylamino)-1-methyl-2-oxo-1,2-dihydropyridine- To a solution of tert-butyl 4-methyl)carbamate (the crude product of the first step) in dichloromethane (3 mL) was added trifluoroacetic acid (2mL). The reaction was stirred at room temperature for 16 hours and concentrated. The residue was purified by preparative EtOAc (EtOAc-EtOAc-EtOAc) Benzo[c]pyrido[3,4-e]azepine-10-sulfonamide (26.5 mg, two-step total yield 24%) as a white solid. LCMS (ESI) [M + H ] + = 460.0, purity ^{100 (UV214nm)%; 1 H} NMR (400MHz, CD 3 OD) δ8.21 (s, 1H), 8.15 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.30-7.24 (m, 2H), 6.67 (s, 1H), 4.84 ( d, J = 10.8 Hz, 1H), 4.17 (d, J = 10.8 Hz, 1H), 3.71 (s, 3H), 3.02 (q, J = 7.2 Hz, 2H), 1.12 (t, J = 7.2 Hz, 3H).

4128:7-(2,6-二氯苯基)-10-((乙基砜)甲基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮4128:7-(2,6-Dichlorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2H-benzo[c]pyrido[3,4-e]aza Zhuo-3(5H)-ketone

步骤1:(5-(2-(2,6-二氯苯甲酰基)-5-((乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯Step 1: (5-(2-(2,6-Dichlorobenzoyl)-5-((ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1,2-di Hydrogen pyridin-4-yl)methyl)carbamic acid tert-butyl ester

将(2-溴-4-(乙基砜甲基)苯基)(2,6-二氯苯基)甲酮(50mg,0.11mmol)，((1-甲基-2-氧代 -5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(62mg,0.17mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(8mg,0.011mmol)和碳酸钾(38mg,0.28mmol)混合于1,4-二氧六环(4mL)和水(0.4mL)中，在氮气保护下加热至90℃搅拌2小时。反应液过滤，滤液浓缩，得(5-(2-(2,6-二氯苯甲酰基)-5-((乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(粗产物)，为黑色油状物。LCMS(ESI)[M+H] ⁺＝593.0. (2-Bromo-4-(ethylsulfonylmethyl)phenyl)(2,6-dichlorophenyl)methanone (50 mg, 0.11 mmol), ((1-methyl-2-oxo-5) -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl)methyl)carbamic acid tert-butyl Ester (62 mg, 0.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (8 mg, 0.011 mmol) and potassium carbonate (38 mg, 0.28 mmol) In 1,4-dioxane (4 mL) and water (0.4 mL), the mixture was heated to 90 ° C under a nitrogen atmosphere and stirred for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to give (5-(2-(2,6-dichlorobenzoyl)-5-((ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo- tert-Butyl 1,2-dihydropyridin-4-yl)methyl)carbamate (crude) as a black oil. LCMS (ESI) [M+H] ⁺ = 593.0.

步骤2:4-(氨甲基)-5-(2-(2,6-二氯苯甲酰基)-5-((乙基砜甲基)苯基)-1-甲基吡啶-2(1H)-酮Step 2: 4-(Aminomethyl)-5-(2-(2,6-dichlorobenzoyl)-5-((ethylsulfonylmethyl)phenyl)-1-methylpyridine-2 ( 1H)-ketone

向(5-(2-(2,6-二氯苯甲酰基)-5-((乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(第一步粗产物)的二氯甲烷(3mL)溶液中加入三氟乙酸(2mL)。反应液在室温下搅拌16小时并浓缩，得4-(氨甲基)-5-(2-(2,6-二氯苯甲酰基)-5-((乙基砜甲基)苯基)-1-甲基吡啶-2(1H)-酮(粗产物)，为黑色油状物。LCMS(ESI)[M+H] ⁺＝493.0 To (5-(2-(2,6-dichlorobenzoyl)-5-((ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridine To a solution of tert-butyl 4-methyl)carbamate (the crude product of the first step) in dichloromethane (3 mL) was added trifluoroacetic acid (2mL). The reaction solution was stirred at room temperature for 16 hours and concentrated to give 4-(aminomethyl)-5-(2-(2,6-dichlorobenzoyl)-5-((ethylsulfonylmethyl)phenyl) -1-methyl-pyridin -2 (1H) - one (crude) as a black oil .LCMS (ESI) [M + H ] + = 493.0

步骤3:7-(2,6-二氯苯基)-10-((乙基砜)甲基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮Step 3: 7-(2,6-Dichlorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2H-benzo[c]pyrido[3,4-e]nitrogen Miscellaneous-3(5H)-ketone

向4-(氨甲基)-5-(2-(2,6-二氯苯甲酰基)-5-((乙基砜甲基)苯基)-1-甲基吡啶-2(1H)-酮(第二步粗产物)的四氢呋喃(3mL)溶液中加入四乙氧基钛(50mg,0.22mmol)。反应液在70℃下搅拌16小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物7-(2,6-二氯苯基)-10-((乙基砜)甲基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮(22.5mg，三步总收率26％)，为白色固体。LCMS(ESI)[M+H] ⁺＝475.0，纯度100％(UV 214nm)； ¹H NMR (400MHz,CD ₃OD)δ8.15(s,1H),7.80(s,1H),7.62(d,J＝8.0Hz,1H),7.52(d,J＝8.4Hz,1H),7.46(d,J＝8.4Hz,1H),7.44-7.29(m,2H),6.67(s,1H),4.85(d,J＝10.8Hz,1H),4.57(s,2H),4.27(d,J＝10.8Hz,1H),3.71(s,3H),3.15(q,J＝7.2Hz,2H),1.41(t,J＝7.2Hz,3H). To 4-(aminomethyl)-5-(2-(2,6-dichlorobenzoyl)-5-((ethylsulfonylmethyl)phenyl)-1-methylpyridine-2 (1H) To a solution of the ketone (the second step of the crude product) in tetrahydrofuran (3 mL), EtOAc (EtOAc, m. The title compound 7-(2,6-dichlorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2H-benzo[c]pyrido[3,4-e]nitrogen Benzene-3(5H)-one (22.5 mg, a three-step total yield of 26%) as a white solid. LCMS (ESI) [M+H] ⁺ = 475.0, purity 100% (UV 214nm); ¹ H NMR (400MHz, CD ₃ OD) δ 8.15 (s, 1H), 7.80 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.46 (d , J = 8.4 Hz, 1H), 7.44 - 7.29 (m, 2H), 6.67 (s, 1H), 4.85 (d, J = 10.8 Hz, 1H), 4.57 (s, 2H), 4.27 (d, J = 10.8 Hz, 1H), 3.71 (s, 3H), 3.15 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H).

4129:7-(2-氯-4-氟苯基)-10-(2-羟基丙烷-2-基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮4129:7-(2-Chloro-4-fluorophenyl)-10-(2-hydroxypropan-2-yl)-2-methyl-2H-benzo[c]pyrido[3,4-e] Azazale-3(5H)-one

步骤1:(5-(2-(2-氯-4-氟苯甲酰基)-5-(2-羟基丙烷-2-基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基))甲基)氨基甲酸叔丁酯Step 1: (5-(2-(2-Chloro-4-fluorobenzoyl)-5-(2-hydroxypropan-2-yl)phenyl)-1-methyl-2-oxo-1, 2-Dihydropyridin-4-yl))methyl)carbamic acid tert-butyl ester

将(2-溴-4-(2-羟基丙烷-2-基)苯基)(2-氯-4-氟苯基)甲酮(136mg,0.4mmol)，((1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(162mg,0.5mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(27mg,0.04mmol)和磷酸钾(154mg,1.1mmol)混合于1,4-二氧六环(5mL)和水(1滴)中，在氮气保护下加热至100℃搅拌2小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/甲醇＝10/1)得(5-(2-(2-氯-4-氟苯甲酰基)-5-(2-羟基丙烷-2-基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基))甲基)氨基甲酸叔丁酯(20mg,11％)，为灰白色固体。LCMS(ESI)[M+H] ⁺＝529.1. (2-Bromo-4-(2-hydroxypropan-2-yl)phenyl)(2-chloro-4-fluorophenyl)methanone (136 mg, 0.4 mmol), ((1-methyl-2-) Oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl)methyl) Tert-butyl carbamate (162 mg, 0.5 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (27 mg, 0.04 mmol) and potassium phosphate (154 mg, 1.1 Methyl) was mixed with 1,4-dioxane (5 mL) and water (1 drop) and heated to 100 ° C under nitrogen for 2 hours. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjj -Hydroxypropan-2-yl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl))methyl)carbamic acid tert-butyl ester (20 mg, 11%) It is an off-white solid. LCMS (ESI) [M+H] ⁺ = 529.1.

步骤2:7-(2-氯-4-氟苯基)-10-(2-羟基丙烷-2-基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮Step 2: 7-(2-Chloro-4-fluorophenyl)-10-(2-hydroxypropan-2-yl)-2-methyl-2H-benzo[c]pyrido[3,4-e Azazale-3(5H)-one

向(5-(2-(2-氯-4-氟苯甲酰基)-5-(2-羟基丙烷-2-基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基))甲基)氨基甲酸叔丁酯(20mg,0.038mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌16小时并浓缩。残余物用制备-HPLC分离纯化得标题化合物7-(2-氯-4-氟苯基)-10-(2-羟基丙烷-2-基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮(12mg,77％)，为白色固体。LCMS(ESI)[M+H] ⁺＝411.1，纯度100％(UV 214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.12(s,1H),7.83(d,J＝1.6Hz,1H),7.58-7.55(m,1H),7.54-7.51(m,1H),7.25-7.11(m,2H),7.11(d,J＝8.0Hz,1H),6.65(s,1H),4.76(d,J＝11.2Hz,1H),4.14(d,J＝11.2Hz,1H),3.71(s,3H),1.62(s,6H). To (5-(2-(2-chloro-4-fluorobenzoyl)-5-(2-hydroxypropan-2-yl)phenyl)-1-methyl-2-oxo-1,2- Trihydroacetic acid (1 mL) was added to a solution of dichloromethane (4 mL). The reaction was stirred at room temperature for 16 hours and concentrated. The residue was purified by preparative-HPLC to give the title compound 7-(2-chloro-4-fluorophenyl)-10-(2-hydroxypropan-2-yl)-2-methyl-2H-benzo[c] Pyrido[3,4-e]azepine-3(5H)-one (12 mg, 77%) as a white solid. LCMS (ESI) [M + H ] + = 411.1, purity ^{100 (UV 214nm)%; 1} H NMR (400MHz, CD 3 OD) δ8.12 (s, 1H), 7.83 (d, J = 1.6Hz, 1H ), 7.58-7.55 (m, 1H), 7.54-7.51 (m, 1H), 7.25-7.11 (m, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 4.76 ( d, J = 11.2 Hz, 1H), 4.14 (d, J = 11.2 Hz, 1H), 3.71 (s, 3H), 1.62 (s, 6H).

4130:7-(2-氯苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮4130: 7-(2-Chlorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyrido[3,4- e] azeoxa-3-one

步骤1:((5-(2-(2-氯苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯Step 1: ((5-(2-(2-Chlorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl-2-oxo-1,2-dihydro) Pyridin-4-yl)methyl)carbamic acid tert-butyl ester

将(2-溴-4-((乙基砜)甲基)苯基)(2-氯苯基)甲酮(120mg,0.30mmol)，((1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(120mg,0.33mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(22mg,0.03mmol)和碳酸钾(124mg,0.90mmol)混合于1,4-二氧六环(1mL)和水(0.05mL)中，在氮气保护下加热至95℃搅拌1小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/甲醇＝30/1(体积比))，得((5-(2-(2-氯苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(80mg,48％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝559.3. (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(2-chlorophenyl)methanone (120 mg, 0.30 mmol), ((1-methyl-2-oxo-5-) (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl)methyl)carbamic acid tert-butyl ester (120 mg, 0.33 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (22 mg, 0.03 mmol) and potassium carbonate (124 mg, 0.90 mmol) were mixed in 1 4, dioxane (1 mL) and water (0.05 mL) were heated to 95 ° C under nitrogen for 1 hour. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjj ((Ethyl sulfonate)methyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)carbamic acid tert-butyl ester (80 mg, 48%) It is a yellow solid. LCMS (ESI) [M+H] ⁺ = 559.3.

步骤2:7-(2-氯苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮Step 2: 7-(2-Chlorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridin[3,4 -e]azepine-3-one

向((5-(2-(2-氯苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(80mg,0.14mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌12小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物7-(2-氯苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(48.4mg,77％)，为白色固体。LCMS(ESI):[M+H] ⁺＝441.3，纯度100％(UV 214nm)； ¹H NMR(400MHz,DMSO-d ₆)δ8.11(s,1H),7.70(s,1H),7.54-7.52(m,1H),7.47-7.43(m,2H),7.42-7.37(m,2H),7.03(d,J＝7.2Hz,1H),6.53(s,1H),4.77(d,J＝10.4Hz,1H),4.62-4.49(m,2H),3.97(d,J＝10.4Hz,1H),3.54(s,3H),3.12-3.06(m,2H),1.23(t,J＝7.6Hz,3H). To ((5-(2-(2-chlorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridine- To a solution of tert-butyl 4-methyl)methyl)carbamate (80 mg, 0.14 mmol) in dichloromethane (4 mL) The reaction solution was stirred at room temperature for 12 hours and concentrated. The residue was purified by preparative-HPLC to give the title compound 7-(2-chlorophenyl)-10-((ethylsulfonyl)methyl)-2-methyl-2,5-dihydro-3H-benzene. [c] Pyrido[3,4-e]azepin-3-one (48.4 mg, 77%) as a white solid. LCMS (ESI): [M + H] + = 441.3, purity ^{100 (UV 214nm)%; 1} H NMR (400MHz, DMSO-d 6) δ8.11 (s, 1H), 7.70 (s, 1H), 7.54 -7.52 (m, 1H), 7.47-7.43 (m, 2H), 7.42-7.37 (m, 2H), 7.03 (d, J = 7.2 Hz, 1H), 6.53 (s, 1H), 4.77 (d, J) = 10.4 Hz, 1H), 4.62-4.49 (m, 2H), 3.97 (d, J = 10.4 Hz, 1H), 3.54 (s, 3H), 3.12-3.06 (m, 2H), 1.23 (t, J = 7.6Hz, 3H).

4131:7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-2,5,6,7-四氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮4131:7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5,6,7-tetrahydro-3H-benzo[c Pyridine[3,4-e]azepin-3-one

步骤1:7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-2,5,6,7-四氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮Step 1: 7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5,6,7-tetrahydro-3H-benzo[ c] Pyrido[3,4-e]azepin-3-one

向7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(16mg,0.035mmol)的甲醇(2mL)溶液中加入氰基硼氢化钠(22mg,0.35mmol)。反应液在65℃下搅拌3小时，然后过滤，滤液浓缩，残余物用制备-HPLC分离纯化，得标题化合物7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-2,5,6,7-四氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(1.7mg,10％)，为白色固体。LCMS(ESI)[M+H] ⁺＝461.0，纯度100％(UV 214nm)； ¹H NMR(400MHz,DMSO-d ₆)δ8.05-7.99(m,3H),7.53(d,J＝1.6Hz,1H),7.33(d,J＝6.4Hz,1H),7.26-7.20(m,2H),6.61-6.59(m,2H),5.36(s,1H),4.46(s,2H),3.81(d,J＝13.6Hz,1H),3.73(s,3H),3.44(d,J＝9.6Hz,1H),3.08(d,J＝7.2Hz,2H),1.34(t,J＝7.6Hz,3H). To 7-(2-chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridin[3 A solution of 4-e]azepin-3-one (16 mg, 0.035 mmol) in MeOH (2 mL). The reaction mixture was stirred at 65 ° C for 3 hours, then filtered, and the filtrate was evaporated. mjjjjjjjjjj Methyl)-2-methyl-2,5,6,7-tetrahydro-3H-benzo[c]pyrido[3,4-e]azepin-3-one (1.7 mg, 10%) , as a white solid. LCMS (ESI) [M + H ] + = 461.0, purity ^{100 (UV 214nm)%; 1} H NMR (400MHz, DMSO-d 6) δ8.05-7.99 (m, 3H), 7.53 (d, J = 1.6 Hz, 1H), 7.33 (d, J = 6.4 Hz, 1H), 7.26-7.20 (m, 2H), 6.61-6.59 (m, 2H), 5.36 (s, 1H), 4.46 (s, 2H), 3.81 (d, J = 13.6 Hz, 1H), 3.73 (s, 3H), 3.44 (d, J = 9.6 Hz, 1H), 3.08 (d, J = 7.2 Hz, 2H), 1.34 (t, J = 7.6 Hz) , 3H).

4132:7-(2-氯-4-氟苯基)-10-(羟甲基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮4132: 7-(2-Chloro-4-fluorophenyl)-10-(hydroxymethyl)-2-methyl-2H-benzo[c]pyrido[3,4-e]azepine-3 (5H)-ketone

步骤1:(2-溴-4-(羟甲基)苯基)(2-氯-4-氟苯基)甲醇Step 1: (2-Bromo-4-(hydroxymethyl)phenyl)(2-chloro-4-fluorophenyl)methanol

向3-溴-4-(2-氯-4-氟苯甲酰基)苯甲酸甲酯(600mg,1.62mmol)的四氢呋喃(15mL)溶液中加入四氢铝锂(186mg,4.87mmol)，反应液在-20℃下搅拌1小时。小心加入1mL水淬灭反应，然后将反应液浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/1(体积比))，得(2-溴-4-(羟甲基)苯基)(2-氯-4-氟苯基)甲醇(500mg,89％)，为无色油状物。LCMS(ESI)[M-H ₂O+H] ⁺＝329.0. To a solution of methyl 3-bromo-4-(2-chloro-4-fluorobenzoyl)benzoate (600 mg, 1.62 mmol) in tetrahydrofuran (15 mL) Stir at -20 ° C for 1 hour. The reaction was quenched by the careful addition of 1 mL of water and then concentrated. The residue is purified by flash chromatography (petroleum ether / ethyl acetate = 1 / 1 (volume ratio)) to give (2-bromo-4-(hydroxymethyl)phenyl) (2-chloro-4-fluorobenzene) Methanol (500 mg, 89%) as a colorless oil. LCMS (ESI) [MH ₂ O + H] ⁺ = 329.0.

步骤2:(2-溴-4-((叔丁基二甲基)硅氧甲基)苯基)(2-氯-4-氟苯基)甲醇Step 2: (2-Bromo-4-((tert-butyldimethyl)silyloxymethyl)phenyl)(2-chloro-4-fluorophenyl)methanol

冰水浴冷却下，向(2-溴-4-(羟甲基)苯基)(2-氯-4-氟苯基)甲醇(200mg,0.58mmol)，吡啶(46mg,0.58mmol)和二氯甲烷(5mL)的混合液中加入叔丁基二甲基氯硅烷(435mg,2.90mmol)。反应液在室温下搅拌12小时。向反应液中加入二氯甲烷(20mL)和水(15mL)，分离有机相。有机相用无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/1)，得(2-溴-4-((叔丁基二甲基)硅氧甲基)苯基)(2-氯-4-氟苯基)甲醇(200mg,75％)，为黄色油状物。LCMS(ESI)[M-H ₂O+H] ⁺＝443.0. (2-Bromo-4-(hydroxymethyl)phenyl)(2-chloro-4-fluorophenyl)methanol (200 mg, 0.58 mmol), pyridine (46 mg, 0.58 mmol) and dichloro To the mixture of methane (5 mL) was added t-butyldimethylchlorosilane (435 mg, 2.90 mmol). The reaction solution was stirred at room temperature for 12 hours. Dichloromethane (20 mL) and water (15 mL) were added to the mixture and the organic layer was separated. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue is purified by flash chromatography (petrole ether / ethyl acetate = 1 / 1) to give (2-bromo-4-((tert-butyldimethyl)siloxymethyl)phenyl) 4-fluorophenyl)methanol (200 mg, 75%) as a yellow oil. LCMS (ESI) [MH ₂ O + H] ⁺ = 443.0.

步骤3:(2-溴-4-((叔丁基二甲基)硅氧甲基)苯基)(2-氯-4-氟苯基)甲酮Step 3: (2-Bromo-4-((tert-butyldimethyl)silyloxymethyl)phenyl)(2-chloro-4-fluorophenyl)methanone

将(2-溴-4-((叔丁基二甲基)硅氧甲基)苯基)(2-氯-4-氟苯基)甲醇(0.20g,0.43mmol)和Dess-Martin试剂(0.37g,0.86mmol)混合于二氯甲烷(15mL)中，在室温下搅拌12小时。蒸除溶剂，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝2/1(体积比))，得(2-溴-4- ((叔丁基二甲基)硅氧甲基)苯基)(2-氯-4-氟苯基)甲酮(0.15g,74％)，为无色油状物。LCMS(ESI)[M+H] ⁺＝459.1 (2-Bromo-4-((tert-butyldimethyl)silyloxymethyl)phenyl)(2-chloro-4-fluorophenyl)methanol (0.20 g, 0.43 mmol) and Dess-Martin reagent ( 0.37 g, 0.86 mmol) was mixed with dichloromethane (15 mL) and stirred at room temperature for 12 hr. The solvent was distilled off, and the residue was purified and purified by flash chromatography ( petroleum ether / ethyl acetate = 2 / 1 (volume ratio) to give (2-bromo-4-((tert-butyldimethyl)siloxymethyl) Phenyl)(2-chloro-4-fluorophenyl)methanone (0.15 g, 74%) as a colourless oil. LCMS (ESI) [M+H] ⁺ =459.1

步骤4:(5-(5-((叔丁基二甲基)硅氧甲基)-2-(2-氯-4-氟苯甲酰基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯Step 4: (5-(5-((tert-Butyldimethyl)silyloxymethyl)-2-(2-chloro-4-fluorobenzoyl)phenyl)-1-methyl-2-oxo Tert-butyl-1,2-dihydropyridin-4-yl)methyl)carbamate

将(2-溴-4-((叔丁基二甲基)硅氧甲基)苯基)(2-氯-4-氟苯基)甲酮(150mg,0.33mmol)，((1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(191mg,0.53mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(32mg,0.044mmol)和碳酸钾(183mg,1.32mmol)混合于1,4-二氧六环(5mL)中，在氮气保护下加热至100℃搅拌1小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/甲醇＝10/1)，得(5-(5-((叔丁基二甲基)硅氧甲基)-2-(2-氯-4-氟苯甲酰基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(100mg,50％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝615.2. (2-Bromo-4-((tert-butyldimethyl)silyloxymethyl)phenyl)(2-chloro-4-fluorophenyl)methanone (150 mg, 0.33 mmol), (1- 1- 5-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl )methyl)carbamic acid tert-butyl ester (191 mg, 0.53 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (32 mg, 0.044 mmol) and potassium carbonate (183 mg, 1.32 mmol) was mixed with 1,4-dioxane (5 mL), and heated to 100 ° C under nitrogen atmosphere and stirred for 1 hour. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjj -(2-Chloro-4-fluorobenzoyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)carbamic acid tert-butyl ester (100 mg, 50%), a yellow oil. LCMS (ESI) [M+H] ⁺ = 615.2.

步骤5:7-(2-氯-4-氟苯基)-10-(羟甲基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮Step 5: 7-(2-Chloro-4-fluorophenyl)-10-(hydroxymethyl)-2-methyl-2H-benzo[c]pyrido[3,4-e]azepine- 3(5H)-ketone

向(5-(5-((叔丁基二甲基)硅氧甲基)-2-(2-氯-4-氟苯甲酰基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(100mg,0.16mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌12小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物7-(2-氯-4-氟苯基)-10-(羟甲基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮(60mg,98％)，为白色固体。LCMS(ESI)[M+H] ⁺＝383.1，纯度100％(UV 214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.13(s,1H),7.70(d,J＝1.6Hz,1H),7.61-7.59(m,1H),7.42(q,J＝1.6Hz,1H),7.26-7.11(m,2H),7.13(d,J＝8.4Hz,1H),6.65(s,1H),4.78(d,J＝10.4Hz,1H),4.76(s,2H),4.14(d,J＝10.4Hz,1H),3.70(s,3H). To (5-(5-((tert-butyldimethyl)silyloxymethyl)-2-(2-chloro-4-fluorobenzoyl)phenyl)-1-methyl-2-oxo- A solution of tert-butyl 1,2-dihydropyridin-4-yl)methyl)carbamate (100 mg, 0.16 mmol) in dichloromethane (4 mL) The reaction solution was stirred at room temperature for 12 hours and concentrated. The residue was purified by preparative-HPLC to give the title compound 7-(2-chloro-4-fluorophenyl)-10-(hydroxymethyl)-2-methyl-2H-benzo[c]pyridine[3] , 4-e]azepine-3(5H)-one (60 mg, 98%) as a white solid. LCMS (ESI) [M+H] ⁺ = 383.1, purity 100% (UV 214nm); ¹ H NMR (400 MHz, CD ₃ OD) δ 8.13 (s, 1H), 7.70 (d, J = 1.6 Hz, 1H) ), 7.61-7.59 (m, 1H), 7.42 (q, J = 1.6 Hz, 1H), 7.26-7.11 (m, 2H), 7.13 (d, J = 8.4 Hz, 1H), 6.65 (s, 1H) , 4.78 (d, J = 10.4 Hz, 1H), 4.76 (s, 2H), 4.14 (d, J = 10.4 Hz, 1H), 3.70 (s, 3H).

4133:7-(2,6-二氯-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮4133: 7-(2,6-Dichloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c] Pyrido[3,4-e]azepin-3-one

步骤1:(2-溴-4-甲基苯基)(2,6-二氯-4-氟苯基)甲醇Step 1: (2-Bromo-4-methylphenyl)(2,6-dichloro-4-fluorophenyl)methanol

将2-溴-1,3-二氯-5-氟苯(3.68g,15.07mmol)的四氢呋喃(25mL)溶液冷却至-20℃，然后缓慢加入异丙基氯化镁的四氢呋喃溶液(2M,7.6mL,15.2mmol)，搅拌3小时。向反应瓶中加入2-溴-4-甲基苯甲醛(1.0g,5.02mmol)的四氢呋喃(5mL)溶液，反应液继续在室温下搅拌12小时。加入饱和氯化铵溶液淬灭反应，然后用乙酸乙酯萃取(20mL x 3)。合并有机相，用稀盐酸及饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/8(体积比))，得(2-溴-4-甲基苯基)(2,6-二氯-4-氟苯基)甲醇(720mg,40％)，为黄色固体。LCMS(ESI)[M-H ₂O+H] ⁺＝344.9. A solution of 2-bromo-1,3-dichloro-5-fluorobenzene (3.68 g, 15.07 mmol) in tetrahydrofuran (25 mL) was cooled to -20 ° C, then isopropylmagnesium chloride in tetrahydrofuran (2M, 7.6 mL) , 15.2 mmol), stirred for 3 hours. A solution of 2-bromo-4-methylbenzaldehyde (1.0 g, 5.02 mmol) in tetrahydrofuran (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hours. The reaction was quenched by the addition of aq. EtOAc (EtOAc) The organic phase was combined, washed with aq. EtOAc EtOAc EtOAc (EtOAc m. 2-Bromo-4-methylphenyl)(2,6-dichloro-4-fluorophenyl)methanol (720 mg, 40%). LCMS (ESI) [MH ₂ O + H] ⁺ = 344.9.

步骤2:(2-溴-4-甲基苯基)(2,6-二氯-4-氟苯基)甲酮Step 2: (2-Bromo-4-methylphenyl)(2,6-dichloro-4-fluorophenyl)methanone

将(2-溴-4-甲基苯基)(2,6-二氯-4-氟苯基)甲醇(720mg,1.99mmol)和Dess-Martin氧化剂(1.26g,2.97mmol)混合于二氯甲烷(10mL)中，在室温下搅拌1小时。将反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/10(体积比))，得(2-溴-4-甲基苯基)(2,6-二氯-4-氟苯基)甲酮(688mg,96％)，为黄色固体。Mixing (2-bromo-4-methylphenyl)(2,6-dichloro-4-fluorophenyl)methanol (720 mg, 1.99 mmol) and Dess-Martin oxidizing agent (1.26 g, 2.97 mmol) in dichloro Methane (10 mL) was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated, and the residue was purified by flash chromatography (ethyl acetate / petroleum ether = 1/10 (by volume)) to give (2-bromo-4-methylphenyl) (2,6) -Dichloro-4-fluorophenyl)methanone (688 mg, 96%) as a yellow solid.

步骤3:(2-溴-4-二溴甲基苯基)(2,6-二氯-4-氟苯基)甲酮Step 3: (2-Bromo-4-dibromomethylphenyl)(2,6-dichloro-4-fluorophenyl)methanone

将N-溴代丁二酰亚胺(1.01g,5.62mmol)，偶氮二异丁腈(31mg,0.19mmol)和(2-溴-4-甲基苯基)(2,6-二氯-4-氟苯基)甲酮(680mg,1.89mmol)混合于四氯化碳(30mL)中，加热至90℃搅拌12小时。将反应液浓缩，得(2-溴-4-二溴甲基苯基)(2,6-二氯-4-氟苯基)甲酮(粗产物，1.7g)，为黄色固体。N-bromosuccinimide (1.01 g, 5.62 mmol), azobisisobutyronitrile (31 mg, 0.19 mmol) and (2-bromo-4-methylphenyl) (2,6-dichloro) 4-Fluorophenyl)methanone (680 mg, 1.89 mmol) was mixed in carbon tetrachloride (30 mL) and heated to 90 ° C for 12 hours. The reaction mixture was concentrated to give (2-bromo-4-dibromomethylphenyl) (2,6-dichloro-4-fluorophenyl)methanone (cr.

步骤4:(2-溴-4-溴甲基苯基)(2,6-二氯-4-氟苯基)甲酮Step 4: (2-Bromo-4-bromomethylphenyl)(2,6-dichloro-4-fluorophenyl)methanone

向(2-溴-4-二溴甲基苯基)(2,6-二氯-4-氟苯基)甲酮(1.7g,3.85mmol)的二氯甲烷(15mL)溶液加入亚磷酸二乙酯(799mg,5.78mmol)和二异丙基乙胺(747mg,5.78mmol)。反应液在室温下搅拌1小时。反应液浓缩后残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝15/1(体积比))，得(2-溴-4-溴甲基苯基)(2,6-二氯-4-氟苯基)甲酮(1.2g,两步收率99％)，为黄色固体。To a solution of (2-bromo-4-dibromomethylphenyl)(2,6-dichloro-4-fluorophenyl)methanone (1.7 g, 3.85 mmol) in dichloromethane (15 mL) Ethyl ester (799 mg, 5.78 mmol) and diisopropylethylamine (747 mg, 5.78 mmol). The reaction solution was stirred at room temperature for 1 hour. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 15 / 1 (volume ratio)) to give (2-bromo-4-bromomethylphenyl) (2,6-dichloro) 4-fluorophenyl)methanone (1.2 g, 99% yield in two steps) as a yellow solid.

步骤5:(2-溴-4-((乙基砜)甲基)苯基)(2,6-二氯-4-氟苯基)甲酮Step 5: (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(2,6-dichloro-4-fluorophenyl)methanone

向(2-溴-4-溴甲基苯基)(2,6-二氯-4-氟苯基)甲酮(1.2g,2.72mmol)的二甲亚砜(20mL)溶液中加入乙烷亚磺酸钠(632mg,5.44mmol)。反应液在室温下搅拌1小时。向反应液中加入乙酸乙酯(20mL)和水(20mL)，分离有机相。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝3/1(体积比))，得(2-溴-4-((乙基砜)甲基)苯基)(2,6-二氯-4-氟苯基)甲酮(900mg,73％)。LCMS(ESI)[M+NH ₄] ⁺＝470.0. Add ethane to a solution of (2-bromo-4-bromomethylphenyl)(2,6-dichloro-4-fluorophenyl)methanone (1.2 g, 2.72 mmol) in dimethyl sulfoxide (20 mL) Sodium sulfinate (632 mg, 5.44 mmol). The reaction solution was stirred at room temperature for 1 hour. Ethyl acetate (20 mL) and water (20 mL) were added to the mixture and the organic phase was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by flash chromatography (petrole ether / ethyl acetate = 3 / 1 (volume ratio)) to give (2-bromo-4-((ethylsulfonyl)methyl)phenyl) (2,6- Dichloro-4-fluorophenyl)methanone (900 mg, 73%). LCMS (ESI) [M+NH ₄ ] ⁺ = 470.0.

步骤6:((5-(2-(2,6-二氯-4-氟苯甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯Step 6: ((5-(2-(2,6-Dichloro-4-fluorobenzoyl)-5-(ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1 , 2-dihydropyridin-4-yl)methylcarbamic acid tert-butyl ester

将(2-溴-4-((乙基砜)甲基)苯基)(2,6-二氯-4-氟苯基)甲酮(100mg,0.22mmol)，(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(122mg,0.22mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(20mg,0.02mmol)和碳酸钾(84mg,0.66mmol)混合于1,4-二氧六环(5mL)和水(0.5mL)中，在氮气保护下加热至95℃搅拌1小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝30/1)，得((5-(2-(2,6-二氯-4-氟苯甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(50mg,37％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝611.0. (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(2,6-dichloro-4-fluorophenyl)methanone (100 mg, 0.22 mmol), (1-methyl-2) -oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl)methyl Tert-butyl carbamate (122 mg, 0.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (20 mg, 0.02 mmol) and potassium carbonate (84 mg, 0.66) Methyl) was mixed with 1,4-dioxane (5 mL) and water (0.5 mL) and heated to 95 ° C under nitrogen for 1 hour. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjj -5-(ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methylcarbamic acid tert-butyl ester (50 mg, 37%) , as a yellow solid. LCMS (ESI) [M+H] ⁺ = 611.0.

步骤7:4-(氨甲基)-5-(2-(2,6-二氯-4-氟苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基吡啶-2(1H)-酮Step 7: 4-(Aminomethyl)-5-(2-(2,6-dichloro-4-fluorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl Pyridine-2(1H)-one

向((5-(2-(2,6-二氯-4-氟苯甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(50mg,0.08mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌1小时并浓缩。残余物用制备-HPLC分离纯化，得4-(氨甲基)-5-(2-(2,6-二氯-4-氟苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基吡啶-2(1H)-酮(30mg,71％)，为白色固体。LCMS(ESI):[M+H] ⁺＝511.1 To ((5-(2-(2,6-Dichloro-4-fluorobenzoyl)-5-(ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1,2 To a solution of tert-butyl dihydropyridin-4-yl)methylcarbamate (50 mg, 0.08 mmol) in dichloromethane (4 mL). The residue is purified by preparative-HPLC to give 4-(aminomethyl)-5-(2-(2,6-dichloro-4-fluorobenzoyl)-5-((ethylsulfonyl)methyl) Phenyl)-1-methylpyridine-2(1H)-one (30 mg, 71%) as a white solid. LCMS (ESI): [M+H] ⁺ = 511.1

步骤8:7-(2,6-二氯-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮Step 8: 7-(2,6-Dichloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c Pyridine[3,4-e]azepin-3-one

向4-(氨甲基)-5-(2-(2,6-二氯-4-氟苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基吡啶- 2(1H)-酮(30mg,0.06mmol)的四氢呋喃(2mL)溶液中加入钛酸四乙酯(0.5mL)。反应液在70℃下搅拌16小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物7-(2,6-二氯-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(4.7mg,16％)，为白色固体。LCMS(ESI):[M+H] ⁺＝493.0，纯度100％(UV 214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.00(s,1H),7.69(d,J＝1.2Hz,1H),7.40-7.43(m,2H),7.19-7.22(m,2H),6.55(s,1H),4.72(d,J＝11.2Hz,1H),4.45(s,2H),4.15(d,J＝11.6Hz,1H),3.60(s,3H),3.16(q,J＝3.2Hz,2H),1.26(t,J＝7.2Hz,3H). To 4-(aminomethyl)-5-(2-(2,6-dichloro-4-fluorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methylpyridine To a solution of 2(1H)-one (30 mg, 0.06 mmol) in tetrahydrofuran (2 mL), EtOAc (EtOAc) The reaction solution was stirred at 70 ° C for 16 hours and concentrated. The residue was purified by preparative EtOAc (EtOAc-EtOAc) Dihydro-3H-benzo[c]pyrido[3,4-e]azepin-3-one (4.7 mg, 16%) was obtained as a white solid. LCMS (ESI): [M + H] + = 493.0, purity ^{100 (UV 214nm)%; 1} H NMR (400MHz, CD 3 OD) δ8.00 (s, 1H), 7.69 (d, J = 1.2Hz, 1H), 7.40-7.43 (m, 2H), 7.19-7.22 (m, 2H), 6.55 (s, 1H), 4.72 (d, J = 11.2 Hz, 1H), 4.45 (s, 2H), 4.15 (d) , J = 11.6 Hz, 1H), 3.60 (s, 3H), 3.16 (q, J = 3.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).

4134:(S)-2-(7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-3-氧代-3,5-二氢-2H-并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺4134: (S)-2-(7-(2-chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2-methyl-3-oxo-3,5-di Hydrogen-2H-and[c]pyrido[3,4-e]azepine-5-yl)acetamide

步骤1:(S)-3-(5-(2-(2-氯-4-氟苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)-3-((S)-1,1-二甲基乙基亚磺酰胺基)丙酸叔丁酯Step 1: (S)-3-(5-(2-(2-Chloro-4-fluorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl-2- Oxo-1,2-dihydropyridin-4-yl)-3-((S)-1,1-dimethylethylsulfinamido)propionic acid tert-butyl ester

将(S)-3-(5-溴-1-甲基-2-氧代-1,2-二氢吡啶-4-基)-3-((S)-1,1-二甲基乙基亚磺酰胺基)丙酸叔丁酯(140mg,0.32mmol),(2-氯-4-氟苯基)(4-((乙基砜)甲基)-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)甲酮(150mg，0.32mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(23mg,0.032mmol)和碳酸钾(133mg,0.96mmol)混合于1,4-二氧六环(5mL)和水(1mL)中，在氮气保护下加热至90℃搅拌1小时。向反应液中加入乙酸乙酯(25mL)和水(15mL)，分离有机相。有机相用无水硫酸钠干燥，过滤并浓缩。残余物用制备TLC分离纯化(二氯甲烷/甲醇＝10/1(体积比))，得(S)-3-(5-(2-(2-氯-4-氟苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)-3-((S)-1,1-二甲基乙基亚磺酰胺基)丙酸叔丁酯(75mg,34％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝695.1. (S)-3-(5-Bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-3-((S)-1,1-dimethylethyl Tert-butyl propionate (140 mg, 0.32 mmol), (2-chloro-4-fluorophenyl)(4-((ethylsulfonyl)methyl)-2-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone (150 mg, 0.32 mmol), [1,1'-bis(diphenylphosphino)di Ferrocene]Palladium(II) chloride (23 mg, 0.032 mmol) and potassium carbonate (133 mg, 0.96 mmol) were mixed in 1,4-dioxane (5 mL) and water (1 mL) and heated under nitrogen. Stir at 90 ° C for 1 hour. Ethyl acetate (25 mL) and water (15 mL) were added to the mixture and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative TLC (dichloromethane / methanol = 10/1 (vol.)) to afford (S)-3-(5-(2-(2-chloro-4-fluorobenzoyl)-5 -((ethylsulfonyl)methyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-3-((S)-1,1-dimethyl Tert-butyl propionate (75 mg, 34%) was obtained as a yellow oil. LCMS (ESI) [M+H] ⁺ = 695.1.

步骤2:(S)-2-(7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酸Step 2: (S)-2-(7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2-methyl-3-oxo-3,5- Dihydro-2H-benzo[c]pyrido[3,4-e]azepine-5-yl)acetic acid

向(S)-3-(5-(2-(2-氯-4-氟苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)-3-((S)-1,1-二甲基乙基亚磺酰胺基)丙酸叔丁酯(75mg,0.11mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌过夜并浓缩。残余物用制备-HPLC分离纯化，得(S)-2-(7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酸(57mg,90％)，为白色固体。LCMS(ESI)[M+H] ⁺＝517.1. To (S)-3-(5-(2-(2-chloro-4-fluorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl-2-oxo -1,2-Dihydropyridin-4-yl)-3-((S)-1,1-dimethylethylsulfinamido)propionic acid tert-butyl ester (75 mg, 0.11 mmol) in dichloromethane Trifluoroacetic acid (1 mL) was added to a solution (4 mL). The reaction was stirred at room temperature overnight and concentrated. The residue was purified by preparative-HPLC to give (S)-2-(7-(2-chloro-4-fluorophenyl)-10-((ethylsulfonyl)methyl)-2-methyl-3- Oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e]azepin-5-yl)acetic acid (57 mg, 90%) as a white solid. LCMS (ESI) [M+H] ⁺ = 517.1.

步骤3:(S)-2-(7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-3-氧代-3,5-二氢-2H-并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺Step 3: (S)-2-(7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2-methyl-3-oxo-3,5- Dihydro-2H-and-[c]pyrido[3,4-e]azepine-5-yl)acetamide

将(S)-2-(7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酸(57mg,0.11mmol)，氯化铵(12mg,0.22mmol),O-(7-氮杂苯并***-1-基)-N,N,N′,N′-四甲基脲六氟磷酸酯(84mg,0.22mmol)和N,N-二异丙基乙胺(43mg,0.33mmol)在N,N-二甲基甲酰胺中混合，并在室温下搅拌2小时。反应液过滤，滤液浓缩。残余物用制备-HPLC分离纯化，得标题化合物(S)-2-(7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-3-氧代-3,5-二氢-2H-并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺(10mg,18％)，为白色固体。LCMS(ESI)[M+H] ⁺＝516.1，纯度100％(UV 214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.13(s,1H),7.79(d,J＝1.2Hz,1H),7.65-7.56(m,1H),7.52(q,J＝2.0Hz,1H),7.24-7.18(m,3H),6.61(s,1H),4.57(s,2H),4.56-4.55(m,1H),3.70(s,3H),3.28-3.22(m,1H),3.15(q,J＝7.2Hz,2H),3.11-3.06(m,1H),1.41(t,J＝7.2Hz,3H). (S)-2-(7-(2-chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2-methyl-3-oxo-3,5-dihydro -2H-benzo[c]pyrido[3,4-e]azepin-5-yl)acetic acid (57 mg, 0.11 mmol), ammonium chloride (12 mg, 0.22 mmol), O-(7-aza Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) and N,N-diisopropylethylamine (43 mg, 0.33 mmol) The mixture was mixed in N,N-dimethylformamide and stirred at room temperature for 2 hours. The reaction solution was filtered and the filtrate was concentrated. The residue was purified by preparative-HPLC to give the title compound (S)-2-(7-(2-chloro-4-fluorophenyl)-10-((ethylsulfonyl)methyl)-2-methyl- 3-oxo-3,5-dihydro-2H-and-[c]pyrido[3,4-e]azepin-5-yl)acetamide (10 mg, 18%) as a white solid. LCMS (ESI) [M+H] ⁺ = 516.1, purity 100% (UV 214nm); ¹ H NMR (400 MHz, CD ₃ OD) δ 8.13 (s, 1H), 7.79 (d, J = 1.2 Hz, 1H) ), 7.65-7.56 (m, 1H), 7.52 (q, J = 2.0 Hz, 1H), 7.24-7.18 (m, 3H), 6.61 (s, 1H), 4.57 (s, 2H), 4.56-4.55 ( m, 1H), 3.70 (s, 3H), 3.28-3.22 (m, 1H), 3.15 (q, J = 7.2 Hz, 2H), 3.11-3.06 (m, 1H), 1.41 (t, J = 7.2 Hz) , 3H).

4135:7-(2,5-二氯苯基)-10-((乙基砜)甲基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮4135: 7-(2,5-Dichlorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2H-benzo[c]pyrido[3,4-e]aza Zhuo-3(5H)-ketone

步骤1:(2-溴-4-甲基苯基)(2,5-二氯苯基)甲醇Step 1: (2-Bromo-4-methylphenyl)(2,5-dichlorophenyl)methanol

将2-溴-1,4-二氯苯(850mg,5mmol)的四氢呋喃(5mL)溶液冷却至-20℃，然后缓慢加入异丙基氯化镁的四氢呋喃溶液(2M,2.5mL,5mmol)，搅拌3小时。另将2-溴-4-甲基苯甲醛(500mg,2.5mmol)的四氢呋喃(5mL)溶液冷却至-20℃，然后缓慢加入前述混合液。反应液继续在室温下搅拌16小时。反应液用乙酸乙酯和饱和氯化铵溶液分离。有机相用稀盐酸及饱和食盐水洗涤，无水硫酸钠干燥并浓缩，得(2-溴-4-甲基苯基)(2,5-二氯苯基)甲醇(粗产物)，为黄色油状物。LCMS(ESI)[M-H ₂O+H] ⁺＝329.0. A solution of 2-bromo-1,4-dichlorobenzene (850 mg, 5 mmol) in tetrahydrofuran (5 mL) was cooled to -20 ° C, then isopropyl magnesium chloride in tetrahydrofuran (2M, 2.5 mL, 5 mmol) hour. Further, a solution of 2-bromo-4-methylbenzaldehyde (500 mg, 2.5 mmol) in tetrahydrofuran (5 mL) was cooled to -20 ° C, and then the mixture was slowly added. The reaction was continued to stir at room temperature for 16 hours. The reaction solution was separated with ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic phase was washed with dilute hydrochloric acid and brine, dried over anhydrous sodium sulfate and evaporated to afford (2-bromo-4-methylphenyl) (2,5-dichlorophenyl)methanol (cr. Oily. LCMS (ESI) [MH ₂ O + H] ⁺ = 329.0.

步骤2:(2-溴-4-甲基苯基)(2,5-二氯苯基)甲酮Step 2: (2-Bromo-4-methylphenyl)(2,5-dichlorophenyl)methanone

将(2-溴-4-甲基苯基)(2,5-二氯苯基)甲醇(步骤1粗产物)和Dess-Martin氧化剂(1.6g,3.75mmol)混合于二氯甲烷(10mL)中，在室温下搅拌16小时。将反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/20(体积比))，得(2-溴-4-甲基苯基)(2,5-二氯苯基)甲酮(640mg,两步总收率74％)，为无色油状物。LCMS(ESI)[M+H] ⁺＝344.9. (2-Bromo-4-methylphenyl)(2,5-dichlorophenyl)methanol (step 1 crude product) and Dess-Martin oxidant (1.6 g, 3.75 mmol) in dichloromethane (10 mL) The mixture was stirred at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated, and the residue was purified by flash chromatography (ethyl acetate / petroleum ether = 1 / 20 (volume ratio) to give (2-bromo-4-methylphenyl) (2,5) -Dichlorophenyl)methanone (640 mg, total yield of 74% in two steps) as a colorless oil. LCMS (ESI) [M+H] ⁺ = 344.9.

步骤3:(2-溴-4-溴甲基苯基)(2,5-二氯苯基)甲酮Step 3: (2-Bromo-4-bromomethylphenyl)(2,5-dichlorophenyl)methanone

将N-溴代丁二酰亚胺(364mg,2.05mmol)，过氧化二苯甲酰(46mg,0.24mmol)和(2-溴-4-溴甲基苯基)(2,5-二氯苯基)甲酮(640mg,1.86mmol)混合于四氯化碳(10mL)中，加热至80℃搅拌6小时。将反应液用乙酸乙酯(100mL)稀释，然后用碳酸钠溶液及饱和食盐水洗涤，无水硫酸钠干燥并浓缩，得(2-溴-4-溴甲基苯基)(2,5-二氯苯基)甲酮(粗产物)。LCMS(ESI):no mass signal.N-bromosuccinimide (364 mg, 2.05 mmol), dibenzoyl peroxide (46 mg, 0.24 mmol) and (2-bromo-4-bromomethylphenyl) (2,5-dichloro) Phenyl)methanone (640 mg, 1.86 mmol) was mixed in carbon tetrachloride (10 mL) and heated to 80 ° C for 6 hours. The reaction mixture was diluted with ethyl acetate (100 mL), and then washed with sodium carbonate and brine, dried over anhydrous sodium sulfate and evaporated to give (2-bromo-4-bromomethylphenyl) (2,5- Dichlorophenyl)methanone (crude product). LCMS (ESI): no mass signal.

步骤4:(2-溴-4-((乙基砜)甲基)苯基)(2,5-二氯苯基)甲酮Step 4: (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(2,5-dichlorophenyl)methanone

向(2-溴-4-溴甲基苯基)(2,5-二氯苯基)甲酮(步骤3的粗产物)的二甲亚砜(5mL)溶液中加入乙烷亚磺酸钠(324mg,2.8mmoL)。反应液在室温下搅拌2小时。向反应液中加入乙酸乙酯(100mL)和水(50mL)，分离有机相。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/1(体积比))，得(2-溴-4-((乙基砜)甲基)苯基)(2,5-二氯苯基)甲酮(280mg,两步总收率34％)。(ESI)[M+NH ₄] ⁺＝453.9. Adding sodium ethanesulfinate to a solution of (2-bromo-4-bromomethylphenyl)(2,5-dichlorophenyl)methanone (the crude product of Step 3) in dimethyl sulfoxide (5 mL) (324 mg, 2.8 mmoL). The reaction solution was stirred at room temperature for 2 hours. Ethyl acetate (100 mL) and water (50 mL) were added to the mixture and the organic phase was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by flash chromatography (petrole ether / ethyl acetate = 1 / 1 (volume ratio)) to give (2-bromo-4-((ethylsulfonyl)methyl)phenyl) (2,5- Dichlorophenyl)methanone (280 mg, total yield of 34% in two steps). (ESI)[M+NH ₄ ] ⁺ =453.9.

步骤5:(5-(2-(2,5-二氯苯甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯Step 5: (5-(2-(2,5-Dichlorobenzoyl)-5-(ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1,2-dihydro Pyridin-4-yl)methylcarbamic acid tert-butyl ester

将(2-溴-4-((乙基砜)甲基)苯基)(2,5-二氯苯基)甲酮(50mg,0.11mmol)，(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(62mg,0.17mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(8mg,0.011mmol)和碳酸钾(38mg,0.28mmol)混合于1,4-二氧六环(4mL)和水(0.4mL)中，在氮气保护下加热至90℃搅拌2小时。反应液过滤，滤液浓缩，得(5-(2-(2,5-二氯苯甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(粗产物)，为黑色油状物。LCMS(ESI)[M+H] ⁺＝593.0. (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(2,5-dichlorophenyl)methanone (50 mg, 0.11 mmol), (1-methyl-2-oxo- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl)methylcarbamic acid tert-butyl Ester (62 mg, 0.17 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (8 mg, 0.011 mmol) and potassium carbonate (38 mg, 0.28 mmol) In 1,4-dioxane (4 mL) and water (0.4 mL), the mixture was heated to 90 ° C under a nitrogen atmosphere and stirred for 2 hours. The reaction solution was filtered, and the filtrate was concentrated to give (5-(2-(2,5-dichlorobenzoyl)-5-(ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1 ,2-Dihydropyridin-4-yl)methylcarbamic acid tert-butyl ester (crude) as a black oil. LCMS (ESI) [M+H] ⁺ = 593.0.

步骤6:7-(2,5-二氯苯基)-10-((乙基砜)甲基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮Step 6: 7-(2,5-Dichlorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2H-benzo[c]pyrido[3,4-e]nitrogen Miscellaneous-3(5H)-ketone

向(5-(2-(2,5-二氯苯甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(步骤5的粗产物)的二氯甲烷(3mL)溶液中加入三氟乙酸(2mL)。反应液在室温下搅拌16小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物7-(2,5-二氯苯基)-10-((乙基砜)甲基)-2-甲基-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮(34mg,两步总收率62％)，为白色固体。LCMS(ESI)[M+H] ⁺＝475.0，纯度100％(UV 214nm)； ¹H NMR(400MHz,CD3OD)δ8.15(s,1H),7.79(s,1H),7.63(s,1H),7.51-7.48(m,2H),7.39(d,J＝8.0Hz,1H),7.21(d,J＝8.0Hz,1H),6.66(s,1H),4.89(d,J＝10.8Hz,1H)),4.57(s,2H),4.18(d,J＝10.8Hz,1H),3.71(s,3H),3.16(q,J＝7.6Hz,2H),1.41(t,J＝7.6Hz,3H). To (5-(2-(2,5-dichlorobenzoyl)-5-(ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridine- To a solution of tert-butyl methyl 4-carbamate (the crude product of Step 5) in dichloromethane (3 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred at room temperature for 16 hours and concentrated. The residue was purified by preparative-HPLC to give the title compound 7-(2,5-dichlorophenyl)-10-((ethylsulfonyl)methyl)-2-methyl-2H-benzo[c]pyridine And [3,4-e]azepine-3(5H)-one (34 mg, total yield of 62% in two steps) as a white solid. LCMS (ESI) [M+H] ⁺ = 475.0, mp. 100% (UV 214nm); ¹ H NMR (400 MHz, CD3OD) δ 8.15 (s, 1H), 7.79 (s, 1H), 7.63 (s, 1H) ), 7.51-7.48 (m, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.66 (s, 1H), 4.89 (d, J = 10.8 Hz) , 1H)), 4.57 (s, 2H), 4.18 (d, J = 10.8 Hz, 1H), 3.71 (s, 3H), 3.16 (q, J = 7.6 Hz, 2H), 1.41 (t, J = 7.6 Hz, 3H).

4136:10-((乙基砜)甲基)-7-(4-氟-2-(三氟甲基)苯基)-2-甲基-2H-苯并[e]吡啶并[4,3-c]氮杂卓-3(5H)-酮4136: 10-((Ethyl sulfonyl)methyl)-7-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-2H-benzo[e]pyrido[4, 3-c]azepine-3(5H)-one

步骤1:(5-(5-((乙基砜)甲基)-2-(4-氟-2-(三氟甲基)苯甲酰基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯Step 1: (5-(5-((Ethyl sulfonyl)methyl)-2-(4-fluoro-2-(trifluoromethyl)benzoyl)phenyl)-1-methyl-2-oxo Tert-butyl-1,2-dihydropyridin-4-yl)methyl)carbamate

将(2-溴-4-((乙基砜)甲基)苯基)(4-氟-2-(三氟甲基)苯基)甲酮(90mg,0.2mmol)，((1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(110mg,0.3mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(20mg,0.026mmol)和磷酸钾(84mg,0.6mmol)混合于1,4-二氧六环(4mL)和水(0.5mL)中，在氮气保护下加热至90℃搅拌1小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/甲醇＝10/1(体积比))，得(5-(5-((乙基砜)甲基)-2-(4-氟-2-(三氟甲基)苯甲酰基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(34mg,28％)，为褐色固体。LCMS(ESI)[M+H] ⁺＝611.0. (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(4-fluoro-2-(trifluoromethyl)phenyl)methanone (90 mg, 0.2 mmol), (1- 1- 5-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl )methyl)carbamic acid tert-butyl ester (110 mg, 0.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (20 mg, 0.026 mmol) and potassium phosphate (84 mg, 0.6 mmol) was mixed with 1,4-dioxane (4 mL) and water (0.5 mL), and heated to 90 ° C under a nitrogen atmosphere for 1 hour. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjj (4-Fluoro-2-(trifluoromethyl)benzoyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)carbamic acid tert-butyl Ester (34 mg, 28%) was obtained as a brown solid. LCMS (ESI) [M+H] ⁺ = 611.0.

步骤2:10-((乙基砜)甲基)-7-(4-氟-2-(三氟甲基)苯基)-2-甲基-2H-苯并[e]吡啶并[4,3-c]氮杂卓-3(5H)-酮Step 2: 10-((Ethyl sulfonyl)methyl)-7-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-2H-benzo[e]pyridin[4 ,3-c]azepine-3(5H)-one

向(5-(5-((乙基砜)甲基)-2-(4-氟-2-(三氟甲基)苯甲酰基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(30mg,0.05mmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(2mL)。反应液在室温下搅拌过夜并浓缩。残余物用制备-HPLC分离纯化，得标题化合物10-((乙基砜)甲基)-7-(4-氟-2-(三氟甲基)苯基)-2-甲基-2H-苯并[e]吡啶并[4,3-c]氮杂卓-3(5H)-酮(3mg,12％)，为白色固体。LCMS(ESI)[M+H] ⁺＝493.1,纯度100％(UV214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.03(s,1H),7.67(s,1H),7.43-7.33(m,4H),7.01(d,J＝8.4Hz,1H),6.52(s,1H),4.68(d,J＝10.8Hz,1H),4.43(s,2H),4.03(d,J＝10.8Hz,1H),3.60(s,3H),2.99(q,J＝7.6Hz,2H),1.26(t,J＝7.6Hz,3H). To (5-(5-((ethylsulfonyl)methyl)-2-(4-fluoro-2-(trifluoromethyl)benzoyl)phenyl)-1-methyl-2-oxo- A solution of tert-butyl 1,2-dihydropyridin-4-yl)methyl)carbamate (30 mg, 0.05 mmol) in dichloromethane (2 mL) The reaction was stirred at room temperature overnight and concentrated. The residue was purified by preparative EtOAc (EtOAc-EtOAc) Benzo[e]pyrido[4,3-c]azepine-3(5H)-one (3 mg, 12%) was obtained as a white solid. LCMS (ESI) [M + H ] + = 493.1, purity ^{100% (UV214nm); 1 H} NMR (400MHz, CD 3 OD) δ8.03 (s, 1H), 7.67 (s, 1H), 7.43-7.33 ( m, 4H), 7.01 (d, J = 8.4 Hz, 1H), 6.52 (s, 1H), 4.68 (d, J = 10.8 Hz, 1H), 4.43 (s, 2H), 4.03 (d, J = 10.8) Hz, 1H), 3.60 (s, 3H), 2.99 (q, J = 7.6 Hz, 2H), 1.26 (t, J = 7.6 Hz, 3H).

4137:7-(2-环丙基-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮4137:7-(2-cyclopropyl-4-fluorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridine And [3,4-e]azepin-3-one

步骤1:7-(2-环丙基-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮Step 1: 7-(2-Cyclopropyl-4-fluorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c] Pyrido[3,4-e]azepin-3-one

将7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(15mg,0.033mmol)，环丙烷基三氟硼酸钾(6mg,0.034mmol)，三(二亚苄基丙酮)二钯(0)(2mg,0.034mmol)和碳酸钾(9mg,0.068mmol)混合于1,4-二氧六环(2mL)中，在氮气保护下加热至110℃搅拌2小时。反应液过滤，滤液浓缩，残余物用制备-HPLC分离纯化，得标题化合物7-(2-环丙基-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(2.1mg,13％)，为白色固体。LCMS(ESI)[M+H] ⁺＝465.1,纯度100％(UV 214nm)； ¹H NMR(400MHz,DMSO-d ₆)δ8.16(s,1H),7.77(s,1H),7.48-7.40(m,2H),7.20(d,J＝8.0Hz,1H),7.05-7.01(m,1H),6.73(d,J＝8.0Hz,1H),6.65(s,1H),4.76(d,J＝10.8Hz,1H),4.55(m,2H),4.15(d,J＝10.8Hz,1H),3.70(s,3H),3.14(q,J＝8.0Hz,2H),1.40(d,J＝7.2Hz,3H),1.20-1.18(m,1H),0.50-0.47(m,2H),0.41-0.39(m,1H),0.30-0.28(m,1H). 7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridin[3 , 4-e]azazin-3-one (15 mg, 0.033 mmol), potassium cyclopropane trifluoroborate (6 mg, 0.034 mmol), tris(dibenzylideneacetone) dipalladium (0) (2 mg, 0.034) Methyl carbonate (9 mg, 0.068 mmol) was mixed with 1,4-dioxane (2 mL) and heated to 110 ° C under nitrogen for 2 hours. The reaction mixture was filtered, and the filtrate was evaporated.jjjjjjjjjjjjjj Base-2,5-dihydro-3H-benzo[c]pyrido[3,4-e]azepin-3-one (2.1 mg, 13%) as a white solid. LCMS (ESI) [M + H ] + = 465.1, purity ^{100 (UV 214nm)%; 1} H NMR (400MHz, DMSO-d 6) δ8.16 (s, 1H), 7.77 (s, 1H), 7.48- 7.40 (m, 2H), 7.20 (d, J = 8.0 Hz, 1H), 7.05-7.01 (m, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 4.76 (d) , J = 10.8 Hz, 1H), 4.55 (m, 2H), 4.15 (d, J = 10.8 Hz, 1H), 3.70 (s, 3H), 3.14 (q, J = 8.0 Hz, 2H), 1.40 (d , J = 7.2 Hz, 3H), 1.20 - 1.18 (m, 1H), 0.50 - 0.47 (m, 2H), 0.41 - 0.39 (m, 1H), 0.30 - 0.28 (m, 1H).

4138:N-(环丙甲基)-N-(7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙基磺酰胺4138: N-(cyclopropylmethyl)-N-(7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)ethylsulfonamide

步骤1:N-(环丙甲基)-N-(7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙基磺酰胺Step 1: N-(cyclopropylmethyl)-N-(7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine And [3,4-e]azepine-10-yl)ethylsulfonamide

将N-(7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙基磺酰胺(25mg,0.06mmol)，碳酸铯(40mg,0.12mmol)和溴甲基环丙烷(16mg,0.12mmol)混合于N,N-二甲基甲酰胺(1mL)中，反应液在室温下搅拌12小时。向反应液中加入二氯甲烷(20mL)和水(15mL)，分离有机相。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。残余物用制备-HPLC纯化，得标题化合物N-(环丙甲基)-N-(7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙基磺酰胺(7.5mg,26％)，为白色固体.LCMS(ESI)[M+H] ⁺＝480.1,纯度100％(UV 214nm)； ¹H NMR(400MHz,CD ₃OD)δ7.91(s,1H),7.57(d,J＝1.0Hz,1H),7.35-7.27(m,3H),7.15(d,J＝8.4Hz,1H),6.95-6.90(m,2H),6.42(s,1H),4.54(d,J＝11.8Hz,1H),3.87(d,J＝11.8Hz,1H),3.51(d,J＝6.8Hz,2H),3.47(s,3H),3.04(q,J＝6.8Hz,2H),1.20(t,J＝6.8Hz,3H),0.85-0.78(m,1H),0.32-0.27(m,2H),0.034-0.007(m,2H). N-(7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e]azepine Benzyl sulfonamide (25 mg, 0.06 mmol), cesium carbonate (40 mg, 0.12 mmol) and bromomethylcyclopropane (16 mg, 0.12 mmol) in N,N-dimethylformamide (1 mL) The reaction solution was stirred at room temperature for 12 hours. Dichloromethane (20 mL) and water (15 mL) were added to the mixture and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by preparative EtOAc (EtOAc-EtOAc) 2H-Benzo[c]pyrido[3,4-e]azepin-10-yl)ethylsulfonamide (7.5 mg, 26%) as a white solid. LCMS (ESI) [M+H] ⁺ =480.1, purity 100% (UV 214nm); ¹ H NMR (400MHz, CD ₃ OD) δ 7.91 (s, 1H), 7.57 (d, J = 1.0 Hz, 1H), 7.35-7.27 (m, 3H) , 7.15 (d, J = 8.4 Hz, 1H), 6.95-6.90 (m, 2H), 6.42 (s, 1H), 4.54 (d, J = 11.8 Hz, 1H), 3.87 (d, J = 11.8 Hz, 1H), 3.51 (d, J = 6.8 Hz, 2H), 3.47 (s, 3H), 3.04 (q, J = 6.8 Hz, 2H), 1.20 (t, J = 6.8 Hz, 3H), 0.85 - 0.78 ( m, 1H), 0.32-0.27 (m, 2H), 0.034-0.007 (m, 2H).

4139:7-(2,3-二氯苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮4139:7-(2,3-Dichlorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridin[3 , 4-e]azazo-3-one

步骤1:(2-溴-4-甲基苯基)(2,3-二氯苯基)甲醇Step 1: (2-Bromo-4-methylphenyl)(2,3-dichlorophenyl)methanol

将1-溴-2,3-二氯苯(1.7g,7.54mmol)的四氢呋喃(25mL)溶液冷却至-20℃，然后缓慢加入异丙基氯化镁的四氢呋喃溶液(2M,7.8mL,7.6mmol)，搅拌3小时。向反应瓶中加入2-溴-4-甲基苯甲醛(500mg,2.5mmol)的四氢呋喃(5mL)溶液，反应液继续在室温下搅拌12小时。加入饱和氯化铵溶液淬灭反应，然后用乙酸乙酯萃取(20mL x 3)。合并有机相，用稀盐酸及饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/8(体积比))，得(2-溴-4-甲基苯基)(2,3-二氯苯基)甲醇(850 mg,98％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝326.8. A solution of 1-bromo-2,3-dichlorobenzene (1.7 g, 7.54 mmol) in tetrahydrofuran (25 mL) was cooled to -20 ° C, then isopropylmagnesium chloride in tetrahydrofuran (2M, 7.8 mL, 7.6 mmol) Stir for 3 hours. A solution of 2-bromo-4-methylbenzaldehyde (500 mg, 2.5 mmol) in tetrahydrofuran (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hr. The reaction was quenched by the addition of aq. EtOAc (EtOAc) The organic phase was combined, washed with aq. EtOAc EtOAc EtOAc (EtOAc m. 2-Bromo-4-methylphenyl)(2,3-dichlorophenyl)methanol (850 mg, 98%) as a yellow solid. LCMS (ESI) [M+H] ⁺ = 326.8.

步骤2:(2-溴-4-甲基苯基)(2,3-二氯苯基)甲酮Step 2: (2-Bromo-4-methylphenyl)(2,3-dichlorophenyl)methanone

将(2-溴-4-甲基苯基)(2,3-二氯苯基)甲醇(850mg,2.46mmol)和Dess-Martin氧化剂(1.60g,3.68mmol)混合于二氯甲烷(10mL)中，在室温下搅拌1小时。将反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/10(体积比))，得(2-溴-4-甲基苯基)(2,3-二氯苯基)甲酮(560mg,66％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝342.8. (2-Bromo-4-methylphenyl)(2,3-dichlorophenyl)methanol (850 mg, 2.46 mmol) and Dess-Martin oxidant (1.60 g, 3.68 mmol) were combined in dichloromethane (10 mL) The mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated, and the residue was purified by flash chromatography (ethyl acetate / petroleum ether = 1/10 (by volume)) to give (2-bromo-4-methylphenyl) (2,3) -Dichlorophenyl)methanone (560 mg, 66%) as a yellow solid. LCMS (ESI) [M+H] ⁺ = 342.8.

步骤3:(2-溴-4-二溴甲基苯基)(2,3-二氯苯基)甲酮Step 3: (2-Bromo-4-dibromomethylphenyl)(2,3-dichlorophenyl)methanone

将N-溴代丁二酰亚胺(1.10g,6.51mmol)，偶氮二异丁腈(53mg,0.33mmol)和(2-溴-4-甲基苯基)(2,3-二氯苯基)甲酮(560mg,1.63mmol)混合于四氯化碳(30mL)中，加热至90℃搅拌12小时。将反应液浓缩，得(2-溴-4-二溴甲基苯基)(2,3-二氯苯基)甲酮(粗产物)。LCMS(ESI)[M+H] ⁺＝523.9. N-bromosuccinimide (1.10 g, 6.51 mmol), azobisisobutyronitrile (53 mg, 0.33 mmol) and (2-bromo-4-methylphenyl) (2,3-dichloro) Phenyl ketone (560 mg, 1.63 mmol) was mixed in carbon tetrachloride (30 mL), and heated to 90 ° C for 12 hours. The reaction solution was concentrated to give (2-bromo-4-dibromomethylphenyl)(2,3-dichlorophenyl)methanone (crude). LCMS (ESI) [M+H] ⁺ = 523.9.

步骤4:(2-溴-4-溴甲基苯基)(2,3-二氯苯基)甲酮Step 4: (2-Bromo-4-bromomethylphenyl)(2,3-dichlorophenyl)methanone

向(2-溴-4-(二溴甲基)苯基)(2,3-二氯苯基)甲酮(600mg,1.20mmol)的二氯甲烷(15mL)溶液加入亚磷酸二乙酯(660mg,4.78mmol)和二异丙基乙胺(620mg,4.78mmol)。反应液在室温下搅拌1小时。反应液浓缩后残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝15/1(体积比))，得(2-溴-4-溴甲基苯基)(2,3-二氯苯基)甲酮(820mg,两步收率99％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝446.9. To a solution of (2-bromo-4-(dibromomethyl)phenyl)(2,3-dichlorophenyl)methanone (600 mg, 1.20 mmol) in dichloromethane (15 mL) 660 mg, 4.78 mmol) and diisopropylethylamine (620 mg, 4.78 mmol). The reaction solution was stirred at room temperature for 1 hour. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 15 / 1 (volume ratio)) to give (2-bromo-4-bromomethylphenyl) (2,3-dichloro) Phenyl)methanone (820 mg, 99% yield in two steps) as a yellow solid. LCMS (ESI) [M+H] ⁺ = 446.9.

步骤5:(2-溴-4-((乙基砜)甲基)苯基)(2,3-二氯苯基)甲酮Step 5: (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(2,3-dichlorophenyl)methanone

向(2-溴-4-溴甲基苯基)(2,3-二氯苯基)甲酮(820mg,1.94mmol)的二甲亚砜(16mL)溶液中加入乙烷亚磺酸钠(450mg,3.88mmol)。反应液在室温下搅拌1小时。向反应液中加入乙酸乙酯(20mL)和水(20mL)，分离有机相。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝3/1(体积比))，得(2-溴-4-((乙基砜)甲基)苯基)(2,3-二氯苯基)甲酮(400mg,47％)。LCMS(ESI)[M+H] ⁺＝436.9. To a solution of (2-bromo-4-bromomethylphenyl)(2,3-dichlorophenyl)methanone (820 mg, 1.94 mmol) in dimethyl sulfoxide (16 mL) 450 mg, 3.88 mmol). The reaction solution was stirred at room temperature for 1 hour. Ethyl acetate (20 mL) and water (20 mL) were added to the mixture and the organic phase was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by flash chromatography (petrole ether / ethyl acetate = 3 / 1 (vol.)) to give (2-bromo-4-((ethylsulfonyl)methyl)phenyl) (2, 3- Dichlorophenyl)methanone (400 mg, 47%). LCMS (ESI) [M+H] ⁺ =436.9.

步骤6:(5-(2-(2,3-二氯苯甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯Step 6: (5-(2-(2,3-Dichlorobenzoyl)-5-(ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1,2-dihydro Pyridin-4-yl)methylcarbamic acid tert-butyl ester

将(2-溴-4-((乙基砜)甲基)苯基)(2,3-二氯苯基)甲酮(200mg,0.46mmol)，(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(184mg,0.50mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(33mg,0.05mmol)和碳酸钾(190mg,1.38mmol)混合于1,4-二氧六环(2mL)和水(0.1mL)中，在氮气保护下加热至95℃搅拌1小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝30/1(体积比))，得(5-(2-(2,3-二氯苯甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(80mg,29％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝592.9. (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(2,3-dichlorophenyl)methanone (200 mg, 0.46 mmol), (1-methyl-2-oxo- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl)methylcarbamic acid tert-butyl Ester (184 mg, 0.50 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (33 mg, 0.05 mmol) and potassium carbonate (190 mg, 1.38 mmol) were mixed in In 1,4-dioxane (2 mL) and water (0.1 mL), the mixture was heated to 95 ° C under nitrogen for 1 hour. The reaction solution was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography (ethyl ether/ethyl acetate=30/1 (vol.)) to give (5-(2-(2,3-dichlorobenzoyl)) -5-(ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methylcarbamic acid tert-butyl ester (80 mg, 29%) It is a yellow solid. LCMS (ESI) [M+H] ⁺ = 592.9.

步骤7:7-(2,3-二氯苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮Step 7: 7-(2,3-Dichlorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridin[ 3,4-e]azepin-3-one

向(5-(2-(2,3-二氯苯甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(80mg,0.13mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌1小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物7-(2,3-二氯苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(48.4mg,75％)，为白色固体。LCMS(ESI):[M+H] ⁺＝475.1,纯度100％(UV 214nm)； ¹H NMR(400MHz,DMSO-d ₆)δ8.11(s,1H),7.74-7.71(m,2H),7.50-7.48(m,2H),7.40-7.38(m,1H),7.07(d,J＝8.0Hz,1H),6.53(s,1H),4.79(d,J＝10.4Hz,1H),4.63(d,J＝13.6Hz,2H),4.00(d,J＝10.4Hz,1H),3.54(s,3H),3.10(q,J＝7.6Hz,2H),1.23(t,J＝7.6Hz,3H). To (5-(2-(2,3-dichlorobenzoyl)-5-(ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridine- To a solution of tert-butyl methylcarbamate (80 mg, 0.13 mmol) in dichloromethane (4 mL) The reaction solution was stirred at room temperature for 1 hour and concentrated. The residue was purified by preparative-HPLC to give the title compound 7-(2,3-dichlorophenyl)-10-((ethylsulfonyl)methyl)-2-methyl-2,5-dihydro-3H -Benzo[c]pyrido[3,4-e]azepin-3-one (48.4 mg, 75%) as a white solid. LCMS (ESI): [M+H] ⁺ = 475.1, purity 100% (UV 214nm); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.11 (s, 1H), 7.74-7.71 (m, 2H) , 7.50-7.48 (m, 2H), 7.40-7.38 (m, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.53 (s, 1H), 4.79 (d, J = 10.4 Hz, 1H), 4.63 (d, J = 13.6 Hz, 2H), 4.00 (d, J = 10.4 Hz, 1H), 3.54 (s, 3H), 3.10 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6) Hz, 3H).

4140:10-((乙基砜)甲基)-2-甲基-7-(2,4,6-三氟苯基)-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮4140: 10-((Ethyl sulfonyl)methyl)-2-methyl-7-(2,4,6-trifluorophenyl)-2,5-dihydro-3H-benzo[c]pyridine [3,4-e]azazo-3-one

步骤1:(2-溴-4-甲基苯基)(2,4,6-三氟苯基)甲醇Step 1: (2-Bromo-4-methylphenyl)(2,4,6-trifluorophenyl)methanol

将2-溴-1,3,5-三氟苯(210mg,1mmol)的四氢呋喃(3mL)溶液冷却至-20℃，然后缓慢加入异丙基氯化镁的四氢呋喃溶液(2M,0.5mL,1mmol)，并在此温度下搅拌3小时。将该溶液加入到2-溴-4-甲基苯甲醛(100mg,0.5mmol)的四氢呋喃(3mL)溶液中，反应液继续在室温下搅拌12小时。加入饱和氯化铵溶液淬灭反应，然后用乙酸乙酯萃取(10mL x 2)。合并有机相，用稀盐酸及饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/15(体积比))，得(2-溴-4-甲基苯基)(2,4,6-三氟苯基)甲醇(150mg,90％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝315.1. A solution of 2-bromo-1,3,5-trifluorobenzene (210 mg, 1 mmol) in tetrahydrofuran (3 mL) was cooled to -20 ° C, then isopropylmagnesium chloride in tetrahydrofuran (2M, 0.5 mL, 1 mmol). It was stirred at this temperature for 3 hours. This solution was added to a solution of 2-bromo-4-methylbenzaldehyde (100 mg, 0.5 mmol) in tetrahydrofurane (3 mL). The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate (10 mL). The organic phase was combined, washed with EtOAc EtOAc (EtOAc m. 2-Bromo-4-methylphenyl)(2,4,6-trifluorophenyl)methanol (150 mg, 90%) LCMS (ESI) [M+H] ⁺ = 315.1.

步骤2:(2-溴-4-甲基苯基)(2,4,6-三氟苯基)甲酮Step 2: (2-Bromo-4-methylphenyl)(2,4,6-trifluorophenyl)methanone

将(2-溴-4-甲基苯基)(2,4,6-三氟苯基)甲醇(800mg,2.55mmol)和Dess-Martin氧化剂(1.6g,3.83mmol)混合于二氯甲烷(10mL)中，在室温下搅拌1小时。将反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/20(体积比))，得(2-溴-4-甲基苯基)(2,4,6-三氟苯基)甲酮(760mg,95％)，为无色油状物。LCMS(ESI)[M+H] ⁺＝331.0 (2-Bromo-4-methylphenyl)(2,4,6-trifluorophenyl)methanol (800 mg, 2.55 mmol) and Dess-Martin oxidant (1.6 g, 3.83 mmol) were mixed in dichloromethane ( In 10 mL), the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated, and the residue was purified by flash chromatography (ethyl acetate / petroleum ether = 1 / 20 (by volume)) to give (2-bromo-4-methylphenyl) (2, 4) , 6-trifluorophenyl)methanone (760 mg, 95%) as a colorless oil. LCMS (ESI) [M+H] ⁺ = 331.0

步骤3:(2-溴-4-二溴甲基苯基)(2,4,6-三氟苯基)甲酮Step 3: (2-Bromo-4-dibromomethylphenyl)(2,4,6-trifluorophenyl)methanone

将N-溴代丁二酰亚胺(1.64g,9.2mmol)，偶氮二异丁腈(120mg,0.46mmol)和(2-溴-4-甲基苯基)(2,4,6-三氟苯基)甲酮(760mg,2.3mmol)混合于四氯化碳(10mL)中，并加热至80℃搅拌12小时。将反应液过滤后浓缩，得(2-溴-4-二溴甲基苯基)(2,4,6-三氟苯基)甲酮 (粗产物，600mg,53％)，为黄色固体。N-bromosuccinimide (1.64 g, 9.2 mmol), azobisisobutyronitrile (120 mg, 0.46 mmol) and (2-bromo-4-methylphenyl) (2,4,6- Trifluorophenyl)methanone (760 mg, 2.3 mmol) was mixed in carbon tetrachloride (10 mL) and heated to 80 ° C for 12 hours. The reaction mixture was filtered and evaporated to give crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal

步骤4:(2-溴-4-溴甲基苯基)(2,4,6-三氟苯基)甲酮Step 4: (2-Bromo-4-bromomethylphenyl)(2,4,6-trifluorophenyl)methanone

向(2-溴-4-二溴甲基苯基)(2,4,6-三氟苯基)甲酮(600mg,1.2mmol)的二氯甲烷(20mL)溶液加入亚磷酸二乙酯(169mg,1.8mmol)和二异丙基乙胺(475mg,3.68mmol)。反应液在室温下搅拌1小时。反应液浓缩后残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝15/1(体积比))，得(2-溴-4-溴甲基苯基)(2,4,6-三氟苯基)甲酮(410mg,70％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝428.0. To a solution of (2-bromo-4-dibromomethylphenyl)(2,4,6-trifluorophenyl)methanone (600 mg, 1.2 mmol) in dichloromethane (20 mL) 169 mg, 1.8 mmol) and diisopropylethylamine (475 mg, 3.68 mmol). The reaction solution was stirred at room temperature for 1 hour. After the reaction mixture was concentrated, the residue was purified by flash chromatography ( petroleum ether / ethyl acetate=15/1 (vol.) to give (2-bromo-4-bromomethylphenyl) (2,4,6-) Trifluorophenyl)methanone (410 mg, 70%) was obtained as a yellow solid. LCMS (ESI) [M+H] ⁺ = 428.0.

步骤5:(2-溴-4-((乙基砜)甲基)苯基)(2,4,6-三氟苯基)甲酮Step 5: (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(2,4,6-trifluorophenyl)methanone

向(2-溴-4-溴甲基苯基)(2,4,6-三氟苯基)甲酮(1.2g,2.72mmol)的二甲亚砜(10mL)溶液中加入乙烷亚磺酸钠(290mg,2.5mmol)。反应液在室温下搅拌1小时。向反应液中加入乙酸乙酯(20mL)和水(20mL)，分离有机相。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝3/1)，得(2-溴-4-((乙基砜)甲基)苯基)(2,4,6-三氟苯基)甲酮(230mg,44％)。LCMS(ESI)[M+H] ⁺＝423.0. Add ethane sulfin to a solution of (2-bromo-4-bromomethylphenyl)(2,4,6-trifluorophenyl)methanone (1.2 g, 2.72 mmol) in dimethyl sulfoxide (10 mL) Sodium (290 mg, 2.5 mmol). The reaction solution was stirred at room temperature for 1 hour. Ethyl acetate (20 mL) and water (20 mL) were added to the mixture and the organic phase was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by flash chromatography (peel ether / ethyl acetate = 3 / 1) to give (2-bromo-4-((ethyl sulfonyl)methyl)phenyl) (2,4,6-trifluoro) Phenyl) ketone (230 mg, 44%). LCMS (ESI) [M+H] ⁺ = 423.0.

步骤6:((5-(5-((乙基砜)甲基)-2-(2,4,6-三氟苯甲酰基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯Step 6: ((5-(5-((ethylsulfonyl)methyl)-2-(2,4,6-trifluorobenzoyl)phenyl)-1-methyl-2-oxo-1 , 2-dihydropyridin-4-yl)methylcarbamic acid tert-butyl ester

将(2-溴-4-((乙基砜)甲基)苯基)(2,4,6-三氟苯基)甲酮(84mg,0.2mmol)，(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(110mg,0.3mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(29mg,0.04mmol)和碳酸钾(127mg,0.6mmol)混合于1,4-二氧六环(4mL)和水(0.4mL)中，在氮气保护下加热至95℃搅拌1小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝10/1(体积比))，得((5-(5-((乙基砜)甲基)-2-(2,4,6-三氟苯甲酰基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(65mg,55％)。LCMS(ESI)[M+H] ⁺＝579.2. (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(2,4,6-trifluorophenyl)methanone (84 mg, 0.2 mmol), (1-methyl-2-oxo -5-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl)methylcarbamic acid tert-Butyl ester (110 mg, 0.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (29 mg, 0.04 mmol) and potassium carbonate (127 mg, 0.6 mmol) It was mixed with 1,4-dioxane (4 mL) and water (0.4 mL), and heated to 95 ° C under nitrogen for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated, and the residue was purified by flash chromatography ( petroleum ether / ethyl acetate = 10/1 (volume ratio) to give ((5-(5-((ethylsulfonyl)methyl))) 2-(2,4,6-Trifluorobenzoyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methylcarbamic acid tert-butyl ester (65 mg , 55%). LCMS (ESI) [M+H] ⁺ = 579.2.

步骤7:10-((乙基砜)甲基)-2-甲基-7-(2,4,6-三氟苯基)-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮Step 7: 10-((Ethyl sulfonyl)methyl)-2-methyl-7-(2,4,6-trifluorophenyl)-2,5-dihydro-3H-benzo[c]pyridine And [3,4-e]azepin-3-one

向((5-(5-((乙基砜)甲基)-2-(2,4,6-三氟苯甲酰基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(65mg,0.11mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌1小时并浓缩。残余物用制备-HPLC分离纯化，得10-((乙基砜)甲基)-2-甲基-7-(2,4,6-三氟苯基)-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(11.9mg,24％)，为白色固体。LCMS(ESI):[M+H] ⁺＝461.1,纯度100％(UV 214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.16(s,1H),7.79(d,J＝1.6Hz,1H),7.53(d,J＝8.0Hz,1H),7.33(d,J＝8.0Hz,2H),6.98-7.01(m,2H),6.66(s,1H),4.85-4.87(m,1H),4.56-4.59(m,2H),4.18(d,J＝10.8Hz,1H),3.70(s,3H),3.15(q,J＝7.6Hz,2H),1.39(t,J＝7.6Hz,3H). To ((5-(5-((ethylsulfonyl)methyl)-2-(2,4,6-trifluorobenzoyl)phenyl)-1-methyl-2-oxo-1,2 To a solution of tert-butyl dihydropyridin-4-yl)methylcarbamate (65 mg, 0.11 mmol) in dichloromethane (4 mL). The residue was purified by preparative-HPLC to give 10-((ethylsulfonyl)methyl)-2-methyl-7-(2,4,6-trifluorophenyl)-2,5-dihydro-3H. -Benzo[c]pyrido[3,4-e]azepin-3-one (11.9 mg, 24%) as a white solid. LCMS (ESI): [M+H] ⁺ = 461.1, purity 100 % (UV 214nm); ¹ H NMR (400MHz, CD ₃ OD) δ 8.16 (s, 1H), 7.79 (d, J = 1.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 2H), 6.98-7.01 (m, 2H), 6.66 (s, 1H), 4.85-4.87 (m, 1H), 4.56-4.59 (m, 2H), 4.18 (d, J) = 10.8 Hz, 1H), 3.70 (s, 3H), 3.15 (q, J = 7.6 Hz, 2H), 1.39 (t, J = 7.6 Hz, 3H).

4141:7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-9-氟-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮4141: 7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-9-fluoro-2-methyl-2,5-dihydro-3H-benzo[c Pyridine[3,4-e]azepin-3-one

步骤1:(2-溴-5-氟-4-甲基苯基)(2-氯-4-氟苯基)甲醇Step 1: (2-Bromo-5-fluoro-4-methylphenyl)(2-chloro-4-fluorophenyl)methanol

将2-氯-4-氟-1-碘苯(1.8g,6.91mmol)的四氢呋喃(20mL)溶液冷却至-20℃，然后缓慢加入异丙基氯化镁的四氢呋喃溶液(2M,3.5mL,7.0mmol)，搅拌3小时。向反应瓶中加入2-溴-5-氟-4-甲基苯甲醛(500mg,2.3mmol)的四氢呋喃(5mL)溶液，反应液继续在室温下搅拌12小时。加入饱和氯化铵溶液淬灭反应，然后用乙酸乙酯萃取(20mL x 3)。合并有机相，用稀盐酸及饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/8(体积比))，得(2-溴-5-氟-4-甲基苯基)(2-氯-4-氟苯基)甲醇(250mg,31％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝330.9. A solution of 2-chloro-4-fluoro-1-iodobenzene (1.8 g, 6.91 mmol) in tetrahydrofuran (20 mL) was cooled to -20 ° C, then isopropylmagnesium chloride in tetrahydrofuran (2M, 3.5 mL, 7.0 mmol) ), stirring for 3 hours. A solution of 2-bromo-5-fluoro-4-methylbenzaldehyde (500 mg, 2.3 mmol) in tetrahydrofuran (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 12 hr. The reaction was quenched by the addition of aq. EtOAc (EtOAc) The organic phase was combined, washed with aq. EtOAc EtOAc EtOAc (EtOAc m. 2-Bromo-5-fluoro-4-methylphenyl)(2-chloro-4-fluorophenyl)methanol (250 mg, 31%). LCMS (ESI) [M+H] ⁺ = 330.9.

步骤2:(2-溴-5-氟-4-甲基苯基)(2-氯-4-氟苯基)甲酮Step 2: (2-Bromo-5-fluoro-4-methylphenyl)(2-chloro-4-fluorophenyl)methanone

将(2-溴-5-氟-4-甲基苯基)(2-氯-4-氟苯基)甲醇(250mg,0.72mmol)和Dess-Martin氧化剂(460mg,1.08mmol)混合于二氯甲烷(6mL)中，在室温下搅拌1小时。将反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/10(体积比))，得(2-溴-5-氟-4-甲基苯基)(2-氯-4-氟苯基)甲酮(450mg,100％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝366.0. Mixing (2-bromo-5-fluoro-4-methylphenyl)(2-chloro-4-fluorophenyl)methanol (250 mg, 0.72 mmol) and Dess-Martin oxidant (460 mg, 1.08 mmol) in dichloro Methane (6 mL) was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated, and the residue was purified by flash chromatography (ethyl acetate / petroleum ether = 1/10 (by volume)) to give (2-bromo-5-fluoro-4-methylphenyl) (2-Chloro-4-fluorophenyl)methanone (450 mg, 100%) as a yellow solid. LCMS (ESI) [M+H] ⁺ = 366.0.

步骤3:(2-溴-4-二溴甲基-5-氟苯基)(2-氯-4-氟苯基)甲酮Step 3: (2-Bromo-4-dibromomethyl-5-fluorophenyl)(2-chloro-4-fluorophenyl)methanone

将N-溴代丁二酰亚胺(930mg,5.21mmol)，偶氮二异丁腈(43mg,0.26mmol)和(2-溴-5-氟-4-甲基苯基)(2-氯-4-氟苯基)甲酮(450mg,1.30mmol)混合于四氯化碳(30mL)中，加热至90℃搅拌12小时。将反应液浓缩，得(2-溴-4-二溴甲基-5-氟苯基)(2-氯-4-氟苯基)甲酮粗产物(500mg)，为黄色固体。LCMS(ESI)[M+H] ⁺＝524.0. N-bromosuccinimide (930 mg, 5.21 mmol), azobisisobutyronitrile (43 mg, 0.26 mmol) and (2-bromo-5-fluoro-4-methylphenyl) (2-chloro) 4-fluorophenyl)methanone (450 mg, 1.30 mmol) was mixed with carbon tetrachloride (30 mL), and stirred at 90 ° C for 12 hours. The reaction mixture was concentrated to give (2-bromo-4-dibromomethyl-5-fluorophenyl)(2-chloro-4-fluorophenyl)methanone as a crude product (500 mg). LCMS (ESI) [M+H] ⁺ = 524.0.

步骤4:(2-溴-4-溴甲基-5-氟苯基)(2-氯-4-氟苯基)甲酮Step 4: (2-Bromo-4-bromomethyl-5-fluorophenyl)(2-chloro-4-fluorophenyl)methanone

向(2-溴-4-二溴甲基-5-氟苯基)(2-氯-4-氟苯基)甲酮(500mg,0.99mmol)的二氯甲烷(6mL)溶液加入亚磷酸二乙酯(550mg,3.97mmol)和二异丙基乙胺(515mg,3.97mmol)。反应液在室温下搅拌1小时。反应液浓缩后残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝15/1(体积比))，得(2-溴-4-溴甲基-5-氟苯基)(2-氯-4-氟苯基)甲酮(450mg,两步收率99％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝445.0. To a solution of (2-bromo-4-dibromomethyl-5-fluorophenyl)(2-chloro-4-fluorophenyl)methanone (500 mg, 0.99 mmol) in dichloromethane (6 mL) Ethyl ester (550 mg, 3.97 mmol) and diisopropylethylamine (515 mg, 3.97 mmol). The reaction solution was stirred at room temperature for 1 hour. The residue was purified by flash chromatography (petroleum ether / ethyl acetate = 15 / 1 (volume ratio)) to give (2-bromo-4-bromomethyl-5-fluorophenyl) (2- Chloro-4-fluorophenyl)methanone (450 mg, 99% yield in two steps) as a yellow solid. LCMS (ESI) [M+H] ⁺ = 445.0.

步骤5:(2-溴-4-((乙基砜)甲基)-5-氟苯基)(2-氯-4-氟苯基)甲酮Step 5: (2-Bromo-4-((ethylsulfonyl)methyl)-5-fluorophenyl)(2-chloro-4-fluorophenyl)methanone

向(2-溴-4-溴甲基-5-氟苯基)(2-氯-4-氟苯基)甲酮(450mg,1.06mmol)的二甲亚砜(6mL)溶液中加入乙基亚磺酸钠(246mg,2.12mmol)。反应液在室温下搅拌1小时。向反应液中加入乙酸乙酯(20mL)和水(20mL)，分离有机相。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝3/1(体积比))，得(2-溴-4-((乙基砜)甲基)-5-氟苯基)(2-氯-4-氟苯基)甲酮(200mg,43％)。LCMS(ESI)[M+H] ⁺＝438.8. Add ethyl (2-bromo-4-bromomethyl-5-fluorophenyl)(2-chloro-4-fluorophenyl)methanone (450 mg, 1.06 mmol) in dimethyl sulfoxide (6 mL) Sodium sulfinate (246 mg, 2.12 mmol). The reaction solution was stirred at room temperature for 1 hour. Ethyl acetate (20 mL) and water (20 mL) were added to the mixture and the organic phase was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by flash chromatography (petrole ether / ethyl acetate = 3 / 1 (volume ratio)) to give (2-bromo-4-((ethylsulfonyl)methyl)-5-fluorophenyl) 2-Chloro-4-fluorophenyl)methanone (200 mg, 43%). LCMS (ESI) [M+H] ⁺ =438.8.

步骤6:(5-(2-(2-氯-4-氟苯甲酰基)-5-(乙基砜甲基)-4-氟苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯Step 6: (5-(2-(2-Chloro-4-fluorobenzoyl)-5-(ethylsulfonylmethyl)-4-fluorophenyl)-1-methyl-2-oxo-1 , 2-dihydropyridin-4-yl)methylcarbamic acid tert-butyl ester

将(2-溴-4-((乙基砜)甲基)-5-氟苯基)(2-氯-4-氟苯基)甲酮(100mg,0.23mmol)，(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(100mg,0.27mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(17mg,0.02mmol)和碳酸钾(95mg,0.69mmo)混合于1,4-二氧六环(1mL)和水(0.05mL)中，在氮气保护下加热至95℃搅拌1小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝30/1(体积比))，得(5-(2-(2-氯-4-氟苯甲酰基)-5-(乙基砜甲基)-4-氟苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(80mg,58％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝594.9. (2-Bromo-4-((ethylsulfonyl)methyl)-5-fluorophenyl)(2-chloro-4-fluorophenyl)methanone (100 mg, 0.23 mmol), (1-methyl- 2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl) Tert-butyl carbamate (100 mg, 0.27 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (17 mg, 0.02 mmol) and potassium carbonate (95 mg, 0.69 mmol) was mixed with 1,4-dioxane (1 mL) and water (0.05 mL), and heated to 95 ° C under nitrogen for 1 hour. The reaction solution was filtered, and the filtrate was concentrated. The residue was purified and purified by flash chromatography ( petroleum ether / ethyl acetate = 30/1 (volume ratio) to give (5-(2-(2-chloro-4-fluorobenzoyl)) -5-(ethylsulfonylmethyl)-4-fluorophenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methylcarbamic acid tert-butyl ester (80 mg , 58%), as a yellow solid. LCMS (ESI) [M+H] ⁺ = 594.9.

步骤7:7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-9-氟-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮Step 7: 7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-9-fluoro-2-methyl-2,5-dihydro-3H-benzo[ c] Pyrido[3,4-e]azepin-3-one

向(5-(2-(2-氯-4-氟苯甲酰基)-5-(乙基砜甲基)-4-氟苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(80mg,0.13mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌1小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-9-氟-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(31.4mg,49％)，为白色固体。LCMS(ESI):[M+H] ⁺＝477.0,纯度100％(UV 214nm)； ¹H NMR(400MHz,DMSO-d ₆)δ8.08(s,1H),7.80(d,J＝6.8Hz,1H),7.64(t,J＝6.4Hz,1H),7.46-7.43(m,1H),7.38-7.36(m,1H),6.91(d,J＝10.0Hz,1H),6.54(s,1H),4.81(d,J＝10.8Hz,1H),4.71(d,J＝13.6Hz,1H),4.52(d,J＝14.0Hz,1H),4.00(d,J＝10.4Hz,1H),3.53(s,3H),3.24-3.18(m,2H),1.29(t,J＝7.2Hz,3H). To (5-(2-(2-chloro-4-fluorobenzoyl)-5-(ethylsulfonylmethyl)-4-fluorophenyl)-1-methyl-2-oxo-1,2 To a solution of tert-butyl dihydropyridin-4-yl)methylcarbamate (80 mg, 0.13 mmol) in dichloromethane (4 mL) The reaction solution was stirred at room temperature for 1 hour and concentrated. The residue was purified by preparative EtOAc (EtOAc-EtOAc) -Dihydro-3H-benzo[c]pyrido[3,4-e]azepin-3-one (31.4 mg, 49%) as a white solid. LCMS (ESI): [M+H] ⁺ = 477.0, purity 100% (UV 214nm); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.08 (s, 1H), 7.80 (d, J = 6.8 Hz) , 1H), 7.64 (t, J = 6.4 Hz, 1H), 7.46-7.43 (m, 1H), 7.38-7.36 (m, 1H), 6.91 (d, J = 10.0 Hz, 1H), 6.54 (s, 1H), 4.81 (d, J = 10.8 Hz, 1H), 4.71 (d, J = 13.6 Hz, 1H), 4.52 (d, J = 14.0 Hz, 1H), 4.00 (d, J = 10.4 Hz, 1H) , 3.53 (s, 3H), 3.24 - 3.18 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H).

4142:N-(9-氯-7-(2-氯-4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙基磺酰胺4142: N-(9-chloro-7-(2-chloro-4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridin[ 3,4-e]azepine-10-yl)ethylsulfonamide

步骤1:(3-溴-4-((2-氯-4-氟苯基)(羟基)甲基)苯基)氨基甲酸叔丁酯Step 1: (3-Bromo-4-((2-chloro-4-fluorophenyl)(hydroxy)methyl)phenyl)carbamic acid tert-butyl ester

将2-氯-4-氟-1-碘苯(7.30g,28.5mmol)的四氢呋喃(25mL)溶液冷却至-20℃，然后缓慢加入异丙基氯化镁的四氢呋喃溶液(2M,14.4mL,28.8mmol)，搅拌3小时。向反应瓶中加入(3-溴-4-甲酰苯基)氨基甲酸叔丁酯(2.85g,9.5mmol)的四氢呋喃(5mL)溶液，反应液继续在室温下搅拌12小时。加入饱和氯化铵溶液淬灭反应，然后用乙酸乙酯萃取(20mL x 3)。合并有机相，用稀盐酸及饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/8(体积比))，得(3-溴-4-((2-氯-4-氟苯基)(羟基)甲基)苯基)氨基甲酸叔丁酯(2.5g,62％)，为黄色固体。A solution of 2-chloro-4-fluoro-1-iodobenzene (7.30 g, 28.5 mmol) in tetrahydrofuran (25 mL) was cooled to -20 ° C, then isopropylmagnesium chloride in tetrahydrofuran (2M, 14.4 mL, 28.8 mmol) ), stirring for 3 hours. A solution of (3-bromo-4-formylphenyl)carbamic acid tert-butyl ester (2.85 g, 9.5 mmol) in tetrahydrofuran (5 mL) was evaporated. The reaction was quenched by the addition of aq. EtOAc (EtOAc) The organic phase was combined, washed with aq. EtOAc EtOAc EtOAc (EtOAc m. tert-Butyl 3-bromo-4-((2-chloro-4-fluorophenyl)(hydroxy)methyl)phenyl)carbamate (2.5 g, 62%).

步骤2:(3-溴-4-((2-氯-4-氟苯甲酰基)苯基)氨基甲酸叔丁酯Step 2: (3-Bromo-4-((2-chloro-4-fluorobenzoyl)phenyl)carbamic acid tert-butyl ester

将(3-溴-4-((2-氯-4-氟苯基)(羟基)甲基)苯基)氨基甲酸叔丁酯(2.5g,5.8mmol)和Dess-Martin氧化剂(7.38g,17.4mmol)混合于二氯甲烷(10mL)中，在室温下搅拌1小时。将反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/10(体积比))，得(3-溴-4-((2-氯-4-氟苯甲酰基)苯基)氨基甲酸叔丁酯(2.4g,97％)，为黄色固体。tert-Butyl 3-bromo-4-((2-chloro-4-fluorophenyl)(hydroxy)methyl)phenyl)carbamate (2.5 g, 5.8 mmol) and Dess-Martin oxidant (7.38 g, 17.4 mmol) was mixed with dichloromethane (10 mL) and stirred at room temperature for 1 hour. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by flash chromatography (ethyl acetate / petroleum ether = 1/10 (volume ratio)) to give (3-bromo-4-((2-chloro-4-fluoro) tert-Butyl benzoyl)phenyl)carbamate (2.4 g, 97%) as a yellow solid.

步骤3:(5-溴-2-氯-4-(2-氯-4-氟苯甲酰基)苯基)氨基甲酸叔丁酯Step 3: (5-Bromo-2-chloro-4-(2-chloro-4-fluorobenzoyl)phenyl)carbamic acid tert-butyl ester

将N-氯代丁二酰亚胺(2.2g,16.8mmol)和(3-溴-4-((2-氯-4-氟苯甲酰基)苯基)氨基甲酸叔丁酯(2.4g,5.6mmol)混合于乙腈(50mL)中，加热至90℃搅拌12小时。将反应液浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/8(体积比))，得(5-溴-2-氯-4-(2-氯-4-氟苯甲酰基)苯基)氨基甲酸叔丁酯(2.1g,81％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝463.9. N-chlorosuccinimide (2.2 g, 16.8 mmol) and (3-bromo-4-((2-chloro-4-fluorobenzoyl)phenyl)carbamic acid tert-butyl ester (2.4 g, 5.6 mmol), mixed with acetonitrile (50 mL), heated to 90 ° C for 12 hours. The reaction was concentrated and the residue was purified by flash chromatography (ethyl acetate / petroleum ether = 1 / 8 (volume ratio)) (5-Bromo-2-chloro-4-(2-chloro-4-fluorobenzoyl)phenyl)carbamic acid tert-butyl ester (2.1 g, 81%) as a yellow solid. LCMS (ESI) H] ⁺ = 463.9.

步骤4:(4-氨基-2-溴-5-氯苯基)(2-氯-4-氟苯基)甲酮Step 4: (4-Amino-2-bromo-5-chlorophenyl)(2-chloro-4-fluorophenyl)methanone

将(5-溴-2-氯-4-(2-氯-4-氟苯甲酰基)苯基)氨基甲酸叔丁酯(2.1g,4.5mmol)和盐酸(4M的二氧六环溶液,20mL)的混合液在室温下搅拌12小时。反应液浓缩，得(4-氨基-2-溴-5-氯苯基)(2-氯-4-氟苯基)甲酮(1.65g,100％)，为白色固体。LCMS(ESI)[M+H] ⁺＝363.9. tert-Butyl (5-bromo-2-chloro-4-(2-chloro-4-fluorobenzoyl)phenyl)carbamate (2.1 g, 4.5 mmol) and hydrochloric acid (4M in dioxane, A mixture of 20 mL) was stirred at room temperature for 12 hours. The reaction mixture was concentrated to give (4-amino-2-bromo-5-chlorophenyl)(2-chloro-4-fluorophenyl)methanone (1.65 g, 100%) as white solid. LCMS (ESI) [M+H] ⁺ = 363.9.

步骤5:N-(5-溴-2-氯-4-(2-氯-4-氟苯甲酰基)苯基)-N-(乙基磺酰基)乙基磺酰胺Step 5: N-(5-Bromo-2-chloro-4-(2-chloro-4-fluorobenzoyl)phenyl)-N-(ethylsulfonyl)ethylsulfonamide

向(4-氨基-2-溴-5-氯苯基)(2-氯-4-氟苯基)甲酮(1.65g,4.5mmol)的二氯甲烷(30mL)溶液中加入三乙胺(4.6g,45.0mmol)和乙基磺酰氯(5.8g,45.0mmol)。反应液在室温下搅拌12小时。向反应液中加入二氯甲烷(20mL)和水(50mL)，分离有机相。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。得N-(5-溴-2-氯-4-(2-氯-4-氟苯甲酰基)苯基)-N-(乙基磺酰基)乙基磺酰胺(1.81g,72％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝546.0. To a solution of (4-amino-2-bromo-5-chlorophenyl)(2-chloro-4-fluorophenyl)methanone (1.65 g, 4.5 mmol) in dichloromethane (30 mL) 4.6 g, 45.0 mmol) and ethylsulfonyl chloride (5.8 g, 45.0 mmol). The reaction solution was stirred at room temperature for 12 hours. Dichloromethane (20 mL) and water (50 mL) were added to the mixture and the organic phase was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate N-(5-Bromo-2-chloro-4-(2-chloro-4-fluorobenzoyl)phenyl)-N-(ethylsulfonyl)ethylsulfonamide (1.81 g, 72%). It is a yellow solid. LCMS (ESI) [M+H] ⁺ = 546.0.

步骤6:N-(5-溴-2-氯-4-(2-氯-4-氟苯甲酰基)苯基)乙基磺酰胺Step 6: N-(5-Bromo-2-chloro-4-(2-chloro-4-fluorobenzoyl)phenyl)ethylsulfonamide

向N-(5-溴-2-氯-4-(2-氯-4-氟苯甲酰基)苯基)-N-(乙基磺酰基)乙基磺酰胺(1.81g,3.3mmol)的四氢呋喃(50mL)溶液中加入10％氢氧化钠水溶液(5mL)。反应液在室温下搅拌0.5小时。向反应液中加入乙酸乙酯(10mL)和水(10mL)，分离有机相。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝2/1(体积比))，得N-(5-溴-2-氯-4-(2-氯-4-氟苯甲酰基)苯基)乙基磺酰胺(1.1g,73％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝453.9. To N-(5-bromo-2-chloro-4-(2-chloro-4-fluorobenzoyl)phenyl)-N-(ethylsulfonyl)ethylsulfonamide (1.81 g, 3.3 mmol) A 10% aqueous solution of sodium hydroxide (5 mL) was added to a solution of tetrahydrofuran (50 mL). The reaction solution was stirred at room temperature for 0.5 hour. Ethyl acetate (10 mL) and water (10 mL) were added to the mixture and the organic phase was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by flash chromatography (peel ether / ethyl acetate = 2 / 1 (vol.)) to give N-(5-bromo-2-chloro-4-(2-chloro-4-fluorobenzoyl) Phenyl)ethylsulfonamide (1.1 g, 73%) as a yellow solid. LCMS (ESI) [M+H] ⁺ = 453.9.

步骤7:((5-(4-氯-2-(2-氯-4-氟苯甲酰基)-5-(乙基磺酰胺基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯Step 7: ((5-(4-Chloro-2-(2-chloro-4-fluorobenzoyl)-5-(ethylsulfonamido)phenyl)-1-methyl-2-oxo- Tert-butyl 1,2-dihydropyridin-4-yl)methyl)carbamate

将N-(5-溴-2-氯-4-(2-氯-4-氟苯甲酰基)苯基)乙基磺酰胺(400mg,0.88mmol)，(1-甲基 -2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(320mg,0.88mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(65mg,0.08mmol)和碳酸钾(365mg,2.64mmol)混合于1,4-二氧六环(5mL)和水(0.5mL)中，在氮气保护下加热至95℃搅拌1小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝30/1(体积比))，得((5-(4-氯-2-(2-氯-4-氟苯甲酰基)-5-(乙基磺酰胺基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(100mg,19％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝612.0. N-(5-Bromo-2-chloro-4-(2-chloro-4-fluorobenzoyl)phenyl)ethylsulfonamide (400 mg, 0.88 mmol), (1-methyl-2-oxo) -5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl)methylcarbamic acid Butyl ester (320 mg, 0.88 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (65 mg, 0.08 mmol) and potassium carbonate (365 mg, 2.64 mmol) The mixture was heated to 95 ° C under a nitrogen atmosphere for 1 hour in 1,4-dioxane (5 mL) and water (0.5 mL). The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjj -fluorobenzoyl)-5-(ethylsulfonamido)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)carbamic acid tert-butyl ester (100 mg, 19%) as a yellow oil. LCMS (ESI) [M+H] ⁺ = 612.0.

步骤8:N-(9-氯-7-(2-氯-4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙基磺酰胺Step 8: N-(9-Chloro-7-(2-chloro-4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)ethylsulfonamide

向((5-(4-氯-2-(2-氯-4-氟苯甲酰基)-5-(乙基磺酰胺基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(100mg,0.16mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌12小时并浓缩。残余物用制备-HPLC分离纯化，得N-(9-氯-7-(2-氯-4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙基磺酰胺(13.6mg,17％)，为白色固体。LCMS(ESI):[M+H] ⁺＝494.0,purity 100％(UV 214nm)； ¹H NMR(400MHz,DMSO-d ₆)δ8.11(s,1H),7.62-7.58(m,2H),7.71-7.38(m,1H),7.33-7.30(m,1H),6.92(s,1H),6.50(s,1H),4.75(d,J＝10.4Hz,1H),3.89(d,J＝10.8Hz,1H),3.52(s,3H),3.21(q,J＝7.2Hz,2H),1.28(t,J＝7.2Hz,3H). To ((5-(4-chloro-2-(2-chloro-4-fluorobenzoyl)-5-(ethylsulfonamido)phenyl)-1-methyl-2-oxo-1, To a solution of tert-butyl 2-dihydropyridin-4-yl)methyl)carbamate (100 mg, 0.16 mmol) in dichloromethane (4 mL) The reaction solution was stirred at room temperature for 12 hours and concentrated. The residue was purified by preparative-HPLC to give N-(9-chloro-7-(2-chloro-4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H- Benzo[c]pyrido[3,4-e]azepin-10-yl)ethylsulfonamide (13.6 mg, 17%) as a white solid. LCMS (ESI): [M+H] ⁺ = 494.0, Purity 100% (UV 214nm); ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.11 (s, 1H), 7.62-7.58 (m, 2H) , 7.71-7.38 (m, 1H), 7.33-7.30 (m, 1H), 6.92 (s, 1H), 6.50 (s, 1H), 4.75 (d, J = 10.4 Hz, 1H), 3.89 (d, J) = 10.8 Hz, 1H), 3.52 (s, 3H), 3.21 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H).

4143:7-(3-氯-5-氟吡啶-2-基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮4143: 7-(3-Chloro-5-fluoropyridin-2-yl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c] Pyrido[3,4-e]azepin-3-one

步骤1:(2-溴-4-甲基苯基)(3-氯-5-氟吡啶-2-基)甲醇Step 1: (2-Bromo-4-methylphenyl)(3-chloro-5-fluoropyridin-2-yl)methanol

将2-溴-3-氯-5-氟吡啶(210mg,1mmol)的四氢呋喃(3mL)溶液冷却至-20℃，然后缓慢加入异丙基氯化镁的四氢呋喃溶液(2M,0.5mL,1mmol)，并在此温度下搅拌3小时。将该溶液慢慢滴加到2-溴-4-甲基苯甲醛(100mg,0.5mmol)的四氢呋喃(3mL)溶液，反应液继续在室温下搅拌12小时。加入饱和氯化铵溶液淬灭反应，然后用乙酸乙酯萃取(10mL x 2)。合并有机相，用稀盐酸及饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/15(体积比))，得(2-溴-4-甲基苯基)(3-氯-5-氟吡啶-2-基)甲醇(90mg,55％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝331.9. A solution of 2-bromo-3-chloro-5-fluoropyridine (210 mg, 1 mmol) in tetrahydrofuran (3 mL) was cooled to -20 ° C, then isopropylmagnesium chloride in tetrahydrofuran (2M, 0.5 mL, 1 mmol) Stir at this temperature for 3 hours. The solution was slowly added dropwise to a solution of 2-bromo-4-methylbenzaldehyde (100 mg, 0.5 mmol) in THF (3 mL). The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate (10 mL). The organic phase was combined, washed with EtOAc EtOAc (EtOAc m. 2-Bromo-4-methylphenyl)(3-chloro-5-fluoropyridin-2-yl)methanol (90 mg, 55%). LCMS (ESI) [M+H] ⁺ = 331.9.

步骤2:(2-溴-4-甲基苯基)(3-氯-5-氟吡啶-2-基)甲酮Step 2: (2-Bromo-4-methylphenyl)(3-chloro-5-fluoropyridin-2-yl)methanone

将(2-溴-4-甲基苯基)(3-氯-5-氟吡啶-2-基)甲醇(910mg,2.75mmol)和Dess-Martin氧化剂(2.4g,5.5mmol)混合于二氯甲烷(20mL)中，在室温下搅拌2小时。将反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/20(体积比))，得(2-溴-4-甲基苯基)(3-氯-5-氟吡啶-2-基)甲酮(600mg,66％)，为无色油状物。LCMS(ESI)[M+H] ⁺＝330.0 Mixing (2-bromo-4-methylphenyl)(3-chloro-5-fluoropyridin-2-yl)methanol (910 mg, 2.75 mmol) and Dess-Martin oxidizing agent (2.4 g, 5.5 mmol) in dichloro Methane (20 mL) was stirred at room temperature for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by flash chromatography (ethyl acetate / petroleum ether = 1 / 20 (volume ratio) to give (2-bromo-4-methylphenyl) (3-chloro) -5-Fluoropyridin-2-yl)methanone (600 mg, 66%) as a colorless oil. LCMS (ESI) [M+H] ⁺ = 330.0

步骤3:(2-溴-4-二溴甲基苯基)(3-氯-5-氟吡啶-2-基)甲酮Step 3: (2-Bromo-4-dibromomethylphenyl)(3-chloro-5-fluoropyridin-2-yl)methanone

将N-溴代丁二酰亚胺(1.3g,7.32mmol)，偶氮二异丁腈(97mg,0.37mmol)和(2-溴-4-甲基苯基)(3-氯-5-氟吡啶-2-基)甲酮(600mg,1.83mmol)混合于四氯化碳(10mL)中，并加热至80℃搅拌12小时。将反应液过滤，滤液浓缩，得(2-溴-4-二溴甲基苯基)(3-氯-5-氟吡啶-2-基)甲酮(600mg,67％)，为黄色固体。N-bromosuccinimide (1.3 g, 7.32 mmol), azobisisobutyronitrile (97 mg, 0.37 mmol) and (2-bromo-4-methylphenyl) (3-chloro-5-) Fluoropyridin-2-yl)methanone (600 mg, 1.83 mmol) was mixed in carbon tetrachloride (10 mL) and stirred at 80 ° C for 12 hours. The reaction mixture was filtered and evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal

步骤4:(2-溴-4-溴甲基苯基)(3-氯-5-氟吡啶-2-基)甲酮Step 4: (2-Bromo-4-bromomethylphenyl)(3-chloro-5-fluoropyridin-2-yl)methanone

向(2-溴-4-二溴甲基苯基)(3-氯-5-氟吡啶-2-基)甲酮(890mg,1.83mmol)的二氯甲烷(20mL)溶液加入亚磷酸二乙酯(505mg,3.66mmol)和二异丙基乙胺(473mg,3.66mmol)。反应液在室温下搅拌1小时，然后浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝15/1(体积比))，得(2-溴-4-溴甲基苯基)(3-氯-5-氟吡啶-2-基)甲酮(530mg,71％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝407.8. To a solution of (2-bromo-4-dibromomethylphenyl)(3-chloro-5-fluoropyridin-2-yl)methanone (890 mg, 1.83 mmol) in dichloromethane (20 mL) Ester (505 mg, 3.66 mmol) and diisopropylethylamine (473 mg, 3.66 mmol). The reaction solution was stirred at room temperature for 1 hour and then concentrated. The residue was purified by flash chromatography (peel ether / ethyl acetate = 15 / 1 (vol.)) to give (2-bromo-4-bromomethylphenyl) (3-chloro-5-fluoropyridine-2) Methyl ketone (530 mg, 71%) as a yellow solid. LCMS (ESI) [M+H] ⁺ = 407.8.

步骤5:(2-溴-4-((乙基砜)甲基)苯基)(3-氯-5-氟吡啶-2-基)甲酮Step 5: (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(3-chloro-5-fluoropyridin-2-yl)methanone

向(2-溴-4-溴甲基苯基)(3-氯-5-氟吡啶-2-基)甲酮(530mg,1.3mmol)的二甲亚砜(10mL)溶液中加入乙烷亚磺酸钠(302mg,2.6mmol)。反应液在室温下搅拌1小时。向反应液中加入乙酸乙酯(20mL)和水(20mL)，分出有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝3/1(体积比))，得(2-溴-4-((乙基砜)甲基)苯基)(3-氯-5-氟吡啶-2-基)甲酮(240mg,44％)。LCMS(ESI)[M+H] ⁺＝422.0. To a solution of (2-bromo-4-bromomethylphenyl)(3-chloro-5-fluoropyridin-2-yl)methanone (530 mg, 1.3 mmol) in dimethylsulfoxide (10 mL) Sodium sulfonate (302 mg, 2.6 mmol). The reaction solution was stirred at room temperature for 1 hour. Ethyl acetate (20 mL) and water (20 mL) were evaporated. The residue was purified by flash chromatography (petrole ether / ethyl acetate = 3 / 1 (volume ratio)) to give (2-bromo-4-((ethylsulfonyl)methyl)phenyl) (3-chloro-) 5-Fluoropyridin-2-yl)methanone (240 mg, 44%). LCMS (ESI) [M+H] ⁺ = 422.0.

步骤6:((5-(2-(3-氯-5-氟吡啶-2-甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯Step 6: ((5-(2-(3-Chloro-5-fluoropyridine-2-formyl)-5-(ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1 , 2-dihydropyridin-4-yl)methylcarbamic acid tert-butyl ester

将(2-溴-4-((乙基砜)甲基)苯基)(3-氯-5-氟吡啶-2-基)甲酮(64mg,0.16mmol)，(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(90mg,0.24mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(24mg,0.032mmol)和碳酸钾(102mg,0.48mmol)混合于1,4-二氧六环(4mL)和水(0.4mL)中，在氮气保护下加热至95℃搅拌1小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝10/1(体积比))，得((5-(2-(3-氯-5-氟吡啶-2-甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(35mg,38％)。LCMS(ESI)[M+H] ⁺＝578.1. (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(3-chloro-5-fluoropyridin-2-yl)methanone (64 mg, 0.16 mmol), (1-methyl-2) -oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl)methyl Tert-butyl carbamate (90 mg, 0.24 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (24 mg, 0.032 mmol) and potassium carbonate (102 mg, 0.48) Methyl) was mixed with 1,4-dioxane (4 mL) and water (0.4 mL) and heated to 95 ° C under nitrogen for 1 hour. The reaction solution was filtered, and the filtrate was concentrated, and the residue was purified by flash chromatography ( petroleum ether / ethyl acetate = 10/1 (volume ratio) to give (5-(2-(3-chloro-5-fluoropyridine)- 2-formyl)-5-(ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methylcarbamic acid tert-butyl ester (35 mg , 38%). LCMS (ESI) [M+H] ⁺ = 578.1.

步骤7:7-(3-氯-5-氟吡啶-2-基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮Step 7: 7-(3-Chloro-5-fluoropyridin-2-yl)-10-((ethylsulfonyl)methyl)-2-methyl-2,5-dihydro-3H-benzo[c Pyridine[3,4-e]azepin-3-one

向((5-(2-(3-氯-5-氟吡啶-2-甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(35mg,0.06mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌1小时并浓缩。残余物用制备-HPLC分离纯化，得7-(3-氯-5-氟吡啶-2-基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(4.1mg,15％)，为白色固体。LCMS(ESI):[M+H] ⁺＝461.1,纯度100％(UV 214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.57(s,1H),8.22(d,J＝8.8Hz,1H),8.08(s,1H),7.71(s,1H),7.38(d,J＝8.0Hz,1H),7.09(d,J＝7.6Hz,1H),6.53(s,1H),4.80(d,J＝10.8Hz,1H),4.62-4.49(m,2H),4.03(d,J＝10.4Hz,2H),3.54(s,3H),3.11(q,J＝7.6Hz,2H),1.24(t,J＝7.6Hz,3H). To ((5-(2-(3-chloro-5-fluoropyridine-2-formyl)-5-(ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1,2 To a solution of tert-butyl dihydropyridin-4-yl)methylcarbamate (35 mg, 0.06 mmol) in dichloromethane (4 mL). The residue is purified by preparative-HPLC to give 7-(3-chloro-5-fluoropyridin-2-yl)-10-((ethylsulfonyl)methyl)-2-methyl-2,5-dihydro -3H-benzo[c]pyrido[3,4-e]azepin-3-one (4.1 mg, 15%) as a white solid. LCMS (ESI): [M+H] ⁺ = 461.1, Purity 100% (UV 214 nm); ¹ H NMR (400 MHz, CD ₃ OD) δ 8.57 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 8.08 (s, 1H), 7.71 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.53 (s, 1H), 4.80 (d, J = 10.8 Hz, 1H), 4.62-4.49 ( m, 2H), 4.03 (d, J = 10.4 Hz, 2H), 3.54 (s, 3H), 3.11 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H).

4144:10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-2H-苯并[b]吡啶并[3,4-d]氮杂卓-3,6(5H,7H)-二酮4144: 10-((Ethyl sulfonyl)methyl)-7-(4-fluorophenyl)-2-methyl-2H-benzo[b]pyrido[3,4-d]azepine-3 ,6(5H,7H)-dione

步骤1:2-(2-甲氧基吡啶-4-基)乙酸甲酯Step 1: Methyl 2-(2-methoxypyridin-4-yl)acetate

将2-甲氧基-4-甲基吡啶(3.7g,30.0mmol)的四氢呋喃(30mL)溶液冷却至-78℃，然后缓慢加入二异丙基氨基锂(1M,75mL,75mmol)，搅拌0.5小时。向反应瓶中加入碳酸二甲酯(8.1g,90mmol)，反应液继续在室温下搅拌2小时。加入饱和氯化铵溶液淬灭反应，然后用乙酸乙酯萃取(50mL x 3)。合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/10(体积比))，得2-(2-甲氧基吡啶-4-基)乙酸甲酯(3.26g,60％)，为无色油状物。LCMS(ESI)[M+H] ⁺＝182.2. A solution of 2-methoxy-4-methylpyridine (3.7 g, 30.0 mmol) in tetrahydrofuran (30 mL) was cooled to -78 °C then EtOAc (1M, 75 mL, hour. Dimethyl carbonate (8.1 g, 90 mmol) was added to the reaction flask, and the mixture was stirred at room temperature for 2 hr. The reaction was quenched by the addition of aq. EtOAc (EtOAc) The organic phase was combined, washed with brine, dried over anhydrous sodium sulfate Methyl (methoxypyridin-4-yl)acetate (3.26 g, 60%) was obtained as a colourless oil. LCMS (ESI) [M+H] ⁺ = 182.2.

步骤2:2-(2-氧代-1,2-二氢吡啶-4-基)乙酸甲酯Step 2: Methyl 2-(2-oxo-1,2-dihydropyridin-4-yl)acetate

将氢溴酸(33％乙酸溶液,3mL)和2-(2-甲氧基吡啶-4-基)乙酸甲酯(1.81g,10mmol)混合于乙酸(10mL)中，在100℃下搅拌4小时。将反应液浓缩得2-(2-氧代-1,2-二氢吡啶 -4-基)乙酸甲酯(粗产物)。LCMS(ESI)[M+H] ⁺＝168.2. Hydrobromic acid (33% acetic acid solution, 3 mL) and methyl 2-(2-methoxypyridin-4-yl)acetate (1.81 g, 10 mmol) were mixed in acetic acid (10 mL) and stirred at 100 ° C 4 hour. The reaction solution was concentrated to give methyl 2-(2-oxo-1,2-dihydropyridin-4-yl)acetate (crude). LCMS (ESI) [M+H] ⁺ = 168.2.

步骤3:2-(1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙酸甲酯Step 3: Methyl 2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)acetate

向2-(2-氧代-1,2-二氢吡啶-4-基)乙酸甲酯(步骤2粗产物)的N,N-二甲基甲酰胺(30mL)溶液中加入碳酸铯(6.56g,20mmol)和碘甲烷(4.56g,30mmol)。反应液在60℃下搅拌4小时。向反应液中加入乙酸乙酯(50mL)和水(50mL)，分离有机相。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝3/1(体积比))，得2-(1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙酸甲酯(540mg,30％)，为白色固体。LCMS(ESI)[M+H] ⁺＝182.2. To a solution of methyl 2-(2-oxo-1,2-dihydropyridin-4-yl)acetate (step 2 crude) in N,N-dimethylformamide (30 mL) g, 20 mmol) and methyl iodide (4.56 g, 30 mmol). The reaction solution was stirred at 60 ° C for 4 hours. Ethyl acetate (50 mL) and water (50 mL) were added to the mixture, and the organic phase was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by flash chromatography (petrole ether / ethyl acetate = 3 / 1 (volume ratio)) to give 2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl) Methyl acetate (540 mg, 30%) as a white solid. LCMS (ESI) [M+H] ⁺ = 182.2.

步骤4:2-(5-溴-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙酸甲酯Step 4: Methyl 2-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)acetate

将N-溴代丁二酰亚胺(0.98g,5.5mmol)，2-(1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙酸甲酯(900mg,5.0mmol)混合于乙腈(15mL)中，加热至80℃搅拌2小时。向反应液中加入二氯甲烷(50mL)和水(50mL)，分离有机相。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝5/1(体积比))，得2-(5-溴-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙酸甲酯(850mg,65％)，为棕色油状物。LCMS(ESI)[M+H] ⁺＝260.0. N-Bromosuccinimide (0.98 g, 5.5 mmol), methyl 2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)acetate (900 mg, 5.0 Methyl) was mixed with acetonitrile (15 mL) and heated to 80 ° C for 2 hours. Dichloromethane (50 mL) and water (50 mL) were added to the mixture and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by flash chromatography (petrole ether / ethyl acetate = 5 / 1 (volume ratio)) to give 2-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridine Methyl 4-methyl)acetate (850 mg, 65%) as a brown oil. LCMS (ESI) [M+H] ⁺ = 260.0.

步骤5:1-((乙基砜)甲基)-4-硝基苯Step 5: 1-((Ethyl sulfonyl)methyl)-4-nitrobenzene

向4-硝基苄基溴(4.3g,20mmol)的N,N-二甲基甲酰胺(25mL)溶液中加入乙烷亚磺酸钠(4.6g,40mmol)。反应液在65℃下搅拌2小时。向反应液中加入水(50mL)，搅拌10分钟后过滤得1-((乙基砜)甲基)-4-硝基苯(4.6g,100％)，为白色固体。To a solution of 4-nitrobenzyl bromide (4.3 g, 20 mmol) in EtOAc (EtOAc) The reaction solution was stirred at 65 ° C for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was stirred for 10 min and then filtered to give 1-((ethylsulfonyl)methyl)-4-nitrobenzene (4.6 g, 100%) as white solid.

步骤6:4-((乙基砜)甲基)苯胺Step 6: 4-((Ethyl sulfonyl)methyl) aniline

将1-((乙基砜)甲基)-4-硝基苯(4.6g,20mmol)，铁粉(5.6g,100mmol)混合于乙醇(120mL)和水(60mL)中，加热至90℃搅拌2小时。向反应液中加入乙酸乙酯(150mL)，分离有机相。有机相用饱和碳酸氢钠溶液，食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。得4-((乙基砜)甲基)苯胺(3.3g,83％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝200.1. 1-((Ethyl sulfonyl)methyl)-4-nitrobenzene (4.6 g, 20 mmol), iron powder (5.6 g, 100 mmol) in ethanol (120 mL) and water (60 mL), and warmed to 90 ° C Stir for 2 hours. Ethyl acetate (150 mL) was added to the mixture and the organic layer was separated. The organic phase was washed with aq. 4-((Ethyl sulfonyl)methyl)aniline (3.3 g, 83%) was obtained as a yellow solid. LCMS (ESI) [M+H] ⁺ = 200.1.

步骤7:4-((乙基砜)甲基)-2-碘苯胺Step 7: 4-((Ethyl sulfonyl)methyl)-2-iodoaniline

将N-碘代丁二酰亚胺(3.71g,1.65mmol)，4-((乙基砜)甲基)苯胺(3.3g,16.5mmol)混合于N,N-二甲基甲酰胺(30mL)中，室温搅拌2小时。向反应液中加入10％硫代硫酸钠(50mL)和乙酸乙酯(50mL)，分离有机相。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(二氯甲烷/甲醇＝20/1(体积比))，得4-((乙基砜)甲基)-2-碘苯胺(2.4g,60％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝326.0. N-iodosuccinimide (3.71 g, 1.65 mmol), 4-((ethylsulfonyl)methyl)aniline (3.3 g, 16.5 mmol) was mixed in N,N-dimethylformamide (30 mL) In the mixture, stir at room temperature for 2 hours. 10% sodium thiosulfate (50 mL) and ethyl acetate (50 mL) were added to the reaction mixture, and the organic phase was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by flash chromatography (dichloromethane / methanol = 20/1 (vol.)) to give 4-((ethylsulfonyl)methyl)-2-iodoaniline (2.4 g, 60%) Yellow solid. LCMS (ESI) [M+H] ⁺ = 326.0.

步骤8:4-((乙基砜)甲基)-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯胺Step 8: 4-((Ethyl sulfonyl)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

将4-((乙基砜)甲基)-2-碘苯胺(2.0g,62mmol)，频那醇硼烷(2.4g,18.6mmol)，双(乙腈)氯化钯(II)(160mg,0.62mmol)，2-双环己基膦-2',6'-二甲氧基联苯(1.02g,2.48mmol)和三乙胺(3.14g,31mmol)混合于1,4-二氧六环(40mL)中，在氮气保护下加热至110℃搅拌2小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(二氯甲烷/乙酸乙酯＝1/1(体积比))，得4-((乙基砜)甲基)-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯胺(1.2g,60％)，为黄色固体。4-((Ethyl sulfonyl)methyl)-2-iodoaniline (2.0 g, 62 mmol), pinacol borane (2.4 g, 18.6 mmol), bis(acetonitrile)palladium(II) chloride (160 mg, 0.62 mmol), 2-biscyclohexylphosphine-2',6'-dimethoxybiphenyl (1.02 g, 2.48 mmol) and triethylamine (3.14 g, 31 mmol) were mixed in 1,4-dioxane ( In 40 mL), it was heated to 110 ° C under nitrogen atmosphere and stirred for 2 hours. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjj 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (1.2 g, 60%) as a yellow solid.

步骤9:2-(5-(2-氨基-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙酸甲酯Step 9: 2-(5-(2-Amino-5-((ethylsulfonyl)methyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl) Methyl acetate

将4-((乙基砜)甲基)-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯胺(600mg,1.85mmol)，2-(5-溴-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙酸甲酯(400mg,1.54mmol)，[1,1'-双 (二苯基膦基)二茂铁]二氯化钯(II)(55mg,0.15mol)和碳酸钾(532mg,3.85mmol)混合于1,4-二氧六环(10mL)中，在氮气保护下加热至90℃搅拌2小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/2(体积比))，得2-(5-(2-氨基-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙酸甲酯(210mg,36％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝379.1. 4-((Ethyl sulfonyl)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (600 mg, 1.85 mmol) , methyl 2-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)acetate (400 mg, 1.54 mmol), [1,1'-bis (two) Phenylphosphino)ferrocene]palladium(II) chloride (55 mg, 0.15 mol) and potassium carbonate (532 mg, 3.85 mmol) were mixed in 1,4-dioxane (10 mL) under nitrogen Heat to 90 ° C and stir for 2 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by flash chromatography ( petroleum ether / ethyl acetate = 1/2 (volume ratio) to give 2-(5-(2-amino-5-((ethyl sulfone)) Methyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)acetate (210 mg, 36%) as a yellow solid. LCMS (ESI) [M+H] ⁺ =379.1.

步骤10:10-((乙基砜)甲基)-2-甲基-2H-苯并[b]吡啶并[3,4-d]氮杂卓-3,6(5H,7H)-二酮Step 10: 10-((Ethyl sulfonyl)methyl)-2-methyl-2H-benzo[b]pyrido[3,4-d]azepine-3,6(5H,7H)-di ketone

将2-(5-(2-氨基-5-((乙基砜)甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)乙酸甲酯(210mg,0.56mmol)和叔丁醇钾(188mg,1.67mmol)混合于四氢呋喃(10mL)中，在室温下搅拌3小时。向反应液中加入饱和食盐水(50mL)和乙酸乙酯(50mL)，分离有机相。有机相用无水硫酸钠干燥，过滤并浓缩。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/1)，得10-((乙基砜)甲基)-2-甲基-2H-苯并[b]吡啶并[3,4-d]氮杂卓-3,6(5H,7H)-二酮(140mg,72％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝347.1. 2-(5-(2-Amino-5-((ethylsulfonyl)methyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)acetate The ester (210 mg, 0.56 mmol) and potassium tert-butoxide (188 mg, 1.67 mmol) were mixed in tetrahydrofuran (10 mL) and stirred at room temperature for 3 hr. Saturated brine (50 mL) and ethyl acetate (50 mL) were added to the mixture, and the organic phase was separated. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by flash chromatography ( petroleum ether / ethyl acetate = 1 / 1) to give 10-((ethylsulfonyl)methyl)-2-methyl-2H-benzene. [b] Pyrido[3,4-d]azepine-3,6(5H,7H)-dione (140 mg, 72%) as a yellow solid. LCMS (ESI) [M+H] ⁺ = 347.1.

步骤11:10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-2H-苯并[b]吡啶并[3,4-d]氮杂卓-3,6(5H,7H)-二酮Step 11: 10-((Ethylsulfonyl)methyl)-7-(4-fluorophenyl)-2-methyl-2H-benzo[b]pyrido[3,4-d]azepine- 3,6(5H,7H)-dione

将10-((乙基砜)甲基)-2-甲基-2H-苯并[b]吡啶并[3,4-d]氮杂卓-3,6(5H,7H)-二酮(80mg,0.23mmol)，1-溴-4-氟苯(60mg,0.35mmol)，N ¹,N ²-二甲基乙烷-1,2-二胺(26mg,0.3mmol),磷酸钾(2454mg,1.16mmol)和碘化亚铜(3mg,0.016mmol)混合于1,4-二氧六环(3mL)中，在氮气保护下加热至110℃搅拌16小时。反应液过滤，滤液浓缩，残余物用制备-HPLC分离纯化，得10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-2H-苯并[b]吡啶并[3,4-d]氮杂卓-3,6(5H,7H)-二酮(3.0mg,3％)，为白色固体。LCMS(ESI):[M+H] ⁺＝441.1,纯度 100％(UV 214nm)； ¹H NMR(400MHz,CD ₃OD)δ8.18(s,1H),7.67(s,1H),7.43(d,J＝8.4Hz,1H),7.20-7.15(m,4H),7.07(d,J＝8.4Hz,1H),6.60(s,1H),4.49(s,2H),3.78(d,J＝12.4Hz,1H)),3.73(s,3H),3.57(d,J＝12.4Hz,1H),3.16(q,J＝7.2Hz,2H),1.41(t,J＝7.2Hz,3H). 10-((Ethyl sulfonyl)methyl)-2-methyl-2H-benzo[b]pyrido[3,4-d]azepine-3,6(5H,7H)-dione ( 80 mg, 0.23 mmol), 1-bromo-4-fluorobenzene (60 mg, 0.35 mmol), N ¹ , N ² -dimethylethane-1,2-diamine (26 mg, 0.3 mmol), potassium phosphate (2454 mg) , 1.16 mmol) and cuprous iodide (3 mg, 0.016 mmol) were mixed in 1,4-dioxane (3 mL) and heated to 110 ° C under nitrogen for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by preparative-HPLC to give 10-((ethylsulfonyl)methyl)-7-(4-fluorophenyl)-2-methyl-2H-benzo[b] Pyridine[3,4-d]azepine-3,6(5H,7H)-dione (3.0 mg, 3%) as a white solid. LCMS (ESI): [M+H] ⁺ = 441.1, purity 100% (UV 214nm); ¹ H NMR (400 MHz, CD ₃ OD) δ 8.18 (s, 1H), 7.67 (s, 1H), 7.43 ( d, J = 8.4 Hz, 1H), 7.20-7.15 (m, 4H), 7.07 (d, J = 8.4 Hz, 1H), 6.60 (s, 1H), 4.49 (s, 2H), 3.78 (d, J) =12.4 Hz, 1H)), 3.73 (s, 3H), 3.57 (d, J = 12.4 Hz, 1H), 3.16 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H) .

4145:7-(3-氯吡啶-4-基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮4145: 7-(3-Chloropyridin-4-yl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridin[3 , 4-e]azazo-3-one

步骤1:(2-溴-4-甲基苯基)(3-氯吡啶-4-基)甲醇Step 1: (2-Bromo-4-methylphenyl)(3-chloropyridin-4-yl)methanol

将4-溴-3-氯吡啶(1.0g,5mmol)的四氢呋喃(30mL)溶液冷却至-20℃，然后缓慢加入异丙基氯化镁的四氢呋喃溶液(2M,2.5mL,5mmol)，搅拌3小时。将该溶液慢慢滴加到2-溴-4-甲基苯甲醛(500mg,2.5mmol)的四氢呋喃(30mL)溶液中，反应液继续在室温下搅拌12小时。加入饱和氯化铵溶液淬灭反应，然后用乙酸乙酯萃取(30mL x 2)。合并有机相，用稀盐酸及饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/10(体积比))，得(2-溴-4-甲基苯基)(3-氯吡啶-4-基)甲醇(350mg,45％)，为黄色固体。LCMS(ESI)[M+H] ⁺＝311.9. A solution of 4-bromo-3-chloropyridine (1.0 g, 5 mmol) in tetrahydrofuran (30 mL) was cooled to -20 ° C, then isopropylmagnesium chloride in tetrahydrofuran (2M, 2.5 mL, 5 mmol). This solution was slowly added dropwise to a solution of 2-bromo-4-methylbenzaldehyde (500 mg, 2.5 mmol) in tetrahydrofuran (30 mL). The reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride and then extracted with ethyl acetate (30mL). The organic phase was combined, washed with EtOAc EtOAc (EtOAc m. 2-Bromo-4-methylphenyl)(3-chloropyridin-4-yl)methanol (350 mg, 45%) as a yellow solid. LCMS (ESI) [M+H] ⁺ = 311.9.

步骤2:(2-溴-4-甲基苯基)(3-氯吡啶-4-基)甲酮Step 2: (2-Bromo-4-methylphenyl)(3-chloropyridin-4-yl)methanone

将(2-溴-4-甲基苯基)(3-氯吡啶-4-基)甲醇(350mg,1.12mmol)和Dess-Martin氧化剂(710mg,1.68mmol)混合于二氯甲烷(10mL)中，在室温下搅拌1小时。将反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/10(体积比))，得(2-溴-4-甲基苯基)(3-氯吡啶-4-基)甲酮(330mg,95％)，为无色油状物。LCMS(ESI)[M+H] ⁺＝312.0 (2-Bromo-4-methylphenyl)(3-chloropyridin-4-yl)methanol (350 mg, 1.12 mmol) and Dess-Martin oxidant (710 mg, 1.68 mmol) in dichloromethane (10 mL) Stir at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated, and the residue was purified by flash chromatography (ethyl acetate / petroleum ether = 1/10 (by volume)) to give (2-bromo-4-methylphenyl) (3-chloro) Pyridin-4-yl)methanone (330 mg, 95%) was obtained as a colorless oil. LCMS (ESI) [M+H] ⁺ = 312.0

步骤3:(2-溴-4-二溴甲基苯基)(3-氯吡啶-4-基)甲酮Step 3: (2-Bromo-4-dibromomethylphenyl)(3-chloropyridin-4-yl)methanone

将N-溴代丁二酰亚胺(1.1g,6.08mmol)，偶氮二异丁腈(80mg,0.3mmol)和(2-溴-4-甲基苯基)(3-氯吡啶-4-基)甲酮(500mg,1.52mmol)混合于四氯化碳(20mL)中，加热至80℃搅拌12小时。将反应液过滤后浓缩，得(2-溴-4-二溴甲基苯基)(3-氯吡啶-4-基)甲酮(480mg,67％)，为黄色固体。N-bromosuccinimide (1.1 g, 6.08 mmol), azobisisobutyronitrile (80 mg, 0.3 mmol) and (2-bromo-4-methylphenyl) (3-chloropyridine-4 Methyl ketone (500 mg, 1.52 mmol) was mixed in carbon tetrachloride (20 mL) and stirred at 80 ° C for 12 hours. The reaction mixture was filtered and evaporated tolulululululululululululululu

步骤4:(2-溴-4-溴甲基苯基)(3-氯吡啶-4-基)甲酮Step 4: (2-Bromo-4-bromomethylphenyl)(3-chloropyridin-4-yl)methanone

向(2-溴-4-二溴甲基苯基)(3-氯吡啶-4-基)甲酮(480mg,1.02mmol)的二氯甲烷(20mL)溶液加入亚磷酸二乙酯(282mg,2.04mmol)和二异丙基乙胺(263mg,2.04mmol)。反应液在室温下搅拌1小时。反应液浓缩后残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝4/1(体积比))，得(2-溴-4-溴甲基苯基)(3-氯吡啶-4-基)甲酮(370mg,75％)，为黄色固体。 LCMS(ESI)[M+H] ⁺＝387.8. To a solution of (2-bromo-4-dibromomethylphenyl)(3-chloropyridin-4-yl)methanone (480 mg, 1.02 mmol) in dichloromethane (20 mL) 2.04 mmol) and diisopropylethylamine (263 mg, 2.04 mmol). The reaction solution was stirred at room temperature for 1 hour. The residue was purified by flash chromatography (petrole ether / ethyl acetate = 4 / 1 (vol.)) to give (2-bromo-4-bromomethylphenyl) (3-chloropyridine) Methyl ketone (370 mg, 75%) as a yellow solid. LCMS (ESI) [M+H] ⁺ = 387.8.

步骤5:(2-溴-4-((乙基砜)甲基)苯基)(3-氯吡啶-4-基)甲酮Step 5: (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(3-chloropyridin-4-yl)methanone

向(2-溴-4-溴甲基苯基)(3-氯吡啶-4-基)甲酮(370mg,0.95mmol)的二甲亚砜(10mL)溶液中加入乙烷亚磺酸钠(220mg,1.9mmol)。反应液在室温下搅拌1小时。向反应液中加入乙酸乙酯(20mL)和水(20mL)，分离有机相。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝3/1(体积比))，得(2-溴-4-((乙基砜)甲基)苯基)(3-氯吡啶-4-基)甲酮(230mg,60％)。LCMS(ESI)[M+H] ⁺＝401.9. To a solution of (2-bromo-4-bromomethylphenyl)(3-chloropyridin-4-yl)methanone (370 mg, 0.95 mmol) in dimethyl sulfoxide (10 mL) 220 mg, 1.9 mmol). The reaction solution was stirred at room temperature for 1 hour. Ethyl acetate (20 mL) and water (20 mL) were added to the mixture and the organic phase was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by flash chromatography (petrole ether / ethyl acetate = 3 / 1 (volume ratio)) to give (2-bromo-4-((ethylsulfonyl)methyl)phenyl) (3-chloropyridine) 4-yl)methanone (230 mg, 60%). LCMS (ESI) [M+H] ⁺ = 401.9.

步骤6:(5-(2-(3-氯吡啶-4-甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯Step 6: (5-(2-(3-Chloropyridine-4-formyl)-5-(ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1,2-dihydro Pyridin-4-yl)methylcarbamic acid tert-butyl ester

将(2-溴-4-((乙基砜)甲基)苯基)(3-氯吡啶-4-基)甲酮(45mg,0.11mmol)，(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(50mg,0.14mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(38mg,0.28mmol)和碳酸钾(38mg,0.28mmol)混合于1,4-二氧六环(4mL)和水(0.4mL)中，在氮气保护下加热至95℃搅拌1小时。反应液过滤，滤液浓缩，得(5-(2-(3-氯吡啶-4-甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(粗产物)，为黑色油状物。LCMS(ESI)[M+H] ⁺＝560.1. (2-Bromo-4-((ethylsulfonyl)methyl)phenyl)(3-chloropyridin-4-yl)methanone (45 mg, 0.11 mmol), (1-methyl-2-oxo- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl)methylcarbamic acid tert-butyl Ester (50 mg, 0.14 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (38 mg, 0.28 mmol) and potassium carbonate (38 mg, 0.28 mmol) The mixture was heated to 95 ° C under a nitrogen atmosphere for 1 hour in 1,4-dioxane (4 mL) and water (0.4 mL). The reaction solution was filtered, and the filtrate was concentrated to give (5-(2-(3-chloropyridine-4-formyl)-5-(ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1 ,2-Dihydropyridin-4-yl)methylcarbamic acid tert-butyl ester (crude) as a black oil. LCMS (ESI) [M+H] ⁺ = 560.1.

步骤7:7-(3-氯吡啶-4-基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮Step 7: 7-(3-Chloropyridin-4-yl)-10-((ethylsulfonyl)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridin[ 3,4-e]azepin-3-one

向(5-(2-(3-氯吡啶-4-甲酰基)-5-(乙基砜甲基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(步骤6的粗产物)的二氯甲烷(3mL)溶液中加入三氟乙酸(2mL)。反应液在室温下搅拌1小时并浓缩。残余物用制备-HPLC分离纯化，得标题化合物7-(3-氯吡啶-4-基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮(12.5mg,两步总收率25％)，为白色固体。LCMS(ESI)[M+H] ⁺＝442.0,纯度100％(UV 214nm)； ¹H NMR(400MHz,CD3OD)δ8.64(d,J＝4.8Hz,1H),8.58(s,1H),8.17(s,1H),7.81(s,1H),7.63(d,J＝4.8Hz,1H),7.52(d,J＝8.0Hz,1H),7.19(d,J＝8.0Hz,1H),6.67(s,1H),4.8(d,J＝10.0Hz,1H),4.22(s,J＝10.0Hz,2H),3.71(s,3H),3.15(q,J＝7.6Hz,2H),1.41(t,J＝7.6Hz,3H). To (5-(2-(3-chloropyridine-4-formyl)-5-(ethylsulfonylmethyl)phenyl)-1-methyl-2-oxo-1,2-dihydropyridine- To a solution of tert-butyl methyl 4-carbamate (the crude product of Step 6) in dichloromethane (3 mL) was added trifluoroacetic acid (2 mL). The reaction solution was stirred at room temperature for 1 hour and concentrated. The residue was purified by preparative EtOAc (EtOAc-EtOAc) -Benzo[c]pyrido[3,4-e]azepin-3-one (12.5 mg, two-step total yield 25%) as a white solid. LCMS (ESI) [M + H ] + = 442.0, purity ^{100 (UV 214nm)%; 1} H NMR (400MHz, CD3OD) δ8.64 (d, J = 4.8Hz, 1H), 8.58 (s, 1H), 8.17(s,1H), 7.81(s,1H), 7.63(d,J=4.8Hz,1H), 7.52(d,J=8.0Hz,1H), 7.19(d,J=8.0Hz,1H), 6.67 (s, 1H), 4.8 (d, J = 10.0 Hz, 1H), 4.22 (s, J = 10.0 Hz, 2H), 3.71 (s, 3H), 3.15 (q, J = 7.6 Hz, 2H), 1.41 (t, J = 7.6 Hz, 3H).

4146:7-(2-氯-4-氟苯基)-5-乙基-10-(乙基砜甲基)-2-甲基-2,5-二氢-3H-苯并[e]吡啶并[4,3-c][1,2]二氮杂卓-3-酮4146: 7-(2-Chloro-4-fluorophenyl)-5-ethyl-10-(ethylsulfonemethyl)-2-methyl-2,5-dihydro-3H-benzo[e] Pyrido[4,3-c][1,2]diazepine-3-one

步骤1:5-(2-(2-氯-4-氟苯甲酰基)-5-(乙基砜甲基)苯基)-4-氟-1-甲基吡啶-2(1H)-酮Step 1: 5-(2-(2-Chloro-4-fluorobenzoyl)-5-(ethylsulfonylmethyl)phenyl)-4-fluoro-1-methylpyridine-2(1H)-one

将(2-氯-4-氟苯基)(4-(乙基砜甲基)-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)甲酮(100mg,0.21mmol)，5-溴-4-氟-1-甲基吡啶-2(1H)-酮(45mg,0.21mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(16mg,0.02mmol)和碳酸钾(89mg,0.63mmol)混合于1,4-二氧六环(5mL)和水(0.5mL)中，在氮气保护下加热至95℃搅拌1小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝30/1(体积比))，得5-(2-(2-氯-4-氟苯甲酰基)-5-(乙基砜甲基)苯基)-4-氟-1-甲基吡啶-2(1H)-酮(36mg,36％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝466.0. (2-Chloro-4-fluorophenyl)(4-(ethylsulfonylmethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)phenyl)methanone (100 mg, 0.21 mmol), 5-bromo-4-fluoro-1-methylpyridine-2(1H)-one (45 mg, 0.21 mmol), [1,1'- double (diphenylphosphino)ferrocene]palladium(II) chloride (16 mg, 0.02 mmol) and potassium carbonate (89 mg, 0.63 mmol) mixed with 1,4-dioxane (5 mL) and water (0.5 In mL), it was heated to 95 ° C under nitrogen for 1 hour. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -5-(Ethyl sulfonylmethyl)phenyl)-4-fluoro-1-methylpyridine-2(1H)-one (36 mg, 36%). LCMS (ESI) [M+H] ⁺ = 466.0.

步骤2:7-(2-氯-4-氟苯基)-5-乙基-10-(乙基砜甲基)-2-甲基-2,5-二氢-3H-苯并[e]吡啶并[4,3-c][1,2]二氮杂卓-3-酮Step 2: 7-(2-Chloro-4-fluorophenyl)-5-ethyl-10-(ethylsulfonemethyl)-2-methyl-2,5-dihydro-3H-benzo[e Pyridine[4,3-c][1,2]diazepine-3-one

将5-(2-(2-氯-4-氟苯甲酰基)-5-(乙基砜甲基)苯基)-4-氟-1-甲基吡啶-2(1H)-酮(36mg,0.08mmol)，乙基肼(24mg,0.4mmol)和碳酸钾(56mg,0.4mmol)混合于乙醇(20mL)中，在氮气保护下加热至80℃搅拌72小时。反应液浓缩，残余物用制备-HPLC分离纯化，得7-(2-氯-4-氟苯基)-5-乙基-10-(乙基砜甲基)-2-甲基-2,5-二氢-3H-苯并[e]吡啶并[4,3-c][1,2]二氮杂卓-3-酮(1mg,3％)，为白色固体。LCMS(ESI):[M+H] ⁺＝488.0,纯度100％(UV 214nm)； ¹H NMR(400MHz,CD ₃OD)δ7.82(s,1H),7.63-7.60(m,2H),7.41-7.39(m,1H),7.33-7.30(m,2H),6.92(d,J＝8.0Hz,1H),6.21(s,1H),4.48(s,2H),3.64(s,3H),3.50(q,J＝7.2Hz,2H),3.11(q,J＝8.2Hz,2H),1.44(t,J＝7.2Hz,3H),1.28(t,J＝6.8Hz,3H). 5-(2-(2-Chloro-4-fluorobenzoyl)-5-(ethylsulfonylmethyl)phenyl)-4-fluoro-1-methylpyridine-2(1H)-one (36mg Ethyl hydrazine (24 mg, 0.4 mmol) and potassium carbonate (56 mg, 0.4 mmol) were mixed with ethanol (20 mL) and heated to 80 ° C under nitrogen atmosphere and stirred for 72 hours. The reaction mixture was concentrated, and the residue was purified by preparative-HPLC to give 7-(2-chloro-4-fluorophenyl)-5-ethyl-10-(ethyl sulfonylmethyl)-2-methyl-2. 5-Dihydro-3H-benzo[e]pyrido[4,3-c][1,2]diazepin-3-one (1 mg, 3%) as a white solid. LCMS (ESI): [M+H] ⁺ = 488.0, purity 100% (UV 214nm); ¹ H NMR (400 MHz, CD ₃ OD) δ 7.82 (s, 1H), 7.63-7.60 (m, 2H), 7.41-7.39 (m, 1H), 7.33-7.30 (m, 2H), 6.92 (d, J = 8.0 Hz, 1H), 6.21 (s, 1H), 4.48 (s, 2H), 3.64 (s, 3H) , 3.50 (q, J = 7.2 Hz, 2H), 3.11 (q, J = 8.2 Hz, 2H), 1.44 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 6.8 Hz, 3H).

4097-P1和4097-P2：(S)-7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]哒嗪并[3,4-e]氮杂卓-3-酮和4097-P1 and 4097-P2: (S)-7-(2-chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5- Dihydro-3H-benzo[c]pyridazino[3,4-e]azepin-3-one and

(R)-7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]哒嗪并[3,4-e]氮杂卓-3-酮(R)-7-(2-chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[ c]pyridazine[3,4-e]azepin-3-one

步骤1：(1-(3-(2-(2-氯-4-氟苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-6-氧代-1,6-二氢哒嗪-4-基)乙基)氨基甲酸叔丁酯Step 1: (1-(3-(2-(2-Chloro-4-fluorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl-6-oxo- 1,6-Dihydropyridazin-4-yl)ethyl)carbamic acid tert-butyl ester

将1-(3-氯-1-甲基-6-氧代-1,6-二氢哒嗪-4-基)乙基)氨基甲酸叔丁酯(50mg,0.17mmol)，(2-氯-4-氟苯基)(4-((乙基砜)甲基)-2-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)甲酮(245mg,0.52mmol)，三(二亚苄基丙酮)二钯(16mg,0.02mmol)，2-双环己基膦-2',4',6'-三异丙基联苯(16mg,0.03mmol)和磷酸钾(92mg,0.43mmol)混合于1,4-二氧六环(4mL)和水(2滴)，在氮气保护下加热至100℃搅拌过夜。反应液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/2)，得标题化合物(20mg,20％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝592.2. 1-(3-Chloro-1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)ethyl)carbamic acid tert-butyl ester (50 mg, 0.17 mmol), (2-chloro 4-fluorophenyl)(4-((ethylsulfonyl)methyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl Phenyl)methanone (245 mg, 0.52 mmol), tris(dibenzylideneacetone)dipalladium (16 mg, 0.02 mmol), 2-biscyclohexylphosphine-2',4',6'-triisopropyl Benzene (16 mg, 0.03 mmol) and potassium phosphate (92 mg, 0.43 mmol) were mixed with 1,4-dioxane (4 mL) and water (2 drops), and the mixture was heated to 100 ° C under nitrogen atmosphere and stirred overnight. The reaction mixture was concentrated and purified mjjjlililililililililililililili LCMS (ESI) [M+H] ⁺ = 592.2.

步骤2：7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]哒嗪并[3,4-e]氮杂卓-3-酮Step 2: 7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c Pyridazine[3,4-e]azepin-3-one

将(1-(3-(2-(2-氯-4-氟苯甲酰基)-5-((乙基砜)甲基)苯基)-1-甲基-6-氧代-1,6-二氢哒嗪-4-基)乙基)氨基甲酸叔丁酯(20mg,0.03mmol)和三氟乙酸(1mL)溶于二氯甲烷(4mL)中，在室温下搅拌过夜。反应液浓缩，残余物用制备-HPLC分离纯化，得标题化合物(2.5mg,13％)，为白色固体。LCMS(ESI)[M+H] ⁺＝474.1； ¹H NMR(400MHz,CD ₃OD)δ8.10-8.09(s,1H),7.66-7.61(m,2H),7.28-7.20(m,3H),7.03(s,1H),4.60(s,1H),4.32-4.30(d,J＝6.4Hz,1H),3.93(s,3H),3.15-3.09(m,2H),1.79-1.77(d,J＝6.8Hz,3H),1.40-1.31(m,3H). (1-(3-(2-(2-chloro-4-fluorobenzoyl)-5-((ethylsulfonyl)methyl)phenyl)-1-methyl-6-oxo-1, tert-Butyl 6-dihydropyridazin-4-yl)ethyl)carbamate (20 mg, 0.03 mmol) and trifluoroacetic acid (1 mL) The reaction mixture was concentrated. LCMS (ESI) [M+H] ⁺ = 474.1; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.10-8.09 (s, 1H), 7.66-7.61 (m, 2H), 7.28-7.20 (m, 3H) ), 7.03 (s, 1H), 4.60 (s, 1H), 4.32-4.30 (d, J = 6.4 Hz, 1H), 3.93 (s, 3H), 3.15-3.09 (m, 2H), 1.79-1.77 ( d, J = 6.8 Hz, 3H), 1.40-1.31 (m, 3H).

步骤3Step 3

将7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]哒嗪并[3,4-e]氮杂卓-3-酮进一步用手性制备-HPLC分离(仪器:SFC-80；柱：OZ-H柱)，手性柱的分离参数：仪器:SFC-80(Thar,Waters)；色谱柱OZ 20*250mm,10um(Daicel)；柱温:35℃；流动相:CO2/MEOH(0.2％Methanol Ammonia)＝45/55；流速:80g/min；背压:100bar；检测波长:214nm；运行时间:4.5min。分别得到两个构型，7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]哒嗪并[3,4-e]氮杂卓-3-酮为白色固体。RTchiral＝2.39min，其为R或S构型，LCMS(ESI)[M+H]+＝473.9,纯度100％(UV 214nm)； ¹H NMR(400MHz,MeOD)δ8.09(s,1H),7.67-7.61(m,2H),7.28-7.03(m,3H),7.02(s,1H),4.60(s,2H),4.31-4.30(d,J＝8.4Hz,1H),3.93(s,3H),3.15-3.09(q,J＝7.6Hz,2H),1.79-1.77(d,J＝8.4Hz,3H),1.42-1.36(t,J＝7.6Hz,3H)。 7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]indole Further separation by hand-HPLC-HPLC separation (instrument: SFC-80; column: OZ-H column), separation parameters of chiral column: Instrument: SFC- 80 (Thar, Waters); column OZ 20*250mm, 10um (Daicel); column temperature: 35 ° C; mobile phase: CO2 / MEOH (0.2% Methanol Ammonia) = 45 / 55; flow rate: 80g / min; back pressure : 100 bar; detection wavelength: 214 nm; running time: 4.5 min. Two configurations were obtained, 7-(2-chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H- Benzo[c]pyridazino[3,4-e]azepin-3-one is a white solid. RTchiral = 2.39 min, which is in the R or S configuration, LCMS (ESI) [M+H]+ = 473.9, purity 100% (UV 214 nm); ¹ H NMR (400 MHz, MeOD) δ 8.09 (s, 1H) , 7.67-7.61 (m, 2H), 7.28-7.03 (m, 3H), 7.02 (s, 1H), 4.60 (s, 2H), 4.31-4.30 (d, J = 8.4 Hz, 1H), 3.93 (s , 3H), 3.15-3.09 (q, J = 7.6 Hz, 2H), 1.79-1.77 (d, J = 8.4 Hz, 3H), 1.42-1.36 (t, J = 7.6 Hz, 3H).

和7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]哒嗪并[3,4-e]氮杂卓-3-酮为白色固体，RTchiral＝3.47min，其为R或S构型，LCMS(ESI)[M+H]+＝473.9,纯度100％(UV 214nm)； ¹H NMR(400MHz,MeOD)δ7.98(s,1H),7.54-7.49(m,2H),7.14-7.08(m,3H),6.91(s,1H),4.48(s,2H),4.19-4.18(d,J＝8.4Hz,1H),3.81(s,3H),3.03-2.97(q,J＝7.6Hz,2H),1.67-1.65(d,J＝8.4Hz,3H),1.30-1.24(t,J＝7.6Hz,3H)。 And 7-(2-chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]indole Oxazolo[3,4-e]azepin-3-one is a white solid, RTchiral = 3.47 min, in R or S configuration, LCMS (ESI) [M+H]+=473.9, purity 100% UV 214nm); ¹ H NMR (400MHz, MeOD) δ 7.98 (s, 1H), 7.54-7.49 (m, 2H), 7.14-7.08 (m, 3H), 6.91 (s, 1H), 4.48 (s, 2H), 4.19-4.18 (d, J=8.4Hz, 1H), 3.81(s, 3H), 3.03-2.97 (q, J=7.6Hz, 2H), 1.67-1.65 (d, J=8.4Hz, 3H ), 1.30-1.24 (t, J = 7.6 Hz, 3H).

4147:N-(9-氯-7-(2-氯-4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)-N-(环丙基甲基)乙基磺酰胺4147: N-(9-chloro-7-(2-chloro-4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridin[ 3,4-e]azepine-10-yl)-N-(cyclopropylmethyl)ethylsulfonamide

步骤1:N-(5-溴-2-氯-4-(2-氯-4-氟苯甲酰基)苯基)-N-(环丙基甲基)乙基磺酰胺Step 1: N-(5-Bromo-2-chloro-4-(2-chloro-4-fluorobenzoyl)phenyl)-N-(cyclopropylmethyl)ethylsulfonamide

向N-(5-溴-2-氯-4-(2-氯-4-氟苯甲酰基)苯基)乙基磺酰胺(200mg,0.44mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入碳酸铯(286.5mg,0.88mmol)和(溴甲基)环丙烷(118mg,0.88mmol)。反应液在50℃下搅拌16小时。向反应液中加入二氯甲烷(20mL)和水(15mL)，分离有机相。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(乙酸乙酯/甲醇＝10/1)，得N-(5-溴-2-氯-4-(2-氯-4-氟苯甲酰基)苯基)-N-(环丙基甲基)乙基磺酰胺(60mg,36％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝507.9. To N-(5-bromo-2-chloro-4-(2-chloro-4-fluorobenzoyl)phenyl)ethylsulfonamide (200 mg, 0.44 mmol) of N,N-dimethylformamide 5 mL) solution was charged with cesium carbonate (286.5 mg, 0.88 mmol) and (bromomethyl)cyclopropane (118 mg, 0.88 mmol). The reaction solution was stirred at 50 ° C for 16 hours. Dichloromethane (20 mL) and water (15 mL) were added to the mixture and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate The residue was purified by flash chromatography (ethyl acetate / methanol = 10/1) to give N-(5-bromo-2-chloro-4-(2-chloro-4-fluorobenzoyl)phenyl)- N-(cyclopropylmethyl)ethylsulfonamide (60 mg, 36%) as a yellow oil. LCMS (ESI) [M+H] ⁺ = 507.9.

步骤2:((5-(4-氯-2-(2-氯-4-氟苯甲酰基)-5-(N-(环丙基甲基)乙基磺酰胺基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯Step 2: ((5-(4-Chloro-2-(2-chloro-4-fluorobenzoyl)-5-(N-(cyclopropylmethyl)ethylsulfonyl)phenyl)-1 -methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)carbamic acid tert-butyl ester

将N-(5-溴-2-氯-4-(2-氯-4-氟苯甲酰基)苯基)-N-(环丙基甲基)乙基磺酰胺(80mg,0.16mmol)，(1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基氨基甲酸叔丁酯(89mg,0.24mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(15mg,0.02mmol)和碳酸钾(66mg,0.48mmol)混合于1,4-二氧六环(5mL)和水(0.5mL)中，在氮气保护下加热至95℃搅拌1小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/甲醇＝30/1)，得((5-(4-氯-2-(2-氯-4-氟苯甲酰基)-5-(N-(环丙基甲基)乙基磺酰胺基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(50mg,48％)，为黄色油状物。LCMS(ESI)[M+H] ⁺＝666.1. N-(5-Bromo-2-chloro-4-(2-chloro-4-fluorobenzoyl)phenyl)-N-(cyclopropylmethyl)ethylsulfonamide (80 mg, 0.16 mmol), (1-Methyl-2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridine -4-yl)-tert-butyl methylcarbamate (89 mg, 0.24 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (15 mg, 0.02 mmol) It was mixed with potassium carbonate (66 mg, 0.48 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL), and heated to 95 ° C under a nitrogen atmosphere for 1 hour. The reaction mixture was filtered, and the filtrate was evaporated. mjjjjjjjjjjjjjjjj -5-(N-(cyclopropylmethyl)ethylsulfonamido)phenyl)-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)amino Tert-butyl formate (50 mg, 48%) was obtained as a yellow oil. LCMS (ESI) [M+H] ⁺ = 666.1.

步骤3:N-(9-氯-7-(2-氯-4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)-N-(环丙基甲基)乙基磺酰胺Step 3: N-(9-Chloro-7-(2-chloro-4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)-N-(cyclopropylmethyl)ethylsulfonamide

向((5-(4-氯-2-(2-氯-4-氟苯甲酰基)-5-(N-(环丙基甲基)乙基磺酰胺基)苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(50mg,0.08mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌12小时并浓缩。残余物用制备-HPLC分离纯化，得N-(9-氯-7-(2-氯-4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)-N-(环丙基甲基)乙基磺酰胺(2.1mg,5％)，为白色固体。LCMS(ESI):[M+H] ⁺＝548.0； ¹H NMR(400MHz,CD ₃OD)δ8.06(s,1H),7.08(s,1H),7.60(d,J＝2.4Hz,1H),7.22-7.16(m,3H),6.58(s,1H),4.79-4.73(m,1H),4.11-4.07(m,1H),3.70-3.42(m,5H),3.30-3.26(m,2H),1.37-1.31(m,3H),1.06-1.01(m,1H),0.42-0.36(m,2H),0.31-0.26(m,2H)。 To ((5-(4-chloro-2-(2-chloro-4-fluorobenzoyl)-5-(N-(cyclopropylmethyl)ethylsulfonyl)phenyl)-1-yl) To a solution of tert-butyl benzyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)carbamate (50 mg, 0.08 mmol) in dichloromethane (4 mL) The reaction solution was stirred at room temperature for 12 hours and concentrated. The residue was purified by preparative-HPLC to give N-(9-chloro-7-(2-chloro-4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H- Benzo[c]pyrido[3,4-e]azepin-10-yl)-N-(cyclopropylmethyl)ethylsulfonamide (2.1 mg, 5%) was obtained as a white solid. LCMS (ESI): [M+H] ⁺ = 548.0; ¹ H NMR (400 MHz, CD ₃ OD) δ 8.06 (s, 1H), 7.08 (s, 1H), 7.60 (d, J = 2.4 Hz, 1H) ), 7.22-7.16 (m, 3H), 6.58 (s, 1H), 4.79-4.73 (m, 1H), 4.11-4.07 (m, 1H), 3.70-3.42 (m, 5H), 3.30-3.26 (m , 2H), 1.37-1.31 (m, 3H), 1.06-1.01 (m, 1H), 0.42-0.36 (m, 2H), 0.31 - 0.26 (m, 2H).

4154:N-(7-(2-氯-4-氟苯基)-9-氟-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺4154: N-(7-(2-chloro-4-fluorophenyl)-9-fluoro-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridin[ 3,4-e]azepine-10-yl)ethanesulfonamide

步骤1:(2-溴-4-((2,4-二甲氧基苄基)氨基)-5-氟苯基)(2-氯-4-氟苯基)甲醇Step 1: (2-Bromo-4-((2,4-dimethoxybenzyl)amino)-5-fluorophenyl)(2-chloro-4-fluorophenyl)methanol

在-20℃和氮气保护下，向2-氯-4-氟-1-碘苯(6.27g,24.3mmol)的四氢呋喃(50mL)溶液中加入异丙基氯化镁(2M四氢呋喃溶液,12.8mL,24.3mmol)。反应液在-20℃搅拌3小时。在-20℃和氮气保护下，向2-溴-4-((2,4-二甲氧基苄基)氨基)-5-氟苯甲醛(3g,8.1mmol)的四氢呋喃(30mL)溶液中加入上述(2-氯-4-氟苯基)溴化镁溶液，反应液升至室温搅拌过夜。反应液中加入氯化铵水溶液(30mL)，用乙酸乙酯(50mL x 3)萃取。有机相用无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(乙酸乙酯/石油醚＝1/8)，得标题化合物(4g,98％)，为黄色固体。Add isopropylmagnesium chloride (2M tetrahydrofuran solution, 12.8 mL, 24.3) to a solution of 2-chloro-4-fluoro-1-iodobenzene (6.27 g, 24.3 mmol) in tetrahydrofuran (50 mL). Mm). The reaction solution was stirred at -20 ° C for 3 hours. To a solution of 2-bromo-4-((2,4-dimethoxybenzyl)amino)-5-fluorobenzaldehyde (3 g, 8.1 mmol) in tetrahydrofuran (30 mL) The above (2-chloro-4-fluorophenyl)magnesium bromide solution was added, and the reaction mixture was stirred at room temperature overnight. An aqueous ammonium chloride solution (30 mL) was added to the mixture, and ethyl acetate (50 mL? The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by EtOAc EtOAcjjjjjj

步骤2:(2-溴-4-((2,4-二甲氧基苄基)氨基)-5-氟苯基)(2-氯-4-氟苯基)甲酮Step 2: (2-Bromo-4-((2,4-dimethoxybenzyl)amino)-5-fluorophenyl)(2-chloro-4-fluorophenyl)methanone

将(2-溴-4-((2,4-二甲氧基苄基)氨基)-5-氟苯基)(2-氯-4-氟苯基)甲醇(4g,8.0mmol)和Dess-Martin氧化剂(4.75g,11.2mmol)混合于二氯甲烷(50mL)中，在室温下搅拌1小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝10/1)，得标题化合物(3.8g，95％)，为黄色固体。LCMS(ESI)[M+H]+＝496.0.(2-Bromo-4-((2,4-dimethoxybenzyl)amino)-5-fluorophenyl)(2-chloro-4-fluorophenyl)methanol (4 g, 8.0 mmol) and Dess -Martin oxidizing agent (4.75 g, 11.2 mmol) was mixed with dichloromethane (50 mL) and stirred at room temperature for 1 hour. The reaction mixture was filtered, EtOAc EtOAcjjjjjjjjj LCMS (ESI) [M+H]+=495.

步骤3:(4-氨基-2-溴-5-氟苯基)(2-氯-4-氟苯基)甲酮Step 3: (4-Amino-2-bromo-5-fluorophenyl)(2-chloro-4-fluorophenyl)methanone

将(2-溴-4-((2,4-二甲氧苄基)氨基)-5-氟苯基)(2-氯-4-氟苯基)甲酮(3.8g,7.6mmol)和三氟乙酸(6.8g,60mmol)溶于二氯甲烷(50mL)中，在室温下搅拌过夜。反应液浓缩，残余物用快速色谱法分离纯化(二氯甲烷/甲醇＝20/1)，得标题化合物(3.0g,99％)，为黄色固体。LCMS(ESI)[M+H]+＝345.9.(2-Bromo-4-((2,4-dimethoxybenzyl)amino)-5-fluorophenyl)(2-chloro-4-fluorophenyl)methanone (3.8 g, 7.6 mmol) and Trifluoroacetic acid (6.8 g, 60 mmol) was dissolved in dichloromethane (50 mL). The reaction mixture was concentrated, EtOAcjjjjjjjjj LCMS (ESI) [M+H]+ = 345.9.

步骤4:N-(5-溴-4-(2-氯-4-氟苯甲酰基)-2-氟苯基)-N-(乙基砜)乙磺酰胺Step 4: N-(5-Bromo-4-(2-chloro-4-fluorobenzoyl)-2-fluorophenyl)-N-(ethylsulfone)ethanesulfonamide

在0℃下，向(4-氨基-2-溴-5-氟苯基)(2-氯-4-氟苯基)甲酮(3g,7.6mmol)和三乙胺(8.7g,86mmol)的二氯甲烷(50mL)溶液中加入乙磺酰氯(11g,86mmol)。反应液在室温下搅拌过夜并浓缩，残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝1/1)，得标题化合物(1.5g,28％)，为黄色固体。LCMS(ESI)[M+Na]+＝553.8.To (4-amino-2-bromo-5-fluorophenyl)(2-chloro-4-fluorophenyl)methanone (3 g, 7.6 mmol) and triethylamine (8.7 g, 86 mmol) at 0 °C Ethyl sulfonyl chloride (11 g, 86 mmol) was added to a solution of dichloromethane (50 mL). The reaction mixture was stirred with EtOAc EtOAc EtOAc. LCMS (ESI) [M+Na]+ = 553.8.

步骤5:N-(5-溴-4-(2-氯-4-氟苯甲酰基)-2-氟苯基)乙磺酰胺Step 5: N-(5-Bromo-4-(2-chloro-4-fluorobenzoyl)-2-fluorophenyl)ethanesulfonamide

向N-(5-溴-4-(2-氯-4-氟苯甲酰基)-2-氟苯基)-N-(乙基砜)乙磺酰胺(1.6g,3.4mmol)的四氢呋喃(10mL)溶液中滴加10％NaOH水溶液(10mL)。混合物在室温下搅拌0.5小时，并用乙酸乙酯(10mL)萃取。有机相用无水硫酸钠干燥，过滤并浓缩。残余物用快速色谱法分离纯化(石油醚/乙酸乙酯＝2/1)，得标题化合物(780mg，63％)，为黄色固体。LCMS(ESI)[M+H]+＝437.9.To N-(5-bromo-4-(2-chloro-4-fluorobenzoyl)-2-fluorophenyl)-N-(ethylsulfone)ethanesulfonamide (1.6 g, 3.4 mmol) in tetrahydrofuran A 10% aqueous NaOH solution (10 mL) was added dropwise to the solution of 10 mL). The mixture was stirred at room temperature for 0.5 hr and extracted with EtOAc EtOAc. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified with EtOAc EtOAcjjjjjjj LCMS (ESI) [M+H]+=437.9.

步骤6:((5-(2-(2-氯-4-氟苯甲酰基)-5-(乙磺酰胺基)-4-氟苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯Step 6: ((5-(2-(2-Chloro-4-fluorobenzoyl)-5-(ethanesulfonamido)-4-fluorophenyl)-1-methyl-2-oxo-1 ,2-dihydropyridin-4-yl)methyl)carbamic acid tert-butyl ester

将N-(5-溴-4-(2-氯-4-氟苯甲酰基)-2-氟苯基)乙磺酰胺(280mg,0.47mmol)，((1-甲基-2-氧代-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(234mg,0.47mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(47mg,0.047mmol)和碳酸钾(266mg,1.41mmol)混合于1,4-二氧六环(5mL)和水(0.5mL)中，在氮气保护下加热至95℃搅拌1小时。反应液过滤，滤液浓缩，残余物用快速色谱法分离纯化(乙酸乙酯/甲醇＝10/1)，得标题化合物(130mg,34％)，为黄色固体。LCMS(ESI)[M+H]+＝596.0.N-(5-Bromo-4-(2-chloro-4-fluorobenzoyl)-2-fluorophenyl)ethanesulfonamide (280 mg, 0.47 mmol), ((1-methyl-2-oxo) -5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridin-4-yl)methyl)carbamic acid tert-Butyl ester (234 mg, 0.47 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (47 mg, 0.047 mmol) and potassium carbonate (266 mg, 1.41 mmol) It was mixed with 1,4-dioxane (5 mL) and water (0.5 mL), and heated to 95 ° C under nitrogen for 1 hour. The reaction mixture was filtered, EtOAcjjjjjjjjjj LCMS (ESI) [M+H]+ = 596.0.

步骤7:N-(7-(2-氯-4-氟苯基)-9-氟-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺Step 7: N-(7-(2-chloro-4-fluorophenyl)-9-fluoro-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)ethanesulfonamide

向((5-(2-(2-氯-4-氟苯甲酰基)-5-(乙磺酰胺基)-4-氟苯基)-1-甲基-2-氧代-1,2-二氢吡啶-4-基)甲基)氨基甲酸叔丁酯(130mg,0.22mmol)的二氯甲烷(4mL)溶液中加入三氟乙酸(1mL)。反应液在室温下搅拌过夜并浓缩。残余物用制备-HPLC分离纯化，得标题化合物(83.4mg,80％)，为黄色固体。LCMS(ESI)[M+H]+＝478.0；1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.13(s,1H),7.60–7.64(m,2H),7.44(d,J＝2.4Hz,1H),7.34–7.38(m,1H),6.6(d,J＝10.4Hz,1H),6.53(s,1H),4.77(dd,J＝10.8Hz,2.4Hz,1H),3.97(dd,J＝9.6Hz,2.4Hz 1H),3.52(s,3H),3.27(q,J＝6.8Hz,2H),1.28(t,J＝7.6Hz,3H).To ((5-(2-(2-chloro-4-fluorobenzoyl)-5-(ethanesulfonyl)-4-fluorophenyl)-1-methyl-2-oxo-1,2 To a solution of tert-butyl dihydropyridin-4-yl)methyl)carbamate (130 mg, 0.22 mmol) in dichloromethane (4 mL) The reaction was stirred at room temperature overnight and concentrated. The residue was purified with EtOAcqqqqqq LCMS (ESI) [M+H] + = 478.0; 1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.13 (s, 1H), 7.60 - 7.64 (m, 2H), 7.44 (d) , J = 2.4 Hz, 1H), 7.34 - 7.38 (m, 1H), 6.6 (d, J = 10.4 Hz, 1H), 6.53 (s, 1H), 4.77 (dd, J = 10.8 Hz, 2.4 Hz, 1H ), 3.97 (dd, J = 9.6 Hz, 2.4 Hz 1H), 3.52 (s, 3H), 3.27 (q, J = 6.8 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H).

效果实施例1：对BET蛋白抑制剂的BRD4(BD1，BD2)酶水平活性测定Effect Example 1: Determination of activity of BRD4 (BD1, BD2) enzyme level of BET protein inhibitor

实验方法：experimental method:

上述实施例中各化合物与BRD4蛋白溴区结构域的结合活性测试采用的是HTRF检测技术，检测化合物的IC ₅₀值。使用DMSO对化合物进行梯度稀释。使用试剂盒中的Diluent Buffer稀释BRD4(BD1、BD2)蛋白和Biotin标记的组蛋白H4肽段，并配制反应液。使用试剂盒中的Detection Buffer稀释Anti-GST-TB ²⁺Cryptate和SA-XL-665，并配置检测液。取384孔板一块，按照排板布置，板上分待测化合物孔，对照孔min(高浓度阳性药)，对照孔max(DMSO)，阳性药对照孔。向孔板中的各孔分别加入对应浓度的化合物或DMSO溶液20nL。继续向孔板中的各孔加入反应液10μL，随后加入检测液10μL。室温下孵育2h后，用Envision检测仪的TR-Fret模式(λex＝340nm，λem1＝615nm，λem2＝665nm)读取荧光数值和HTRF信号值。 Each of the above embodiments BRD4 activity test compound binding domain of protein used is bromine region HTRF detection technology, IC ₅₀ values of the test compound. The compounds were serially diluted using DMSO. The BRD4 (BD1, BD2) protein and the Biotin-labeled histone H4 peptide were diluted using Diluent Buffer in the kit, and the reaction solution was prepared. Dilute Anti-GST-TB ²⁺ Cryptate and SA-XL-665 using the Detection Buffer in the kit and configure the test solution. Take a 384-well plate and arrange according to the plate arrangement. The plate is divided into test compound holes, control well min (high concentration positive drug), control hole max (DMSO), positive drug control well. 20 nL of the corresponding concentration of compound or DMSO solution was added to each well in the well plate. 10 μL of the reaction solution was further added to each well of the well plate, and then 10 μL of the test solution was added. After incubation for 2 h at room temperature, the fluorescence values and HTRF signal values were read using the TR-Fret mode of the Envision detector (λex = 340 nm, λem1 = 615 nm, λem2 = 665 nm).

数值处理：抑制率＝(Max-Signal)/(Max-Min)*100％。Max：Biotin标记的组蛋白H4肽段与蛋白完全结合的HTRF信号值。Min：加入高浓度阳性药后Biotin标记的组蛋白H4肽段与蛋白完全不结合的HTRF本底值。Signal：化合物相应浓度下的HTRF信号值。以化合物浓度和相应的抑制率做四参数曲线拟合，得到相应化合物的IC ₅₀。 Numerical processing: inhibition rate = (Max-Signal) / (Max-Min) * 100%. Max: HTRF signal value for the binding of the biotin-labeled histone H4 peptide to the protein. Min: HTRF background value of the Biotin-labeled histone H4 peptide fragment that does not bind to the protein at all after the addition of a high concentration of the positive drug. Signal: The HTRF signal value at the corresponding concentration of the compound. A four-parameter curve fit was performed with the compound concentration and the corresponding inhibition rate to obtain the IC _{50 of the} corresponding compound.

表1 为化合物BRD4实验生物活性结果Table 1 shows the biological activity results of the compound BRD4

由表1可以看出，本发明提供的部分化合物与BRD4蛋白溴区结构域的结合活性良好。As can be seen from Table 1, some of the compounds provided by the present invention have good binding activity to the bromine domain of the BRD4 protein.

效果实施例2：对MV-4-11细胞的抑制作用Effect Example 2: Inhibition of MV-4-11 cells

对上述实施例中各化合物对MV-4-11细胞的抑制作用进行测定的抑制作用进行测定，具体操作如下：The inhibitory effect of the inhibition of the inhibition of MV-4-11 cells by each compound in the above examples was measured, and the specific operation was as follows:

实验方法：experimental method:

第1天：细胞种板Day 1: Cell seed plate

1.显微镜下观察，确定细胞状态良好；1. Observed under the microscope to determine that the cells are in good condition;

2.将细胞转移到15mL离心管中，1000rpm离心5min，弃上清；2. Transfer the cells to a 15 mL centrifuge tube, centrifuge at 1000 rpm for 5 min, and discard the supernatant;

3.加入完全培养基(IMDM+10％FBS)，吹打成单细胞悬液，Vi-cell细胞计数仪计数，用完全培养基将细胞悬液调整到所需细胞密度；3. Add complete medium (IMDM + 10% FBS), blow into a single cell suspension, count on a Vi-cell cytometer, and adjust the cell suspension to the desired cell density with complete medium;

4.接种至96孔板中，每孔100μL使细胞数为15000/孔，空白对照加入100μL完全培养基；4. Inoculate into a 96-well plate, 100 μL per well to make the number of cells 15000 / well, and add 100 μL of complete medium to the blank control;

5. 37℃、5％CO ₂培养过夜。 5. Incubate overnight at 37 ° C, 5% CO ₂ .

第2天：加药Day 2: Dosing

1.1000×化合物板配制1.1000× compound plate preparation

1.1将待测化合物用DMSO配成10mM的工作液。将STS用DMSO配成2mM的工作液。1.1 The test compound was formulated into a 10 mM working solution in DMSO. STS was formulated into 2 mM working solution in DMSO.

1.2在圆型底96孔板中A至H行的第2列加入60μL 10mM待测化合物(或STS)的工作液，3-11列加入40μL DMSO，用排枪从第2列中吸取20μL药物溶液至第3列，吹打混合均匀；再从第3列中吸取20μL溶液至第4列，吹打混合均匀，依次继续将药物进行3倍比稀释，共10个浓度。96孔板的第1和第12列补充40μL DMSO。1.2 Add 60 μL of 10 mM test compound (or STS) working solution to the second column of row A to H in a round bottom 96-well plate, add 40 μL of DMSO to columns 3-11, and draw 20 μL of drug solution from the second column with a lance. To the third column, mix thoroughly by pipetting; then take 20 μL of the solution from the third column to the fourth column, mix thoroughly by blowing, and continue to dilute the drug by 3 times in total, for a total of 10 concentrations. Columns 1 and 12 of the 96-well plate were supplemented with 40 μL of DMSO.

2.中间板配制2. Intermediate plate preparation

取无菌V型底96深孔板，每孔加入495μL无FBS的RPMI 1640培养基，吸取1000×化合物板中的稀释好的化合物(或DMSO)5μL加入对应位置的V型底96孔板中，充分吹打均匀。A sterile V-bottom 96 deep-well plate was prepared, and 495 μL of FBS-free RPMI 1640 medium was added to each well, and 5 μL of the diluted compound (or DMSO) in a 1000× compound plate was added to the V-bottom 96-well plate at the corresponding position. , blow it evenly.

3.药物加入3. Drug addition

3.1从培养箱中取出细胞板，显微镜下观察。取中间板中稀释好的化合物或DMSO加入细胞板中，每孔11μL。3.1 Remove the cell plate from the incubator and observe under a microscope. The diluted compound or DMSO from the middle plate was added to the cell plate at 11 μL per well.

3.2将细胞置于37℃、5％CO ₂中继续培养72h。 3.2 The cells were incubated for 72 h at 37 ° C, 5% CO ₂ .

第5天：CellTiter-Glo检测细胞活性Day 5: CellTiter-Glo detects cell viability

1.将CellTiter-Glo缓冲液和反应底物从冰箱中取出，平衡至室温后将缓冲液倒入装有底物的棕色瓶中，上下颠倒使底物粉末充分溶解。1. The CellTiter-Glo buffer and the reaction substrate were taken out from the refrigerator, and after equilibrating to room temperature, the buffer was poured into a brown bottle containing the substrate, and the substrate powder was sufficiently dissolved upside down.

2.将细胞在显微镜下观察，细胞板平衡至室温。2. The cells were observed under a microscope and the cell plates were equilibrated to room temperature.

3.将配制好的CellTiter-Glo加入96孔板中，每孔100μL。3. Add the prepared CellTiter-Glo to a 96-well plate at 100 μL per well.

4.将细胞板置于摇床上震荡10min，然后常温静置10min。4. Place the cell plate on a shaker for 10 min, then let stand for 10 min at room temperature.

5.在孔板底部贴上白色封膜，Enspire微孔板检测仪检测各孔化学发光信号。5. A white seal film is attached to the bottom of the well plate, and the Enspire microplate detector detects the chemiluminescence signal of each well.

6.使用XLfit进行数据处理。抑制率％＝(d-c)/(d-b)×100，其中d为DMSO处理组的信号值，c为化合物处理组的信号值，b为仅含有培养基和DMSO而不含细胞的空白组的信号值。数据用XLfit软件中f(x)205[fit＝(A+((B-A)/(1+((C/x) ^{^D}))))]方程进行拟合。 6. Use XLfit for data processing. Inhibition rate % = (dc) / (db) × 100, where d is the signal value of the DMSO-treated group, c is the signal value of the compound-treated group, and b is the signal of the blank group containing only the medium and DMSO but no cells. value. Data using XLfit software f (x) 205 [fit = (A + ((BA) / (1 + ((C / x) ^ D))))] Equation fit.

表2 为化合物MV-4-11细胞实验生物活性结果。Table 2 shows the results of experimental biological activity of compound MV-4-11 cells.

表2Table 2

化合物Compound	MV-4-11(μM)MV-4-11 (μM)
(+)-JQ1(+)-JQ1	0.2480.248
41064106	0.2040.204
41074107	0.0270.027
41084108	0.1020.102
41094109	0.1420.142
41104110	0.0100.010
41114111	0.0960.096
41134113	0.0080.008
41144114	0.0060.006
41154115	0.1330.133
41164116	0.0630.063
41174117	0.0040.004
41184118	0.2640.264
41194119	0.1380.138
41204120	0.0190.019
41214121	0.2440.244
41224122	0.1620.162
41234123	0.0100.010
41244124	0.0180.018
41254125	0.0060.006
41264126	--
41274127	--
41284128	0.0400.040
41294129	--
41304130	0.0510.051
41314131	0.1520.152
41324132	--
41334133	0.0900.090
41344134	0.0810.081

41354135	0.0430.043
41364136	0.2060.206
41374137	0.1530.153
41384138	0.0570.057
41394139	0.0200.020
41404140	0.0550.055
41414141	0.1310.131
41424142	0.0160.016
41434143	0.1890.189
41444144	0.3300.330
41454145	0.3580.358
41464146	0.0300.030
4097-P14097-P1	0.03740.0374

该表中“-”表示未测试。The "-" in the table indicates that it was not tested.

由表2可以看出，本发明提供的部分化合物对MV-4-11细胞具有良好的抑制作用。As can be seen from Table 2, some of the compounds provided by the present invention have a good inhibitory effect on MV-4-11 cells.

效果实施例3：对肝微粒体中代谢稳定性实验Effect Example 3: Metabolic stability test in liver microsomes

对上述实施例中部分化合物的肝微粒体中代谢稳定性进行测定，具体操作如下：The metabolic stability of the liver microsomes of some of the compounds in the above examples was determined as follows:

实验方法：experimental method:

1.缓冲液C的配制：1. Preparation of buffer C:

缓冲液A：1.0L的0.1M磷酸二氢钾缓冲液(含1.0mM EDTA)；Buffer A: 1.0 L of 0.1 M potassium dihydrogen phosphate buffer (containing 1.0 mM EDTA);

缓冲液B：1.0L的0.1M磷酸氢二钾缓冲液(含1.0mM EDTA)；Buffer B: 1.0 L of 0.1 M dibasic potassium phosphate buffer (containing 1.0 mM EDTA);

缓冲液C：用缓冲液A滴定500mL缓冲液B，至pH 7.4。Buffer C: 500 mL Buffer B was titrated with Buffer A to pH 7.4.

2. 10mM储备液的配制：2. Preparation of 10 mM stock solution:

10mM受试化合物：称取一定量的受试化合物溶于DMSO。10 mM test compound: A certain amount of the test compound was weighed and dissolved in DMSO.

10mM对照品：5.455mg的酮色林溶于1mL的DMSO。10 mM control: 5.455 mg of ketanserin was dissolved in 1 mL of DMSO.

3.给药溶液的配制：3. Preparation of the drug solution:

500μM溶液：将5μL的10mM储备液(见步骤2)加入到95μL ACN中；500 μM solution: 5 μL of 10 mM stock solution (see step 2) was added to 95 μL of ACN;

1.5μM给药溶液(溶解于肝微粒体溶液中)：1.5 μM dosing solution (dissolved in liver microsome solution):

将18.75μL的20mg/mL肝微粒体加入到479.75μL缓冲液C中，然后再加入1.5μL的500μM溶液，轻微振荡混匀。18.75 μL of 20 mg/mL liver microsomes were added to 479.75 μL of buffer C, and then 1.5 μL of 500 μM solution was added, and the mixture was gently shaken.

4. 6mM NADPH溶液的配制：4. Preparation of 6mM NADPH solution:

称取NADPH 15mg，然后加入3mL缓冲液C，配制成6mM的NADPH溶液。NADPH 15 mg was weighed, and then 3 mL of buffer C was added to prepare a 6 mM NADPH solution.

5.将30L的1.5μM给药溶液(见步骤3)分别加入到96孔板上设置为不同时间点(0分钟、5分钟、15分钟、30分钟、45分钟)的孔中，复样数为2。5. Add 30 L of 1.5 μM dosing solution (see step 3) to the wells of 96-well plates set at different time points (0 minutes, 5 minutes, 15 minutes, 30 minutes, 45 minutes). Is 2.

6.制备0分钟样品：先将135μL ACN(含内标)加入到0分钟的孔中，再加入15L的6mM NADPH溶液。6. Preparation of a 0 minute sample: 135 μL of ACN (with internal standard) was first added to the 0 minute well, followed by 15 L of 6 mM NADPH solution.

7.将含1.5μM给药溶液的96孔板和NADPH溶液在37℃水浴中预热5分钟。7. The 96-well plate containing the 1.5 μM dosing solution and the NADPH solution were preheated in a 37 ° C water bath for 5 minutes.

8.将预热的15L的6mM NADPH溶液加入到设置为5分钟、15分钟、30分钟、45分钟点的孔中，启动反应并开始计时。8. Pre-heated 15 L of 6 mM NADPH solution was added to the wells set at 5 minutes, 15 minutes, 30 minutes, 45 minutes to initiate the reaction and start timing.

9.在计时器显示5分钟、15分钟、30分钟和45分钟时，加入135μL ACN(含内标)终止反应。9. At 5 minutes, 15 minutes, 30 minutes, and 45 minutes of the timer display, 135 μL of ACN (with internal standard) was added to stop the reaction.

10.涡旋振荡10min，在离心机(Thermo Multifuge×3R)上采用5594×g将样品离心15分钟。10. Vortex for 10 min and centrifuge the sample for 5 minutes on a centrifuge (Thermo Multifuge x 3R) using 5594 x g.

11.从离心后的样品中取出50μL上清液，转移至已加入100μL超纯水的96孔样品板中，混合，最后将样品送至LC-MS/MS分析。11. Remove 50 μL of the supernatant from the centrifuged sample, transfer to a 96-well sample plate to which 100 μL of ultrapure water has been added, mix, and finally send the sample to LC-MS/MS for analysis.

数据处理：data processing:

1.计算公式：1. Calculation formula:

半衰期(T _1/2)＝0.693/K(K是以浓度对数为纵坐标，培养时间为横坐标作直线回归所获得的速率常数) Half-life (T _1/2 )=0.693/K (K is the rate constant obtained by linear regression of the logarithm of the concentration as the ordinate and the incubation time as the abscissa)

内在清除率(CL _int)＝(0.693/T _1/2)×(1/(肝微粒体浓度(0.5mg/mL)))×换算系数(见表3) Intrinsic clearance rate (CL _int ) = (0.693 / T _1/2 ) × (1/ (liver microsomal concentration (0.5 mg / mL))) × conversion factor (see Table 3)

表3 在小鼠、大鼠、犬、猴和人肝微粒体*中的内在清除率计算时的换算系数。Table 3 Conversion factors at the time of calculation of intrinsic clearance in mouse, rat, canine, monkey, and human liver microsomes*.

*Handbook of Essential Pharmacokinetics，Pharmacodynamics and Drug Metabolism for Industrial Scientists，Younggil Kwon(Author)*Handbook of Essential Pharmacokinetics, Pharmacodynamics and Drug Metabolism for Industrial Scientists, Younggil Kwon (Author)

**换算系数＝(每克肝脏所含的肝微粒体蛋白)×(每千克体重的肝脏重量)** Conversion factor = (hepatic microsomal protein per gram of liver) × (hepatic weight per kilogram of body weight)

2.根据下面的方程式，使用Excel软件对化合物含量和反应时间作图并计算半衰期(分钟)2. Calculate the compound content and reaction time and calculate the half-life (minutes) according to the equation below using Excel software.

Y＝(Y ₀–Plateau)×e ^(-K*X)+Plateau Y=(Y ₀ –Plateau)×e ^(-K*X) +Plateau

Y ₀代表0分钟时的化合物含量；Y代表化合物含量；X代表时间点；K代表化合 Y ₀ represents the compound content at 0 minutes; Y represents the compound content; X represents the time point; K represents the compound

物降解速率常数；Plateau代表化合物可能达到的最低含量(在此定义为0)。The rate of degradation of the material; Plateau represents the lowest possible content of the compound (defined herein as 0).

T _1/2＝0.693/K。 T _1/2 =0.693/K.

表4 为化合物肝微粒体中代谢稳定实验结果Table 4 shows the results of metabolic stability experiments in compound liver microsomes.

表4Table 4

本发明提供的部分化合物肝微粒稳定性较好。The partial compound liver microparticles provided by the invention have good stability.

效果实施例4：药物代谢动力学研究Effect Example 4: Pharmacokinetic Study

对实施例4113,4133.4135和4142开展了静脉或口服给药后雌性Balb/c nude小鼠的药物代谢动力学研究。The pharmacokinetic studies of female Balb/c nude mice after intravenous or oral administration were performed on Examples 4113, 4133.4135 and 4142.

具体实验步骤：Specific experimental steps:

6只雌性Balb/c nude小鼠,体重范围18-20克。分成静脉及口服两组(3只/每组)，动物人工固定后，静脉组:0.5mg/kg(5mL/kg)由尾静脉注入(N＝3)；口服组:2mg/kg(10mL/kg)由灌胃注入(N＝3)。在取样时间点经由眼球后采血抽大约20μL，置于EDTA-2K试管。样品立刻加入40μL双蒸水稀释、涡旋直至混合充分。血样储存在约-70℃，交由BA组分析用(LC/MS)。30μL血样加入200μl H ₂O and 30μL IS***,200ng/mL)，使用LLE分层，加入1mL MTBW作为有机提取溶剂。混合物涡旋10min，10,000rpm离心5min。850μL上清液在氮气下蒸发直至干燥。干燥后的提取物使用150μL 50％甲醇重新混匀，涡旋2min后使用5μL上清液注入LC-MS/MS进行分析。 Six female Balb/c nude mice weighing 18-20 grams. Divided into two groups (3/group), after artificial fixation, the intravenous group: 0.5mg/kg (5mL/kg) was injected from the tail vein (N=3); the oral group: 2mg/kg (10mL/ Kg) was injected by gavage (N=3). Approximately 20 μL of blood was drawn through the eyeball at the sampling time point and placed in an EDTA-2K test tube. The sample was immediately diluted with 40 μL of double distilled water and vortexed until well mixed. Blood samples were stored at approximately -70 ° C and submitted to the BA group for analysis (LC/MS). 30 μL of blood sample was added with 200 μl of H ₂ O and 30 μL of IS dexamethasone, 200 ng/mL), layered with LLE, and 1 mL of MTBW was added as an organic extraction solvent. The mixture was vortexed for 10 min and centrifuged at 10,000 rpm for 5 min. 850 μL of the supernatant was evaporated under nitrogen until dry. The dried extract was re-mixed with 150 μL of 50% methanol, vortexed for 2 min, and then analyzed by injecting 5 μL of the supernatant into LC-MS/MS.

整个动物实验给药过程均未见动物有异常临床表现。No abnormal clinical manifestations were observed in the whole animal experimental administration.

PK参数计算使用非房室模型，WinNonlin 6.4软件计算。PK parameter calculations were calculated using a non-compartmental model, WinNonlin 6.4 software.

表5 为选取化合物的小鼠PK数据。Table 5 shows mouse PK data of selected compounds.

表5table 5

由表5可以看出，本发明提供的部分化合物在小鼠体内展现了优良的药代动力学性质。As can be seen from Table 5, some of the compounds provided by the present invention exhibited excellent pharmacokinetic properties in mice.

虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。While the invention has been described with respect to the preferred embodiments of the embodiments of the embodiments of the invention modify. Accordingly, the scope of the invention is defined by the appended claims.

Claims

一种如式I所示的苯并七元杂环类化合物、其互变异构体、其溶剂化物、其药学上可接受的盐或其前药：A benzo seven-membered heterocyclic compound of the formula I, a tautomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof:

其中，Z为CH或N；Where Z is CH or N;

X为N、NH或C(＝O)；Y为C、CH或N；
代表Y和X为单键或双键相连； X is N, NH or C(=O); Y is C, CH or N;
Representing Y and X as single or double bonds;

R ¹为-H、C ₁-C ₅的烷基、C ₃-C ₇环烷基、被一个或多个R ⁰取代的C ₁-C ₅的烷基、或-(CH ₂)n ₀C(＝O)N(R ^R1)(R ^R2)； R ¹ is -H, C ₁ -C ₅ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₅ alkyl substituted by one or more R ⁰ , or -(CH ₂ )n ₀ C(=O)N(R ^R1 )(R ^R2 );

R ⁰为C ₁-C ₅的烷氧基或-OH； R ⁰ is a C ₁ -C ₅ alkoxy group or -OH;

n ₀为0或1； n ₀ is 0 or 1;

R ^R1和R ^R2独立地为-H或C ₁-C ₅的烷基； R ^R1 and R ^{R2 are} independently -H or C ₁ -C ₅ alkyl;

Q为“被一个或多个R ^Q1取代的苯基”、或者为“被一个或多个R ^Q2取代的5-6元杂芳基”，所述的5-6元杂芳基中的杂原子为N和/或O，杂原子个数为1-3个； Q is "phenyl substituted by one or more R ^Q1 " or "5-6 membered heteroaryl substituted by one or more R ^Q2 ", which is heterozygous in the 5-6 membered heteroaryl The atom is N and/or O, and the number of heteroatoms is 1-3;

所述R ^Q1和R ^Q2独立地为-H、卤素、卤代或未取代的C ₁-C ₅的烷基、C ₃-C ₇环烷基、或、C ₁-C ₅的烷氧基； The R ^Q1 and R ^{Q2 are} independently -H, halogen, halogenated or unsubstituted C ₁ -C ₅ alkyl, C ₃ -C ₇ cycloalkyl, or C ₁ -C ₅ alkoxy ;

n为0、1或2；当n为1时，所述R位于Y的对位或间位；n is 0, 1, or 2; when n is 1, the R is in the para or meta position of Y;

R独立地为卤素、羟基取代的C ₁-C ₅的烷基、-N(R ^2e)(CH ₂)n ^β2-S(＝O) ₂(R ²ⁱ)、-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)、-(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)、-S(＝O)(R ²ⁱ)或-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)； R is independently a halogen, a hydroxy-substituted C ₁ -C ₅ alkyl group, -N(R ^2e )(CH ₂ )n ^β2 -S(=O) ₂ (R ²ⁱ ), -(CH ₂ )n ^β2 N (R ^2k )S(=O) ₂ (R ^2d ), -(CH ₂ )n ^β2 -S(=O) ₂ N(R ^2f )(R ^2g ), -S(=O)(R ²ⁱ ) or -C ₁ -C ₆ alkyl-S(=O) ₂ (R ²ⁱ );

所述n ^β2独立地为0、1或2； The n ^{β2 is} independently 0, 1, or 2;

所述R ^2d、R ^2e、R ^2f、R ^2g、R ²ⁱ和R ^2k各自独立地为-H、C ₁-C ₆的烷基、被1个或多个卤素取代C ₁-C ₆的烷基、或3-7元环烷基； The R ^2d , R ^2e , R ^2f , R ^2g , R ²ⁱ and R ^2k are each independently -H, a C ₁ -C ₆ alkyl group, and a C ₁ -C ₆ alkane substituted by one or more halogens a base, or a 3-7 membered cycloalkyl group;

或者，当n为2、且两个R相邻时，相邻的两个R与它们连接的原子共同形成含1 个或多个杂原子或者砜基的5-6元杂环烃基；Alternatively, when n is 2 and two R are adjacent, the adjacent two Rs together with the atoms to which they are attached form a 5-6 membered heterocycloalkyl group having one or more heteroatoms or sulfone groups;

W为CH或N；W is CH or N;

R ²为氢、-NR ^2-1R ^2-2或-C(＝O)NR ^2-3R ^2-4； R ² is hydrogen, -NR ^2-1 R ^2-2 or -C(=O)NR ^2-3 R ^2-4 ;

R ^2-1、R ^2-2、R ^2-3和R ^2-4各自独立地为氢、C ₁-C ₅的烷基或C ₃-C ₆环烷基； R ^2-1 , R ^2-2 , R ^2-3 and R ^2-4 are each independently hydrogen, C ₁ -C ₅ alkyl or C ₃ -C ₆ cycloalkyl;

但所述式I所示的苯并七元杂环类化合物不为以下化合物：However, the benzoheptacyclic heterocyclic compound represented by the formula I is not the following compound:

6-(4-氟苯基)-2-甲基-9-(甲基砜甲基)-5-氧代2,4,5,6-四氢苯并[b]吡咯并[3,4-d]吖庚因-3-腈；6-(4-Fluorophenyl)-2-methyl-9-(methylsulfonemethyl)-5-oxo 2,4,5,6-tetrahydrobenzo[b]pyrrolo[3,4 -d] 吖gyne-3-nitrile;

6-(4-氟苯基)-2-甲基-9-(甲基砜甲基)-5-氧代2,4,5,6-四氢苯并[b]吡咯并[3,4-d]吖庚因-3-羧酰胺；6-(4-Fluorophenyl)-2-methyl-9-(methylsulfonemethyl)-5-oxo 2,4,5,6-tetrahydrobenzo[b]pyrrolo[3,4 -d] anthraquinone-3-carboxamide;

6-(4-氟苯基)-2-甲基-9-(甲基砜甲基)-2,4,5,6-四氢苯并[b]吡咯并[3,4-d]吖庚因-3-腈；6-(4-Fluorophenyl)-2-methyl-9-(methylsulfonemethyl)-2,4,5,6-tetrahydrobenzo[b]pyrrolo[3,4-d]indole Gyne-3-nitrile;

6-(4-氟苯基)-2-甲基-9-(甲基砜甲基)-2,4,5,6-四氢苯并[b]吡咯并[3,4-d]吖庚因-3-羧酰胺；6-(4-Fluorophenyl)-2-methyl-9-(methylsulfonemethyl)-2,4,5,6-tetrahydrobenzo[b]pyrrolo[3,4-d]indole Gyne-3-carboxamide;

9-氟-6-(4-氟苯基)-2-甲基-2,4,5,6-四氢吡啶并[2,3-b]吡咯并[3,4-d]吖庚因-3-羧酰胺；9-fluoro-6-(4-fluorophenyl)-2-methyl-2,4,5,6-tetrahydropyrido[2,3-b]pyrrolo[3,4-d]azepine -3-carboxamide;

7-(4-氟苯基)-2-甲基-10-(甲基砜甲基)-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮；7-(4-Fluorophenyl)-2-methyl-10-(methylsulfonemethyl)-2H-benzo[c]pyrido[3,4-e]azepine-3(5H)- ketone;

7-(4-氟苯基)-2-甲基-10-(甲基砜甲基)-6,7-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮甲酸盐；7-(4-Fluorophenyl)-2-methyl-10-(methylsulfonemethyl)-6,7-dihydro-2H-benzo[c]pyrido[3,4-e]aza Zhuo-3(5H)-ketoformate;

7-(4-氟苯基)-2-甲基-10-(甲基砜甲基)-6,7-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮；7-(4-Fluorophenyl)-2-methyl-10-(methylsulfonemethyl)-6,7-dihydro-2H-benzo[c]pyrido[3,4-e]aza Zhuo-3(5H)-one;

7-(4-氟苯基)-2-甲基-10-(乙基砜甲基)-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮；7-(4-Fluorophenyl)-2-methyl-10-(ethylsulfonemethyl)-2H-benzo[c]pyrido[3,4-e]azepine-3(5H)- ketone;

7-(4-氯苯基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；7-(4-chlorophenyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyrido[3,4-e]azepin-3-one;

7-(4-氯苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；7-(4-Chlorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyrido[3,4-e] Azaoxa-3-one;

7-(2,4-二氟苯基)-2-甲基-10-(乙基砜甲基)-2H-苯并[c]吡啶并[3,4-e]氮杂卓-3(5H)-酮；7-(2,4-Difluorophenyl)-2-methyl-10-(ethylsulfonemethyl)-2H-benzo[c]pyrido[3,4-e]azepine-3 ( 5H)-ketone;

7-(4-氯-2-氟苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；7-(4-Chloro-2-fluorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridin[3, 4-e]azepin-3-one;

(S)-2-(7-(4-氟苯基)-2-甲基-10-(甲基砜甲基)-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺；(S)-2-(7-(4-fluorophenyl)-2-methyl-10-(methylsulfonylmethyl)-3-oxo-3,5-dihydro-2H-benzo[c Pyridine[3,4-e]azepin-5-yl)acetamide;

(S)-N-乙基-2-(7-(4-氟苯基)-2-甲基-10-(甲基砜甲基)-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺；(S)-N-ethyl-2-(7-(4-fluorophenyl)-2-methyl-10-(methylsulfonemethyl)-3-oxo-3,5-dihydro-2H -benzo[c]pyrido[3,4-e]azepin-5-yl)acetamide;

(S)-2-(7-(4-氯苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)-N-乙基乙酰胺；(S)-2-(7-(4-chlorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e] Azaoxa-5-yl)-N-ethylacetamide;

(S)-2-(7-(4-氯苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)-乙酰胺；(S)-2-(7-(4-chlorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e] Aza-pyridyl-5-yl)-acetamide;

(S)-2-(7-(4-氯苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)-N-异丙基乙酰胺；(S)-2-(7-(4-chlorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e] Aza-pyridyl-5-yl)-N-isopropylacetamide;

N-(7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；N-(7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e]azepine- 10-based) ethanesulfonamide;

7-(4-氟苯基)-10-甲氧基-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；7-(4-Fluorophenyl)-10-methoxy-2-methyl-2,5-dihydro-3H-benzo[c]pyrido[3,4-e]azepine-3- ketone;

7-(4-氟苯基)-9-甲氧基-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；7-(4-Fluorophenyl)-9-methoxy-2-methyl-2,5-dihydro-3H-benzo[c]pyrido[3,4-e]azepine-3- ketone;

(S)-N-乙基-2-(7-(4-氟苯基)-10-甲氧基-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺；(S)-N-ethyl-2-(7-(4-fluorophenyl)-10-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[ c] pyrido[3,4-e]azepin-5-yl)acetamide;

10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-2,5-二氢-3H-二吡啶并[2,3-c:3',4'-e]氮杂卓-3-酮；10-((Ethyl sulfonyl)methyl)-7-(4-fluorophenyl)-2-methyl-2,5-dihydro-3H-dipyrido[2,3-c:3',4 '-e】azepine-3-one;

(S)-N-乙基-2-(7-(4-氟苯基)-9-甲氧基-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺；(S)-N-ethyl-2-(7-(4-fluorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H-benzo[ c] pyrido[3,4-e]azepin-5-yl)acetamide;

N-(7-(4-氯苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；N-(7-(4-chlorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e]azepine- 10-based) ethanesulfonamide;

(S)-7-(4-氯苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-7-(4-chlorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyrido[3,4-e]azepine-3 -ketone;

(S)-10-((乙基砜)甲基)-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridine [3,4-e]azepin-3-one;

(R)-10-((乙基砜)甲基)-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(R)-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridine [3,4-e]azepin-3-one;

7-(4-氯苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-二吡啶并[3,4-c:3',4'-e]氮杂卓-3-酮；7-(4-Chlorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-dipyrido[3,4-c:3',4 '-e】azepine-3-one;

7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridin[3, 4-e]azepin-3-one;

(S)-2-(7-(4-氯苯基)-2-甲基-3-氧代-3,5-二氢-2H-二吡啶并[2,3-c:3',4'-e]氮杂卓-5-基)乙酰胺；(S)-2-(7-(4-chlorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-dipyrido[2,3-c:3',4 '-e>azepine-5-yl)acetamide;

(S)-2-(7-(4-氯苯基)-2-甲基-3-氧代-3,5-二氢-2H-二吡啶并[2,3-c:3',4'-e]氮杂卓-5-基)-N-乙基乙酰胺；(S)-2-(7-(4-chlorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-dipyrido[2,3-c:3',4 '-e>azepine-5-yl)-N-ethylacetamide;

N-(9-氯-7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；N-(9-chloro-7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e] Aza-indene-10-yl)ethanesulfonamide;

(S)-2-(7-(4-氯苯基)-9-氟-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)-N-乙基乙酰胺；(S)-2-(7-(4-chlorophenyl)-9-fluoro-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridin[3, 4-e]azepine-5-yl)-N-ethylacetamide;

(S)-N-乙基-2-(8-氟-7-(4-氟苯基)-9-甲氧基-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺；(S)-N-ethyl-2-(8-fluoro-7-(4-fluorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H -benzo[c]pyrido[3,4-e]azepin-5-yl)acetamide;

(S)-N-乙基-2-(10-氟-7-(4-氟苯基)-9-甲氧基-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺；(S)-N-ethyl-2-(10-fluoro-7-(4-fluorophenyl)-9-methoxy-2-methyl-3-oxo-3,5-dihydro-2H -benzo[c]pyrido[3,4-e]azepin-5-yl)acetamide;

(S)-10-((乙基砜)甲基)-7-(4-氯苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-chlorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridine [3,4-e]azepin-3-one;

(S)-5-乙基-10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-5-ethyl-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-2-methyl-2,5-dihydro-3H-benzo[c] Pyrido[3,4-e]azepin-3-one;

9-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；9-((Ethyl sulfonyl)methyl)-7-(4-fluorophenyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyrido[3,4-e] Azaoxa-3-one;

(R)-10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-5-(三氟甲基)-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(R)-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-2-methyl-5-(trifluoromethyl)-2,5-dihydro-3H-benzene And [c] pyrido[3,4-e]azepin-3-one;

10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基螺[苯并[c]吡啶并[3,4-e]氮杂卓-5,1'-环丙烷]-3(2H)-酮；10-((Ethyl sulfonyl)methyl)-7-(4-fluorophenyl)-2-methylspiro[benzo[c]pyrido[3,4-e]azepine-5,1' -cyclopropane]-3(2H)-one;

(S)-5-环丙基-10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-5-cyclopropyl-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-2-methyl-2,5-dihydro-3H-benzo[c Pyridine[3,4-e]azepin-3-one;

(S)-7-(4-氟苯基)-2,5-二甲基-10-((三氟甲基砜)甲基)-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-7-(4-fluorophenyl)-2,5-dimethyl-10-((trifluoromethylsulfone)methyl)-2,5-dihydro-3H-benzo[c] Pyrido[3,4-e]azepin-3-one;

(S)-10-((异丙基砜)甲基)-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((isopropylsulfone)methyl)-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridine And [3,4-e]azepin-3-one;

(S)-7-(4-氟苯基)-2,5-二甲基-10-((环丙基砜)甲基)-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-7-(4-fluorophenyl)-2,5-dimethyl-10-((cyclopropylsulfone)methyl)-2,5-dihydro-3H-benzo[c]pyridine And [3,4-e]azepin-3-one;

(S)-7-(2,4-二氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-7-(2,4-difluorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c Pyridine[3,4-e]azepin-3-one;

(S)-5-乙基-10-((乙基砜)甲基)-7-(4-氯苯基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-5-ethyl-10-((ethylsulfone)methyl)-7-(4-chlorophenyl)-2-methyl-2,5-dihydro-3H-benzo[c] Pyrido[3,4-e]azepin-3-one;

(5S)-10-((乙基亚砜)甲基)-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(5S)-10-((ethyl sulfoxide)methyl)-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridine And [3,4-e]azepin-3-one;

(S)-N-(7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；(S)-N-(7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4 -e]azepine-10-yl)ethanesulfonamide;

(S)-N-(7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)甲氨基磺酰胺；(S)-N-(7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4 -e]azepine-10-yl)methylaminosulfonamide;

(S)-1-乙基-3-(7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)脲；(S)-1-ethyl-3-(7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine And [3,4-e]azepine-10-yl)urea;

(S)-N-乙基-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-磺酰胺；(S)-N-ethyl-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridin[3 , 4-e]azepine-10-sulfonamide;

(S)-10-((乙基砜)甲基)-7-(4-甲氧基苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-methoxyphenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c] Pyrido[3,4-e]azepin-3-one;

(S)-10-((乙基砜)甲基)-7-(4-羟基苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-hydroxyphenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridine [3,4-e]azepin-3-one;

(S)-10-((乙基砜)甲基)-7-(4-氟-3-甲氧基苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-fluoro-3-methoxyphenyl)-2,5-dimethyl-2,5-dihydro-3H-benzene And [c] pyrido[3,4-e]azepin-3-one;

(S)-10-((乙基砜)甲基)-7-(4-氟-3-羟基苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-fluoro-3-hydroxyphenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[ c] pyrido[3,4-e]azepin-3-one;

(S)-N-(9-氟-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；(S)-N-(9-fluoro-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)ethanesulfonamide;

(S)-N-乙基-2-(10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺；(S)-N-ethyl-2-(10-((ethylsulfonyl)methyl)-7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro -2H-benzo[c]pyrido[3,4-e]azepin-5-yl)acetamide;

(S)-2-(10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酸；(S)-2-(10-((ethylsulfonyl)methyl)-7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo [c] Pyrido[3,4-e]azepine-5-yl)acetic acid;

(S)-2-(10-((乙基砜)甲基)-7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-5-基)乙酰胺；(S)-2-(10-((ethylsulfonyl)methyl)-7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo [c] Pyrido[3,4-e]azepin-5-yl)acetamide;

(S)-10-((乙基砜)甲基)-7-(4-氟苯基)-9-甲氧基-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-9-methoxy-2,5-dimethyl-2,5-dihydro-3H-benzene And [c] pyrido[3,4-e]azepin-3-one;

(S)-10-((乙基砜)甲基)-7-(4-氟苯基)-9-羟基-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-9-hydroxy-2,5-dimethyl-2,5-dihydro-3H-benzo[ c] pyrido[3,4-e]azepin-3-one;

(S)-N-(9-氯-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙基磺酰胺；(S)-N-(9-chloro-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)ethylsulfonamide;

(S)-7-(4-氟苯基)-2,5-二甲基-10-((甲基砜)甲基)-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-7-(4-fluorophenyl)-2,5-dimethyl-10-((methylsulfone)methyl)-2,5-dihydro-3H-benzo[c]pyridine [3,4-e]azepin-3-one;

(S)-10-((乙基砜)甲基)-7-(4-氟苯基)-5-异丙基-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4- e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-5-isopropyl-2-methyl-2,5-dihydro-3H-benzo[c Pyridine[3,4-e]azepin-3-one;

(S)-N-(7-(4-氯苯基)-9-氟-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；(S)-N-(7-(4-chlorophenyl)-9-fluoro-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)ethanesulfonamide;

(S)-N-(9-氯-5-乙基-7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；(S)-N-(9-chloro-5-ethyl-7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c] Pyrido[3,4-e]azepin-10-yl)ethanesulfonamide;

(S)-N-(5-乙基-9-氟-7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；(S)-N-(5-ethyl-9-fluoro-7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c] Pyrido[3,4-e]azepin-10-yl)ethanesulfonamide;

(S)-N-(9-氯-7-(4-氯苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；(S)-N-(9-chloro-7-(4-chlorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)ethanesulfonamide;

(S)-10-氨基-9-氯-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-amino-9-chloro-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridin[3,4 -e]azepine-3-one;

(S)-10-氨基-9-氟-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-amino-9-fluoro-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridin[3,4 -e]azepine-3-one;

(S)-(7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)甲磺酰胺；(S)-(7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4-e Azapine-10-yl)methanesulfonamide;

(S)-1-(7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)-N-甲基甲磺酰胺；(S)-1-(7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4 -e]azepine-10-yl)-N-methylmethanesulfonamide;

(S)-1-(7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10基)-N,N-二甲基甲磺酰胺；(S)-1-(7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4 -e]azepine-10-)-N,N-dimethylmethanesulfonamide;

(S)-N-(9-氟-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)甲磺酰胺；(S)-N-(9-fluoro-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)methanesulfonamide;

(S)-4-(10-((乙基砜)甲基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡唑并[3,4-e]氮杂卓-7-基)苯甲腈；(S)-4-(10-((ethylsulfonyl)methyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrazolo[ 3,4-e]azepine-7-yl)benzonitrile;

(S)-N-(9-氯-5-环丙基-7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；(S)-N-(9-chloro-5-cyclopropyl-7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c Pyridine[3,4-e]azepin-10-yl)ethanesulfonamide;

10-((乙基砜)甲基)-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[e]吡啶并[4,3-c][1,2]二氮杂卓-3-酮；10-((Ethyl sulfonyl)methyl)-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[e]pyrido[4,3 -c][1,2]diazepine-3-one;

(S)-N-(9-氯-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)甲磺酰胺；(S)-N-(9-chloro-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)methanesulfonamide;

(S)-N-(9-氯-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)环丙基磺酰胺；(S)-N-(9-chloro-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)cyclopropylsulfonamide;

10-((乙基砜)甲基)-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]哒嗪并[3,4-e]氮杂卓-3-酮；10-((Ethyl sulfonyl)methyl)-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridazine[3, 4-e]azepin-3-one;

10-((乙基砜)甲基)-7-(4-氟苯基)-5-(甲氧基甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；10-((Ethyl sulfonyl)methyl)-7-(4-fluorophenyl)-5-(methoxymethyl)-2-methyl-2,5-dihydro-3H-benzo[c Pyridine[3,4-e]azepin-3-one;

(S)-N-(9-氟-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)丙酰胺；(S)-N-(9-fluoro-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyridine [3,4-e]azepine-10-yl)propionamide;

(S)-N-(5-环丙基-9-氟-7-(4-氟苯基)-2-甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)乙磺酰胺；(S)-N-(5-cyclopropyl-9-fluoro-7-(4-fluorophenyl)-2-methyl-3-oxo-3,5-dihydro-2H-benzo[c Pyridine[3,4-e]azepin-10-yl)ethanesulfonamide;

(S)-10-((乙基砜)甲基)-9-氟-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-9-fluoro-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[ c] pyrido[3,4-e]azepin-3-one;

(S)-9-氯-10-((乙基砜)甲基)-7-(4-氟苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-9-chloro-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[ c] pyrido[3,4-e]azepin-3-one;

(S)-10-((乙基砜)甲基)-7-(4-氟-2-甲氧基苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-fluoro-2-methoxyphenyl)-2,5-dimethyl-2,5-dihydro-3H-benzene And [c] pyrido[3,4-e]azepin-3-one;

(S)-10-((乙基砜)甲基)-7-(4-氟苯基)-5-(2-羟乙基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(4-fluorophenyl)-5-(2-hydroxyethyl)-2-methyl-2,5-dihydro-3H- Benzo[c]pyrido[3,4-e]azepin-3-one;

10-((乙基砜)甲基)-7-(4-氟-3-甲氧基苯基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；10-((Ethyl sulfonyl)methyl)-7-(4-fluoro-3-methoxyphenyl)-2-methyl-2,5-dihydro-3H-benzo[c]pyridin[ 3,4-e]azepin-3-one;

(S)-2-(7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)-N-甲基丙烷-2-磺酰胺；(S)-2-(7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4 -e]azepine-10-yl)-N-methylpropane-2-sulfonamide;

1-((S)-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)-N-甲基乙烷-1-磺酰胺；1-((S)-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c]pyrido[3,4 -e]azepine-10-yl)-N-methylethane-1-sulfonamide;

N-(9-氟-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[e]吡啶并[4,3-c][1,2]二氮杂卓-10-基)乙磺酰胺；N-(9-fluoro-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[e]pyrido[4,3 -c][1,2]diazepine-10-yl)ethanesulfonamide;

7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[e]吡啶并[4,3-c][1,2]二氮杂卓-3-酮；7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[e]pyridine [4,3-c][1,2]diazepine-3-one;

10-((乙基砜)甲基)-7-(4-氟苯基)-9-甲氧基-2-甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；10-((Ethyl sulfonyl)methyl)-7-(4-fluorophenyl)-9-methoxy-2-methyl-2,5-dihydro-3H-benzo[c]pyridin[ 3,4-e]azepin-3-one;

N-(9-氟-7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢吡啶-2H-苯并[c]哒嗪并[3,4-e]氮杂卓-10-基)乙磺酰胺；N-(9-fluoro-7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydropyridine-2H-benzo[c]pyridazine[3 , 4-e]azepine-10-yl)ethanesulfonamide;

7-(2-氯-4-氟-5-甲氧基苯基)-10-((乙基砜)甲基)-2-甲基-2,5-二氢-3H-苯并[c]吡啶并 [3,4-e]氮杂卓-3-酮；7-(2-Chloro-4-fluoro-5-methoxyphenyl)-10-((ethylsulfone)methyl)-2-methyl-2,5-dihydro-3H-benzo[c Pyridine[3,4-e]azepin-3-one;

7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]哒嗪并[3,4-e]氮杂卓-3-酮；7-(2-Chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c]pyridazine And [3,4-e]azepin-3-one;

7-(2-氯-4-氟苯基)-2-甲基-10-((甲基砜)甲基)-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；7-(2-Chloro-4-fluorophenyl)-2-methyl-10-((methylsulfone)methyl)-2,5-dihydro-3H-benzo[c]pyridin[3, 4-e]azepin-3-one;

1-(7-(4-氟苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[e]吡啶并[4,3-c][1,2]二氮杂卓-10-基)-N-甲基甲磺酰胺；1-(7-(4-fluorophenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[e]pyrido[4,3-c][ 1,2]diazepine-10-yl)-N-methylmethanesulfonamide;

10-((乙基砜)甲基)-7-(4-氟-3-甲氧基苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]哒嗪并[3,4-e]氮杂卓-3-酮；10-((Ethyl sulfonyl)methyl)-7-(4-fluoro-3-methoxyphenyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[c] Pyridazine[3,4-e]azepin-3-one;

(S)-7-(2-氯-4-氟苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-7-(2-chloro-4-fluorophenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro-3H-benzo[ c] pyrido[3,4-e]azepin-3-one;

(S)-7-(2-氯-4-氟-5-甲氧基苯基)-10-((乙基砜)甲基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-7-(2-chloro-4-fluoro-5-methoxyphenyl)-10-((ethylsulfone)methyl)-2,5-dimethyl-2,5-dihydro -3H-benzo[c]pyrido[3,4-e]azepin-3-one;

(S)-1-(7-(4-氟-3-甲氧基苯基)-2,5-二甲基-3-氧代-3,5-二氢-2H-苯并[c]吡啶并[3,4-e]氮杂卓-10-基)-N-甲基甲磺酰胺；(S)-1-(7-(4-fluoro-3-methoxyphenyl)-2,5-dimethyl-3-oxo-3,5-dihydro-2H-benzo[c] Pyrido[3,4-e]azepin-10-yl)-N-methylmethanesulfonamide;

(S)-10-((乙基砜)甲基)-7-(3-氟-4-甲氧基苯基)-2,5-二甲基-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮；(S)-10-((ethylsulfone)methyl)-7-(3-fluoro-4-methoxyphenyl)-2,5-dimethyl-2,5-dihydro-3H-benzene And [c] pyrido[3,4-e]azepin-3-one;

(S)-10-((乙基砜)甲基)-2,5-二甲基-7-(吡啶-4-基)-2,5-二氢-3H-苯并[c]吡啶并[3,4-e]氮杂卓-3-酮。(S)-10-((ethylsulfone)methyl)-2,5-dimethyl-7-(pyridin-4-yl)-2,5-dihydro-3H-benzo[c]pyridine [3,4-e]azepin-3-one.
如权利要求1所述的式I所示的苯并七元杂环类化合物、其互变异构体、其溶剂化物、其药学上可接受的盐或其前药，其特征在于，当所述R ¹为C ₁-C ₅的烷基时，所述的C ₁-C ₅的烷基为C ₁-C ₃的烷基； A benzo seven-membered heterocyclic compound of the formula I according to claim 1, a tautomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, characterized in that When R ¹ is a C ₁ -C ₅ alkyl group, the C ₁ -C ₅ alkyl group is a C ₁ -C ₃ alkyl group;

和/或，当所述R ¹为“被一个或多个R ⁰取代的C ₁-C ₅的烷基”时，所述的C ₁-C ₅的烷基为C ₁-C ₃的烷基； And/or, when said R ¹ is "C ₁ -C ₅ alkyl substituted by one or more R ⁰ ", said C ₁ -C ₅ alkyl group is a C ₁ -C ₃ alkane base;

和/或，当所述R ^R1或R ^R2为“C ₁-C ₅的烷基”时，所述的C ₁-C ₅的烷基为C ₁-C ₃的烷基； And/or, when R ^R1 or R ^R2 is “C ₁ -C ₅ alkyl group”, the C ₁ -C ₅ alkyl group is a C ₁ -C ₃ alkyl group;

和/或，当所述R ^Q1或R ^Q2为“卤代或未取代的C ₁-C ₅的烷基”时，所述的C ₁-C ₅的烷基为C ₁-C ₃的烷基； And/or, when the R ^Q1 or R ^Q2 is a "halogenated or unsubstituted C ₁ -C ₅ alkyl group", the C ₁ -C ₅ alkyl group is a C ₁ -C ₃ alkane base;

和/或，当所述R为“羟基取代的C ₁-C ₅的烷基”中的“C ₁-C ₅的烷基”时，所述的C ₁-C ₅的烷基为C ₁-C ₃的烷基； And / or, when R is the "hydroxy-substituted C ₁ -C ₅ alkyl" in "C ₁ -C ₅ alkyl", said C ₁ -C ₅ alkyl group is a C ₁ -C ₃ alkyl;

和/或，当所述R ¹、R ^Q1和R ^Q2各自独立地为C ₃-C ₇环烷基时，所述C ₃-C ₇环烷基为环丙基； And/or, when the R ¹ , R ^Q1 and R ^Q2 are each independently a C ₃ -C ₇ cycloalkyl group, the C ₃ -C ₇ cycloalkyl group is a cyclopropyl group;

和/或，当所述R ¹为“被一个或多个R ⁰取代的C ₁-C ₅的烷基”，所述R ⁰为多个时，所述R ⁰相同或不同； And/or, when R ¹ is “C ₁ -C ₅ alkyl substituted by one or more R ⁰ ”, when R ⁰ is plural, R ^{0 is the} same or different;

和/或，当所述R ¹为“被一个R ⁰取代的C ₁-C ₅的烷基”时，所述“被一个R ⁰取代的C ₁-C ₅的烷基”为2-羟基乙基、或甲氧基甲基； And/or, when the R ¹ is "C ₁ -C ₅ alkyl substituted by one R ⁰ ", the "C ₁ -C ₅ alkyl substituted by one R ⁰ " is a 2-hydroxy group Ethyl or methoxymethyl;

和/或，当所述R ¹不为氢且Z为CH时，所述Z中的碳原子为手性碳原子；所述的手性碳原子的构型为R型、S型、或R型和S型的混合物； And/or, when R ^{1 is} not hydrogen and Z is CH, the carbon atom in Z is a chiral carbon atom; the configuration of the chiral carbon atom is R type, S type, or R a mixture of type and S type;

和/或，当所述R ⁰、R ^Q1和R ^Q2各自独立的为C ₁-C ₅的烷氧基时，所述C ₁-C ₅的烷氧基为C ₁-C ₃的烷氧基； And/or, when the R ⁰ , R ^Q1 and R ^Q2 are each independently a C ₁ -C ₅ alkoxy group, the C ₁ -C ₅ alkoxy group is a C ₁ -C ₃ alkoxy group. base;

和/或，所述n ₀为1； And/or, the n ₀ is 1;

和/或，当所述Q为“被一个或多个R ^Q1取代的苯基”，所述R ^Q1为多个时，所述的R ^Q1相同或不同； And/or, when the Q is “phenyl substituted by one or more R ^Q1 ”, and the R ^Q1 is plural, the R ^{Q1 is the} same or different;

和/或，当所述Q为“被一个或多个R ^Q1取代的苯基”，所述R ^Q1为1个时，所述R ^Q1连在所述的苯基的邻位、间位或对位；当存在2个R ^Q1时，所述的R ^Q1连在所述的苯基的邻位和对位、或者、间位和对位；当存在3个R ^Q1时，所述的R ^Q1连在所述的苯基的邻位、邻位和对位； And/or, when Q is "phenyl substituted by one or more R ^Q1 ", when R ^Q1 is 1, the R ^{Q1 is} attached to the ortho, meta or Alignment; when there are 2 R ^Q1 , the R ^{Q1 is} attached to the ortho and para, or meta and para positions of the phenyl; when there are 3 R ^Q1 , the R ^{Q1 is} attached to the ortho, ortho and para positions of the phenyl group;

和/或，当所述Q为“被一个或多个R ^Q2取代的5-6元杂芳基”，所述R ^Q2为多个时，所述的R ^Q2相同或不同； And/or, when Q is "5-6 membered heteroaryl substituted by one or more R ^Q2 ", when R ^Q2 is plural, said R ^{Q2 is the} same or different;

和/或，当所述Q为“被一个或多个R ^Q2取代的5-6元杂芳基”时，所述的“5-6元杂芳基”为吡啶基或嘧啶基； And/or, when the Q is "5-6 membered heteroaryl substituted by one or more R ^Q2 ", the "5-6 membered heteroaryl" is pyridyl or pyrimidinyl;

和/或，当所述R ^Q1和R ^Q2各自独立地为“卤代或未取代的C ₁-C ₅的烷基”时，卤素的个数为一个或多个；当有多个卤素时，所述的卤素相同或不同； And/or, when the R ^Q1 and R ^Q2 are each independently "halogenated or unsubstituted C ₁ -C ₅ alkyl", the number of halogens is one or more; when there are multiple halogens , the halogens are the same or different;

和/或，所述卤素为氟、氯或溴；And/or, the halogen is fluorine, chlorine or bromine;

和/或，当所述R为-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)时，所述-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)为-N(R ^2k)S(＝O) ₂(R ^2d)； And/or, when R is -(CH ₂ )n ^β2 N(R ^2k )S(=O) ₂ (R ^2d ), the -(CH ₂ )n ^β2 N(R ^2k )S(= O) ₂ (R ^2d ) is -N(R ^2k )S(=O) ₂ (R ^2d );

和/或，当所述R为(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)时，所述(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)为-S(＝O) ₂N(R ^2f)(R ^2g)或-CH ₂-S(＝O) ₂N(R ^2f)(R ^2g)； And/or, when R is (CH ₂ )n ^β2 -S(=O) ₂ N(R ^2f )(R ^2g ), the (CH ₂ )n ^β2 -S(=O) ₂ N ( R ^2f )(R ^2g ) is -S(=O) ₂ N(R ^2f )(R ^2g ) or -CH ₂ -S(=O) ₂ N(R ^2f )(R ^2g );

和/或，当所述R为-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)时，所述C ₁-C ₆的烷基为C ₁-C ₃的烷基； And/or, when the R is -C ₁ -C ₆ alkyl-S(=O) ₂ (R ²ⁱ ), the C ₁ -C ₆ alkyl group is a C ₁ -C ₃ alkyl group ;

和/或，所述n ^β2独立地为0或1； And/or, the n ^{β2 is} independently 0 or 1;

和/或，当所述R ^2d、R ^2e、R ^2f、R ^2g、R ²ⁱ和R ^2k各自独立地为C ₁-C ₆的烷基时，所述C ₁-C ₆的烷基为C ₁-C ₃的烷基； And/or, when the R ^2d , R ^2e , R ^2f , R ^2g , R ²ⁱ and R ^2k are each independently a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is C _1- C ₃ alkyl;

和/或，当所述R ^2d、R ^2e、R ^2f、R ^2g、R ²ⁱ和R ^2k各自独立地为被1个或多个卤素取代C ₁-C ₆的烷基时，所述C ₁-C ₆的烷基为C ₁-C ₃的烷基； And/or, when the R ^2d , R ^2e , R ^2f , R ^2g , R ²ⁱ and R ^2k are each independently substituted by a C ₁ -C ₆ alkyl group by one or more halogens, the C ₁ The alkyl group of -C ₆ is a C ₁ -C ₃ alkyl group;

和/或，当所述R ^2d、R ^2e、R ^2f、R ^2g、R ²ⁱ和R ^2k各自独立地为被1个或多个卤素取代C ₁-C ₆的烷基时，所述卤素为氟或氯； And/or, when R ^2d , R ^2e , R ^2f , R ^2g , R ²ⁱ and R ^2k are each independently substituted by a C ₁ -C ₆ alkyl group by one or more halogens, the halogen is Fluorine or chlorine;

和/或，当所述R ^2d、R ^2e、R ^2f、R ^2g、R ²ⁱ和R ^2k各自独立地为被1个或多个卤素取代C ₁-C ₆的烷基时，所述多个为2个或3个；所述卤素相同或不同； And/or when the R ^2d , R ^2e , R ^2f , R ^2g , R ²ⁱ and R ^2k are each independently substituted by a C ₁ -C ₆ alkyl group by one or more halogens, 2 or 3; the halogens are the same or different;

和/或，当所述R ^2d、R ^2e、R ^2f、R ^2g、R ²ⁱ和R ^2k各自独立地为3-7元环烷基时，所述3-7元环烷基为环丙基； And/or, when R ^2d , R ^2e , R ^2f , R ^2g , R ²ⁱ and R ^2k are each independently a 3-7 membered cycloalkyl group, the 3-7 membered cycloalkyl group is a cyclopropyl group. ;

和/或，当所述n为2，且两个R相邻时，相邻的两个R与它们连接的原子共同形成含1个或多个杂原子或者砜基的5-6元杂环烃基时，所述多个为2或3；And/or, when the n is 2 and the two Rs are adjacent, the adjacent two Rs together with the atoms to which they are joined form a 5-6 membered heterocyclic ring having one or more heteroatoms or sulfone groups. In the case of a hydrocarbon group, the plurality is 2 or 3;

和/或，当所述n为2，且两个R相邻时，相邻的两个R与它们连接的原子共同形成含1个或多个杂原子或者砜基的5-6元杂环烃基时，所述杂原子为N、O或S；And/or, when the n is 2 and the two Rs are adjacent, the adjacent two Rs together with the atoms to which they are joined form a 5-6 membered heterocyclic ring having one or more heteroatoms or sulfone groups. In the case of a hydrocarbon group, the hetero atom is N, O or S;

和/或，当所述的R ^2-1、R ^2-2、R ^2-3和R ^2-4各自独立地为C ₁-C ₅的烷基时，所述C ₁-C ₅的烷基为C ₁-C ₃的烷基； And/or, when said R ^2-1 , R ^2-2 , R ^2-3 and R ^2-4 are each independently a C ₁ -C ₅ alkyl group, said C ₁ -C ₅ alkane a group of C ₁ -C ₃ alkyl;

和/或，当所述的R ^2-1、R ^2-2、R ^2-3和R ^2-4各自独立地为C ₃-C ₆环烷基时，所述C ₃-C ₆环烷为环丙基。 And/or, when said R ^2-1 , R ^2-2 , R ^2-3 and R ^2-4 are each independently a C ₃ -C ₆ cycloalkyl group, said C ₃ -C ₆ cycloalkane It is a cyclopropyl group.
如权利要求2所述的式I所示的苯并七元杂环类化合物、其互变异构体、其溶剂化物、其药学上可接受的盐或其前药，其特征在于，当所述R ¹为C ₁-C ₅的烷基时，所述C ₁-C ₅的烷基为甲基、乙基、正丙基或异丙基； A benzo seven-membered heterocyclic compound of the formula I according to claim 2, a tautomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, characterized in that When R ¹ is a C ₁ -C ₅ alkyl group, the C ₁ -C ₅ alkyl group is a methyl group, an ethyl group, a n-propyl group or an isopropyl group;

和/或，当所述R ¹为“被一个R ⁰取代的C ₁-C ₅的烷基”时，所述的C ₁-C ₅的烷基为甲基、乙基、正丙基或异丙基； And/or, when the R ¹ is "C ₁ -C ₅ alkyl substituted by one R ⁰ ", the C ₁ -C ₅ alkyl group is methyl, ethyl, n-propyl or Isopropyl;

和/或，当所述R ^R1或R ^R2为“C ₁-C ₅的烷基”时，所述的C ₁-C ₅的烷基为甲基、乙基、正丙基或异丙基； And/or, when R ^R1 or R ^R2 is "C ₁ -C ₅ alkyl", the C ₁ -C ₅ alkyl group is methyl, ethyl, n-propyl or isopropyl. ;

和/或，当所述R ^Q1或R ^Q2为“卤代或未取代的C ₁-C ₅的烷基”时，所述的C ₁-C ₅的烷基为甲基、乙基、正丙基或异丙基； And/or, when the R ^Q1 or R ^Q2 is a "halogenated or unsubstituted C ₁ -C ₅ alkyl group", the C ₁ -C ₅ alkyl group is a methyl group, an ethyl group, a positive Propyl or isopropyl;

和/或，当所述R为“羟基取代的C ₁-C ₅的烷基”中的“C ₁-C ₅的烷基”时，所述的C ₁-C ₅的烷基为甲基、乙基、正丙基或异丙基； And / or, when R is the "hydroxy-substituted C ₁ -C ₅ alkyl" in "C ₁ -C ₅ alkyl", said C ₁ -C ₅ alkyl groups are methyl , ethyl, n-propyl or isopropyl;

和/或，当所述R ⁰、R ^Q1和R ^Q2各自独立的为C ₁-C ₅的烷氧基时，所述C ₁-C ₅的烷氧基为甲氧基、乙氧基、正丙氧基或异丙氧基； And/or, when the R ⁰ , R ^Q1 and R ^Q2 are each independently a C ₁ -C ₅ alkoxy group, the C ₁ -C ₅ alkoxy group is a methoxy group, an ethoxy group, N-propoxy or isopropoxy;

和/或，当所述Q为“被一个或多个R ^Q1取代的苯基”，所述的“被一个或多个R ^Q1取代的苯基”为4-氟苯基、2-甲基-4氟苯基、2-三氟甲基-4氟苯基、2，6二氯苯基、2，5 二氯苯基、2，3二氯苯基、2-环丙基-4氟-苯基、2-氯苯基、2，6二氯-4氟苯基、2,4,6-三氟苯基、4-羟基苯基、3-羟基-4-氟苯基、4-甲氧基苯基、4-氯苯基、4-氰基苯基、3-氯苯基、3-氟苯基、4-氰基苯基、2,4-二氟苯基、2,4-二氯苯基、2-氟-4-氯苯基、2-氯-4-氟-5-甲氧基苯基、3-甲氧基-4-氟苯基、3-甲氧基-4-氯苯基、4-甲氧基-3-氟苯基、2-甲氧基-4-氟苯基、2-氯-4-氟苯基、或2-氟-4-氰基苯； And/or, when Q is "phenyl substituted by one or more R ^Q1 ", said "phenyl substituted by one or more R ^Q1 " is 4-fluorophenyl, 2-methyl -4fluorophenyl, 2-trifluoromethyl-4fluorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 2,3-dichlorophenyl, 2-cyclopropyl-4fluoro -phenyl, 2-chlorophenyl, 2,6-dichloro-4-fluorophenyl, 2,4,6-trifluorophenyl, 4-hydroxyphenyl, 3-hydroxy-4-fluorophenyl, 4- Methoxyphenyl, 4-chlorophenyl, 4-cyanophenyl, 3-chlorophenyl, 3-fluorophenyl, 4-cyanophenyl, 2,4-difluorophenyl, 2,4 -dichlorophenyl, 2-fluoro-4-chlorophenyl, 2-chloro-4-fluoro-5-methoxyphenyl, 3-methoxy-4-fluorophenyl, 3-methoxy- 4-chlorophenyl, 4-methoxy-3-fluorophenyl, 2-methoxy-4-fluorophenyl, 2-chloro-4-fluorophenyl, or 2-fluoro-4-cyanobenzene ;

和/或，当所述Q为“被一个或多个R ^Q2取代的5-6元杂芳基”时，所述的“5-6元杂芳基”为吡啶基； And/or, when the Q is "5-6 membered heteroaryl substituted by one or more R ^Q2 ", the "5-6 membered heteroaryl" is pyridyl;

和/或，当所述R为(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)时，所述(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)为S(＝O) ₂N(R ^2g)H； And/or, when R is (CH ₂ )n ^β2 -S(=O) ₂ N(R ^2f )(R ^2g ), the (CH ₂ )n ^β2 -S(=O) ₂ N ( R ^2f )(R ^2g ) is S(=O) ₂ N(R ^2g )H;

和/或，当所述R为-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)时，所述C ₁-C ₆的烷基为甲基、乙基、正丙基或异丙基； And/or, when the R is -C ₁ -C ₆ alkyl-S(=O) ₂ (R ²ⁱ ), the C ₁ -C ₆ alkyl group is methyl, ethyl, n-propyl Base or isopropyl;

和/或，当所述R ^2d、R ^2e、R ^2f、R ^2g、R ²ⁱ和R ^2k各自独立地为C ₁-C ₆的烷基时，所述C ₁-C ₆的烷基为甲基、乙基或异丙基； And/or, when R ^2d , R ^2e , R ^2f , R ^2g , R ²ⁱ and R ^2k are each independently a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group is A Base, ethyl or isopropyl;

和/或，当所述R为-N(CH ₂)n ^β2(R ^2e)S(＝O) ₂(R ²ⁱ)时，所述R ^2e为3-7元环烷基；R ²ⁱ为C ₁-C ₆的烷基； And/or, when R is -N(CH ₂ )n ^β2 (R ^2e )S(=O) ₂ (R ²ⁱ ), the R ^2e is a 3-7 membered cycloalkyl group; R ²ⁱ is C _1- C ₆ alkyl;

和/或，当所述R为-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)时，所述R ^2k为-H；R ^2d为C ₁-C ₆的烷基； And/or, when R is -(CH ₂ )n ^β2 N(R ^2k )S(=O) ₂ (R ^2d ), the R ^2k is -H; and R ^2d is C ₁ -C ₆ alkyl;

和/或，当所述R为-(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)时，所述R ^2f为氢；R ^2g为-H或C ₁-C ₆的烷基； And/or, when R is -(CH ₂ )n ^β2 -S(=O) ₂ N(R ^2f )(R ^2g ), the R ^2f is hydrogen; R ^2g is -H or C ₁ - C ₆ alkyl;

和/或，当所述R为-S(＝O) ₂(R ²ⁱ)时，所述R ²ⁱ为C ₁-C ₆的烷基、卤素取代的C ₁-C ₆的烷基或3-7元环烷基； And/or, when R is -S(=O) ₂ (R ²ⁱ ), the R ²ⁱ is a C ₁ -C ₆ alkyl group, a halogen-substituted C ₁ -C ₆ alkyl group or 3- 7-membered cycloalkyl;

和/或，当所述n为2，且两个R相邻时，相邻的两个R与它们连接的原子共同形成含多个杂原子的5-6元杂环烃基时，所述杂原子为一个N原子，一个S原子；And/or, when the n is 2 and the two Rs are adjacent, when the adjacent two Rs together with the atoms to which they are joined form a 5-6 membered heterocycloalkyl group containing a plurality of hetero atoms, the hetero The atom is an N atom and an S atom;

和/或，当所述的R ^2-1、R ^2-2、R ^2-3和R ^2-4各自独立地为C ₁-C ₅的烷基时，所述C ₁-C ₅的烷基为甲基、乙基、正丙基或异丙基。 And/or, when said R ^2-1 , R ^2-2 , R ^2-3 and R ^2-4 are each independently a C ₁ -C ₅ alkyl group, said C ₁ -C ₅ alkane The group is methyl, ethyl, n-propyl or isopropyl.
如权利要求3所述的式I所示的苯并七元杂环类化合物、其互变异构体、其溶剂化物、其药学上可接受的盐或其前药，其特征在于，当所述R为“羟基取代的C ₁-C ₅的烷基”时，所述的所述羟基取代的C ₁-C ₅的烷基为
A benzoheptacyclic heterocyclic compound of the formula I according to claim 3, a tautomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, characterized in that When R is a "hydroxy-substituted C ₁ -C ₅ alkyl group", the hydroxy-substituted C ₁ -C ₅ alkyl group is

和/或，当所述R ⁰、R ^Q1或R ^Q2为C ₁-C ₅的烷氧基时，所述C ₁-C ₅的烷氧基为甲氧基； And/or, when the R ⁰ , R ^Q1 or R ^Q2 is a C ₁ -C ₅ alkoxy group, the C ₁ -C ₅ alkoxy group is a methoxy group;

和/或，当所述Q为“被一个或多个R ^Q2取代的5-6元杂芳基”时，所述“被一个或多个R ^Q2取代的5-6元杂芳基”为
And/or, when the Q is "5-6 membered heteroaryl substituted by one or more R ^Q2 ", the "5-6 membered heteroaryl substituted by one or more R ^Q2 " is

和/或，当所述R为(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)时，所述(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)为
And/or, when R is (CH ₂ )n ^β2 -S(=O) ₂ N(R ^2f )(R ^2g ), the (CH ₂ )n ^β2 -S(=O) ₂ N ( R ^2f )(R ^2g ) is

和/或，当所述R为-N(R ^2e)(CH ₂)n ^β2-S(＝O) ₂(R ²ⁱ)时，所述-N(R ^2e)(CH ₂)n ^β2-S(＝O) ₂(R ²ⁱ)为
And/or, when R is -N(R ^2e )(CH ₂ )n ^β2 -S(=O) ₂ (R ²ⁱ ), the -N(R ^2e )(CH ₂ )n ^β2 -S (=O) ₂ (R ²ⁱ ) is

和/或，当所述R为-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)时，所述-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)为如
And/or, when R is -(CH ₂ )n ^β2 N(R ^2k )S(=O) ₂ (R ^2d ), the -(CH ₂ )n ^β2 N(R ^2k )S(= O) ₂ (R ^2d ) is as

和/或，当所述R为-S(＝O)(R ²ⁱ)时，所述-S(＝O)(R ²ⁱ)为
And/or, when R is -S(=O)(R ²ⁱ ), the -S(=O)(R ²ⁱ ) is

和/或，当所述R为-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)时，所述-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)为-(CH ₂)n ^β2-S(＝O) ₂(R ²ⁱ)、n ^β2为1、2、3或4； And/or, when the R is -C ₁ -C ₆ alkyl-S(=O) ₂ (R ²ⁱ ), the -C ₁ -C ₆ alkyl-S(=O) ₂ ( R ²ⁱ ) is -(CH ₂ )n ^β2 -S(=O) ₂ (R ²ⁱ ), and n ^β2 is 1, ^2, 3 or 4;

和/或，当所述n为2，且两个R相邻时，相邻的两个R与它们连接的原子共同形成含1个或多个杂原子或者砜基的5-6元杂环烃基时，所述5-6元杂环烃基为
或
And/or, when the n is 2 and the two Rs are adjacent, the adjacent two Rs together with the atoms to which they are joined form a 5-6 membered heterocyclic ring having one or more heteroatoms or sulfone groups. In the case of a hydrocarbon group, the 5-6 membered heterocycloalkyl group is
or

和/或，当所述R为-N(CH ₂)n ^β2(R ^2e)S(＝O) ₂(R ²ⁱ)时，所述R ^2e为3-7元环烷基；R ²ⁱ为乙基； And/or, when R is -N(CH ₂ )n ^β2 (R ^2e )S(=O) ₂ (R ²ⁱ ), the R ^2e is a 3-7 membered cycloalkyl group; R ²ⁱ is B base;

和/或，当所述R为-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)时，所述R ^2k为-H；R ^2d为C ₁-C ₃的烷基； And/or, when R is -(CH ₂ )n ^β2 N(R ^2k )S(=O) ₂ (R ^2d ), the R ^2k is -H; and R ^2d is C ₁ -C ₃ alkyl;

和/或，当所述R为-(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)时，所述R ^2f为氢；R ^2g为-H或乙基； And/or, when R is -(CH ₂ )n ^β2 -S(=O) ₂ N(R ^2f )(R ^2g ), the R ^2f is hydrogen; R ^2g is -H or ethyl;

和/或，当所述R为-S(＝O) ₂(R ²ⁱ)，所述R ²ⁱ为卤素取代的C ₁-C ₆的烷基时，所述R ²ⁱ为-CF ₃； And/or, when R is -S(=O) ₂ (R ²ⁱ ), wherein R ²ⁱ is a halogen-substituted C ₁ -C ₆ alkyl group, said R ²ⁱ is -CF ₃ ;

和/或，当所述R为-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)时，所述-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)为
And/or, when the R is -C ₁ -C ₆ alkyl-S(=O) ₂ (R ²ⁱ ), the -C ₁ -C ₆ alkyl-S(=O) ₂ ( R ²ⁱ ) is

和/或，当所述n为2，且两个R相邻时，相邻的两个R与它们连接的原子共同形成含多个杂原子的5-6元杂环烃基，所述杂原子为一个N原子，一个S原子时，所述S原子和N原子相邻。And/or, when the n is 2 and the two Rs are adjacent, the adjacent two Rs together with the atoms to which they are joined form a 5-6 membered heterocycloalkyl group containing a plurality of heteroatoms, the hetero atom When it is an N atom and an S atom, the S atom and the N atom are adjacent to each other.
如权利要求1所述的式I所示的苯并七元杂环类化合物、其互变异构体、其溶剂化物、其药学上可接受的盐或其前药，其特征在于，The benzoheptacyclic heterocyclic compound of the formula I according to claim 1, a tautomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, characterized in that

所述R ^R1和R ^R2均为氢； The R ^R1 and R ^R2 are both hydrogen;

和/或，所述
为
And/or, said
for

和/或，所述的“被一个或多个R ^Q1取代的苯基”为4-氟苯基、2-甲基-4氟苯基、2-三氟甲基-4氟苯基、2，6二氯苯基、2，5二氯苯基、2，3二氯苯基、2-环丙基-4氟氯苯基、2-氯苯基、2，6二氯-4氟苯基、2,4,6-三氟苯基、2,4-二氯苯基、3-甲氧基-4-氯苯基或2-氯-4-氟苯基； And/or the "phenyl group substituted by one or more R ^Q1 " is 4-fluorophenyl, 2-methyl-4fluorophenyl, 2-trifluoromethyl-4fluorophenyl, 2 ,6-dichlorophenyl, 2,5-dichlorophenyl, 2,3-dichlorophenyl, 2-cyclopropyl-4fluorochlorophenyl, 2-chlorophenyl, 2,6-dichloro-4-fluorobenzene Base, 2,4,6-trifluorophenyl, 2,4-dichlorophenyl, 3-methoxy-4-chlorophenyl or 2-chloro-4-fluorophenyl;

和/或，当所述的R ^Q1连在所述的苯基的邻位时，所述R ^Q1为卤素、卤代或未取代的C ₁-C ₅的烷基、C ₃-C ₇环烷基或C ₁-C ₅的烷氧基；当所述的R ^Q1连在所述的苯基的间位时，所述R ^Q1可为卤素或C ₁-C ₅的烷氧基；当所述的R ^Q1连在所述的苯基的对位时，所述R ^Q1为卤素或C ₁-C ₅的烷氧基； And/or, when said R ^{Q1 is} attached to the ortho position of said phenyl group, said R ^Q1 is halogen, halogenated or unsubstituted C ₁ -C ₅ alkyl group, C ₃ -C ₇ ring An alkyl group or a C ₁ -C ₅ alkoxy group; when said R ^{Q1 is} attached to the meta position of said phenyl group, said R ^Q1 may be a halogen or a C ₁ -C ₅ alkoxy group; When R ^{Q1 is} attached to the para position of the phenyl group, the R ^Q1 is a halogen or a C ₁ -C ₅ alkoxy group;

和/或，所述n＝1或2；当所述n为2时，一个R位于所述Y的对位，另一个R位于所述Y的间位；And/or, the n=1 or 2; when the n is 2, one R is in the alignment of the Y, and the other R is in the meta position of the Y;

和/或，R ²为氢； And/or, R ² is hydrogen;

和/或，当所述R为卤素、羟基取代的C ₁-C ₅的烷基、-N(CH ₂)n ^β2(R ^2e)S(＝O) ₂(R ²ⁱ)、-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)、-(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)、-(CR ^2xR ^2y)-S(＝O) ₂N(R ^2f)(R ^2g)、-(CH ₂)n ^β2-S(＝O)(R ²ⁱ)或-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)。 And/or when R is halogen, hydroxy-substituted C ₁ -C ₅ alkyl, -N(CH ₂ )n ^β2 (R ^2e )S(=O) ₂ (R ²ⁱ ), -(CH ₂ n ^{β 2} N(R ^2k )S(=O) ₂ (R ^2d ), -(CH ₂ )n ^β2 -S(=O) ₂ N(R ^2f )(R ^2g ), -(CR ^2x R ^2y ) -S(=O) ₂ N(R ^2f )(R ^2g ), -(CH ₂ )n ^β2 -S(=O)(R ²ⁱ ) or -C ₁ -C ₆ alkyl-S(=O) ₂ (R ²ⁱ ).
如权利要求1所述的式I所示的苯并七元杂环类化合物、其互变异构体、其溶剂化物、其药学上可接受的盐或其前药，其特征在于，所述n为1时，所述R为卤素、羟基取代的C ₁-C ₅的烷基、-N(CH ₂)n ^β2(R ^2e)S(＝O) ₂(R ²ⁱ)、-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)、-(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)、-S(＝O) ₂N(R ^2f)(R ^2g)、-CH ₂-S(＝O) ₂N(R ^2f)(R ^2g)、-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)或相邻的两个R与其相邻的C形成含1个或多个杂原子的5-6元杂环烃基； The benzoheptacyclic heterocyclic compound of the formula I according to claim 1, a tautomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, characterized in that When n is 1, the R is a halogen, a hydroxy-substituted C ₁ -C ₅ alkyl group, -N(CH ₂ )n ^β2 (R ^2e )S(=O) ₂ (R ²ⁱ ), -(CH _{2 )} n ^β2 N(R ^2k )S(=O) ₂ (R ^2d ), -(CH ₂ )n ^β2 -S(=O) ₂ N(R ^2f )(R ^2g ), -S(=O) ₂ N(R ^2f )(R ^2g ), -CH ₂ -S(=O) ₂ N(R ^2f )(R ^2g ), -C ₁ -C ₆ alkyl-S(=O) ₂ (R ²ⁱ ) Or two adjacent R and its adjacent C form a 5-6 membered heterocycloalkyl group containing one or more heteroatoms;

所述n为2时，一个R为羟基取代的C ₁-C ₅的烷基、-N(CH ₂)n ^β2(R ^2e)S(＝O) ₂(R ²ⁱ)、-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)、-(CH ₂)n ^β2-S(＝O) ₂N(R ^2f)(R ^2g)、-S(＝O) ₂N(R ^2f)(R ^2g)、-CH ₂-S(＝O) ₂N(R ^2f)(R ^2g)或-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)；另一个R为卤素； When n is 2, one R is a hydroxy-substituted C ₁ -C ₅ alkyl group, -N(CH ₂ )n ^β2 (R ^2e )S(=O) ₂ (R ²ⁱ ), -(CH ₂ ) n ^β2 N(R ^2k )S(=O) ₂ (R ^2d ), -(CH ₂ )n ^β2 -S(=O) ₂ N(R ^2f )(R ^2g ), -S(=O) ₂ N (R ^2f )(R ^2g ), -CH ₂ -S(=O) ₂ N(R ^2f )(R ^2g ) or -C ₁ -C ₆ alkyl-S(=O) ₂ (R ²ⁱ ); Another R is a halogen;

和/或，当Z为N时，所述式I所示的苯并七元杂环类化合物可为式I-2所示的化合物：And/or, when Z is N, the benzo seven-membered heterocyclic compound of formula I may be a compound of formula I-2:

各取代基定义如权利要求1-5中至少一项所述；
Each substituent is as defined in at least one of claims 1-5;

和/或，式I所示的苯并七元杂环类化合物为如下式I-3、I-4、I-5、I-6、II、III或IV所示的任一结构的化合物：And/or the benzoheptacyclic heterocyclic compound represented by Formula I is a compound of any of the following formulas I-3, I-4, I-5, I-6, II, III or IV:

当R ¹不为氢时，例如

When R ^{1 is} not hydrogen, for example

当R ¹不为氢时，例如

When R ^{1 is} not hydrogen, for example

和/或，所述Z为N时，
为
所述R ¹为乙基； And/or, when the Z is N,
for
The R ¹ is an ethyl group;

和/或，所述Q为“被一个或多个R ^Q1取代的苯基”； And/or, the Q is "phenyl substituted by one or more R ^Q1 ";

和/或，所述Z为CH，所述
为
And/or, said Z is CH, said
for
如权利要求1所述的式I所示的苯并七元杂环类化合物、其互变异构体、其溶剂化物、其药学上可接受的盐或其前药，其特征在于，所述的化合物I选自以下方案：The benzoheptacyclic heterocyclic compound of the formula I according to claim 1, a tautomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, characterized in that Compound I is selected from the following schemes:

方案一：Z为CH或N；Scheme 1: Z is CH or N;

为

for

R ¹为-H、C ₁-C ₅的烷基、C ₃-C ₇环烷基、被一个或多个R ⁰取代的C ₁-C ₅的烷基、或-(CH ₂)n ₀C(＝O)N(R ^R1)(R ^R2)； R ¹ is -H, C ₁ -C ₅ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₅ alkyl substituted by one or more R ⁰ , or -(CH ₂ )n ₀ C(=O)N(R ^R1 )(R ^R2 );

当Z为CH，R ¹不为氢时，其连接的碳原子为手性碳原子；所述的手性碳原子的构型可为R型、S型、或R型和S型的混合物； When Z is CH and R ^{1 is} not hydrogen, the carbon atom to which it is attached is a chiral carbon atom; the configuration of the chiral carbon atom may be a mixture of R type, S type, or R type and S type;

R ⁰为C ₁-C ₅的烷氧基或-OH； R ⁰ is a C ₁ -C ₅ alkoxy group or -OH;

n ₀为0或1； n ₀ is 0 or 1;

R ^R1和R ^R2各自独立地为-H或C ₁-C ₅的烷基； R ^R1 and R ^R2 are each independently -H or a C ₁ -C ₅ alkyl group;

R为“-C ₁-C ₆的烷基-S(＝O) ₂(R ²ⁱ)”例如-(CH ₂)n ^β2-S(＝O) ₂(R ²ⁱ)、n ^β2为1、2、3或4，又例如-CH ₂-S(＝O) ₂(R ²ⁱ)，还例如
R is "-C ₁ -C ₆ alkyl-S(=O) ₂ (R ²ⁱ )" such as -(CH ₂ )n ^β2 -S(=O) ₂ (R ²ⁱ ), n ^β2 is 1, 2 , 3 or 4, again for example -CH ₂ -S(=O) ₂ (R ²ⁱ ), also for example

所述n ^β2为0、1或2； The n ^β2 is 0, 1 or 2;

所述R ^2d、R ^2e、R ^2f、R ^2g、R ²ⁱ和R ^2k各自独立地为-H、C ₁-C ₆的烷基、被1个或多个卤素取代C ₁-C ₆的烷基、或3-7元环烷基； The R ^2d , R ^2e , R ^2f , R ^2g , R ²ⁱ and R ^2k are each independently -H, a C ₁ -C ₆ alkyl group, and a C ₁ -C ₆ alkane substituted by one or more halogens a base, or a 3-7 membered cycloalkyl group;

n为0、1或2；当n为1或2时，至少一个R位于Y的对位或间位；n is 0, 1, or 2; when n is 1 or 2, at least one R is located at the para or meta position of Y;

Q为“被一个或多个R ^Q1取代的苯基”； Q is "phenyl substituted by one or more R ^Q1 ";

所述R ^Q1和R ^Q2各自独立地为-H、卤素、卤代或未取代的C ₁-C ₅的烷基、C ₃-C ₇环烷基、或C ₁-C ₅的烷氧基； The R ^Q1 and R ^Q2 are each independently -H, halogen, halogenated or unsubstituted C ₁ -C ₅ alkyl, C ₃ -C ₇ cycloalkyl, or C ₁ -C ₅ alkoxy ;

W为CH或N；W is CH or N;

R ²为氢、-NR ^2-1R ^2-2或-C(＝O)NR ^2-3R ^2-4； R ² is hydrogen, -NR ^2-1 R ^2-2 or -C(=O)NR ^2-3 R ^2-4 ;

R ^2-1、R ^2-2、R ^2-3和R ^2-4各自独立地为氢、C ₁-C ₅的烷基或C ₃-C ₆环烷基； R ^2-1 , R ^2-2 , R ^2-3 and R ^2-4 are each independently hydrogen, C ₁ -C ₅ alkyl or C ₃ -C ₆ cycloalkyl;

其他取代基定义如权利要求1-6中至少一项中所述；Other substituent definitions as described in at least one of claims 1-6;

方案二：Option II:

Z为CH或N；Z is CH or N;

为

for

R ¹为-H、C ₁-C ₅的烷基、C ₃-C ₇环烷基、被一个或多个R ⁰取代的C ₁-C ₅的烷基、或-(CH ₂)n ₀C(＝O)N(R ^R1)(R ^R2)； R ¹ is -H, C ₁ -C ₅ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₅ alkyl substituted by one or more R ⁰ , or -(CH ₂ )n ₀ C(=O)N(R ^R1 )(R ^R2 );

当Z为CH，R ¹不为氢时，其连接的碳原子为手性碳原子；所述的手性碳原子的构型可为R型、S型、或R型和S型的混合物； When Z is CH and R ^{1 is} not hydrogen, the carbon atom to which it is attached is a chiral carbon atom; the configuration of the chiral carbon atom may be a mixture of R type, S type, or R type and S type;

R ⁰为C ₁-C ₅的烷氧基(例如C ₁-C ₃的烷氧基，再例如甲氧基)或-OH； R ⁰ is a C ₁ -C ₅ alkoxy group (for example, a C ₁ -C ₃ alkoxy group, such as a methoxy group) or -OH;

n ₀为0或1； n ₀ is 0 or 1;

R ^R1和R ^R2各自独立地为-H或C ₁-C ₅的烷基； R ^R1 and R ^R2 are each independently -H or a C ₁ -C ₅ alkyl group;

R为-(CH ₂)n ^β2N(R ^2k)S(＝O) ₂(R ^2d)，或-N(CH ₂)n ^β2(R ^2e)S(＝O) ₂(R ²ⁱ)； R is -(CH ₂ )n ^β2 N(R ^2k )S(=O) ₂ (R ^2d ), or -N(CH ₂ )n ^β2 (R ^2e )S(=O) ₂ (R ²ⁱ );

所述n ^β2为0、1或2(例如0或1)； The n ^β2 is 0, 1 or 2 (eg 0 or 1);

所述R ^2d、R ^2e、R ^2f、R ^2g、R ²ⁱ和R ^2k各自独立地为-H、C ₁-C ₆的烷基、被1个或多个卤素取代C ₁-C ₆的烷基、或3-7元环烷基； The R ^2d , R ^2e , R ^2f , R ^2g , R ²ⁱ and R ^2k are each independently -H, a C ₁ -C ₆ alkyl group, and a C ₁ -C ₆ alkane substituted by one or more halogens a base, or a 3-7 membered cycloalkyl group;

n为0、1或2；当n为1或2时，至少一个R位于Y的对位或间位；n is 0, 1, or 2; when n is 1 or 2, at least one R is located at the para or meta position of Y;

Q为“被一个或多个R ^Q1取代的苯基”、或者“被一个或多个R ^Q2取代的5-6元杂芳基”； Q is "phenyl substituted by one or more R ^Q1 " or "5-6 membered heteroaryl substituted by one or more R ^Q2 ";

所述R ^Q1和R ^Q2各自独立地为-H、卤素、卤代或未取代的C ₁-C ₅的烷基、C ₃-C ₇环烷基、或C ₁-C ₅的烷氧基； The R ^Q1 and R ^Q2 are each independently -H, halogen, halogenated or unsubstituted C ₁ -C ₅ alkyl, C ₃ -C ₇ cycloalkyl, or C ₁ -C ₅ alkoxy ;

W为CH或N；W is CH or N;

R ²为氢、-NR ^2-1R ^2-2或-C(＝O)NR ^2-3R ^2-4； R ² is hydrogen, -NR ^2-1 R ^2-2 or -C(=O)NR ^2-3 R ^2-4 ;

R ^2-1、R ^2-2、R ^2-3和R ^2-4各自独立地为氢、C ₁-C ₅的烷基或C ₃-C ₆环烷基； R ^2-1 , R ^2-2 , R ^2-3 and R ^2-4 are each independently hydrogen, C ₁ -C ₅ alkyl or C ₃ -C ₆ cycloalkyl;

其他取代基定义如权利要求1-6中至少一项中所述；Other substituent definitions as described in at least one of claims 1-6;

方案三：third solution:

Z为CH或N；Z is CH or N;

为

for

R ¹为-H、C ₁-C ₅的烷基、C ₃-C ₇环烷基、被一个或多个R ⁰取代的C ₁-C ₅的烷基、或-(CH ₂)n ₀C(＝O)N(R ^R1)(R ^R2)； R ¹ is -H, C ₁ -C ₅ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₅ alkyl substituted by one or more R ⁰ , or -(CH ₂ )n ₀ C(=O)N(R ^R1 )(R ^R2 );

R ⁰为C ₁-C ₅的烷氧基或-OH； R ⁰ is a C ₁ -C ₅ alkoxy group or -OH;

n ₀为0或1； n ₀ is 0 or 1;

R ^R1和R ^R2各自独立地为-H或C ₁-C ₅的烷基； R ^R1 and R ^R2 are each independently -H or a C ₁ -C ₅ alkyl group;

R为-CH ₂-S(＝O) ₂N(R ^2f)(R ^2g)例如
R is -CH ₂ -S(=O) ₂ N(R ^2f )(R ^2g ), for example

所述n ^β2为0、1或2； The n ^β2 is 0, 1 or 2;

所述R ^2d、R ^2e、R ^2f、R ^2g、R ²ⁱ和R ^2k各自独立地为-H、C ₁-C ₆的烷基、被1个或多个卤素取代C ₁-C ₆的烷基、或3-7元环烷基； The R ^2d , R ^2e , R ^2f , R ^2g , R ²ⁱ and R ^2k are each independently -H, a C ₁ -C ₆ alkyl group, and a C ₁ -C ₆ alkane substituted by one or more halogens a base, or a 3-7 membered cycloalkyl group;

n为0、1或2；当n为1或2时，至少一个R位于Y的对位或间位；n is 0, 1, or 2; when n is 1 or 2, at least one R is located at the para or meta position of Y;

Q为“被一个或多个R ^Q1取代的苯基”、或者“被一个或多个R ^Q2取代的5-6元杂芳基”； Q is "phenyl substituted by one or more R ^Q1 " or "5-6 membered heteroaryl substituted by one or more R ^Q2 ";

所述R ^Q1和R ^Q2各自独立地为-H、卤素、卤代或未取代的C ₁-C ₅的烷基、C ₃-C ₇环烷基、或C ₁-C ₅的烷氧基； The R ^Q1 and R ^Q2 are each independently -H, halogen, halogenated or unsubstituted C ₁ -C ₅ alkyl, C ₃ -C ₇ cycloalkyl, or C ₁ -C ₅ alkoxy ;

W为CH或N；W is CH or N;

R ²为氢、-NR ^2-1R ^2-2或-C(＝O)NR ^2-3R ^2-4； R ² is hydrogen, -NR ^2-1 R ^2-2 or -C(=O)NR ^2-3 R ^2-4 ;

R ^2-1、R ^2-2、R ^2-3和R ^2-4各自独立地为氢、C ₁-C ₅的烷基或C ₃-C ₆环烷基； R ^2-1 , R ^2-2 , R ^2-3 and R ^2-4 are each independently hydrogen, C ₁ -C ₅ alkyl or C ₃ -C ₆ cycloalkyl;

其他取代基定义如权利要求1-6中至少一项中所述；Other substituent definitions as described in at least one of claims 1-6;

方案四：Option 4:

Z为CH或N；Z is CH or N;

为

for

R ¹为-H、C ₁-C ₅的烷基、C ₃-C ₇环烷基、被一个或多个R ⁰取代的C ₁-C ₅的烷基、或-(CH ₂)n ₀C(＝O)N(R ^R1)(R ^R2)； R ¹ is -H, C ₁ -C ₅ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₅ alkyl substituted by one or more R ⁰ , or -(CH ₂ )n ₀ C(=O)N(R ^R1 )(R ^R2 );

R ⁰为C ₁-C ₅的烷氧基或-OH； R ⁰ is a C ₁ -C ₅ alkoxy group or -OH;

n ₀为0或1； n ₀ is 0 or 1;

R ^R1和R ^R2各自独立地为-H或C ₁-C ₅的烷基； R ^R1 and R ^R2 are each independently -H or a C ₁ -C ₅ alkyl group;

R为-S(＝O) ₂N(R ^2f)(R ^2g)例如-S(＝O) ₂N(R ^2g)H，又例如
R is -S(=O) ₂ N(R ^2f )(R ^2g ) such as -S(=O) ₂ N(R ^2g )H, for example

所述n ^β2为0、1或2； The n ^β2 is 0, 1 or 2;

所述R ^2d、R ^2e、R ^2f、R ^2g、R ²ⁱ和R ^2k各自独立地为-H、C ₁-C ₆的烷基、被1个或多个卤素取代C ₁-C ₆的烷基、或3-7元环烷基； The R ^2d , R ^2e , R ^2f , R ^2g , R ²ⁱ and R ^2k are each independently -H, a C ₁ -C ₆ alkyl group, and a C ₁ -C ₆ alkane substituted by one or more halogens a base, or a 3-7 membered cycloalkyl group;

n为0、1或2；当n为1或2时，至少一个R位于Y的对位或间位；n is 0, 1, or 2; when n is 1 or 2, at least one R is located at the para or meta position of Y;

Q为“被一个或多个R ^Q1取代的苯基”、或者“被一个或多个R ^Q2取代的5-6元杂芳基”； Q is "phenyl substituted by one or more R ^Q1 " or "5-6 membered heteroaryl substituted by one or more R ^Q2 ";

所述R ^Q1和R ^Q2各自独立地为-H、卤素、卤代或未取代的C ₁-C ₅的烷基、C ₃-C ₇环烷基、或C ₁-C ₅的烷氧基； The R ^Q1 and R ^Q2 are each independently -H, halogen, halogenated or unsubstituted C ₁ -C ₅ alkyl, C ₃ -C ₇ cycloalkyl, or C ₁ -C ₅ alkoxy ;

W为CH或N；W is CH or N;

R ²为氢、-NR ^2-1R ^2-2或-C(＝O)NR ^2-3R ^2-4； R ² is hydrogen, -NR ^2-1 R ^2-2 or -C(=O)NR ^2-3 R ^2-4 ;

R ^2-1、R ^2-2、R ^2-3和R ^2-4各自独立地为氢、C ₁-C ₅的烷基或C ₃-C ₆环烷基； R ^2-1 , R ^2-2 , R ^2-3 and R ^2-4 are each independently hydrogen, C ₁ -C ₅ alkyl or C ₃ -C ₆ cycloalkyl;

其他取代基定义如权利要求1-6中至少一项中所述；Other substituent definitions as described in at least one of claims 1-6;

方案五：Option 5:

Z为CH或N；Z is CH or N;

为

for

R ¹为-H、C ₁-C ₅的烷基、C ₃-C ₇环烷基、被一个或多个R ⁰取代的C ₁-C ₅的烷基、或-(CH ₂)n ₀C(＝O)N(R ^R1)(R ^R2)； R ¹ is -H, C ₁ -C ₅ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₅ alkyl substituted by one or more R ⁰ , or -(CH ₂ )n ₀ C(=O)N(R ^R1 )(R ^R2 );

R ⁰为C ₁-C ₅的烷氧基(例如C ₁-C ₃的烷氧基，再例如甲氧基)或-OH； R ⁰ is a C ₁ -C ₅ alkoxy group (for example, a C ₁ -C ₃ alkoxy group, such as a methoxy group) or -OH;

n ₀为0或1； n ₀ is 0 or 1;

R ^R1和R ^R2各自独立地为-H或C ₁-C ₅的烷基； R ^R1 and R ^R2 are each independently -H or a C ₁ -C ₅ alkyl group;

R为羟基取代的C ₁-C ₅的烷基； R is a hydroxy-substituted C ₁ -C ₅ alkyl group;

所述n ^β2为0、1或2； The n ^β2 is 0, 1 or 2;

所述R ^2d、R ^2e、R ^2f、R ^2g、R ²ⁱ和R ^2k各自独立地为-H、C ₁-C ₆的烷基、被1个或多个卤素取代C ₁-C ₆的烷基、或3-7元环烷基； The R ^2d , R ^2e , R ^2f , R ^2g , R ²ⁱ and R ^2k are each independently -H, a C ₁ -C ₆ alkyl group, and a C ₁ -C ₆ alkane substituted by one or more halogens a base, or a 3-7 membered cycloalkyl group;

n为0、1或2；当n为1或2时，至少一个R位于Y的对位或间位；n is 0, 1, or 2; when n is 1 or 2, at least one R is located at the para or meta position of Y;

Q为“被一个或多个R ^Q1取代的苯基”、或者“被一个或多个R ^Q2取代的5-6元杂芳基”； Q is "phenyl substituted by one or more R ^Q1 " or "5-6 membered heteroaryl substituted by one or more R ^Q2 ";

所述R ^Q1和R ^Q2各自独立地为-H、卤素、卤代或未取代的C ₁-C ₅的烷基、或C ₁-C ₅的烷氧基； The R ^Q1 and R ^Q2 are each independently -H, halogen, halogenated or unsubstituted C ₁ -C ₅ alkyl, or C ₁ -C ₅ alkoxy;

W为CH或N；W is CH or N;

R ²为氢、-NR ^2-1R ^2-2或-C(＝O)NR ^2-3R ^2-4； R ² is hydrogen, -NR ^2-1 R ^2-2 or -C(=O)NR ^2-3 R ^2-4 ;

R ^2-1、R ^2-2、R ^2-3和R ^2-4各自独立地为氢、C ₁-C ₅的烷基或C ₃-C ₆环烷基； R ^2-1 , R ^2-2 , R ^2-3 and R ^2-4 are each independently hydrogen, C ₁ -C ₅ alkyl or C ₃ -C ₆ cycloalkyl;

其他取代基定义如权利要求1-6中至少一项中所述。Other substituents are defined as described in at least one of claims 1-6.
如权利要求1所述的式I所示的苯并七元杂环类化合物、其互变异构体、其溶剂化物、其药学上可接受的盐或其前药，其特征在于，所述的化合物I选自以下任一结构：The benzoheptacyclic heterocyclic compound of the formula I according to claim 1, a tautomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof or a prodrug thereof, characterized in that Compound I is selected from any of the following structures:

其中，所述化合物4097-P1和4097-P2在下述条件下的保留时间分别为2.39min和 3.47min；Wherein the retention times of the compounds 4097-P1 and 4097-P2 under the following conditions were 2.39 min and 3.47 min, respectively;

SFC中，色谱柱为OZ柱，规格为20*250mm，粒径10um；流动相为超临界CO ₂/MEOH(0.2％甲醇胺)＝45/55；流速:80g/min。 In the SFC, the column is an OZ column with a size of 20*250 mm and a particle size of 10 μm; the mobile phase is supercritical CO _{2 /} MEOH (0.2% methanolamine) = 45/55; and the flow rate is 80 g/min.
本发明提供同了一种如式I所示的化合物的制备方法，其包含以下方法：The present invention provides a process for the preparation of a compound of formula I, which comprises the following method:

方法一：包含下列步骤：Method 1: Includes the following steps:

将如式(II-1)所示的中间体化合物与Q’进行Ullmann偶联反应，即可；The Ullmann coupling reaction of the intermediate compound represented by the formula (II-1) with Q' may be carried out;

其中，所述的各取代基均如权利要求1-7至少一项中所述，Q’为结构片段Q反应位点上相应的卤化物；Wherein each of the substituents is as described in at least one of claims 1 to 7, and Q' is a corresponding halide on the reaction site of the structural fragment Q;

方法二：Method Two:

一种如式III所示的含七元环的化合物的制备方法，其包含下述步骤：将如式III-1所示的中间体化合物进行环合反应，即可；A method for preparing a seven-membered ring-containing compound represented by formula III, which comprises the steps of: subjecting an intermediate compound represented by formula III-1 to a cyclization reaction;

其中，所述的各取代基如权利要求1-7中至少一项中所述；Wherein each of the substituents is as described in at least one of claims 1-7;

方法三、一种如式IV所示的含七元环的化合物的制备方法，其包含下述步骤：将如式IV-1所示的中间体化合物进行环合反应，即可；Process 3, a method for preparing a seven-membered ring-containing compound as shown in Formula IV, which comprises the steps of: subjecting an intermediate compound represented by Formula IV-1 to a cyclization reaction;

其中，所述的各取代基如权利要求1-7中至少一项中所述。Wherein each of the substituents is as described in at least one of claims 1-7.
一种如权利要求1-8至少一项中所述的如式I所示的苯并氮杂环类化合物、其互变异构体、光学异构体、溶剂化物、其药学上可接受的盐或其前药在制备溴结构域抑制剂中的应用。A benzoazepine heterocyclic compound of the formula I, a tautomer, an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable thereof, according to any one of claims 1-8 The use of a salt or a prodrug thereof for the preparation of a bromodomain inhibitor.
一种如权利要求1-8至少一项中所述的如式I所示的苯并氮杂环类化合物、其互变异构体、光学异构体、溶剂化物、其药学上可接受的盐或其前药在制备治疗和/预防需要调节溴结构域与乙酰化蛋白的结合能力来治疗和/或预防的疾病的药物中的应用。A benzoazepine heterocyclic compound of the formula I, a tautomer, an optical isomer thereof, a solvate thereof, or a pharmaceutically acceptable thereof, according to any one of claims 1-8 The use of a salt or a prodrug thereof for the preparation of a medicament for the treatment and prevention of a disease requiring modulation of the binding ability of a bromodomain to an acetylated protein for treatment and/or prevention.
如权利要求11所述的应用，其特征在于，所述的需要调节溴结构域与乙酰化蛋白的结合能力来治疗和/或预防的疾病选自听神经瘤、急性白血病、急性淋巴细胞性白血病、急性髓细胞性白血病、急性t-细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌、支气管癌、***、软骨肉瘤、脊索瘤、绒毛膜癌、慢性白血病、慢性淋巴细胞性白血病、慢性髓细胞性(粒细胞性)白血病、慢性骨髓性白血病、结肠癌、结肠直肠癌、颅咽管瘤、囊腺癌、弥漫性大B-细胞淋巴瘤、不良增生性变化、胚胎癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食管癌、***受体阳性乳腺癌、原发性血小板增多症、尤因氏肉瘤、纤维肉瘤、滤泡性淋巴瘤、生殖细胞睾丸癌、神经胶质瘤、成胶质细胞瘤、神经胶质肉瘤、重链病、血管母细胞瘤、肝癌、肝细胞癌、激素不敏感性***癌、平滑肌肉瘤、白血病、脂肪肉瘤、肺癌、***内皮肉瘤、***肉瘤、淋巴母细胞白血病、淋巴瘤、膀胱、乳腺、结肠、肺、卵巢、胰腺、***、皮肤和子宫的恶性肿瘤和过度增生障碍、T-细胞或B-细胞源淋巴恶性肿瘤、白血病、淋巴瘤、髓样癌、髓母细胞瘤、黑色素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、骨髓性白血病、骨髓瘤、粘液肉瘤、神经母细胞瘤、NUT中线癌(NMC)、非小细胞肺癌、少突神经胶质瘤、口腔癌、骨原性肉瘤、卵巢癌、胰腺癌、***状腺癌、***状癌、松果体瘤、真性红细胞增多症、***癌、直肠癌、肾细胞癌、成视网膜细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、***瘤、皮肤癌、小细胞肺癌、实体瘤、小细胞肺癌、胃癌、鳞状细胞癌、滑膜瘤、汗腺瘤、甲状腺癌、原发性巨球蛋白血症、睾丸肿瘤、子宫癌和肾母细胞瘤中的一种或多种。The use according to claim 11, wherein the disease which requires modulation of the binding ability of the bromodomain to the acetylated protein for treatment and/or prevention is selected from the group consisting of acoustic neuroma, acute leukemia, acute lymphocytic leukemia, Acute myeloid leukemia, acute t-cell leukemia, basal cell carcinoma, cholangiocarcinoma, bladder cancer, brain cancer, breast cancer, bronchial cancer, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytes Leukemia, chronic myeloid (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, poor proliferative changes, embryo Cancer, endometrial cancer, endothelial sarcoma, ependymoma, epithelial cancer, erythroleukemia, esophageal cancer, estrogen receptor-positive breast cancer, essential thrombocythemia, Ewing's sarcoma, fibrosarcoma, follicular Lymphoma, germ cell testicular cancer, glioma, glioblastoma, glial sarcoma, heavy chain disease, hemangioblastoma, liver cancer, hepatocellular carcinoma Hormone-insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphatic endothelial sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma, bladder, breast, colon, lung, ovary, pancreas, prostate, skin and Malignant tumors and hyperproliferative disorders of the uterus, T-cell or B-cell-derived lymphoid malignancies, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, Myeloid leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline cancer (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillary Adenocarcinoma, papillary carcinoma, pineal tumor, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland cancer, seminoma, skin cancer, small cells Lung cancer, solid tumor, small cell lung cancer, gastric cancer, squamous cell carcinoma, synovial tumor, sweat adenoma, thyroid cancer, primary macroglobulinemia, testicular swelling , Uterine cancer and Wilms tumor in one or more.
如权利要求1-8至少一项中所述的如式I所示的苯并氮杂环类化合物、其互变异构体、光学异构体、溶剂化物、其药学上可接受的盐或其前药在制备用于治疗和/或预防肿瘤、肺部疾病、炎性疾病或自身免疫疾病的药物中的应用。A benzazepine heterocyclic compound, a tautomer, an optical isomer, a solvate thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1-8 The use of the prodrug thereof for the preparation of a medicament for the treatment and/or prevention of a tumor, a lung disease, an inflammatory disease or an autoimmune disease.
如权利要求13所述的应用，其特征在于，所述的肺部疾病、炎性疾病或自身免疫疾病选自：艾迪生病、急性痛风、强直性脊柱炎、哮喘、动脉粥样硬化、白塞病、大疱性皮肤病、慢性阻塞性肺病、克罗恩病、皮炎、湿疹、巨细胞性动脉炎、肾小球性肾炎、肝炎、下垂体炎、炎性肠病、川崎病、狼疮性肾炎、多发性硬化、心肌炎、肌炎、肾炎、器官移植排斥、骨关节炎、胰腺炎、心包炎、结节性多动脉炎、局限性肺炎、原发性胆汁性肝硬化、银屑病、银屑病性关节炎、类风湿性关节炎、巩膜炎、硬化性胆管炎、脓毒症、***性红斑狼疮、高安氏动脉炎、中毒性休克、甲状腺炎、I型糖尿病、溃疡性结肠炎、葡萄膜炎、白癜风、脉管炎和韦格纳肉芽肿中的一种或多种。The use according to claim 13, wherein said pulmonary disease, inflammatory disease or autoimmune disease is selected from the group consisting of: Addison's disease, acute gout, ankylosing spondylitis, asthma, atherosclerosis, white Stable disease, bullous skin disease, chronic obstructive pulmonary disease, Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypopituitaritis, inflammatory bowel disease, Kawasaki disease, lupus Nephritis, multiple sclerosis, myocarditis, myositis, nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, nodular polyarteritis, localized pneumonia, primary biliary cirrhosis, psoriasis , psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, high Ankyrin arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colon One or more of inflammation, uveitis, vitiligo, vasculitis, and Wegener's granulomatosis.
一种药物组合物，其包含如权利要求1-8至少一项中所述的如式I所示的苯并氮杂环类化合物、其互变异构体、光学异构体、溶剂化物、其药学上可接受的盐或其前药，和至少一种药用辅料。A pharmaceutical composition comprising the benzazepine heterocyclic compound of formula I, a tautomer, an optical isomer thereof, a solvate thereof, according to any one of claims 1-8, a pharmaceutically acceptable salt thereof or a prodrug thereof, and at least one pharmaceutically acceptable adjuvant.