WO2008138232A1

WO2008138232A1 - Pyrrolo-nitrogenous heterocyclic derivatives, the preparation and the pharmaceutical use thereof

Info

Publication number: WO2008138232A1
Application number: PCT/CN2008/001352
Authority: WO
Inventors: Peng Cho Tang; Yidong Su; Yali Li; Lei Zhang; Fuqiang Zhao; Jialiang Yang; Ying Zhou; Pingyan Bie; Guangtao Qian; Minggang Ju
Original assignee: Shanghai Hengrui Pharmaceutical Co., Ltd.
Priority date: 2007-05-14
Filing date: 2008-05-14
Publication date: 2008-11-20

Abstract

The invention provides new pyrrolo-nitrogenous heterocyclic derivatives represented by formula (I) or their salts, the preparation thereof, pharmaceutical compositions containing such derivatives and the use of such derivatives as therapeutic agents, especially as protein kinase inhibitors, wherein each substituent in formula (I) is same as defined in the description.

Description

吡咯并 N杂环类衍生物、其制备方法及其在医药上的应用技术领域本发明涉及一种新的吡咯并 N杂环类衍生物，它们的制备方法及其含有它们的药物组合物和它们作为治疗剂特别是作为蛋白激酶抑制剂的用途。背景技术 TECHNICAL FIELD The present invention relates to a novel pyrrolo-N heterocyclic derivative, a process for producing the same, a pharmaceutical composition containing the same, and a pharmaceutical composition containing the same, and a pharmaceutical composition thereof They are useful as therapeutic agents, particularly as protein kinase inhibitors. Background technique

细胞的信号传导是一种基础的作用机制，在信号传导过程中，来自细胞外的刺激被传递到细胞内部，进而调节不同细胞的进程。这些信号可调节多种生理响应，包括细胞增殖、分化、凋亡和运动等，它们以不同种类溶解因子形式存在，包括以旁分泌因子、自分泌因子和内分泌因子为主的生长因子。通过与特定跨膜受体结合，生长因子配体将细胞外信号传递到细胞内信号途径，从而引起个体细胞对细胞外信号的反应。很多信号传递过程是利用蛋白磷酸化的可逆过程，涉及到特定蛋白激酶和磷酰化酶。 Cellular signaling is a fundamental mechanism of action. During signal transduction, extracellular stimuli are transmitted to the interior of the cell, which in turn regulates the progression of different cells. These signals regulate a variety of physiological responses, including cell proliferation, differentiation, apoptosis, and exercise, which exist as different types of lytic factors, including growth factors that are predominantly paracrine, autocrine, and endocrine. By binding to specific transmembrane receptors, growth factor ligands transmit extracellular signals to intracellular signaling pathways, causing individual cells to respond to extracellular signals. Many signaling processes are reversible processes that utilize protein phosphorylation involving specific protein kinases and phosphorylating enzymes.

蛋白激酶（PKs)是对蛋白质的酪氨酸、丝氨酸、苏氨酸残基上的羟基的磷酸化起催化作用的酶。在信号传导过程中，蛋白激酶和磷酰化酶的反向机制能够平衡和调节信号流。一个蛋白质磷酸化状态能影响其构象、酶的活性、细胞定位，蛋白激酶和磷酸酶的相应作用被修改，磷酰化在信号传导中是一个重要的调节机制，在信号传导过程中的异常会导致细胞的非正常分化、转化和生长。例如，细胞可通过将其一部分 DNA转化为致癌基因而成为癌细胞，酪氨酸激酶就是这样的致癌基因所编码的生长因子受体蛋白；酪氨酸激酶还可以突变为活化形式而导致多种人类细胞的变异，也可以说，过度表达的正常酪氨酸激酶可以引起不正常细胞增殖。 Protein kinases (PKs) are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine, and threonine residues of proteins. The reverse mechanism of protein kinases and phosphorylases balances and regulates signal flow during signaling. A protein phosphorylation state can affect its conformation, enzyme activity, cell localization, and the corresponding roles of protein kinases and phosphatases are modified. Phosphorylation is an important regulatory mechanism in signal transduction, and abnormalities during signal transduction. Lead to abnormal differentiation, transformation and growth of cells. For example, a cell can become a cancer cell by converting a portion of its DNA into an oncogene, a growth factor receptor protein encoded by such an oncogene; a tyrosine kinase can also be mutated into an activated form resulting in a variety of Variations in human cells, it can be said that over-expressed normal tyrosine kinases can cause abnormal cell proliferation.

酪氨酸激酶 (PKs)可以方便地分成两类：蛋白酪氨酸激酶 (PTKs)和丝氨酸一苏氨酸激酶 (STKs)。 PTKs使蛋白质上的酪氨酸残基磷酸化， STKs使蛋白质上的丝氨酸、苏氨酸残基磷酸化。酪氨酸激酶不仅可以是受体型 (包括细胞外域、细胞内域和跨膜细胞域)还可以是非受体型 (包括全部细胞内域)。 PTK活性的一个主要方面是它们涉及到作为细胞表面蛋白生长因子受体。具有 PTK活性的生长因子受体被称为受体酪氨酸激酶（"RTKs"),在人类基因中 90种酪氨酸激酶被识别，其中约 60种是受体型，约 30种是非受体型，这些生长因子受体家族可进一步分为 20种受体酪氨酸激酶亚族和 10种非受体酪氨酸激酶亚族 (Robinson等, Oncogene, 2000, !£，5548-5557)。 Tyrosine kinases (PKs) can be conveniently divided into two classes: protein tyrosine kinases (PTKs) and serine-threonine kinases (STKs). PTKs phosphorylate tyrosine residues on proteins, and STKs phosphorylate serine and threonine residues on proteins. Tyrosine kinases can be not only receptor type (including extracellular domain, intracellular domain and transmembrane cell domain) but also non-receptor type (including all intracellular domains). A major aspect of PTK activity is that they are involved as cell surface protein growth factor receptors. Growth factor receptors with PTK activity are called receptor tyrosine kinases ("RTKs"), and 90 tyrosine kinases are recognized in human genes, of which about 60 are receptor types and about 30 are non-receptive. The growth factor receptor family can be further divided into 20 receptor tyrosine kinase subfamilies and 10 non-receptor tyrosine kinase subfamilies (Robinson et al, Oncogene, 2000, !£, 5548-5557) .

RTKs亚族包括以下几种：（l)EGF族，如 EGF, TGFa, Neu和 erbB等；（2)胰岛素家族，包括胰岛素受体、*** I受体 (IGF1)和胰岛素受体相关性受体 (IRR)); (3)111型家族，如血小板衍生生长因子受体 (PDGF, 包括 PDGFa和 PDGFP受体)、干细胞因子 RTKs(SCF RTK, 通常称作 c-Kit)、 fins-相关酪氨酸激酶 3(Flt3)受体酪氨酸激酶和集落刺激因子 1受体 (CSF-1R)酪氨酸激酶等。它们在控制细胞生长及分化方面起着关键的作用，也是导致产生生长因子和细胞因子的细胞信号的关键传递者 (参见 Schlessinger and Ullrich, Neuron 1992, 9, 3'83)。一部分非限制性激酶包括 Abl, ARaf, ATK, ATM, bcr-abl, Blk, BRaf, Brk， Btk, CDK1, CDK2, CDK3, CDK4, CDK5， CDK6, CDK7, CDK8, CDK9, CHK, AuroraA, AuroraB, AuroraC, cfms, c-fms, c-Kit, c-Met, cRafl, CSF1R, CSK, c-Src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Fps, Frk, Fyn, GSK， gsk3a, gsk3b, Hck, Chic, Axl, Pim-1, Plh-1 , IGF-1R, IKK, IKKl, IKK2, I 3, INS-R, Integrin-linlced kinase, Jal , JAKl, JAK2, JAK3, JNK, JNK: Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKB1, PKB2, PKB3, PKC, PKCa, PKCb, PKCd, PKCe, PKCg, PKC1 , PKCm, PKCz, PLK1, Polo-like kinase, PYK2, tie_1? tie₂, TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1, VEGF-R2, Yes和 Zap70等。人们认为 PKs与中枢神经***疾病如老年痴呆症 (参见 Mandelkow, E. M.等. FEBS Lett. 1992, 314, 315; Sengupta, A.等. Mol. Cell. Biochem. 1997, 167,99)、痛感 (参见 Yashpal, K. J. Neurosci. 1995, 15, 3263-72)、炎症例如关节炎（参见 Badger, J. Pharmn Exp. Ther. 1996, 279, 1453)、牛皮癣（参见 Dvir,等， J. Cell Biol. 1991, 113, 857)、骨骼疾病例如骨质疏松 (参见 Tanaka等, Nature, 1996, 383, 528)、癌症（参见 Hunter and Pines, Cell 1994, 79, 573)、动脉硬化症 (参见 Hajjar and Pomerantz, FASEB J. 1992, 6， 2933)、血栓症（参见 Salari, FEBS 1990,263,104)、代谢紊乱如糖尿病（参见 Borthwick, A. C. 等. Biochem. Biophys. Res. Commun. 1995,210,738),血管增生性疾病如血管生成 (参见 Stmwn等 Cancer Res. 1996, 56, 3540; Jackson等 J. Pharm. Exp. Ther. 1998, 284, 687)、自身免疫疾病和移植排斥反应（参见 Bolen and Brugge, Ann. Rev. Immunol. 1997, 15, 371)、传染病如病毒（参见 Littler, E. Nature 1992,358,160)和真菌感染 (参见 Lum, R. T. PCT Int AppL, WO 9805335 Al 980212)等疾病的靶点有密切的联系。 The RTKs subfamily includes the following: (1) EGF family, such as EGF, TGFa, Neu and erbB, etc.; (2) Insulin family, including insulin receptor, insulin-like growth factor I receptor (IGF1) and insulin receptor-related Sexual receptors (IRR); (3) family 111, such as platelet-derived growth factor receptors (PDGF, including PDGFa and PDGFP receptors), stem cell factor RTKs (SCF RTK, commonly referred to as c-Kit), fins- Related tyrosine Enzyme 3 (Flt3) receptor tyrosine kinase and colony stimulating factor 1 receptor (CSF-1R) tyrosine kinase and the like. They play a key role in controlling cell growth and differentiation and are key players in cell signaling leading to the production of growth factors and cytokines (see Schlessinger and Ullrich, Neuron 1992, 9, 3'83). A portion of the non-limiting kinases include Abl, ARaf, ATK, ATM, bcr-abl, Blk, BRaf, Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CHK, AuroraA, AuroraB, AuroraC, cfms, c-fms, c-Kit, c-Met, cRafl, CSF1R, CSK, c-Src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Fps, Frk, Fyn, GSK, gsk3a, gsk3b, Hck, Chic, Axl, Pim-1, Plh-1, IGF-1R, IKK, IKKl, IKK2, I 3, INS -R, Integrin-linlced kinase, Jal, JAKl, JAK2, JAK3, JNK, JNK: Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKB1, PKB2, PKB3, PKC, PKCa, PKCb, PKCd, PKCe, PKCg, PKC1, PKCm, PKCz, PLK1, Polo-like kinase, PYK2, tie _1? tie ₂ , TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1, VEGF-R2, Yes and Zap70, and the like. PKs are thought to be associated with central nervous system diseases such as Alzheimer's disease (see Mandelkow, EM et al. FEBS Lett. 1992, 314, 315; Sengupta, A. et al. Mol. Cell. Biochem. 1997, 167, 99), pain (see Yashpal, KJ Neurosci. 1995, 15, 3263-72), inflammation such as arthritis (see Badger, J. Pharmn Exp. Ther. 1996, 279, 1453), psoriasis (see Dvir, et al, J. Cell Biol. 1991, 113, 857), bone diseases such as osteoporosis (see Tanaka et al, Nature, 1996, 383, 528), cancer (see Hunter and Pines, Cell 1994, 79, 573), atherosclerosis (see Hajjar and Pomerantz, FASEB) J. 1992, 6, 2933), thrombosis (see Salari, FEBS 1990, 263, 104), metabolic disorders such as diabetes (see Borthwick, AC et al. Biochem. Biophys. Res. Commun. 1995, 210, 738), vascular proliferative diseases such as Angiogenesis (see Stmwn et al. Cancer Res. 1996, 56, 3540; Jackson et al. J. Pharm. Exp. Ther. 1998, 284, 687), autoimmune diseases and transplant rejection (see Bolen and Brugge, Ann. Rev. Immunol) 1997, 15, 371), infectious diseases such as viruses (see Littler, E. Nature 1992, 358, 160) is closely related to the target of diseases such as fungal infection (see Lum, RT PCT Int AppL, WO 9805335 Al 980212).

PTKs信号传导过程中，特定生长因子 (配体)之间在细胞外相互作用，随后受体二聚，瞬间内激活蛋白激酶的内在活性，并进行磷酰化。内部信号传导分子的结合位点产生，生成了与细胞质信号分子的复合物，促进各种细胞应答例如细胞 *** (增殖)，对胞外微环境代谢作用的表达等。 During PTKs signaling, specific growth factors (ligands) interact extracellularly, followed by receptor dimerization, which activates the intrinsic activity of the protein kinase and phosphorylates. The binding site of the internal signaling molecule is generated to form a complex with the cytoplasmic signaling molecule, promoting various cellular responses such as cell division (proliferation), expression of extracellular microenvironment metabolism, and the like.

受体酪氨酸激酶磷酰化的结合位点也是与信号传导分子 SH2(与 src同源)域具有高度亲和力的结合位点。很多与受体酪氨酸激酶相关的细胞内底物蛋白已被确定，可分为两类：（1)有催化区底物 (2)无催化区底物，但可作为结合体，且与某些有催化活性的分子相关。受体或蛋白与底物 SH2域相互作用的特异性是通过靠近磷酰化酪氨酸残基的氨基酸序列来确定的， SH2域与磷酰化酪氨酸序列周围的氨基酸序列与特定受体结合的差异性与底物磷酰化的差异性是一致的。蛋白酪氨酸激酶机能可通过表达模式和配体可用性来确定，也可由特定受体激活的下游区信号传导路径来确定。因此，磷酰化提供了一个重要可调节的步骤，此步骤可确定由特定受体激活的信号传导的选择性和分化因子受体。受体酪氨酸激酶的非正常表达或突变可能导致不可控制的细胞增殖 (如恶性肿瘤生长)或关键发展过程的缺失等。， The binding site for phosphorylation of the receptor tyrosine kinase is also a binding site with a high affinity for the SH2 (synchronous to src) domain of the signaling molecule. Many intracellular substrate proteins associated with receptor tyrosine kinases have been identified and can be divided into two categories: (1) substrate with catalytic domain (2) substrate without catalytic region, but can be used as a combination, and Certain catalytically active molecules are related. The specificity of the interaction of a receptor or protein with the substrate SH2 domain is determined by the amino acid sequence near the phosphorylated tyrosine residue, the amino acid sequence surrounding the SH2 domain and the phosphorylated tyrosine sequence and the specific receptor The difference in binding is consistent with the difference in substrate phosphorylation. Protein tyrosine kinase function can be determined by expression pattern and ligand availability, as well as by downstream region signaling pathways activated by specific receptors. Therefore, phosphorylation provides an important adjustable step that can be determined A selective and differentiation factor receptor for signaling that is activated by a specific receptor. Abnormal expression or mutation of a receptor tyrosine kinase may result in uncontrolled cell proliferation (such as malignant tumor growth) or loss of key developmental processes. ,

酪氨酸激酶，在大部分人类肿瘤，如白血病、乳腺癌、 ***癌、非小细胞肺癌 (包括腺癌、肺鳞状上皮细胞癌)、胃肠癌 (包括结肠癌、直肠癌和胃癌)、膀胱癌、食管癌、卵巢癌、胰腺癌等癌症中，都会出现突变或过度表达。通过对人类肿瘤细胞进行检测，酪氨酸激酶广泛性与关联性进一步得到了确认。例如：在人类癌症包括肺癌、脑癌、颈癌、胃肠癌、乳腺癌、食管癌、卵巢癌、子宫癌、膀胱癌和甲状腺癌中， EGFR酪氨酸激酶会发生突变和过度表达。 Tyrosine kinases, in most human tumors, such as leukemia, breast cancer, prostate cancer, non-small cell lung cancer (including adenocarcinoma, lung squamous cell carcinoma), gastrointestinal cancer (including colon cancer, rectal cancer, and gastric cancer) In cancers such as bladder cancer, esophageal cancer, ovarian cancer, and pancreatic cancer, mutations or overexpression may occur. The broadness and relevance of tyrosine kinases have been further confirmed by detection of human tumor cells. For example: In human cancers including lung cancer, brain cancer, cervical cancer, gastrointestinal cancer, breast cancer, esophageal cancer, ovarian cancer, uterine cancer, bladder cancer and thyroid cancer, EGFR tyrosine kinase is mutated and overexpressed.

"HER" 或 "Erb"受体酪氨酸激酶亚族包括 EGFR,HER2,HER3和 HER4。这些亚族由胞外糖基化配体结合域、跨膜域及可将蛋白质上的酪氨酸序列进行磷酰化的胞内细胞质催化域所组成。受体酪氨酸激酶催化活性可通过受体过度表达或配体介导二聚合被激活。 HER2家族聚合体有同型二聚体和异型二聚体两种形式。同型二聚化的一个例子是 HERl(EGFR)与 EGF家族配体 (包括 EGF,转化生长因子 a， betacellulin, 与肝磷脂结合的 EGF， epiregulin) 的聚合，四种 HER酪氨酸激酶之间的异型二聚合可通过与 heregulin (也叫 neuregulin)家族配体的结合被加速。虽然 HER3的受体之一没有酶活性，但 HER2与 HER3,或 HER3 与 HER4 的异型二聚也可显著地刺激酪氨酸激酶受体二聚合。在各种类型细胞中，受体过度表达可激活 HER2激酶的活性。受体同型二聚体和异型二聚体的激活可将受体和其他细胞内蛋白质酪氨酸序列进行磷酰化，随后细胞内信号途径如微管相关蛋白激酶 (MAP激酶)和磷脂酰肌醇 (-3)激酶 (PI3激酶)也被激活，这些信号途径的激活促使细胞增殖，抑制细胞调亡。 The "HER" or "Erb" receptor tyrosine kinase subfamily includes EGFR, HER2, HER3 and HER4. These subfamilies consist of an extracellular glycosylation ligand binding domain, a transmembrane domain, and an intracellular cytoplasmic catalytic domain that phosphorylates the tyrosine sequence on the protein. The receptor tyrosine kinase catalytic activity can be activated by receptor overexpression or ligand-mediated dimerization. The HER2 family of polymers has both homodimers and heterodimers. An example of homodimerization is the polymerization of HER1 (EGFR) with EGF family ligands (including EGF, transforming growth factor a, betacellulin, heparin-binding EGF, epiregulin), between four HER tyrosine kinases. The heterodimerization can be accelerated by binding to the heregulin (also known as neuregulin) family of ligands. Although one of the receptors for HER3 has no enzymatic activity, heterodimerization of HER2 with HER3, or HER3 and HER4, also significantly stimulates tyrosine kinase receptor dimerization. In various cell types, receptor overexpression activates the activity of HER2 kinase. Activation of receptor homodimers and heterodimers phosphorylates receptors and other intracellular protein tyrosine sequences, followed by intracellular signaling pathways such as microtubule-associated protein kinases (MAP kinases) and phosphatidylcholines Alcohol (-3) kinase (PI3 kinase) is also activated, and activation of these signaling pathways promotes cell proliferation and inhibits cell apoptosis.

RTK另一个亚族包括胰岛素受体 (IR)，*** -1受体 (IGF-1R),胰岛素受体相关受体 (IRR)。 IR， IGF-1R与胰岛素， IGF-I和 IGF- II相互作用，生成了由两种完全胞外糖基化 ot亚基和两个穿过细胞膜且含有酪氨酸激酶域 β亚基构成的异四聚体。 Another subfamily of RTK includes the insulin receptor (IR), the insulin-like growth factor-1 receptor (IGF-1R), and the insulin receptor-related receptor (IRR). IR, IGF-1R interacts with insulin, IGF-I and IGF-II, resulting from two completely extracellular glycosylated ot subunits and two tyrosine kinase domain beta subunits that cross the cell membrane Heterotetramer.

RTK第三个亚族是指血小板源生长因子受体 (PDGFR)族，其中包括 PDGFRci, PDGFRp, CSFIR, c-Kit和 c-fms。这些受体由含有各种免疫球蛋白样环糖基化胞外域和一个胞外域所组成，其中胞内域中酪氨酸激酶区被不相关的氨基酸序列阻断。 The third subgroup of RTK refers to the platelet-derived growth factor receptor (PDGFR) family, including PDGFRci, PDGFRp, CSFIR, c-Kit and c-fms. These receptors are composed of a variety of immunoglobulin-like cyclic glycosylated extracellular domains and an extracellular domain in which the tyrosine kinase domain in the intracellular domain is blocked by an unrelated amino acid sequence.

· 血小板源生长因子受体，如 PDGFRa和 PDGFRp等也是跨膜酪氨酸激酶受体。当它们与配体相结合时，或形成同型二聚物 (PDGF-AA，PDGF-BB)，或异型二聚物 (PDGF-AB)o 随后受体二聚，酪氨酸激酶被活化，向下游区发信号来促进肿瘤生长。基因突变是受体不依赖于与配体结合而被激活的原因，也是肿瘤生成的驱动力。在多种不同的肿瘤细胞株内，特别是***癌、结肠癌、卵巢癌、前列酰癌、肉瘤和胶质瘤的细胞中，都发现能够激活 PDGFR生长因子一 PDGF的表达，其中脑瘤， ***癌 (包括腺癌和骨转移癌)恶性神经胶质过多症研究数据有研究价值。 c-Kit是 PDGF受体家族的成员，当其与配体 SCF (干细胞因子)相结合时，活性被激活。在各种不同的实体瘤中对 c-Kit表达模式进行了研究，在肉瘤，胃肠道胶质瘤 (GIST), ***瘤和类癌瘤中， c-Kit有过量表达。 [参见 Weber等， J. Clin. Oncol. 22(14S), 9642 (2004)]。 GIST是一种非上皮细胞瘤，大多数存在于胃部，少数分布于小肠，在食道中存在很少，也有分布在肝、腹膜腔等部位。 GIST源于 Cajal *** (ICC)， ICC可部分形成肠自主神经***，参与控制胃动力。大多数 (50〜 80%)GIST产生是由于 c-Kit基因发生突变，在消化道内， c-Kit/CD117染色阳性的一般都为 GIST, c-Kit突变能够使其不依赖于 SCF激活便具有 c-Kit机能，从而使细胞 ***率增加，导致基因组的不稳定。在畸变肥大细胞瘤、肥大细胞增生病、骨髓增生综合征、荨麻疹等疾病中，也可检测到 c-Kit的表达，在急性 AML和恶性淋巴瘤中也有 c-Kit的表达，在小细胞支气管癌、 ***瘤、无性细胞瘤、睾丸、上皮内瘤样变、黑素瘤、***癌、成神经细胞瘤、尤因肉瘤都有 c-Kit表达 (参见 ScMtte et al" innovartis 3/2001)。众所周知， RET(rearranged during transfection)。原癌基因点遗传突变是致瘤的，患有多发性内分泌腺瘤病 2 (MEN 2)病人可能会导致患有嗜铬细胞瘤、甲状腺髓样癌和甲状旁腺腺瘤和增生等病症 (见 Huang et al., Cancer Res. 60， 6223-6 (2000))。 · Platelet-derived growth factor receptors such as PDGFRa and PDGFRp are also transmembrane tyrosine kinase receptors. When they bind to a ligand, either form a homodimer (PDGF-AA, PDGF-BB), or a heterodimer (PDGF-AB) o followed by receptor dimerization, the tyrosine kinase is activated, The downstream zone signals to promote tumor growth. Mutations in genes are responsible for receptors that are not dependent on binding to ligands and are a driving force for tumorigenesis. It is found to activate PDGFR growth factor-PDGF expression in a variety of different tumor cell lines, particularly breast cancer, colon cancer, ovarian cancer, prodryolyzed carcinoma, sarcoma and glioma cells, of which brain tumors, The research data of malignant gliosis in prostate cancer (including adenocarcinoma and bone metastases) has research value. c-Kit is a member of the PDGF receptor family and its activity is activated when it binds to the ligand SCF (stem cell factor). The c-Kit expression pattern was studied in various solid tumors, and c-Kit was overexpressed in sarcoma, gastrointestinal glioma (GIST), seminoma and carcinoid tumors. [See Weber et al, J. Clin. Oncol. 22 (14S), 9642 (2004)]. GIST is a non-epithelial cell tumor, most of which is present in the stomach, a few in the small intestine, rarely in the esophagus, but also in the liver, peritoneal cavity and other parts. GIST is derived from Cajal interstitial cells (ICC), which partially forms the intestinal autonomic nervous system and is involved in the control of gastric motility. Most (50~80%) GIST production is due to mutation of c-Kit gene. In the digestive tract, c-Kit/CD117 staining is generally GIST, and c-Kit mutation can make it independent of SCF activation. c-Kit function, resulting in increased cell division rate, leading to instability of the genome. In the cases of distorted mast cell tumor, mast cell proliferative disease, myeloproliferative syndrome, urticaria and other diseases, c-Kit expression can also be detected, and c-Kit expression is also found in acute AML and malignant lymphoma, in small cells. Bronchial carcinoma, seminoma, dysgerminoma, testis, intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, Ewing's sarcoma have c-Kit expression (see ScMtte et al" innovartis 3/ 2001). It is well known that RET (rearranged during transfection). Proto-oncogene point genetic mutation is tumorigenic, and patients with multiple endocrine neoplasia 2 (MEN 2) may cause pheochromocytoma and medullary thyroid Cancer and parathyroid adenomas and hyperplasia (see Huang et al., Cancer Res. 60, 6223-6 (2000)).

因胎肝激酶 (Flk)受体亚族与 PDGFR亚族很相似，有时被归于该族。此亚族由含激酶***域-受体胎肝激酶 -1( DR/FLK-1, VEGFR2), Flk-1R, Flk-4和 fms样酪氨酸激酶 l (Flt-l)所组成。 Because the fetal liver kinase (Flk) receptor subfamily is very similar to the PDGFR subfamily, it is sometimes attributed to this family. This subfamily consists of a kinase-containing insertion domain-receptor fetal liver kinase-1 (DR/FLK-1, VEGFR2), Flk-1R, Flk-4 and fms-like tyrosine kinase l (Flt-1).

酪氨酸激酶生长因子受体家族的另外一个成员是成纤维细胞生长因子 (FGF) 受体亚族。此亚族由四个受体， FGFRl-4、七个配体和 FGF1-7组成。虽然目前尚未确定，但这些受体是由包含各种免疫球蛋白样环糖基化的一个胞外域和一个其中酪氨酸激酶序列被不相关的氨基酸序列所阻断的细胞内域组成。 Another member of the tyrosine kinase growth factor receptor family is the fibroblast growth factor (FGF) receptor subfamily. This subfamily consists of four receptors, FGFR1-4, seven ligands and FGF1-7. Although not yet determined, these receptors are composed of an extracellular domain comprising various immunoglobulin-like cycloglycosylation and an intracellular domain in which the tyrosine kinase sequence is blocked by an unrelated amino acid sequence.

酪氨酸激酶生长因子受体家族的另外一个成员是血管内皮生长因子 (VEGF)受体亚族。与 PDGF相似， VEGF是二聚糖蛋白，但生物学功能和体内靶细胞特异性不同。特别是， VEGFR与血管生成有关，通过抑制 VEGFRs来抑制血管生成，正应用于临床***，且取得了较好疗效。 VEGF在各种恶性实体肿瘤中，如肺癌、乳腺癌、非霍奇金恶性淋巴瘤、卵巢癌、胰腺癌、恶性胸膜间皮瘤和黑素瘤有强烈表达，且与癌变进程相关，在白血球过多症和淋巴瘤中也有表达。除了其血管生成活性， VEGFR, VEGF配体也可以通过在肿瘤细胞内直接通过 pro-survival性质促进肿瘤生长， PDGF也具有血管生成作用。新生血管生成的过程对于肿瘤持续生长起着关键作用，正常情况下，新生血管的生成在人的生理过程如胚胎生长、伤口愈合和女性生殖的各个过程都是非常重要的。然而，非预料或者病理学上的血管生成却与疾病的一系列状态相关，如糖尿病视网膜病、牛皮癣、癌症、类风湿性关节炎、动脉粥样化、卡波济 (氏)肉瘤和血管瘤等。血管内皮细胞的生成激活血管生成，具有刺激体内血管内皮细胞中的的生成活性一些多肽已经被确认，包括酸性、碱性的成纤维细胞生长因子 (aFGF and bFGF)和血管内皮生长因子。由于 VEGF受体的限制表达，其生长因子的活性与 aFGF and bFGF活性相比，对内皮细胞相对来讲具有特异性。最近的证据表明， VEGF在正常情况和病理学情况下的血管生成和血管渗透过程中，都是非常重要的刺激剂。 VEGF能够诱导血管萌芽表型，它诱导内皮细胞增殖、蛋白酶的表达和迁移来促进毛细血管生成，从而形成超渗透、不成熟的血管网络，这是典型的病理学血管生成的典型特征。人们期望拮抗 VEGF活性在治疗与血管生成作用或者血管渗透性相关的疾病如肿瘤特别是抑制肿瘤生长能够有应用的价值。 Another member of the tyrosine kinase growth factor receptor family is the vascular endothelial growth factor (VEGF) receptor subfamily. Similar to PDGF, VEGF is a dimeric glycoprotein, but its biological function is different from that of in vivo target cells. In particular, VEGFR is involved in angiogenesis, inhibits angiogenesis by inhibiting VEGFRs, and is being used in clinical treatment of tumors, and has achieved good results. VEGF is strongly expressed in various malignant solid tumors such as lung cancer, breast cancer, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, malignant pleural mesothelioma, and melanoma, and is associated with the progression of cancer, in white blood cells. Excessive symptoms and lymphoma are also expressed. In addition to its angiogenic activity, VEGFR, VEGF ligands can also promote tumor growth by directly pro-survival properties in tumor cells, and PDGF also has an angiogenic effect. The process of neovascularization plays a key role in the continued growth of the tumor. Under normal circumstances, the formation of new blood vessels is very important in various processes of human physiological processes such as embryo growth, wound healing and female reproduction. However, unanticipated or pathological angiogenesis is associated with a range of conditions of the disease, such as diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and hemangioma. Wait. The production of vascular endothelial cells activates angiogenesis and has been shown to stimulate the production of vascular endothelial cells in vivo. Some peptides have been identified, including Acidic, basic fibroblast growth factor (aFGF and bFGF) and vascular endothelial growth factor. Due to the restricted expression of the VEGF receptor, its growth factor activity is relatively specific to endothelial cells compared to aFGF and bFGF activity. Recent evidence suggests that VEGF is a very important stimulator during angiogenesis and vascular infiltration in both normal and pathological conditions. VEGF induces a vascular sprouting phenotype that induces endothelial cell proliferation, protease expression and migration to promote capillary formation, thereby forming a super-osmotic, immature vascular network, which is typical of typical pathological angiogenesis. It is expected that antagonizing VEGF activity can be of value in the treatment of diseases associated with angiogenesis or vascular permeability, such as tumors, particularly tumor growth inhibition.

FLT3(Fms样酪氨酸激酶)是酪氨酸激酶 (ΡΤΚ)Ι11型家族成员，在成人和幼儿急性髓细胞样白血病 (AML)、急性髓细胞样白血病、骨髓增生异常综合征等白血球过多症中， FLT3基因非正常表达。 35 %的急性髓细胞样白血病病人的 FLT3突变被激活且预后不良，大多数的突变都有在近膜域的结构内复制的现象， 5— 10 %的病人天冬酰氨 835发生点突变， FLT3的酪氨酸激酶活性被激活，致使在配体缺失的情况下也有信号存在且发生增殖。据研究，有突变形式受体表达的患者治愈的几率降低。总之，在人白血球过多症和骨髓增生异常综合征中， FLT3突变都与肿瘤的发生相关。 FLT3 (Fms-like tyrosine kinase) is a member of the tyrosine kinase (ΡΤΚ)Ι11 family and has excessive white blood cells in adult and young children with acute myeloid leukemia (AML), acute myeloid leukemia, and myelodysplastic syndrome. In the case of the disease, the FLT3 gene is abnormally expressed. In 35 % of patients with acute myeloid leukemia, FLT3 mutations are activated and the prognosis is poor. Most of the mutations have intrastructural replication in the proximal membrane domain, and 5-10% of patients have a point mutation in asparagine 835. The tyrosine kinase activity of FLT3 is activated, resulting in the presence of a signal and proliferation in the absence of a ligand. According to the study, the probability of cure in patients with mutant form of receptor expression is reduced. In conclusion, in human leukemia and myelodysplastic syndromes, FLT3 mutations are associated with tumorigenesis.

经证实肝细胞生长因子 (HGF)受体 (c-MET或 HGFR)酪氨酸激酶与肿瘤生成、增强细胞运动性、侵袭和转移密切相关 (参见 Ma, P.C等 (2003b). Cancer Metastasis i?ev， 22, 309-25; Maulik, G.等 &Q02b). Cytokine Growth Factor Rev, 13, 41-59)。各种肿瘤包括小细胞肺癌 (SCLC)中的过度表达或突变可激活 c-MET(HGFR) (参见 Ma, P.C.等 (2003a). Cancer Res, 63, 6272-6281)。 Hepatocyte growth factor (HGF) receptor (c-MET or HGFR) tyrosine kinases have been shown to be closely associated with tumorigenesis, cell motility, invasion and metastasis (see Ma, PC et al. (2003b). Cancer Metastasis i? Ev, 22, 309-25; Maulik, G. et al. & Q02b). Cytokine Growth Factor Rev, 13, 41-59). Overexpression or mutation in various tumors, including small cell lung cancer (SCLC), activates c-MET (HGFR) (see Ma, P.C. et al. (2003a). Cancer Res, 63, 6272-6281).

原癌基因 c-Met编码肝细胞生长因子受体,是具有酪氨酸激酶活性的细胞膜糖蛋白,对多种细胞增殖、分化具有重要的生理调节作用. c-met基因在许多恶性肿瘤中过表达，是甲状腺滤泡上皮细胞癌变的重要因素,并与甲状腺癌的病理分期、侵袭及转移密切相关。 The proto-oncogene c-Met encodes a hepatocyte growth factor receptor, which is a cell membrane glycoprotein with tyrosine kinase activity, which has important physiological regulation effects on various cell proliferation and differentiation. The c-met gene has been used in many malignant tumors. Expression is an important factor in the carcinogenesis of thyroid follicular epithelial cells and is closely related to the pathological stage, invasion and metastasis of thyroid cancer.

关于 PKT亚族， Plowman等在 DN&P 7(6): 334-339 (1994)中有更为详细描述，该文献作为一整体通过引用结合到本文中。 With regard to the PKT subfamily, Plowman et al. are described in more detail in DN & P 7(6): 334-339 (1994), which is incorporated herein by reference in its entirety.

除了 PTKs以外，还存在另外的细胞酶家族，称作受体酪氨酸激酶抑制剂，并在此使用后一名称，缩写为 "CTK"。 CTKs本身缺少细胞外域和跨膜域。目前，已经在 1 1个亚族 (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack和 LIMK)中已经鉴定超过 24种 CTKs。在目前为止， Src亚族 CTKs数目似乎最多，包括 Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr和 Yrk，且 Src亚族酶与肿瘤生成有关。关于 CTKs更为详尽的描述，可参见 iBolen, 1993, Oncogen 8: 2025-2031 , 其全文包括任何附图作为一整体提出，通过引用结合到本文中。 In addition to PTKs, there are additional families of cellular enzymes called receptor tyrosine kinase inhibitors, and the latter name is used here, abbreviated as "CTK". CTKs themselves lack the extracellular domain and the transmembrane domain. Currently, more than 24 CTKs have been identified in 11 subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack and LIMK). So far, the number of Src subfamily CTKs seems to be the highest, including Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk, and Src subfamily enzymes are involved in tumorigenesis. For a more detailed description of CTKs, see iBolen, 1993, Oncogen 8: 2025-2031, the entire disclosure of which is incorporated herein by reference.

与 CTKs相类似，丝氨酸-苏氨酸激酶或 STKs , 在细胞内占据主导地位，虽然仅有几种 STK型受体激酶。 STKs是最普遍的细胞溶质激酶，即它发挥其功能在部分细胞质中，而不是在胞质细胞器中。胞质溶胶是细胞内一个区域，在此大多数细胞中间代谢和生物合成活性发生；如蛋白质是在胞质溶胶核糖体上进行合成的。 Similar to CTKs, serine-threonine kinases or STKs are dominant in cells, although there are only a few STK-type receptor kinases. STKs are the most common cytosolic kinase, ie it plays its part in the ministry In the cytoplasm, not in the cytoplasmic organelles. The cytosol is a region within the cell where metabolic and biosynthetic activities occur in most cells; for example, proteins are synthesized on cytosol ribosomes.

与过度增殖相关疾病如癌症等的特征之一是对细胞传导途径进行破坏，细胞传导途径通过细胞周期来控制进程。在真核细胞中，细胞周期与蛋白质的磷酰化有序的级联反应密切相关，在信号传导的机制中， PKs很多家族似乎在细胞***周期级联中都起着关键的作用。 One of the characteristics of diseases such as cancer associated with hyperproliferation is the destruction of the cell conduction pathway, which controls the process through the cell cycle. In eukaryotic cells, the cell cycle is closely related to the phosphorylation order cascade of proteins. In the signaling mechanism, many families of PKs appear to play a key role in the cell division cycle cascade.

关于癌症，提出两个主要的假设解释过度细胞增殖，该增殖驱动与已知由 PK 调节的功能相关的肿瘤发展。即，人们觉得恶性肿瘤生长是由于控制细胞***或增殖的机制被破坏引起的。原癌基因蛋白质产物能够干扰调节细胞生长和增殖的信号传导途径，这些原癌基因的蛋白质产物包括上面讨论的细胞外生长因子，跨膜生长因子 PTK受体 (RTKs)，细胞质 PTKs(CTKs)和细胞溶质 STKs。 With regard to cancer, two major hypotheses are proposed to explain excessive cell proliferation, which drives tumor development associated with functions known to be regulated by PK. That is, it is thought that the growth of malignant tumors is caused by the destruction of the mechanism that controls cell division or proliferation. Proto-oncogene protein products can interfere with signaling pathways that regulate cell growth and proliferation. The protein products of these proto-oncogenes include the extracellular growth factors discussed above, transmembrane growth factor PTK receptors (RTKs), cytoplasmic PTKs (CTKs), and Cytosolic STKs.

人们期待着能够合成具有抗肿瘤细胞增殖活性的抑制剂，希望能够抑制 PTKs、 CTKs或者 STKs中的一种或者多种，有效地治疗和改善由 PTKs、 CTKs或者 STKs 以及血管生成作用介导的超增殖生理紊乱。 It is expected to be able to synthesize inhibitors with anti-tumor cell proliferation activity, and hope to inhibit one or more of PTKs, CTKs or STKs, effectively treating and improving super-mediated by PTKs, CTKs or STKs and angiogenesis. Proliferative physiological disorders.

本发明的目的在于在酪氨酸激酶抑制剂 SU-11248 以及专利文献 The object of the present invention is to tyrosine kinase inhibitor SU-11248 and patent literature

(US-6599902B2)报道的生物活性相当不错的吡咯环稠合结构 X的基础上，设计并合成了吡咯并六元 N杂类衍生物，并得到了更好的药理数据，为了改善吡咯并六元 N杂环类衍生物的在动物体内的药代吸收，本发明设计了具有通式 (I)所示的类似物。本发明的化合物同现有技术中具体公开的化合物具有较大的结构差异，且表现 (US-6599902B2) Based on the reported highly active pyrrole ring fused structure X, a pyrrole hexa-N-derivative derivative was designed and synthesized, and better pharmacological data were obtained, in order to improve pyrrole The pharmacological absorption of the N-heterocyclic derivative in animals, the present invention has been designed to have an analog of the formula (I). The compounds of the present invention have large structural differences and manifestations with the compounds specifically disclosed in the prior art.

v IN-048 v IN-048

SU-11248 ^λ 发明内容为了克服现有技术的不足之处，本发明的目的在于提供一种通式 ((1)所示的新的吡咯并 Ν杂环衍生物，以及它们的互变异构体、对映体、非对映体、消旋体和药学上可接受的盐，以及代谢产物和代谢前体或前药，其中所述的互变异构体包括 Ζ构型和 Ε构型。

SU-11248 ^λ SUMMARY OF THE INVENTION In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide a novel pyrroloindole heterocyclic derivative of the formula ((1), and their tautomerism Isomers, enantiomers, diastereomers, racemates and pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs, wherein the tautomers include anthracene and anthracene .

其中- among them-

X选自碳原子或氮原子； X is selected from a carbon atom or a nitrogen atom;

Rx 和 R₂在各种情况下各自独立地选自氢原子或焼基； Rx and R ₂ are each independently selected from a hydrogen atom or a fluorenyl group in each case;

选自垸基、三氟甲基、芳基或芳烷基，其中烷基，芳基或芳烷基进一步被一个或多个卤素所取代； Selected from a mercapto group, a trifluoromethyl group, an aryl group or an aralkyl group, wherein the alkyl group, the aryl group or the aralkyl group is further substituted by one or more halogens;

选自烷基，环烷基，杂环烷基，芳基，杂芳基， -(CH₂)_n(OCH₂CH₂)_rR_u， -[CH₂CH(OH)]_rCH2NR₉R₁₀或 -(CH^NRgR^ 其中烷基，环烷基，杂环烷基，芳基，杂芳基，杂环芳基进一步被一个或多个芳基，羟基，氨基，酰胺基，氨基羰基，烷氧基，芳氧基，氨基垸基，羟基烷基，杂环垸基，羧酸，羧酸酯或 -NR₉R₁₍₎ 所取代； Selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -(CH ₂ ) _n (OCH ₂ CH ₂ ) _r R _u , -[CH ₂ CH(OH)] _r CH2NR ₉ R ₁₀ or - (CH ^ NRgR ^ wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocyclyl aryl group further substituted by one or more aryl, hydroxyl, amino, amide group, aminocarbonyl , alkoxy, aryloxy, aminoguanidino, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or substituted with -NR ₉ R _{1 ()} ;

当 X为氮原子时， R₅不存在， R₆， R₇, R₈分别独立地选自氢原子或卤素；当 X为碳原子时， R₅，， R₇, R₈分别独立地选自氢原子、卤素、羟垸基、浣基、环烷基、杂环烷基、芳基、杂芳基、羟基、氰基、硝基、 -OR₉、 -0[CH₂CH₂0]_rRn , -NR₉R₁₀、 -(CH₂)_nC0₂R₉、 -(C¾)_nCONR₉R₁₀、 -COR₉ '、 -NR₉COR₁₀、 -S0₂R₉或 -NHCO₂R₁₀, 其中芳基、杂芳基、环烷基、杂环烷基进一步被一个或多个选自烷基、烷氧基或卤素的取代基所取代；和 R_1C分别选自氢原子，垸基，环垸基，芳基，杂环烷基，杂芳基，其中上述的烷基，环烷基，芳基，杂环垸基，杂芳基进一步被一个或多个烷基，芳基，卤代芳基，羟基，氨基，氰基，垸氧基，芳氧基，羟烷基，杂环垸基，羧酸、羧酸酯或 -NR₉R_{1 Q}所取代； When X is a nitrogen atom, R ₅ is absent, and R ₆ , R ₇ and R ₈ are each independently selected from a hydrogen atom or a halogen; when X is a carbon atom, R ₅ , R ₇ and R ₈ are independently selected. From hydrogen atom, halogen, hydroxydecyl, decyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, cyano, nitro, -OR ₉ , -0[CH ₂ CH ₂ 0] _r Rn , -NR ₉ R ₁₀ , -(CH ₂ ) _n C0 ₂ R ₉ , -(C3⁄4) _n CONR ₉ R ₁₀ , -COR ₉ ', -NR ₉ COR ₁₀ , -S0 ₂ R ₉ or -NHCO ₂ R ₁₀ , wherein aryl, heteroaryl, cycloalkyl, heterocycloalkyl is further substituted by one or more substituents selected from alkyl, alkoxy or halogen; and R _1C are each selected from a hydrogen atom, Anthracenyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, wherein alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl is further substituted by one or more alkyl, aryl Base, haloaryl, hydroxy, amino, cyano, decyloxy, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or substituted with -NR ₉ R _{1 Q} ;

同时 R₉和 R_1G—起形成一个 4〜8元杂环基，其中 5〜8元杂环内含有一个到多个 N， 0， S杂原子，并且 4〜8元杂环上进一歩被一个或多个烷基，卤素，芳基，杂芳基，卤代垸基，羟基，氰基，烷氧基，芳氧基，氨烷基，羟垸基，杂环烷基，羧酸，羧酸酯或 -NR₉R_1Q所取代； At the same time, R ₉ and R _{1G together} form a 4 to 8 membered heterocyclic group, wherein the 5 to 8 membered heterocyclic ring contains one to a plurality of N, 0, S heteroatoms, and the 4 to 8 membered heterocyclic ring is further Or a plurality of alkyl, halogen, aryl, heteroaryl, haloalkyl, hydroxy, cyano, alkoxy, aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxy Substituted by an acid ester or -NR ₉ R _1Q ;

Ri,选自氢原子或烷基； Ri, selected from a hydrogen atom or an alkyl group;

n是 2~6； n is 2~6;

z是 1〜4； z is 1~4;

r是 1 ~6； r is 1 ~ 6;

或其医药上可以接受的盐。在本发明的通式 (I)所述的化合物或其盐中，更优选的是是甲基。 Or a pharmaceutically acceptable salt thereof. More preferably, the compound of the formula (I) or a salt thereof of the present invention is a methyl group.

在本发明的通式 (I)所述的化合物或其盐中，更优选的是和是氢原子。进一步，本发明包括下其盐- In the compound of the formula (I) of the present invention or a salt thereof, more preferably, and is a hydrogen atom. Further, the present invention includes the following salts -

其中： among them:

Ri 和分别选自氢原子或烷基； Ri and are respectively selected from a hydrogen atom or an alkyl group;

R₃ 选自烷基，三氟甲基，芳基，芳垸基，其中烷基，芳基或芳烷基进一歩被一个或多个卤素所取代； R _{3 is} selected from the group consisting of alkyl, trifluoromethyl, aryl, aryl fluorenyl, wherein the alkyl, aryl or aralkyl group is further substituted with one or more halogens;

¾ 选自烷基，环烷基，杂环垸基，芳基，杂芳基， -(CH₂)_n(OCH₂CH₂)_rR„， -[CH₂CH(OH)]_rCH₂NR₉R₁₀或 -(CH₂)_nNR₉R₁₀，其中垸基，环烷基，杂环垸基，芳基，杂芳基，杂环芳基进一歩被一个或多个芳基，羟基，氨基，酰胺基，氨基羰基，烷氧基，芳氧基，氨基烷基，羟基烷基，杂环烷基，羧酸，羧酸酯或 -NR₉R₁₀ 所取代； 3⁄4 selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -(CH ₂ ) _n (OCH ₂ CH ₂ ) _r R„, -[CH ₂ CH(OH)] _r CH ₂ NR ₉ R ₁₀ or -(CH ₂ ) _n NR ₉ R ₁₀ , wherein an indenyl group, a cycloalkyl group, a heterocyclic fluorenyl group, an aryl group, a heteroaryl group, a heterocyclic aryl group is further substituted with one or more aryl groups, a hydroxy, amino, amido, aminocarbonyl, alkoxy, aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or -NR ₉ R ₁₀ substituted;

当 X为氮原子时， 1 ₅不存在， R₆， R₇， R₈分别独立地选自氢原子或卤素；当 X为碳原子时， R₅， R₆， R₇, R₈分别独立地选自氢原子、素、羟烷基、垸基、环烷基、杂环烷基、芳基、杂芳基、羟基、氰基、硝基、 -OR₉、 -0[CH₂CH₂0]_rRn , -NR₉Ri。、 -(CH₂)_nC0₂R₉、 -(CH₂)nCONR9R₁₀ -COR₉、 -NR₉COR₁₍₎、 -S0₂R₉ 或 -NHC0₂R_1Q，其中芳基、杂芳基、环垸基、杂环烷基进一步被一个或多个选自烷基、烷氧基或卤素的取代基所取代； When X is a nitrogen atom, 1 ₅ is absent, and R ₆ , R ₇ , and R ₈ are each independently selected from a hydrogen atom or a halogen; when X is a carbon atom, R ₅ , R ₆ , R ₇ , and R ₈ are each independently Selected from hydrogen atom, hydroxy, hydroxyalkyl, decyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, cyano, nitro, -OR ₉ , -0[CH ₂ CH ₂ 0] _r Rn , -NR ₉ Ri. _{_{, - (CH 2) n C0}} 2 R 9, - (CH 2) nCONR9R 10 -COR 9, -NR 9 COR 1 (), -S0 2 R 9 or -NHC0 ₂ R _1Q, wherein the aryl, heteroaryl a cyclodecyl group, a heterocycloalkyl group, further substituted with one or more substituents selected from alkyl, alkoxy or halogen;

R₉和 R_1Q分别选自氢原子，烷基，环垸基，芳基，杂环垸基，杂芳基，其中上述的烷基，环烷基，芳基，杂环垸基，杂芳基进一步被一个或多个垸基，芳基，卤代芳基，羟基，氨基，氰基，烷氧基，芳氧基，羟垸基，杂环垸基，羧酸、羧酸酯或 -NR₉R_1Q所取代； R ₉ and R _1Q are each selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heterocyclic fluorenyl group, a heteroaryl group, wherein the above alkyl group, a cycloalkyl group, an aryl group, a heterocyclic fluorenyl group, a heteroaryl group Further further by one or more fluorenyl, aryl, haloaryl, hydroxy, amino, cyano, alkoxy, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or Replaced by NR ₉ R _1Q ;

同时和 R_1D—起形成一个 4〜8元杂环基，其中 5〜8元杂环内含有一个到多个 N， 0, S杂原子，并且 4〜8元杂环上进一歩被一个或多个垸基，卤素，芳基，杂芳基，卤代烷基，羟基，氯基，烷氧基，芳氧基，氨焼基，羟垸基，杂环垸基，羧酸，羧酸酯或 -NR₉R_1Q所取代； R_u选自氢原子或烷基; Simultaneously with R _1D to form a 4 to 8 membered heterocyclic group, wherein the 5 to 8 membered heterocyclic ring contains one to a plurality of N, 0, S heteroatoms, and the 4 to 8 membered heterocyclic ring is subjected to one or more Sulfhydryl, halogen, aryl, heteroaryl, haloalkyl, hydroxy, chloro, alkoxy, aryloxy, amidino, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or Replaced by NR ₉ R _1Q ; R _{u is} selected from a hydrogen atom or an alkyl group;

n是 2〜6； n is 2 to 6;

r是 1〜6_; r is 1~6 _;

或其医药上可以接受的盐。歩，本发明包括下其盐: Or a pharmaceutically acceptable salt thereof.歩, the invention includes the following salts:

其中 - among them -

R₃ 选自烷基，三氟甲基，芳基，芳烷基，其中烷基，芳基或芳烷基进一步被一个或多个卤素所取代； R _{3 is} selected from the group consisting of alkyl, trifluoromethyl, aryl, aralkyl, wherein alkyl, aryl or aralkyl is further substituted by one or more halogens;

R4 选自烷基，环烷基，杂环烷基，芳基，杂芳基， -(CI^^OCftCH^Rn , -[CH₂CH(OH)]_rCH₂NR9R₁₀或 -(CH₂)_nNR₉R₁₀，其中烷基，环烷基，杂环垸基，芳基，杂芳基，杂环芳基进一步被一个或多个芳基，羟基，氨基，酰胺基，氨基羰基，垸氧基，芳氧基，氨基烷基，羟基烷基，杂环烷基，羧酸，羧酸酯或 -NR₉R₁₀ 所取代； R4 is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -(CI^^OCftCH^Rn, -[CH ₂ CH(OH)] _r CH ₂ NR9R ₁₀ or -(CH ₂ _n NR ₉ R ₁₀ , wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroaryl is further substituted by one or more aryl, hydroxy, amino, amide, aminocarbonyl, Alkoxy, aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or substituted with -NR ₉ R ₁₀ ;

当 X为氮原子时， R₅不存在， R₆， R₇， R₈分别独立地选自氢原子或卤素；当 X 为碳原子时， R₅， R₆， R₇, R₈分别独立地选自氢原子、卤素、羟烧基、烷基、环烷基、杂环烷基、芳基、杂芳基、羟基、氰基、硝基、 -OR₉、 -0[CH₂CH₂0]_rR_n, -NR₉R_l0、 -(CH₂)_nC0₂R₉ > -(CH₂)_nCONR₉R₁₀、 -COR₉、 -NR₉CORi₀、 -S0₂R₉ 或 -NHCO₂R₁₀, 其中芳基、杂芳基、环烷基、杂环烷基进一步被一个或多个选自烷基、垸氧基或卤素的取代基所取代； When X is a nitrogen atom, R ₅ is absent, and R ₆ , R ₇ and R ₈ are each independently selected from a hydrogen atom or a halogen; when X is a carbon atom, R ₅ , R ₆ , R ₇ and R ₈ are each independently Selected from hydrogen atom, halogen, hydroxyalkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, cyano, nitro, -OR ₉ , -0[CH ₂ CH ₂ 0] _r R _n , -NR ₉ R _l0 , -(CH ₂ ) _n C0 ₂ R ₉ > -(CH ₂ ) _n CONR ₉ R ₁₀ , -COR ₉ , -NR ₉ CORi ₀ , -S0 ₂ R ₉ or -NHCO ₂ R ₁₀ , wherein aryl, heteroaryl, cycloalkyl, heterocycloalkyl is further substituted by one or more substituents selected from alkyl, decyloxy or halogen;

R₉和分别选自氢原子，烷基，环垸基，芳基，杂环烷基，杂芳基，其中上述的垸基，环垸基，芳基，杂环烷基，杂芳基进一歩被一个或多个垸基，芳基，卤代芳基，羟基，氨基，氰基，垸氧基，芳氧基，羟烷基，杂环垸基，羧酸、羧酸酯或 -NR₉R_1G所取代； R ₉ and each independently selected from the group consisting of a hydrogen atom, an alkyl group, a cyclodecyl group, an aryl group, a heterocycloalkyl group, a heteroaryl group, wherein the above-mentioned indenyl group, cyclodecyl group, aryl group, heterocycloalkyl group, heteroaryl group Monoterpene by one or more fluorenyl, aryl, haloaryl, hydroxy, amino, cyano, decyloxy, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or -NR Substituted by ₉ R _1G ;

同时 R₉ 和 R_1Q—起形成一个 4〜8元杂环基，其中 5〜8元杂环内含有一个到多个 N， 0， S杂原子，并且 4〜8元杂环上进一步被一个或多个烷基，卤素，芳基，杂芳基，卤代烷基，羟基，氰基，垸氧基，芳氧基，氨烷基，羟垸基，杂环垸基，羧酸，羧酸酯或 -NR₉R_1Q所取代; Rn选自氢原子或烷基； Meanwhile, R ₉ and R _{1Q together} form a 4 to 8 membered heterocyclic group, wherein the 5 to 8 membered heterocyclic ring contains one to a plurality of N, 0, S hetero atoms, and the 4 to 8 membered heterocyclic ring is further subjected to a Or a plurality of alkyl, halogen, aryl, heteroaryl, haloalkyl, hydroxy, cyano, decyloxy, aryloxy, aminoalkyl, hydroxyalkyl, heterocyclic a mercapto group, a carboxylic acid, a carboxylic acid ester or a substituent of -NR ₉ R _1Q ; Rn is selected from a hydrogen atom or an alkyl group;

n是 2〜6； n is 2 to 6;

r是 1—6； r is 1-6;

或其医药上可以接受的盐。本发明的典型化合物包括，但不限于: Or a pharmaceutically acceptable salt thereof. Typical compounds of the invention include, but are not limited to:

8001352

\

N— N—

。 2-(5-氟 -2-氧代 -1,2-二氢 -Π引哚 -3-次甲基) -5-(2-二甲基氨基-乙基) -3-甲基 -5，6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 . 2-(5-fluoro-2-oxo-1,2-dihydro-indole hydrazin-3-methyl)-5-(2-dimethylamino-ethyl)-3-methyl-5 ,6,7,8-tetrahydro-1H-pyrrolo[3,2-c] azepine

-4-酮 -4-ketone

H H

N-{3-[5-(2-二甲基氨基-乙基) -3-甲基 -4- 氧代 -1,4,5,6,7,8-六氢-卩比咯并 [3,2-c] 吖庚因 -2-亚甲基] -5-氟 -2-氧代 -2，3-二氢 -1H-吲哚 -7-基}-甲酰胺 N-{3-[5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-indole-pyrrolo[ 3,2-c] azepine-2-methylidene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl}-carboxamide

N-{3-[5-(2-二甲基氨基-乙基) -3-甲基 -4- 氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基}-2-羟基-乙酰胺

N-{3-[5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3, 2-c] azepine-2-methylidene-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide

0 -[4-(2,3-二氟-苯基) -2-氧代 -1,2-二氢-吲 ρ 、 o r" 0 -[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dihydro-吲 ρ , o r"

哚 -3-次甲基] -3-甲基 -5-(2-吡咯烷 -1 -基- 乙基) -5,6，7,8-四氢 -1H-口比咯并 [3，2-c] 口丫庚因 -4-酮 Indole-3-methylidene]-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-oral ratio [3, 2-c] 丫丫因 -4- ketone

H H

N-{5-氟 -3-[3-甲基 -4-氧代 -5-(2-吡咯烷小基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2，3-二氢 -1H-吲哚 -7-基}-甲酰胺 N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidinyl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrole And [3,2-c] azepine-2-methyl]-2-oxo-2,3-dihydro-1H-indol-7-yl}-carboxamide

N-{3-[3-甲基 -4-氧代 -5-(2-吡咯烷 -1 -基- 乙基) -1，4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2，3-二氢 -1H-吲哚 -5-基}-乙酰胺N-{3-[3-Methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[ 3,2-c] azepine-2-methyl]-2-oxo-2,3-dihydro-1H-indol-5-yl}-acetamide

P T/CN2 08/001352

PT/CN2 08/001352

0 2-(5-氟 -2-氧代 -1，2-二氢』引哚 -3-次甲

0 2-(5-fluoro-2-oxo-1,2-dihydro) 哚-3-次甲

\ ^N 基) -3-甲基 -5-(2-吡咯烷 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 \ ^N -based)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c] 4-ketone

H H

Q 2-(5-溴 -2-氧代 -1,2-二氢』引哚 -3-次甲 o r-⁷ 基) -3-甲基 -5-(2-吡咯烷小基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚Q 2-(5-Bromo-2-oxo-1,2-dihydro) 哚-3-methyl-r- ⁷ -yl)-3-methyl-5-(2-pyrrolidine-based-B -5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]

H \ z、因 -4-酮 H \ z, in-4-ketone

2-(5-氯 -2-氧代 -1,2-二氢』引哚 -3-次甲 o ⁷ 基) -3-甲基 -5-(2-吡咯垸- 1 -基-乙基) -5，6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚2-(5-chloro-2-oxo-1,2-dihydro) 哚-3--3-methyl- ^7- (3-pyridinium-1-yl-ethyl -5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]

H 因 -4-酮 H in -4-ketone

0 3-甲基 -2-(2-氧代 -5-苯基 -1,2-二氢』引哚 o r¹ -3-次甲基 )-5-(2-吡咯烷 - 1 -基-乙基) -5,6,7，8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 0 3-methyl-2-(2-oxo-5-phenyl-1,2-dihydro) oxime or ^1-3 -methylol)-5-(2-pyrrolidine-1-yl- Ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one

2-(4-溴 -2-氧代 - 1 ,2-二氢 -B引哚 -3-次甲基) -3-甲基 -5-(2-吡咯烷小基-乙基) -5,6,7,8-四氢- 1H-吡咯并 [3,2-c] 吖庚因 -4-酮2-(4-Bromo-2-oxo-1,2-dihydro-B 哚-3-methylol)-3-methyl-5-(2-pyrrolidinyl-ethyl)-5 ,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one

2-(7-溴 -5-氟 -2-氧代 -1,2-二氢』引哚 -3-次甲基) -3-甲基 -5-(2-吡咯垸 -1 -基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro)indol-3-ylmethyl)-3-methyl-5-(2-pyrrole-1-yl- Ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one

N-{3-[5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6，7,8-六氢-口比略并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 N-{3-[5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-oral ratio slightly [3 ,2-c] azepine-2-methylidene-2-oxo-2,3-dihydro-1H-indole

-5-基乙酰胺 -5-yl acetamide

1352

在本发明的另一个方面，是一种药物组合物，含有本发明通式 (I)的化合物或其药学上可接受的盐或前药，及药学上可以接受的载体。在本发明的另一个方面，是涉及蛋白激酶催化活性的调节方法，包括使蛋白激酶与本发明通式 (I)的化合物或药学上可接受的盐接触。此蛋白激酶选自受体酪氨酸激酶、非受体酪氨酸激酶和丝氨酸-苏氨酸激酶。其中，本发明所述的药学上可接受的盐为本发明化合物与化合物与选自以下的酸形成的盐：苹果酸、乳酸、马来酸、盐酸、甲磺酸、硫酸、磷酸、柠檬酸、酒石酸、乙酸或三氟乙酸。进一步，本发明包括下述通式（IC)或者 (ID)所示的化合物，其作为通式 (I)化合物合成的中间体：

In another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the formula (I) according to the invention, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier. In another aspect of the invention, a method of modulating protein kinase catalytic activity comprising contacting a protein kinase with a compound of formula (I) or a pharmaceutically acceptable salt of the invention. This protein kinase is selected from the group consisting of a receptor tyrosine kinase, a non-receptor tyrosine kinase, and a serine-threonine kinase. Wherein the pharmaceutically acceptable salt of the present invention is a salt of the compound of the present invention and a compound with an acid selected from the group consisting of malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid , tartaric acid, acetic acid or trifluoroacetic acid. Further, the present invention includes a compound represented by the following formula (IC) or (ID) as an intermediate for the synthesis of the compound of the formula (I):

(IC) (ID) 其中-(IC) (ID) among them-

R₂分别选自氢原子或烷基； R _{2 is} each selected from a hydrogen atom or an alkyl group;

¾选自烷基，三氟甲基，芳基，芳垸基，其中烷基，芳基或芳烧基进一步被一个或多个卤素所取代； 3⁄4 is selected from the group consisting of alkyl, trifluoromethyl, aryl, aryl fluorenyl, wherein the alkyl, aryl or aryl group is further substituted by one or more halogens;

¾选自烷基，环烷基，杂环垸基，芳基，杂芳基， -(CHb OCHsCH^Ru, -[CH₂CH(OH)]_rCH₂NR₉R_1Q或 -(CH₂)_n R₉R_l()，其中垸基，环烷基，杂环烷基，芳基，杂芳基，杂环芳基进一步被一个或多个芳基，羟基，氨基，酰胺基，氨基羰基，烷氧基，芳氧基，氨基烷基，羟基垸基，杂环烷基，羧酸，羧酸酯或 -NR₉R₁₀ 所取代； 3⁄4 is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -(CHb OCHsCH^Ru, -[CH ₂ CH(OH)] _r CH ₂ NR ₉ R _1Q or -(CH ₂ _n R ₉ R _l() wherein fluorenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroaryl is further substituted by one or more aryl, hydroxy, amino, amide, amino a carbonyl group, an alkoxy group, an aryloxy group, an aminoalkyl group, a hydroxyindenyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or a -NR ₉ R ₁₀ ;

和 R_1Q分别选自氢原子，垸基，环垸基，芳基，杂环烷基，杂芳基，其中上述的烷基，环垸基，芳基，杂环烷基，杂芳基进一步被一个或多个垸基，芳基，卤代芳基，羟基，氨基，氰基，烷氧基，芳氧基，羟烷基，杂环烷基，羧酸、羧酸酯或 -NR₉R_i()所取代； And R _1Q are each selected from the group consisting of a hydrogen atom, a fluorenyl group, a cyclodecyl group, an aryl group, a heterocycloalkyl group, a heteroaryl group, wherein the above alkyl group, cyclodecyl group, aryl group, heterocycloalkyl group, heteroaryl group further By one or more fluorenyl, aryl, haloaryl, hydroxy, amino, cyano, alkoxy, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or -NR ₉ Replaced by R _i() ;

同时 R₉和 R_1Q—起形成一个 4〜8元杂环基，其中 5〜8元杂环内含有一个到多个 N， 0， S杂原子，并且 4〜8元杂环上进一步被一个或多个烷基，卤素，芳基，杂芳基，卤代烷基，羟基，氰基，烷氧基，芳氧基，氨烷基，羟烷基，杂环烷基，羧酸，羧酸酯或 -NR₉R_1Q所取代； Meanwhile, R ₉ and R _{1Q together} form a 4 to 8 membered heterocyclic group, wherein the 5 to 8 membered heterocyclic ring contains one to a plurality of N, 0, S hetero atoms, and the 4 to 8 membered heterocyclic ring is further subjected to a Or a plurality of alkyl, halogen, aryl, heteroaryl, haloalkyl, hydroxy, cyano, alkoxy, aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester Or replaced by -NR ₉ R _1Q ;

R_u选自氢原子或烷基； R _{u is} selected from a hydrogen atom or an alkyl group;

n是 2〜6； n is 2 to 6;

z是 1~4； z is 1~4;

r是 1〜6。在本发明的另一个方面，是治疗或预防与蛋白质激酶有关的疾病的哺乳动物的方法，包括对该哺乳动物给药治疗有效剂量的本发明药物组合物，该组合物中含有本发明化合物或其药学上可接受的盐，以及药学上可接受的载体或赋形剂。与蛋白质激酶有关的疾病选自 VEGFR-2, EGFR, HER-2, HER-3, HER-4, PDGFR, c-Kit, c-Met, FGFR, Flt3相关的疾病。与蛋白质激酶有关的疾病还可以是白血病，糖尿病，自免疫病，过度增生病，牛皮癣，骨关节炎，类风湿性关节炎，血管生成，心血管病，多发性成血管细胞瘤 (Von-Heppel-Lindau), 炎症，纤维变性病。与蛋白质激酶有关的疾病还可以是鳞状细胞癌，肾细胞癌，卡波济氏肉瘤 (Kaposi), 非小细胞肺癌，小细胞肺癌，淋巴癌，甲状腺癌，乳腺癌，头颈癌，子宫癌，食道癌，黑素癌，膀胱癌，生殖泌尿癌，胃肠癌，神经胶质癌，结肠直肠癌和卵巢癌。优选的，所述的哺乳动物是人。进一步，本发明上述治疗或预防与蛋白质激酶有关的疾病的哺乳动物的方法，优选治疗患有癌症的哺乳动物的方法包括同时向需要治疗的哺乳动物给药治疗有效量的其它选自紫杉酚或卡铂的抗癌药物。所述哺乳动物优选为人。本发明的另一方面涉及本发明化合物在制备治疗与蛋白质激酶有关的疾病的药物中的用途。其中所述与蛋白质激酶有关的疾病选自与 VEGFR-2, EGFR, HER-2, HER-3, HER-4, PDGFR, c-Kit, c-Met, FGFR或 Flt3相关的疾病；或者，其中所述与蛋白激酶有关的疾病选自白血病，糖尿病，自免疫病，过度增生病，牛皮癣，骨关节炎，类风湿性关节炎，血管生成，心血管病，多发性成血管细胞瘤，炎症或纤维变性病；或者所述与蛋白激酶有关的疾病是癌症，选自鳞状细胞癌，肾细胞癌，卡波济氏肉瘤，非小细胞肺癌，小细胞肺癌，淋巴癌，甲状腺癌，乳腺癌，头颈癌，子宫癌，食道癌，黑素癌，膀胱癌，生殖泌尿癌，胃肠癌，神经胶质癌，结肠直肠癌或卵巢癌。在本发明的另一个方面，是制备中间体 (ic)所示化合物的制备方法，包括以下步骤： r is 1 to 6. In another aspect of the invention, a method of treating or preventing a mammal associated with a protein kinase, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition of the invention, the composition comprising a compound of the invention or A pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. The disease associated with protein kinases is selected from the group consisting of VEGFR-2, EGFR, HER-2, HER-3, HER-4, PDGFR, c-Kit, c-Met, FGFR, Flt3 related diseases. Protein kinase-related diseases can also be leukemia, diabetes, autoimmune disease, hyperproliferative disease, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, cardiovascular disease, multiple hemangioblastoma (Von-Heppel) -Lindau), inflammation, fibrosis. Protein kinase-related diseases can also be squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma (Kaposi), non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid cancer, breast cancer, head and neck cancer, uterine cancer. , esophageal cancer, melanoma, bladder cancer, genitourinary cancer, gastrointestinal cancer, glial cancer, colorectal cancer and ovarian cancer. Preferably, the mammal is a human. Further, the method of the above-mentioned mammal for treating or preventing a protein kinase-related disease, preferably a method of treating a mammal having cancer, comprises simultaneously administering a treatment to a mammal in need of treatment. An effective amount of another anticancer drug selected from the group consisting of taxol or carboplatin. The mammal is preferably a human. Another aspect of the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of a disease associated with a protein kinase. Wherein the protein kinase-associated disease is selected from the group consisting of a disease associated with VEGFR-2, EGFR, HER-2, HER-3, HER-4, PDGFR, c-Kit, c-Met, FGFR or Flt3; The protein kinase-related disease is selected from the group consisting of leukemia, diabetes, autoimmune disease, hyperproliferative disease, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, cardiovascular disease, multiple hemangioblastoma, inflammation or Fibrosis disease; or the protein kinase-related disease is cancer, selected from the group consisting of squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma, non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid cancer, breast cancer , head and neck cancer, uterine cancer, esophageal cancer, melanoma, bladder cancer, genitourinary cancer, gastrointestinal cancer, glial cancer, colorectal cancer or ovarian cancer. In another aspect of the invention, there is provided a process for the preparation of a compound of the intermediate (ic), which comprises the steps of:

将原料吡咯甲基羧酸二酯 IC-1室温条件下，四氢呋喃溶液中，醋酸存在下与硝酸铈胺反应得到吡咯甲醛羧酸二酯 IC-2; The pyrrole methyl carboxylic acid diester IC-1 is obtained by reacting the raw material pyrrole methyl carboxylic acid diester IC-1 at room temperature in tetrahydrofuran solution with acetic acid in the presence of acetic acid;

IC-1 IC-2 化合物吡咯甲醛羧酸二酯 IC-2在无水四氢呋喃中，与 (乙酯基亚甲基)三苯基正膦发生魏悌希 (Wittig)反应得到化合物吡咯乙氧羰基乙烯基二羧酸酯 IC-3; IC-1 IC-2 compound pyrrole formaldehyde carboxylic acid diester IC-2 in anhydrous tetrahydrofuran, (Wittig) reaction with (ethyl ester benzylidene) triphenylphosphorane to obtain compound pyrrole ethoxycarbonyl vinyl Dicarboxylate IC-3;

IC-2 IC-3 IC-2 IC-3

钯 /碳催化下，吡咯乙氧羰基乙烯基二羧酸酯 IC-3在无水乙醇中，经氢气室温还原得酯 IC-4; Palladium/carbon catalyzed, pyrrole ethoxycarbonyl vinyl dicarboxylate IC-3 is reduced in anhydrous ethanol at room temperature to obtain ester IC-4;

吡咯乙氧羰基乙基二羧酸酯 IC-4在氢氧化锂水溶液水解得到吡咯羧基乙基二羧酸酯 IC-5;

IC-4 Pyrrole ethoxycarbonylethyl dicarboxylate IC-4 is hydrolyzed in aqueous lithium hydroxide to obtain pyrrole carboxyethyl dicarboxylate IC-5;

IC-4

吡咯羧基乙基二羧酸酯 IC-5在无水四氢呋喃中， -20〜- 5Ό下，经硼烷的四氢呋喃溶液酸酯 IC-6; Pyrrole carboxyethyl dicarboxylate IC-5 in anhydrous tetrahydrofuran, -20~-5 ,, borane in tetrahydrofuran acid ester IC-6;

IC-5 IC-6 吡咯羟丙基二羧酸酯 IC-6在无水二氯甲烷中， -20〜- 5°C，三乙胺存在下，甲磺酰化得酸酯 IC-7; IC-5 IC-6 pyrrole hydroxypropyl dicarboxylate IC-6 in anhydrous dichloromethane, -20~- 5 ° C, in the presence of triethylamine, methanesulfonylation to give the acid ester IC-7;

IC-6 IC-7 IC-6 IC-7

接下来，吡咯甲磺酰氧丙基二羧酸酯 IC-7与不同的胺反应得到吡咯酰胺酸酯 IC-8;

Next, pyrrole mesylate oxypropyl dicarboxylate IC-7 is reacted with a different amine to obtain pyrrolamidate IC-8;

IC-7 IC-8 IC-7 IC-8

吡咯酰胺二羧酸酯 IC-8在无水甲苯中，与三甲基铝加热回流得到吡咯并七元 N 杂环酯 IC-9;

Pyrrole amide dicarboxylate IC-8 in anhydrous toluene, and refluxed with trimethylaluminum to obtain pyrrole penta-N heterocyclic ester IC-9;

IC-8 IC-9 IC-8 IC-9

吡咯并七元 N杂环酯 IC-9在氩气氛下，与三氟乙酸加热 30〜50°C得到吡咯并七元 N杂环甲醛 IC;

Pyrrolo-seven-membered N-heterocyclic ester IC-9 under argon atmosphere, and trifluoroacetic acid heated 30~50 ° C to obtain pyrrole hexamethylene N heterocyclic formaldehyde IC;

IC-9 IC IC-9 IC

其中： R₂，和的定义同上。在本发明的另一个方面，是制备中间体 (ID)所示化合物的制备方法，包括以下步骤： Where: R ₂ , and are as defined above. In another aspect of the invention, there is provided a process for the preparation of a compound of the intermediate (ID), which comprises the steps of:

氩气氛下，吡咯甲醛羧酸二酯 IC-2室温条件下，在无水四氢呋喃中与格氏试剂溴化环丙基镁反应得到吡咯环丙基羟基羧酸二酯 ID-1； Under a argon atmosphere, pyrrole formaldehyde carboxylic acid diester IC-2 is reacted with Grignard reagent cyclopropylmagnesium bromide in anhydrous tetrahydrofuran to obtain pyrrolecyclopropyl hydroxycarboxylic acid diester ID-1;

吡咯环丙基羟基羧酸二酯 ID-1室温下，在甲醇溶剂中与氢溴酸反应得到溴化丁烯基吡咯二酯 ID-2;

Pyrrolecyclopropyl hydroxycarboxylic acid diester ID-1 is reacted with hydrobromic acid in methanol solvent at room temperature to obtain bromobutenylpyrrolediester ID-2;

钯 /碳催化下，溴化丁烯基吡咯二酯 ID-2在无水乙醇中，经氢气室温还原得到溴化丁基吡咯二酯 ID-3 ; Palladium/carbon catalyzed brominated butyryl pyrrole diester ID-2 in anhydrous ethanol at room temperature to obtain bromobutylpyrroledicarboxylate ID-3;

ID-2 ID-3 ID-2 ID-3

溴化丁基吡咯二酯 ID-3在二氯甲烷中，加热回流与不同的胺反应得到吡咯酰胺二羧 Bromobutylpyrroledicarboxylate ID-3 is reacted with different amines in dichloromethane under reflux to give pyrrolidinamine dicarboxyl

吡咯酰胺二羧酸二酯 ID-4在无水甲苯中，与三甲基铝加热回流得到吡咯并八

Pyrrole amide dicarboxylic acid diester ID-4 in anhydrous toluene, heated to reflux with trimethylaluminum to obtain pyrrole and eight

其中： R₂， R₃和的定义同上 _t 进一步，本发明的另一方面是制备吡咯并 N杂环类衍生物的制备方法，包括在碱 (如三乙胺，哌啶)存在下，将醛和吲哚酮反应，反应液加热 2〜12小时，其中上述醛为下列通式 Wherein: R _2, R ₃ and _t are as defined above further, another aspect of the present invention is a method of preparing pyrrole and N heterocyclic derivative, in the presence of a base (such as triethylamine, piperidine), and The aldehyde and the fluorenone are reacted, and the reaction liquid is heated for 2 to 12 hours, wherein the above aldehyde is of the following formula

吲哚酮为下列通式所述的化合物 Anthrone is a compound of the formula

其中： X， Ri , R₂， R₃， R4, R₅， Re> R₇和的定义同上。 Wherein: X, Ri, R ₂ , R ₃ , R4, R ₅ , Re> R ₇ and are as defined above.

本发明涉及鉴别蛋白激酶催化活性的化合物，使表达该蛋白激酶的细胞与本发明化合物或盐接触，然后检测对细胞的效果。本发明还涉及鉴别蛋白激酶催化活性的化合物，使人工重组合成激酶蛋白与本发明化合物或盐接触，然后用 Elisa方法检测对激酶活性的影响。发明的详细说明除非有相反陈述，下列用在说明书和权利要求书中的术语具有下述含义。 "烷基 "指饱和的脂族烃基团，包括 1至 20个碳原子的直链和支链基团。优选含有 1至 10个碳原子的中等大小烷基，例如甲基、乙基、丙基、 2-丙基、正丁基、异丁基、叔丁基、戊基等。更优选的是含有 1至 4个碳原子的低级烷基，例如甲基、乙基、丙基、 2-丙基、正丁基、异丁基或叔丁基等。垸基可以取代的或未取代的，当被取代时，优选的基团为卤素、羟基、低级垸氧基、芳基、芳氧基、杂芳基、杂环烷基、 -OR₉、 -NR₉Rio^ -COR₉、 -0[CH₂C¾0]_rR_u、 -NR₉COR₁₀、 -S0₂R₉ 或 -NHCO₂R₁₀。 The present invention relates to a compound which discriminates the catalytic activity of a protein kinase, which contacts a cell expressing the protein kinase with a compound or salt of the present invention, and then detects the effect on the cell. The present invention also relates to a compound which discriminates the catalytic activity of a protein kinase by contacting an artificially recombinant synthetic kinase protein with a compound or salt of the present invention, and then detecting the effect on the kinase activity by the Elisa method. DETAILED DESCRIPTION OF THE INVENTION Unless otherwise stated, the following terms used in the specification and claims have the following meanings. "Alkyl" means a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to medium-sized alkyl groups having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like. More preferred are lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like. Sulfhydryl may be substituted or unsubstituted Preferred groups, when substituted, are halogen, hydroxy, lower decyloxy, aryl, aryloxy, heteroaryl, heterocycloalkyl, -OR ₉ , -NR ₉ Rio^ -COR ₉ , -0[CH ₂ C3⁄40] _r R _u , -NR ₉ COR ₁₀ , -S0 ₂ R ₉ or -NHCO ₂ R ₁₀ .

"环垸基"指 3至 8元全碳单环、全碳 5元 /6元或 6元 /6元稠合环或多环稠合环 ("稠合' '环系意味着***中的每个环与体系中的其他环共享毗邻的一对碳原子)基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的 π 电子***。环烷基的实例有环丙基、环丁基、环戊基、环戊烯、环己垸、环己二烯、金刚烷、环庚烷、环庚三烯等。环烷基可以是取代或未取代的。当被取代时，取代基优选为一个或多个取代基，独立地选自由低级垸基、三卤烷基、卤素、羟基、低级烷氧基、芳基 (可选自被一个或多个基团取代，取代基是彼此独立地是卤素、羟基、低级烷基或低级烷氧基)、芳氧基 (可选自被一个或多个基团取代，取代基彼此独立地是卤素、羟基、低级烷基或低级烷氧基)、 6元杂芳基 (环中具有 1至 3个氮原子，环中的碳可选地被一个或多个基团取代，取代基彼此独立地是卤素、羟基、低级烷基或低级垸氧基)、 5元杂芳基 (具有 1至 3个选自氮、氧和硫的杂原子，该基团的碳和氮原子可选地被一个或多个基团取代，取代基彼此独立地是卤素、羟基、低级垸基或低级烷氧基)、或 5或 6元杂环垸基 (具有 1至 3个选自氮、氧和硫的杂原子，该基团的碳和氮原子 (如果有的话)，可选地被一个或多个基团取代，取代基彼此独立地是卤素、羟基、低级垸基或低级烷氧基)、巯基、（低级烷基) 硫基、氰基、硝基、羧酸、羧酸酯、 -OR₉、 -NR₉R_1G、 -COR₉、 -0[CH₂CH₂0]_rR_n、 -NR₉COR₁₀、 -S0₂R₉或- NHCO₂R₁₀。 "Cyclopentyl" means a 3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6 fused or polycyclic fused ring ("fused" ring means in the system Each ring shares an adjacent pair of carbon atoms) groups with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. Examples of the group are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentene, cyclohexyl, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene, etc. The cycloalkyl group may be substituted or not. When substituted, the substituent is preferably one or more substituents independently selected from the group consisting of lower fluorenyl, trihaloalkyl, halogen, hydroxy, lower alkoxy, aryl (optionally selected from one or Substituted by a plurality of groups, the substituents are independently of each other a halogen, a hydroxyl group, a lower alkyl group or a lower alkoxy group), an aryloxy group (which may be selected by one or more groups, and the substituents are independently of each other a halogen , hydroxy, lower alkyl or lower alkoxy), 6-membered heteroaryl (having from 1 to 3 nitrogen atoms in the ring, optionally in the ring Substituted by one or more groups, the substituents are, independently of each other, halogen, hydroxy, lower alkyl or lower decyloxy), 5-membered heteroaryl (having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur) The carbon and nitrogen atoms of the group are optionally substituted by one or more groups, the substituents being, independently of each other, halogen, hydroxy, lower fluorenyl or lower alkoxy), or 5 or 6 membered heterocyclic fluorenyl (having from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, the carbon and nitrogen atoms of the group, if any, optionally substituted by one or more groups, the substituents being independently of each other Halogen, hydroxy, lower fluorenyl or lower alkoxy), fluorenyl, (lower alkyl) thio, cyano, nitro, carboxylic acid, carboxylic acid ester, -OR ₉ , -NR ₉ R _1G , -COR ₉ -0[CH ₂ CH ₂ 0] _r R _n , -NR ₉ COR ₁₀ , -S0 ₂ R ₉ or -NHCO ₂ R ₁₀ .

"链烯基"指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基。代表性实例包括但不限于乙烯基、 1-丙烯基、 2-丙烯基、 1-， 2-或 3-丁烯基等。所述的链烯基可以由一个或多个选自以下的取代基任选取代：卤素、三卤甲基、羟基、硝基、氰基、烷氧基、烷基、羧酸、羧酸酯、 -OR₉、 -NR₉R_1G、 -COR₉、 -0[CH₂CH₂0]_rR_u、 -NR₉CORi。、 -S0₂R₉或- NHCO₂R₁₀。 "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like. The alkenyl group may be optionally substituted by one or more substituents selected from the group consisting of: halogen, trihalomethyl, hydroxy, nitro, cyano, alkoxy, alkyl, carboxylic acid, carboxylic acid ester -OR ₉ , -NR ₉ R _1G , -COR ₉ , -0[CH ₂ CH ₂ 0] _r R _u , -NR ₉ CORi. , -S0 ₂ R ₉ or - NHCO ₂ R ₁₀ .

"炔基"指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基。代表性实例包括但不限于乙炔基、 1-丙炔基、 2-丙炔基、 1-， 2-或 3-丁炔基等。所述. 的炔基可以由一个或多个选自以下的取代基任选取代：卤素、三卤甲基、羟基、硝基、氰基、烷氧基、烷基、羧酸、羧酸酯、 -OR₉、 -NR₉R₁₀. -COR₉、 -0[CH₂CH₂0]_rR„、 -NR₉COR₁₀、 -S0₂R₉或- NHCO₂R_10o "Alkynyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. The alkynyl group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, nitro, cyano, alkoxy, alkyl, carboxylic acid, carboxylic acid esters. , -OR ₉ , -NR ₉ R ₁₀ . -COR ₉ , -0[CH ₂ CH ₂ 0] _r R„, -NR ₉ COR ₁₀ , -S0 ₂ R ₉ or - NHCO ₂ R _10o

"芳基"指具有至少一个芳环结构的基团，即具有共轭的 π电子体系的芳环，包括碳环芳基、杂芳即和联芳基。所述的芳基可以由一个或多个选自以下的取代基任选取代：卤素、三卤甲基、羟基、硝基、氰基、垸氧基、烷基、羧酸、羧酸酯、 -OR₉、 -NR₉R₁₍₎、 -COR₉、 -0[CH₂CH₂0]_rR_u、 -NR₉CORi。、 -S0₂R₉或 -NHCO₂Ri₀。 "Aryl" means a group having at least one aromatic ring structure, that is, an aromatic ring having a conjugated π-electron system, including a carbocyclic aryl group, a heteroaryl group, and a biaryl group. The aryl group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, nitro, cyano, decyloxy, alkyl, carboxylic acid, carboxylic acid ester, -OR ₉ , -NR ₉ R ₁₍₎ , -COR ₉ , -0[CH ₂ CH ₂ 0] _r R _u , -NR ₉ CORi. , -S0 ₂ R ₉ or -NHCO ₂ Ri ₀ .

"杂芳基"指具有 1至 3个杂原子作为环原子，其余的环原子为碳的芳基，杂原子包括氧、硫和氮。所述环可以是 5元或 6元环。杂环芳基基团的实例包括呋喃基、噻吩基、吡啶基、吡咯、 N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基等。所述的杂芳基可以由一个或多个选自以下的取代基任选取代：卤素、三卤甲基、羟基、硝基、氰基、垸氧基、垸基、羧酸、羧酸酯、 -0 、 -NR₉R_1Q、 -COR₉、

"Heteroaryl" means an aryl group having from 1 to 3 heteroatoms as ring atoms, the remaining ring atoms being carbon, and heteroatoms including oxygen, sulfur and nitrogen. The ring may be a 5- or 6-membered ring. Examples of heterocyclic aryl groups include furan Base, thienyl, pyridyl, pyrrole, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl and the like. The heteroaryl group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, nitro, cyano, decyloxy, decyl, carboxylic acid, carboxylic acid esters. , -0, -NR ₉ R _1Q , -COR ₉ ,

-NR₉COR_1G、 -S0₂R₉或 -NHC0₂Rio。 _{_{_{-NR 9 COR 1G, -S0 2 R}}} 9 or -NHC0 ₂ Rio.

"杂环烷基"指单环或稠环基团，在环中，具有 5至 9个环原子，其中一个或两个环原子选自氮、氧或 S(0)n (其中 n是整数 0至 2)的杂原子，其余环原子为碳。这些环还可以具有一个或多个双键、不过，这些环不具有完全共轭的 π电子***。未取代的杂环烷基包括但不限于吡咯烷基、哌啶子基、哌嗉子基、吗啉基、硫代吗啉基、高哌嗪其等、杂环烷基可以是取代的或未取代的。当被取代时，取代基优选为一个或多个选自以下的取代基任选取代：卤素、三卤甲基、羟基、硝基、氰基、烷氧基、垸基、羧酸、羧酸酯、 -OR₉、 -NR₉R_1Q、 -COR₉、 -0[CH₂CH₂0]_rR_u、 -NR₉COR₁₀, -S0₂R₉或 -NHCO₂R₁₀。 "Heterocycloalkyl" means a monocyclic or fused ring radical having from 5 to 9 ring atoms in the ring wherein one or two ring atoms are selected from nitrogen, oxygen or S(0)n (where n is an integer) From 0 to 2), the remaining ring atoms are carbon. These rings may also have one or more double bonds, however, these rings do not have a fully conjugated pi-electron system. Unsubstituted heterocycloalkyl includes, but is not limited to, pyrrolidinyl, piperidino, piperidino, morpholinyl, thiomorpholinyl, homopiperazine, etc., heterocycloalkyl can be substituted or Unsubstituted. When substituted, the substituent is preferably optionally substituted with one or more substituents selected from the group consisting of: halogen, trihalomethyl, hydroxy, nitro, cyano, alkoxy, decyl, carboxylic, carboxylic acid Ester, -OR ₉ , -NR ₉ R _1Q , -COR ₉ , -0[CH ₂ CH ₂ 0] _r R _u , -NR ₉ COR ₁₀ , -S0 ₂ R ₉ or -NHCO ₂ R ₁₀ .

"羟基 "指 -OH基团。 "Hydroxy" means an -OH group.

"烷氧基"指 -O- (垸基)和 -O- (未取代的环烷基)。代表性实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。所述的烷氧基可以由一个或多个选自以下的取代基任选取代：卤素、三卤甲基、羟基、硝基、氰基、烷氧基、烷基、羧酸、羧酸酯、 -OR₉、 -NR₉R_1Q、 -COR₉、 -0[CH₂CH₂0]_rRn . -NR₉COR₁₀, -S0₂R₉或 - NHCO₂R₁₀。 "Alkoxy" means -O-(indenyl) and -O-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, nitro, cyano, alkoxy, alkyl, carboxylic acid, carboxylic acid ester -OR ₉ , -NR ₉ R _1Q , -COR ₉ , -0[CH ₂ CH ₂ 0] _r Rn . -NR ₉ COR ₁₀ , -S0 ₂ R ₉ or -NHCO ₂ R ₁₀ .

"卤代垸氧基 "指 -O- (卤代烷基)。代表性实例包括但不限于三氟甲氧基、三溴甲氧基等。 "Halodecyloxy" means -O-(haloalkyl). Representative examples include, but are not limited to, trifluoromethoxy, tribromomethoxy, and the like.

"芳氧基"指 -0-芳基和 -0-杂芳基，芳基和杂芳基定义同上。代表性实例包括但不限于苯氧基、吡啶氧基、呋喃氧基、噻吩氧基、嘧啶氧基、吡嗪氧基等及其衍生物。所述的芳氧基可以由一个或多个选自以下的取代基任选取代：卤素、三卤甲基、羟基、硝基、氰基、烷氧基、烷基、羧酸、羧酸酯、 -OR₉、 -NR₉Rio -COR₉、 -0[C¾C¾0]_rR_u、 -NR₉CORio -S0₂R₉或 -NHCO₂R_I0。 "Aryloxy" means -O-aryl and -0-heteroaryl, and aryl and heteroaryl are as defined above. Representative examples include, but are not limited to, phenoxy, pyridyloxy, furanoxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof. The aryloxy group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, nitro, cyano, alkoxy, alkyl, carboxylic acid, carboxylic acid esters. , -OR ₉ , -NR ₉ Rio -COR ₉ , -0[C3⁄4C3⁄40] _r R _u , -NR ₉ CORio -S0 ₂ R ₉ or -NHCO ₂ R _I0 .

"羟垸基"指 -(CH₂)_nOH。 "Hydroxycarbonyl" means -(CH ₂ ) _n OH.

"卤素"指氟、氯、溴或碘，优选氟或氯。 "Halogen" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.

"三卤甲基"指 -CX₃，其中 X是如上所定义的卤素。 "Trihalomethyl" means -CX ₃ wherein X is a halogen as defined above.

"可选 "或"可选的 "意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如， "可选被烷基取代的杂环基团"意味着垸基可以但不必存在，该说明包括杂环基团被垸基取代的情形和杂环基团不被烷基取代的情形。 "Optional" or "optional" means that the event or environment described subsequently may, but need not, occur, including where the event or environment occurs or does not occur. For example, "optionally substituted with an alkyl group" means that a fluorenyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted by a thiol group and the case where the heterocyclic group is not substituted by an alkyl group.

"药物组合物 "表示一种或多种本文所述化合物或其生理学上 /药学上可接受的盐或前体药物与其他化学组分的混合物，其他组分例如生理学 /药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。本发明化合物的合成方法为了完成本发明的目的，本发明釆用如下技术方案： "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as a physiological/pharmaceutically acceptable carrier. And excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism. Methods of Synthesizing the Compounds of the Invention In order to accomplish the objectives of the present invention, the present invention employs the following technical solutions:

本发明化合物可通过本领域已知的方法合成。在实施例中提供了这些化合物的合 The compounds of the invention can be synthesized by methods known in the art. Combinations of these compounds are provided in the examples

原料吡咯甲基羧酸二酯 IC-1室温条件下，四氢呋喃溶液中，醋酸存在下与硝酸铈胺反应得到吡咯甲醛羧酸二酯 IC-2; 得到的化合物吡咯甲醛羧酸二酯 IC-2在无水四氢呋喃中，与 (乙酯基亚甲基)三苯基正膦发生魏悌希反应得到化合物吡咯乙氧羰基乙烯基二羧酸酯 IC-3; 钯 /碳催化下，吡咯乙氧羰基乙烯基二羧酸酯 IC-3在无水乙醇中，经氢气室温还原得到吡咯乙氧羰基乙基二羧酸酯 IC-4; 吡咯乙氧羰基乙基二羧酸酯 IC-4在氢氧化锂水溶液水解得到吡咯羧基乙基二羧酸酯 IC-5; 吡咯羧基乙基二羧酸酯 IC-5在无水四氢呋喃中， -20〜- 5°C下，经硼烷的四氢呋喃溶液还原成的吡咯羟丙基二羧酸酯 IC-6; 进一步，吡咯羟丙基二羧酸酯 IC-6在无水二氯甲垸中， -20〜- 5°C，三乙胺存在下，甲磺酰化得到吡咯甲磺酰氧丙基二羧酸酯 IC-7; 接下来，吡咯甲磺酰氧丙基二羧酸酯 IC-7与不同的胺反应得到吡咯酰胺二羧酸酯 IC-8; 吡咯酰胺二羧酸酯 IC-8在无水甲苯中，与三甲基铝加热回流得到吡咯并七元 N杂环酯 IC-9;吡咯并七元 N杂环酯 IC-9在氩气氛下，与三氟乙酸加热 30〜50°C得到吡咯并七元 N杂环甲醛 IC;吡咯并七元 N杂环甲醛 IC在碱 (如三乙胺，哌啶)存在下和吲哚酮加热 2〜12小时得到吡咯并七元 N杂环衍生物 (IA)。 The pyrrole methyl carboxylic acid diester IC-1 is reacted with cerium nitrate in the presence of acetic acid at room temperature to obtain pyrrole formaldehyde carboxylic acid diester IC-2; the obtained compound pyrrole formaldehyde carboxylic acid diester IC-2 In the anhydrous tetrahydrofuran, the reaction with (ethyl ester benzylidene) triphenylphosphorane to obtain the compound pyrrole ethoxycarbonyl vinyl dicarboxylate IC-3; palladium / carbon catalyzed, pyrrole ethoxycarbonyl ethene Pyrodiethoxycarbonylethyldicarboxylate IC-4 is obtained by reduction of hydrogen carboxylic acid ester IC-3 in anhydrous ethanol at room temperature; pyrrole ethoxycarbonylethyldicarboxylate IC-4 in lithium hydroxide Hydrolysis of aqueous solution to obtain pyrrole carboxyethyl dicarboxylate IC-5; pyrrole carboxyethyl dicarboxylate IC-5 in anhydrous tetrahydrofuran, -20~- 5 ° C, reduced by borane in tetrahydrofuran solution Pyrrole hydroxypropyl dicarboxylate IC-6; further, pyrrole hydroxypropyl dicarboxylate IC-6 in anhydrous dichloromethane, -20~-5 ° C, in the presence of triethylamine, methyl sulfonate Acylation gives pyrrole mesylate oxypropyl dicarboxylate IC-7; next, pyrrole mesylate oxypropyl dicarboxylate IC-7 is different The reaction gives the pyrrole amide dicarboxylate IC-8; the pyrrole amide dicarboxylate IC-8 in anhydrous toluene, and refluxed with trimethylaluminum to obtain pyrrolo-7-heterocyclic heterocyclic ester IC-9; pyrrole VII The N-heterocyclic ester IC-9 is heated under an argon atmosphere with trifluoroacetic acid at 30 to 50 ° C to obtain pyrrolo-seven-membered N-heterocyclic formaldehyde IC; pyrrolo-seven-membered N-heterocyclic formaldehyde IC in a base such as triethylamine The pyrrole and seven-membered N-heterocyclic derivative (IA) is obtained by heating the fluorenone in the presence of piperidine for 2 to 12 hours.

氩气氛下，吡咯甲醛羧酸二酯 IC-2室温条件下，在无水四氢呋喃中与格氏试剂溴化环丙基镁反应得到吡咯环丙基羟基羧酸二酯 ID-1 ; 吡咯环丙基羟基羧酸二酯 ID-1 室温下，在甲醇溶剂中与氢溴酸反应得到溴化丁烯基吡咯二酯 ID-2; 钯 / 碳催化下，溴化丁烯基吡咯二酯 ID-2在无水乙醇中，经氢气室温还原得到溴化丁 ·· 基吡咯二酯 ID-3; 溴化丁基吡咯二酯 ID-3在二氯甲垸中，加热回流与不同的胺反应得到吡咯酰胺二羧酸二酯 ID-4;.吡咯酰胺二羧酸二酯 ID-4在无水甲苯中，与三甲基铝加热回流得到吡咯并八元 N杂环醛 ID; 吡咯并八元 N杂环甲醛 IC在碱 (如三乙胺，哌啶)存在下和吲哚酮加热 2〜12小时得到吡咯并七元 N杂环衍生物 (IB)。其中，通式 (I)分子中双键的构型为 z构型 (顺式)，这一点通过核磁数据可以推断。通常在吡咯环上 NH的化学位移为 9ppm左右，而得到的化合物中吡咯环上的 NH在 14ppm左右,主要原因是吡咯环上的 NH与临近的吲哚酮羰基的氧有分子内氢键作用，导致 NH的化学位移移向低场。这一点在专利 WO0160814(Su-11248) 中也进行了描述。 Under an argon atmosphere, pyrrole formaldehyde carboxylic acid diester IC-2 is reacted with Grignard reagent cyclopropyl magnesium bromide in anhydrous tetrahydrofuran to obtain pyrrolecyclopropyl hydroxycarboxylic acid diester ID-1; Hydroxycarboxylic acid diester ID-1 is reacted with hydrobromic acid in methanol solvent to obtain bromobutenylpyrrolediester ID-2 at room temperature; palladium/carbon catalyzed, butenylpyrroledicarboxylate ID- 2 in anhydrous ethanol, reduced by hydrogen at room temperature to obtain butyl hexyl pyrrole dicarboxylate ID-3; bromobutylpyrroledicarboxylate ID-3 in dichloromethane, heated reflux and reacted with different amines Pyrrolamide dicarboxylic acid diester ID-4; pyrrole amide dicarboxylic acid diester ID-4 in anhydrous toluene, heated under reflux with trimethylaluminum to obtain pyrrole octagonal N heterocyclic aldehyde ID; pyrrole octa The N heterocyclic formaldehyde IC is heated in the presence of a base (e.g., triethylamine, piperidine) and anthrone for 2 to 12 hours to give a pyrrole penta-N heterocyclic derivative (IB). Among them, the configuration of the double bond in the molecule of the general formula (I) is the z configuration (cis), which can be inferred by the nuclear magnetic data. Usually, the chemical shift of NH on the pyrrole ring is about 9 ppm, and the NH on the pyrrole ring in the obtained compound is about 14 ppm, mainly because the NH on the pyrrole ring has an intramolecular hydrogen bond with the oxygen of the adjacent fluorenone carbonyl. , causing the chemical shift of NH to shift to the lower field. This is also described in the patent WO0160814 (Su-11248).

本发明涉及一种药物组合物，其含有治疗有效剂量的本发明化合物或其盐和药学载体。 The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a salt thereof and a pharmaceutical carrier.

进一步，本发明涉及通式 (I)化合物或其盐在制备酪氨酸激酶抑制剂药物中的用途。换言之，本发明还提供含有药物有效剂量的上述化合物组合物，以及所述的化合物和 /或含有该化合物的药物组合物在制备酪氨酸激酶抑制剂中的用途。 Further, the present invention relates to the use of a compound of the formula (I) or a salt thereof for the preparation of a tyrosine kinase inhibitor drug. In other words, the present invention also provides a composition comprising the above compound in an effective amount, and the use of the compound and/or a pharmaceutical composition containing the same in the preparation of a tyrosine kinase inhibitor.

以下结合实施例用于进一步描述本发明，但这些实施例并不限制着本发明的范围。实施例化合物的结构是通过核磁共振 ( MR)或质谱 (MS)来确定的。 NMR位移 (δ)以百万分之一 (ppm)的单位给出。 NMR的测定是用 Bmker AVANCE-400核磁仪，测定溶剂为氘代氯仿 (CDC1₃)、氘代二甲基亚砜 (DMSO-D₆)，内标为四甲基硅烷 (TMS)，化学位移是以 10—⁶(ppm)作为单位给出。 The invention is further described below in conjunction with the examples, but these examples are not intended to limit the scope of the invention. The structure of the example compounds was determined by nuclear magnetic resonance (MR) or mass spectrometry (MS). The NMR shift (δ) is given in parts per million (ppm). NMR was measured using a Bmker AVANCE-400 nuclear magnetic apparatus. The solvent was deuterated chloroform (CDC1 ₃ ), deuterated dimethyl sulfoxide (DMSO-D ₆ ), internal standard tetramethylsilane (TMS), chemical shift. is 10- ⁶ (ppm) given as a unit.

MS的测定用 FINNIG AN LCQAd (ESI)质谱仪。 The MS was measured using a FINNIG AN LCQAd (ESI) mass spectrometer.

激酶 VEGFR平均抑制率的测定使用 HTScan酶标仪 (Cell Signaling公司）。激酶 EGFR/HER— 2平均抑制率的测定用 NovoStar酶标仪 (德国 BMG公司）。薄层硅胶使用烟台黄海 HSGF254或青岛 GF254硅胶板。 The average inhibition rate of the kinase VEGFR was measured using an HTScan microplate reader (Cell Signaling). The average inhibition rate of the kinase EGFR/HER-2 was measured using a NovoStar plate reader (BMG, Germany). Thin layer silica gel is used in Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.

柱层析一般使用烟台黄海硅胶 200~300目硅胶为载体。 Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

DMSO-D₆: 氘代二甲基亚砜； DMSO-D ₆ : deuterated dimethyl sulfoxide;

CDC1₃: 氘代氯仿； CDC1 ₃ : deuterated chloroform;

制备实施例： Preparation examples:

实施例 1 Example 1

5-(2-二乙氨基-乙基) -2-(5-氟 -2-氧代 -1，2-二氢 -吲哚 -3-次甲基 )-3-甲基 -3a,5,6,7，8,8_a- 六氢 -1H-吡咯 [3,2-c] 吖庚因 - -酮 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methylmethyl)-3-methyl-3a,5 ,6,7,8,8 _a - hexahydro-1H-pyrrole [3,2-c] azepine-ketone

第一歩

First

5-甲酰基 -3-甲基 -1Η-吡咯 -2，4-二羟酸 2-叔丁酯 4_乙酯室温下，将 3,5-二甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 la(30 g，0.113 mol) 搅拌下溶解于 300 ml四氢呋喃中，再加入 360 ml醋酸和 300 ml水。加毕搅拌均勾，一次性加入硝酸铈胺 (246 g， 0.449 mol)。混合物于室温下继续搅拌约 0.5小时，反应液由桔红色变成橙黄色，点板监测表明反应完全，停止反应。将反应液倾入 800 ml冰水中，有浅黄色固体析出，混合物继续搅拌 0.5小时后抽滤，固体真空干燥，得到标题标题产物 5-甲酰基 -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 lb(3L13 g，浅黄色固体)，产率： 98%。 5-formyl-3-methyl-1Η-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4_ethyl ester 3,5-dimethyl-1H-pyrrole-2,4- at room temperature 2-tert-Butyl dihydroxy ester 4-ethyl ester la (30 g, 0.113 mol) was dissolved in 300 ml of tetrahydrofuran with stirring, and then 360 ml of acetic acid and 300 ml of water were added. Add the stirring to the hook and add guanamine nitrate (246 g, 0.449 mol) in one shot. The mixture was stirred at room temperature for about 0.5 hours, and the reaction mixture turned from orange to orange, and the spot was monitored to indicate that the reaction was complete and the reaction was stopped. The reaction mixture was poured into ice-water (400 ml), EtOAc (EtOAc m. - 2-tert-butyl dihydroxy acid 4-ethyl ester lb (3 L 13 g, pale yellow solid), Yield: 98%.

MS m/z (ESI): 282·0(Μ+1)。第二步 MS m/z (ESI): 282·0 (Μ +1). Second step

5-(2-乙氧羰基-乙烯基) -3-甲基- 1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯氩气氛下，将 5-甲酰基 -3-甲基 -1Η-吡咯 -2，4-二羟酸 2-叔丁酯 4-乙酯 lb(23 g， 81.7 mmol), (乙酯基亚甲基)三苯基正膦 (34.66 g， 99.4 mmol)搅拌下溶解于 450 ml 四氢呋喃中，室温过夜搅拌。点板监测反应至原料反应完全，停止反应，反应混合物减压浓縮得到黄色油状液体。将混合物溶解于正己垸和乙酸乙酯的混合溶剂 (V: V=20: 1)中，于砂芯漏斗减压柱层分离得到标题产物 5-(2-乙氧羰基-乙烯基) -3- 甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 lc(24 g, 浅黄色固体)，产率： 84%。 MS m/z (ESI): 352.1(M+l)c 第三步 5-(2-ethoxycarbonyl-vinyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 5-aryl-3- Methyl-1 Η-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester lb (23 g, 81.7 mmol), (ethyl ester benzylidene) triphenylphosphorane (34.66 g, 99.4 Methylene) was dissolved in 450 ml of tetrahydrofuran with stirring and stirred at room temperature overnight. The reaction was monitored by spotting until the reaction of the starting material was complete, the reaction was stopped, and the reaction mixture was concentrated under reduced pressure to give a yellow oily liquid. The mixture was dissolved in a mixed solvent of n-hexane and ethyl acetate (V: V = 20:1), and the title product 5-(2-ethoxycarbonyl-vinyl) -3 was obtained. Methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester lc (24 g, pale yellow solid), Yield: 84%. MS m/z (ESI): 352.1 (M+l)c third step

5-(2-乙氧羰基-乙基) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4」乙酯氯气氛下，将 5-(2-乙氧羰基-乙烯基) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4- 乙酯 lc(24 g， 68.3 mmol)搅拌下溶解于 180 ml无水乙醇中，再加入钯 /碳 (10%， 2.44 g), 继续于室温下搅拌过夜。点板表明原料反应完全，停止反应。过滤除去钯 /碳，少量乙醇洗涤滤渣，滤液于减压下蒸除溶剂，得到标题产物 5-(2-乙氧羰基-乙基) -3- 甲基 -1H-吡咯 -2，4-二羟酸 2-叔丁酯 4-乙酯 ld(23 g，白色固体)，产率： 95 %。 MS m/z (ESI): 354·40(Μ+1)。第四步 5-(2-ethoxycarbonyl-ethyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4" ethyl ester in a chlorine atmosphere, 5-(2-ethoxyl) Carbonyl-vinyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester lc (24 g, 68.3 mmol) was dissolved in 180 ml of absolute ethanol with stirring. Additional palladium on carbon (10%, 2.44 g) was added and stirring was continued at room temperature overnight. The dot plate indicates that the starting material is completely reacted and the reaction is stopped. The palladium/carbon was removed by filtration, and the residue was washed with a small amount of ethanol, and the solvent was evaporated to give the title product 5-(2-ethoxycarbonyl-ethyl)-3-methyl-1H-pyrrole-2,4-di. 2-tert-butyl hydroxy acid 4-ethyl ester ld (23 g, white solid), Yield: 95%. MS m/z (ESI): 354.40 (Μ +1). the fourth step

5-(2-羧基-乙基) -3-甲基 -1Η-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯室温下，将 5-(2-乙氧羰基-乙基) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 ld(23.6 g， 66.8 mmol)搅拌下溶解于 190 ml四氢呋喃和 90 ml甲醇中。向反应液中滴加氢氧化锂水溶液 (80 ml, 10 mol/L, 0.8 mol), 反应液逐渐由浅黄色变成青色。继续搅拌 1 小时，点板监测反应至原料反应完全，停止反应。反应液减压蒸除四氢呋喃和甲醇，于冰浴下边搅拌边滴加盐酸溶液 (2 mol/L)调节 pH值至 2左右，有大量白色固体析出。混合物抽滤，干燥后得到标题产物 5-(2-羧基-乙基) -3-甲基 -1H- 吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 le(24 g，白色固体)，产率： 98%。 5-(2-carboxy-ethyl)-3-methyl-1Η-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 5-(2-ethoxycarbonyl-ethyl) at room temperature 3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester ld (23.6 g, 66.8 mmol) was dissolved in 190 ml of tetrahydrofuran and 90 ml of methanol with stirring. An aqueous lithium hydroxide solution (80 ml, 10 mol/L, 0.8 mol) was added dropwise to the reaction solution, and the reaction liquid gradually changed from light yellow to cyan. Stirring was continued for 1 hour, and the reaction was monitored by spotting until the reaction of the starting material was complete and the reaction was stopped. The reaction liquid was evaporated under reduced pressure of tetrahydrofuran and methanol, and a hydrochloric acid solution (2 mol/L) was added dropwise thereto under stirring in an ice bath to adjust the pH to about 2, and a large amount of white solid was precipitated. The mixture was suction filtered and dried to give the title product 5-(2-carboxy-ethyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester (24 g, White solid), Yield: 98%.

MS m/z (ESI): 326.1(M+1)。第五步 MS m/z (ESI): 326.1 (M+1). the fifth step

5-(3-羟基-丙基) -3-甲基 -1Η-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯氩气氛下，将干燥的 5-(2-羧基-乙基) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4- 乙酯 le(9.75 g， 30 mmol)搅拌下溶解于 90 ml无水四氢呋喃中，用冰盐浴控制反应体系温度在 -10〜- 5°C，向反应体系中缓慢滴加硼烷的四氢呋喃溶液 (90 ml, 1 mol/L, 90 mmol)。加毕，撤去冰盐浴，反应液自然升温至室温，继续搅拌 2〜3小时，点板表明原料反应完全，停止反应。反应混合物减压下蒸除溶剂，加入 100 ml饱和碳酸氢钠和 100 ml乙酸乙酯，搅拌至溶解。混合物用乙酸乙酯萃取 (100 mlx3)，合并有机相，用饱和氯化钠洗涤 (lOO mlxl), 无水硫酸镁干燥，抽滤除去千燥剂，滤液浓缩得到标题产物 5-(3-羟基-丙基) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 lf(9.2 g, 浅黄色油状物)，产率： 98%。 5-(3-Hydroxy-propyl)-3-methyl-1Η-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester Under dry argon, dry 5-(2-carboxy- Ethyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester le (9.75 g, 30 mmol) was dissolved in 90 ml of anhydrous tetrahydrofuran with stirring. The salt bath was used to control the temperature of the reaction system at -10 to -5 ° C, and a solution of borane in tetrahydrofuran (90 ml, 1 mol/L, 90 mmol) was slowly added dropwise to the reaction system. After the addition, the ice salt bath was removed, and the reaction solution was naturally warmed to room temperature, and stirring was continued for 2 to 3 hours. The plate indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction mixture was evaporated to dryness under reduced pressure, and then evaporated and evaporated. The mixture was extracted with ethyl acetate (100 ml×3), EtOAcjjjjjjjjjjjjjjjjj -propyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester lf (9.2 g, pale yellow oil), Yield: 98%.

MS m/z (ESI): 312.3(M+l)o 第六步 MS m/z (ESI): 312.3(M+l)o Step 6

5-(3-甲磺酰氧-丙基) -3-甲基 -1Η-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯氩气氛下，将 5-(3-羟基-丙基) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 (9.20 g, 30 mmol)搅拌下溶解于 150 ml二氯甲烷中，用冰盐浴控制温度在 -10°C 左右。缓慢加入三乙胺 (7.0 ml, 50 mmol),加毕缓慢加入甲磺酰氯 (3.5 ml, 45 mmol), 搅拌均匀后撤去冰盐浴，反应体系温度自然升至室温，继续搅拌 4小时。点板表明原料反应完全，加入少量的冰淬灭反应。反应混合物用稀盐酸 (0.5 mol/L, 80mlx2) 洗涤除去三乙胺，用饱和碳酸钠洗涤 (80mlx2)除去过量的盐酸，再用饱和氯化钠洗漆 (80mlxl)，反应液减压蒸除溶剂，得到标题产物 5-(3-甲磺酰氧-丙基) -3-甲基 -1H- 吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 (11.4 g，棕色油状物)，产率： 99%。 5-(3-methanesulfonyloxy-propyl)-3-methyl-1Η-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 5-(3-hydroxyl group) under argon atmosphere -propyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester (9.20 g, 30 mmol) was dissolved in 150 ml of dichloromethane with stirring, and the temperature was controlled at -10 °C with an ice salt bath. Triethylamine (7.0 ml, 50 mmol) was slowly added, and methanesulfonyl chloride (3.5 ml, 45 mmol) was added slowly. After stirring, the ice salt bath was removed, and the temperature of the reaction system was naturally raised to room temperature, and stirring was continued for 4 hours. The dot plate indicates that the starting material is completely reacted, and a small amount of ice is added to quench the reaction. The reaction mixture was washed with dilute hydrochloric acid (0.5 mol/L, 80 ml×2) to remove triethylamine, and washed with saturated sodium carbonate (80 ml×2) to remove excess hydrochloric acid, and then washed with saturated sodium chloride (80 ml×l), and the reaction mixture was evaporated under reduced pressure. Solvent, the title product 5-(3-methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester (11.4 g, brown oil ()), Yield: 99%.

MS m/z (ESI): 390.5(M+l 第七步 MS m/z (ESI): 390.5 (M+l step 7)

5-[3-(2-二乙氨基-乙氨基) -丙基 ]-3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯室温下将 5-(3-甲磺酰氧-丙基) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 (8.24 g, 21 mmol)搅拌下溶解于 Ν,Ν-二乙基乙二胺 (15 ml, 100 mmol), 并搅拌过夜。点板表明原料反应完全，停止反应。反应液中加入 100 ml乙酸乙酯和 100 ml 饱和氯化钠，搅拌 5 min后分层萃取。有机相用饱和氯化钠洗涤 (100 ml><4)除去 Ν,Ν-二乙基乙二胺，无水硫酸镁干燥，抽滤除去干燥剂，滤液浓缩得到黄褐色油状物。油状物柱层析得到标题产物 5-[3-(2-二乙氨基-乙氨基) -丙基 ]-3-甲基 -1Η-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 (8.2 g，无色油状物)，产率： 95%。 5-[3-(2-Diethylamino-ethylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 5-5 at room temperature (3-Methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester (8.24 g, 21 mmol) was dissolved in hydrazine with stirring. Ν-Diethylethylenediamine (15 ml, 100 mmol) and stirred overnight. The dot plate indicates that the starting material is completely reacted and the reaction is stopped. 100 ml of ethyl acetate and 100 ml of saturated sodium chloride were added to the reaction mixture, and the mixture was stirred for 5 min and then extracted with a layer. The organic phase was washed with saturated sodium chloride (100 ml <<>><>><>>>> Column chromatography on oil gave the title product 5-[3-(2-diethylamino-ethylamino)-propyl]-3-methyl-l-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4 - ethyl ester (8.2 g, colorless oil), yield: 95%.

MS m/z (ESI): 410.2(M+1)。第八步 MS m/z (ESI): 410.2 (M+l). Eighth step

5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c]吖庚因 -2-羧酸叔丁酯 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine Tert-butyl 2-carboxylate

氩气氛下，将 5-[3-(2-二乙氨基-乙氨基) -丙基 ]-3-甲基 -1H-吡咯 -2,4-二羟酸 2- 叔丁酯 4-乙酯 (3.547 g， 8.67 mmol)搅拌下溶解于 70 ml甲苯中，于室温下搅拌 10分钟，再加入三甲基铝的甲苯溶液 (5.6 ml， 2 mol/L, 11.27 mmol), 继续于室温下搅拌 30分钟至瓶内不再有白烟。反应液于油浴中加热回流 4小时，点板表明原料基本消失，停止反应。待反应体系温度自然降至室温后，加入 10 ml乙醇 (95%) 淬灭反应，再加入 60 ml乙醇 (无水)，所得混和液用硅藻土过滤，并用乙醇 (无水， 200 mlx4)洗涤，减压蒸除溶剂，柱层析得到标题产物 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c]吖庚因 -2-羧酸叔丁酯 (0.413 g，白色固体)，产率： 75.7% 5-[3-(2-Diethylamino-ethylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester under argon atmosphere (3.547 g, 8.67 mmol) Dissolved in 70 ml of toluene with stirring, stirred at room temperature for 10 minutes, then added a solution of trimethylaluminum in toluene (5.6 ml, 2 mol/L, 11.27 mmol), stirring at room temperature There will be no more white smoke in the bottle for 30 minutes. The reaction solution was heated to reflux in an oil bath for 4 hours, and the plate indicated that the material was substantially disappeared and the reaction was stopped. After the temperature of the reaction system was naturally lowered to room temperature, 10 ml of ethanol (95%) was added to quench the reaction, and then 60 ml of ethanol (anhydrous) was added, and the resulting mixture was filtered through celite, and ethanol (anhydrous, 200 ml x 4) was used. After washing, the solvent was evaporated under reduced pressure, and then purified to give the title product 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8- Hydrogen-pyrrolo[3,2-c]azepine-2-carboxylic acid tert-butyl ester (0.413 g, white solid), Yield: 75.7%

MS m7z (ESI): 364.1(M+1)。第九步 MS m7z (ESI): 364.1 (M+1). Step 9

-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5，6,7，8-六氢-吡咯并 [3,2-c]吖庚因 -2-甲醛氩气氛下，将 5-(2-二乙氨基-乙基)- 3-甲基 -4-氧代 -1 ,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-羧酸叔丁酯 li(0.413 g， 1.14 nunol)搅拌下溶解于三氟醋酸 (1.5 ml, 20 mmol) 中，并于 40Ό油浴中反应 5分钟，再于冰盐浴中搅拌至温度降至 -5°C，加入原甲酸三乙酯 (0.34 ml, 1.7 mmol), 继续搅拌 2分钟。撤去冰盐浴，反应液温度自然升至室温，继续搅拌约 2小时。点板表明原料反应完全，停止反应。向反应体系中加入 3 ml冰水和 10 ml二氯甲烷，再用氢氧化钠溶液 (2 mol/L)调节 pH至 11左右，用二氯甲烷萃取 (10 mlx3)混合液。合并有机相，有机相用无水硫酸镁干燥，抽滤除去干燥剂，滤液减压浓缩得到黄色油状物。油状物经柱层析得到标题产物 5-(2- 二乙氨基-乙基) -3-甲基 -4-氧代 -1 ,4,5,6,7，8-六氢-吡咯并 [3，2-c] 吖庚因 -2-甲醛 lj(0.271 g, 浅棕色油状物)，产率： 55 %。 -(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine- 2-formaldehyde 5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2- under argon atmosphere c] azepine-tert-butyl 2-carboxylate li (0.413 g, 1.14 nunol) was dissolved in trifluoroacetic acid (1.5 ml, 20 mmol) with stirring, and reacted in a 40 Ό oil bath for 5 minutes, then on ice Stir in the salt bath until the temperature dropped to -5 ° C. Triethyl orthoformate (0.34 ml, 1.7 mmol) was added and stirring was continued for 2 min. The ice salt bath was removed, the temperature of the reaction solution was naturally raised to room temperature, and stirring was continued for about 2 hours. The dot plate indicates that the starting material is completely reacted and the reaction is stopped. 3 ml of ice water and 10 ml of dichloromethane were added to the reaction system, and the pH was adjusted to about 11 with a sodium hydroxide solution (2 mol/L), and the mixture was extracted with dichloromethane (10 ml x 3). The combined organic layers were dried with EtOAc EtOAc. The oil was subjected to column chromatography to give the title product 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[ 3,2-c] azepine-2-carbaldehyde lj (0.271 g, light brown oil), yield: 55 %.

MS m/z (ESI): 292·3(Μ+1)。第十步 ^_ 5-(2-二乙氨基-乙基) -2-(5-氟 -2-氧代 -1 ,2-二氢 -吲哚 -3-次甲基 )-3-甲基 -3a,5,6,7,8,8a- 六氢 -1H-吡咯 [3,2-c] 吖庚因 -4-酮 , MS m/z (ESI): 292·3 (Μ +1). Step 10 ^_ 5-(2-Diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methyl)-3-methyl -3a,5,6,7,8,8a-hexahydro-1H-pyrrole[3,2-c]azepine-4-one,

室温下，将 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 - 1 ,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 lj(0.271 g， 0.93 mmol)禾 Β 5-氟 -1,3-二氢-口引哚 -2-酮 (0.127 g, 0.84 mmol) 搅拌下溶解于 1.4 ml无水乙醇中，避光搅拌 10分钟。再加入六氢吡啶 (0.15 ' ml， 1.49 mmol), 氩气保护，于 70°C油浴中回流约 1.5小时，反应体系中有大量桔黄色固体析出，点板表明原料反应完全，停止反应。撤去油浴，反应体系温度自然冷却至室温，抽滤并干燥得到标题产物 5-(2-二乙氨基-乙基) -2-(5-氟 -2-氧代 - 1 ,2-二氢- 吲哚 -3-次甲基 )-3-甲基 -3a,5,6,7，8,8a-六氢 -1H-吡咯 [3,2-c]吖庚因 -4-酮 1(0.288 g，桔黄色固体)，产率： 80.76%。 5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c at room temperature ] aglycone-2-formaldehyde lj (0.271 g, 0.93 mmol) and 5-fluoro-1,3-dihydro-purin-2-one (0.127 g, 0.84 mmol) dissolved in 1.4 ml without stirring In water ethanol, stir for 10 minutes in the dark. Further, hexahydropyridine (0.15' ml, 1.49 mmol) was added, and the mixture was argon-protected and refluxed in an oil bath at 70 ° C for about 1.5 hours. A large amount of an orange solid precipitated in the reaction system, and the plate indicated that the reaction of the starting material was complete and the reaction was stopped. The oil bath was removed, the temperature of the reaction system was naturally cooled to room temperature, suction filtered and dried to give the title product 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro - indole-3-methyl)-3-methyl-3a,5,6,7,8,8a-hexahydro-1H-pyrrole[3,2-c]azepin-4-one 1 ( 0.288 g, orange solid), Yield: 80.76%.

MS m/z (ESI): 425.3(M+1)。 MS m/z (ESI): 425.3 (M+1).

'HNMR(400 MHZ, DMSO-d6) δ 13.710(s, 1H,吡咯环 -NH)， 10.903(s, 1H, 吲哚 -NH)， 7.753~7.782(dd, 1H, -ArH), 7.744(s, 1H, -CH=C), 6.914~6.965(m, lH, -ArH)， 6.834~6.867(m, 1H， -ArH), 3.483-3.518(t, 2H,七环内 -CH₂N)， 3.336~3.364(t, 2H,七环外接酰胺氮 -C¾)， 2.907~2.944(t， 2H, 七环内 -CH₂C=C)， 2.529-2.581 (m, 6H, 3 X -CH₂N)， 2.455(s, 3H, P比咯环 -CH₃)， 2.040~2.079(m₅ 2H, 七环内 - CH₂) , 0.956~0.992(t, 6H, 2 X -CH₃)。 'HNMR (400 MHZ, DMSO-d6) δ 13.710 (s, 1H, pyrrole ring-NH), 10.903 (s, 1H, 吲哚-NH), 7.753~7.782 (dd, 1H, -ArH), 7.744(s , 1H, -CH=C), 6.914~6.965(m, lH, -ArH), 6.834~6.867(m, 1H, -ArH), 3.483-3.518(t, 2H, hepta-CH ₂ N), 3.336~3.364(t, 2H, heptacyclic external amide nitrogen-C3⁄4), 2.907~2.944 (t, 2H, heptacyclic-CH ₂ C=C), 2.529-2.581 (m, 6H, 3 X -CH ₂ N ), 2.455 (s, 3H, P is more than ring-CH ₃ ), 2.040 to 2.079 (m ₅ 2H, hepta-CH ₂ ), 0.956 to 0.992 (t, 6H, 2 X -CH ₃ ).

' 实施例 2 'Example 2

2-(5-氯 -2-氧代 -1 ,2-二氢 -吲哚 -3-次甲基 )-5-(2-二乙氨基-乙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮

重复本发明实施例 1第十步反应，不同的是使用实施例 1第九步中所得到的化合物 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1，4,5,6,7,8-六氢-吡咯并 [3,2-c]吖庚因 -2- 甲醛 lj和 5-氯 -1，3-二氢』引哚 -2-酮作原料，得到标题产物 2-(5-氯 -2-氧代 -1,2-二氢- H引哚 -3-次甲基 )-5-(2-二乙氨基-乙基) -3-甲基 -5,6,7,8-四氢 -1Η-吡咯并 [3,2-c]吖庚因 -4-酮 2(27 mg，桔红色固体)，产率： 60.0%。 2-(5-Chloro-2-oxo-1,2-dihydro-indol-3-methyl)-5-(2-diethylamino-ethyl)-3-methyl-5,6 ,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one

The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used. ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde lj and 5-chloro-1,3-dihydroindol-2-one Starting material, the title product 2-(5-chloro-2-oxo-1,2-dihydro-H-indol-3-methyl)-5-(2-diethylamino-ethyl)-3- Methyl-5,6,7,8-tetrahydro-1indole-pyrrolo[3,2-c]azepin-4-one 2 (27 mg, orange solid), Yield: 60.0%.

MS m/z (ESI): 441.1(M+1)。 MS m/z (ESI): 441.1 (M + 1).

iHNMR OO MHz, DMSO-d6) δ 13.663(s, 1H,吡咯环 -NH)， 11.002(s, 1H，吲哚 -NH), 7.987-7.991 (d, 1H, -ArH), 7.798(s, 1H, -CH=C), 7.132~7.158(dd, 1H, -ArH), 6.867~6.888(d, 1H, -ArH), 3.483-3.518(t, 2H,七环内 -CH₂N)， 3.336~3.364(t, 2H,七环外接酰胺氮 -CH₂)， 2.907~2.944(t, 2H,七环内 -CH₂C=C)， 2.529-2.581 (m, 6H, 3 X -CH₂N)， 2.455(s, 3H, 吡咯环 -CH₃)， 2.040~2.079(m, 2H, 七环内 -CH2)， 0.956~0.992(t, 6H， 2 X-CH₃)。实施例 3 iHNMR OO MHz, DMSO-d6) δ 13.663 (s, 1H, pyrrole ring-NH), 11.002 (s, 1H, 吲哚-NH), 7.987-7.991 (d, 1H, -ArH), 7.798(s, 1H , -CH=C), 7.132~7.158(dd, 1H, -ArH), 6.867~6.888(d, 1H, -ArH), 3.483-3.518(t, 2H, hepta-CH ₂ N), 3.336~ 3.364(t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.907~2.944 (t, 2H, hepta-CH ₂ C=C), 2.529-2.581 (m, 6H, 3 X -CH ₂ N) , 2.455 (s, 3H, pyrrole ring-CH ₃ ), 2.040 to 2.079 (m, 2H, hepta-CH2), 0.956 to 0.992 (t, 6H, 2 X-CH ₃ ). Example 3

5-(2-二乙氨基-乙基) -2-[5-氟 -6-(4-氟-苄氨基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-3-甲 - -四氢 -1H-吡咯并 [3,2-c]吖庚因 -4-酮 5-(2-diethylamino-ethyl)-2-[5-fluoro-6-(4-fluoro-benzylamino)-2-oxo-1,2-dihydro-indol-3--3- 3-methyl-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one

第一步

first step

2,4-二硝基 -5-氟-苯乙酸 2,4-dinitro-5-fluoro-phenylacetic acid

室温下，将 3-氟-苯乙酸 3a(31.5 g， 0.204 mol)加入到 64 ml硫酸 (98%)中，控制温度在 35 °C滴加硝酸 (65%— 68%)及硫酸 (98%)的混合溶液 100 ml(V:V=l:l 加毕，控制反应体系温度在 °C左右搅拌，点板跟踪至原料消失。将冰加入反应液中，待冰融化后过滤，得到标题产物 2，4-二硝基 -5-氟-苯乙酸 3b(49 g，浅黄色油状液体)。 3-Fluoro-phenylacetic acid 3a (31.5 g, 0.204 mol) was added to 64 ml of sulfuric acid (98%) at room temperature, and nitric acid (65% - 68%) and sulfuric acid (98%) were added at 35 °C. The mixed solution is 100 ml (V: V = l: l is added, the temperature of the reaction system is controlled to be stirred at about °C, and the point plate is traced until the starting material disappears. The ice is added to the reaction solution, and the ice is melted and filtered to obtain the title product. 2,4-Dinitro-5-fluoro-phenylacetic acid 3b (49 g, pale yellow oily liquid).

MS m/z (ESI): 243.5(M-l 第二步 MS m/z (ESI): 243.5 (M-l second step

2,4-二胺基 -5-氟-苯乙酸 2,4-diamino-5-fluoro-phenylacetic acid

室温下，将 2,4-二硝基 -5-氟-苯乙酸 3b (10 g, 38.7 mmol)搅拌下溶解于 150 ml 甲醇中，加入钯 /碳 )，氢气氛下，在压强为 0.3 MPa下氢化。点板跟踪至原料消失，停止反应。反应液过滤两次，滤液减压浓缩得到标题产物 2,4-二胺基 -5-氟-苯乙酸 3c(7.12 g，棕色固体)，直接做下一歩。第三步 2,4-Dinitro-5-fluoro-phenylacetic acid 3b (10 g, 38.7 mmol) was dissolved in 150 ml of methanol with stirring at room temperature, and palladium/carbon was added under a hydrogen atmosphere at a pressure of 0.3 MPa. Under hydrogenation. The plate is tracked until the material disappears and the reaction is stopped. The reaction solution was filtered twice, and the filtrate was evaporated evaporated evaporated. third step

5-氟 -6-胺基 -2-吲哚酮 5-fluoro-6-amino-2-indanone

室温下，将 2,4-二胺基 -5-氟-苯乙酸 3c(7.12 g， 38.7 mmol)搅拌下溶解于 100 ml 盐酸 (1 mol/L), 加热回流 1小时，点板跟踪至原料消失，停止反应。将反应液冷却至室温，继续用冰水浴冷却，滴加 100 ml氢氧化钠 (1 mol/L)中和反应液。用乙酸乙酯萃取反应液 (125 mLX 4)，合并有机相，有机相用饱和氯化钠溶液 (100 mLX 1) 洗涤，用无水硫酸镁干燥，过滤除去干燥剂，滤液减压浓缩，得到标题产物 5-氟 -6- 胺基 -1,3-二氢 -2-吲哚酮 3d(5.3 g，黄色固体)，产率： 82.8%。 2,4-Diamino-5-fluoro-phenylacetic acid 3c (7.12 g, 38.7 mmol) was dissolved in 100 ml of hydrochloric acid (1 mol/L) with stirring at room temperature, and heated under reflux for 1 hour. Disappear, stop the reaction. The reaction solution was cooled to room temperature, and then cooled in an ice water bath, and 100 ml of sodium hydroxide (1 mol/L) was added dropwise to neutralize the reaction mixture. The reaction mixture was extracted with EtOAc (EtOAc (EtOAc) (EtOAcjjjjjjj The title product 5-fluoro-6-amino-1,3-dihydro-2-indanone 3d (5.3 g, yellow solid), yield: 82.8%.

MS m/z (ESI): 165.3(M-1)。第四步 MS m/z (ESI): 165.3 (M-1). the fourth step

5-氟 -6-(4-氟-苄氨基) -1,3-二氢 -吲哚 -2-酮 5-fluoro-6-(4-fluoro-benzylamino)-1,3-dihydro-indol-2-one

室温下，将 5-氟 -6-胺基 -1,3-二氢 -2-吲哚酮 3d(2.26 g, 13.6 mmol)搅拌下溶解于 5-Fluoro-6-amino-1,3-dihydro-2-indanone 3d (2.26 g, 13.6 mmol) was dissolved in stirring at room temperature

40 ml乙醇中，用冰浴将上述溶液冷却至 0°C，加入 4-氟-苯甲醛 (1.5 ml, 13.6 mmol), 加毕室温搅拌 1小时。加入四氢硼酸钠 (1.08 g, 28.5 mmol), 加热回流 18小时，点板表明原料反应完全，停止反应。反应液自然冷却至室温。加入冰水，有大量固体析出，抽滤，滤饼用水洗涤 (50 mlX 3)后经柱层析得到标题产物 5-氟 -6-(4-氟-苄氨基) -1,3-二氢 -吲哚 -2-酮 3e(1.67 g，白色固体)，产率： 45%。 The solution was cooled to 0 ° C in 40 ml of ethanol, and 4-fluoro-benzaldehyde (1.5 ml, 13.6 mmol) was added and stirred at room temperature for 1 hour. Sodium tetrahydroborate (1.08 g, 28.5 mmol) was added and the mixture was heated to reflux for 18 hours. The reaction solution was naturally cooled to room temperature. After adding ice water, a large amount of solid precipitated, suction filtration, and the filter cake was washed with water (50 ml×3) and then subjected to column chromatography to give the title product 5-fluoro-6-(4-fluoro-benzylamino)-1,3-dihydrol. -Indol-2-one 3e (1.67 g, white solid), Yield: 45%.

MS m/z (ESI): 275(M+1)。第五步 MS m/z (ESI): 275 (M+1). the fifth step

5-(2-二乙氨基-乙基) -2-[5-氟 -6-(4-氟-苄氨基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c]吖庚因 -4-酮 5-(2-diethylamino-ethyl)-2-[5-fluoro-6-(4-fluoro-benzylamino)-2-oxo-1,2-dihydro-indol-3--3- 3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one

重复本发明实施例 1第十步反应，不同的是使用实施例 1第九歩中所得到的化合物 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 lj和 5-氟 -6-(4-氟-节氨基) -1，3-二氢 -吲哚 -2-酮 3e作原料，得到标题产物 5-(2-二乙氨基-乙基) -2-[5-氟 -6-(4-氟-苄氨基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-3-甲基 -5,6，7，8-四氢 -1H-吡咯并 [3，2-c]吖庚因 -4-酮 3(61 mg，红褐色固体)，产率： 62.2 %。 The tenth step of the first embodiment of the present invention was repeated except that the compound obtained in the ninth example of Example 1 was used, 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1. ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde lj and 5-fluoro-6-(4-fluoro-amino group)-1,3 -Dihydro-indol-2-one 3e as a starting material to give the title product 5-(2-diethylamino-ethyl)-2-[5-fluoro-6-(4-fluoro-benzylamino)-2- Oxo-1,2-dihydro-indol-3-ylmethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine 4-ketone 3 (61 mg, reddish brown solid), Yield: 62.2%.

MS m/z (ESI): 548.3(M+1)。 MS m/z (ESI): 548.3 (M+1).

^NMR OO MHz, DMSO-d6) δ 13.416(s, 1H，吡咯环 -NH)， 10.520(s, 1H, 吲哚 -NH), 7.573~7.602(d, 1H, -ArH), 7.366-7.40 l(m, 2H, -ΑιΉ), 7.350(s, 1H, -CH-C), 7.141~7.185(m, 2H, -ArH), 6.410~6.415(m, 1H, -ArH), 6.038~6.057(d, 1H， -ArH), 4.346-4.36 l(d, 2H,苯胺 -CH₂)， 3.466~3.501(t, 2H,七环内 -CH₂N)， 3.336~3.364(t, 2H, 七环外接酰胺氮 -CH₂)， 2.907~2.944(t, 2H,七环内 -C¾C=C)， 2.529-2.58 l(m, 6H, 3 X -C¾N)， 2.388(s, 3H, 吡咯环 -CH₃)， 2.011 -2.039(m, 2H, 七环内 -CH₂)， 0.967-1.063(t, 6H, 2 X -CH₃)。实施例 4 ^NMR OO MHz, DMSO-d6) δ 13.416 (s, 1H, pyrrole ring-NH), 10.520 (s, 1H, 吲哚-NH), 7.573~7.602 (d, 1H, -ArH), 7.366-7.40 l (m, 2H, -ΑιΉ), 7.350(s, 1H, -CH-C), 7.141~7.185(m, 2H, -ArH), 6.410~6.415(m, 1H, -ArH), 6.038~6.057(d , 1H, -ArH), 4.346-4.36 l(d, 2H, aniline-CH ₂ ), 3.466~3.501 (t, 2H, hepta-CH ₂ N), 3.336~3.364(t, 2H, seven-ring external Amide nitrogen-CH ₂ ), 2.907~2.944 (t, 2H, heptacyclic-C3⁄4C=C), 2.529-2.58 l(m, 6H, 3 X -C3⁄4N), 2.388(s, 3H, pyrrole ring-CH ₃ ), 2.011 -2.039 (m, 2H, hepta-CH ₂ ), 0.967-1.063 (t, 6H, 2 X -CH ₃ ). Example 4

2-(7-溴 -5-氟 -2-氧代 -1,2-二氢』引哚 -3-次甲基 )-5-(2-二乙氨基-乙基) -3-甲基 -5,6,7,8- 四氢 -1H-吡咯并 [3,2-c] 吖庚因 - -酮 2-(7-bromo-5-fluoro-2-oxo-1,2-dihydroindol-3-pyridyl-3-methyl)-5-(2-diethylamino-ethyl)-3-methyl -5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-ketone

第一步

first step

7-溴 -5-氟 -1,3-二氢 -吲哚 -2-酮室温下，将 5-氟 -1,3-二氢 -吲哚 -2-酮 4a(1.5 g， 0.01 mol)搅拌下溶解于 15 ml 乙腈中，逐滴加入一溴代丁二酰亚胺 (1.8 g， 0.01 mol), 加毕过夜搅拌，有大量固体析出。点板表明原料反应完全，停止反应。反应液抽滤得到标题产物 7-溴 -5-氟 -1,3-二氢』引哚 -2-酮 4b(2 g，灰白色固体)，产率： 87% 7-bromo-5-fluoro-1,3-dihydro-indol-2-one 5-Fluoro-1,3-dihydro-indol-2-one 4a (1.5 g, 0.01 mol) was dissolved in 15 ml of acetonitrile with stirring at room temperature, and monobromosuccinimide was added dropwise. 1.8 g, 0.01 mol), after stirring overnight, a large amount of solid precipitated. The dot plate indicates that the starting material is completely reacted and the reaction is stopped. The reaction mixture was suction-filtered to give the titled product, 7-bromo-5-fluoro-1,3-dihydro-pyridin-2-one 4b (2 g, off-white solid), yield: 87%

MS m/z (ESI): (M-l MS m/z (ESI): (M-l

~ ^少 ~ ^ less

2-(7-溴 -5-氟 -2-氧代 -1，2-二氢 -吲哚 -3-次甲基 )-5-(2-二乙氨基-乙基) -3-甲基 -5,6,7,8- 四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 2-(7-Bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-methyl)-5-(2-diethylamino-ethyl)-3-methyl -5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one

重复本发明实施例 1第十步反应，不同的是使用实施例 1第九步中所得到的化合物 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3，2-c] 吖庚因 -2- 甲醛 lj和 7-溴 -5-氟 -1,3-二氢 -Π引哚 -2-酮 4b作原料，得到标题产物 2-(7-溴 -5-氟 -2- 氧代 -1,2-二氢引哚 -3-次甲基 )-5-(2-二乙氨基-乙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 4(55 mg，土黄色固体)，产率： 61.1 %。 The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used. ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-formaldehyde lj and 7-bromo-5-fluoro-1,3-dihydro-indole 2-ketone 4b was used as the starting material to give the title product 2-(7-bromo-5-fluoro-2-oxo-1,2-dihydroindole-3-methyl)-5-(2-di- Amino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 4 (55 mg, tarnish solid) Yield: 61.1%.

MS m/z (ESI): 503.6(M+1)。 MS m/z (ESI): 503.6 (M + 1).

^NMR OO MHz, DMSO-d6) δ 13.653(s, 1H，吡咯环 -NH)， 11.181(s, IH, 吲哚 -NH), 7.848~7.876(dd, IH, -AxH), 7.794(s, IH, -CH=C), 7.242-7.270(dd, IH, -ArH), 3.485~3.520(t, 2H, 七环内 -CH₂N)， 3.338~3.366(t, 2H, 七环外接酰胺氮 -CH₂)， 2.932〜2.969(t, 2H，七环内 -CH₂C=C)， 2.527-2.582(m, 6H, 3 X - CH₂N)， 2.470(s, 3H, 吡咯环 -CH₃)， 2.031~2.093(m, 2H,七环内 -CH₂)， 0.954~0.990(t, 6H, 2 -CH 实施例 5 ^NMR OO MHz, DMSO-d6) δ 13.653 (s, 1H, pyrrole ring-NH), 11.181 (s, IH, 吲哚-NH), 7.848~7.876 (dd, IH, -AxH), 7.794 (s, IH, -CH=C), 7.242-7.270(dd, IH, -ArH), 3.485~3.520(t, 2H, hepta-CH ₂ N), 3.338~3.366(t, 2H, heptacyclic external amide nitrogen -CH ₂ ), 2.932~2.969 (t, 2H, hepta-CH ₂ C=C), 2.527-2.582 (m, 6H, 3 X - CH ₂ N), 2.470 (s, 3H, pyrrole ring-CH ₃ ), 2.031~2.093 (m, 2H, hepta-CH ₂ ), 0.954~0.990 (t, 6H, 2 -CH Example 5

2-(5-溴 -2-氧代 -1,2-二氢』引哚 -3-次甲基 )-5-(2-二乙氨基-乙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3，2-c] 吖庚因 -4- 2-(5-Bromo-2-oxo-1,2-dihydroindol-3-pyridyl-3-methyl)-5-(2-diethylamino-ethyl)-3-methyl-5,6 ,7,8-tetrahydro-1H-pyrrolo[3,2-c] azepine-4-

重复本发明实施例 1第十步反应，不同的是使用实施例 1第九步中所得到的化合物 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1，4，5，6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 甲醛 lj和 5-溴 -1,3-二氢 -Π引哚 -2-酮作原料，得到标题产物 2-(5-溴 -2-氧代 -1,2-二氢- 吲哚 -3-次甲基 )-5-(2-二乙氨基-乙基) -3-甲基 -5,6，7,8-四氢- 1H-吡咯并 [3,2-c] 吖庚因 -4-酮 5(59 mg，黄色固体)，产率： 67.8%。

The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used. ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-formaldehyde lj and 5-bromo-1,3-dihydro-indole-2-one As a starting material, the title product 2-(5-bromo-2-oxo-1,2-dihydro-indol-3-methyl)-5-(2-diethylamino-ethyl)-3- Methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 5 (59 mg, yellow solid), Yield: 67.8%.

MS m/z (ESI): 485.5(M+1)。 P T/CN2008/001352 MS m/z (ESI): 485.5 (M+1). PT/CN2008/001352

^]HNMR(400 MHz, DMSO-d6) δ 13.660(s, 1H,吡咯环 -NH)， 11.008(s₅ 1H, 吲哚 -NH), 8.113~8.117(d, 1H, -ArH), 7.803(s, 1H, -CH=C), 7.260~7.286(dd, 1¾ -ArH), 6.825~6.845(d, 1H, -ArH), 3.482-3.516(t, 2H,七环内 -CH₂N)， 3.336~3.364(t, 2H,七环外接酰胺氮 -CH₂)， 2.907~2.944(t, 2H,七环内 -CH₂C=C)， 2.490~2.578(m, 6H, 3 X -CH₂N)， 2.464(s, 3H, 吡咯环 -CH₃)， 2.039~2.067(m, 2H, 七环内 - CH₂)， 0.954~0.990(t, 6H, 2 X-CH₃) c 实施例 6 ^{] HNMR (400 MHz, DMSO-} d6) δ 13.660 (s, 1H, pyrrole ring _{-NH), 11.008 (s 5 1H} , indole -NH), 8.113 ~ 8.117 (d , 1H, -ArH), 7.803 (s , 1H, -CH=C), 7.260~7.286(dd, 13⁄4 -ArH), 6.825~6.845(d, 1H, -ArH), 3.482-3.516(t, 2H, hepta-CH ₂ N), 3.336 ~3.364(t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.907~2.944 (t, 2H, hepta-CH ₂ C=C), 2.490~2.578 (m, 6H, 3 X -CH ₂ N ), 2.464 (s, 3H, pyrrole ring-CH ₃ ), 2.039~2.067 (m, 2H, hepta-CH ₂ ), 0.954 to 0.990 (t, 6H, 2 X-CH ₃ ) c Example 6

5-(2-二乙氨基-乙基) -2-[4-(2，3-二氟-苯基) -2-氧代 -1，2-二氢 -吲哚 -3-次甲基 ]-3-甲基 -5, -四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 5-(2-diethylamino-ethyl)-2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indole-3-methine ]-3-methyl-5,-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one

第一步

first step

4-(4,4,5,5-四甲基 -[1,3，2]二氧杂硼垸 -2-基) -1H-吲哚 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboroin-2-yl)-1H-indole

氩气氛下，将 4-溴 -1H-吲哚 6a(29.4 g， 150 mmol)搅拌下溶解于 600 ml二甲基亚砜中，依次加入频哪醇乙硼烷 (41.9 g， 165 mmol), 醋酸钾 (44.1 g, 450 mmol)和 Ι,Γ-双 (二苯膦基)二茂铁二氯化钯 (3.6 g， 4.8 mmol), 加毕，反应液于 80°C油浴中搅拌 22小时，点板表明原料反应完全，停止反应。反应液中加入 2 L水，用乙酸乙酯萃取 (2 LX 3)，合并有机相，有机相用饱和氯化钠洗涤 (2 LX 5), 无水硫酸钠干燥，抽滤除去干燥剂，滤液减压浓缩。所得固体柱层析后重结晶得到标题产物 4-(4,4，5,5-四甲基 -[1,3,2]二氧杂硼烷 -2-基) -1H-吲哚 6b(20 g，白色固体)，产率： 60 %。 4-Bromo-1H-indole 6a (29.4 g, 150 mmol) was dissolved in 600 ml of dimethyl sulfoxide under stirring in an argon atmosphere, followed by the addition of pinacol diborane (41.9 g, 165 mmol). Potassium acetate (44.1 g, 450 mmol) and hydrazine, hydrazine-bis(diphenylphosphino)ferrocene palladium dichloride (3.6 g, 4.8 mmol), after completion, the reaction mixture was stirred in an oil bath at 80 ° C. Hours, the dot plate indicates that the raw material reaction is complete and the reaction is stopped. 2 L of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (2 L×3). The organic phase was combined and washed with saturated sodium chloride (2L×5), dried over anhydrous sodium sulfate and filtered. Concentrate under reduced pressure. The obtained solid column was subjected to chromatography and crystallized to give the title product 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaboran-2-yl)-1H-indole 6b ( 20 g, white solid), Yield: 60%.

MS m/z (ESI): 243.9(M+1)。第二步 MS m/z (ESI): 243.9 (M + 1). Second step

4-(2,3-二氟-苯基) -1H-吲哚 T N2008/001352 氩气氛下，将 4-(4,4,5,5-四甲基 -[1,3,2]二氧杂硼烷 -2-基) -1H-吲哚 6b(1.22 g， 5 mmol)搅拌下溶解于 20 ml四氢呋喃中，加入 1-溴 -2,3-二氟-苯 (0.97 g， 5 mmol), 四 (三苯基膦)钯 (0.17 g， 0.15 11111101)和7 1^氢氧化钠溶液 ^1/1^)。加毕，反应体系在 75°C油浴中搅拌过夜，点板表明原料反应完全，停止反应。反应液自然冷却至室温，用乙酸乙酯萃取 (20 mlX 3)，合并有机相，有机相用饱和氯化钠洗涤 (10 ml X I), 无水硫酸钠干燥，抽滤除去干燥剂，滤液减压浓缩。所得固体柱层析得到标题产物 4-(2,3-二氟-苯基) -1H-吲哚 6c(800 mg，白色固体)，产率： 70%。 4-(2,3-difluoro-phenyl)-1H-indole T N2008/001352 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 6b (1.22 g) under argon atmosphere , 5 mmol) was dissolved in 20 ml of tetrahydrofuran with stirring, and 1-bromo-2,3-difluoro-benzene (0.97 g, 5 mmol), tetrakis(triphenylphosphine)palladium (0.17 g, 0.15 11111101) and 7 1^Sodium hydroxide solution ^1/1^). After the addition, the reaction system was stirred overnight in an oil bath at 75 ° C, and the plate indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was cooled to room temperature, then extracted with ethyl acetate (20 ml×3). The organic phase was combined, and the organic phase was washed with saturated sodium chloride (10 ml XI), dried over anhydrous sodium sulfate. Concentrated by pressure. The obtained solid was subjected to EtOAc EtOAcjjjjjjj

MS m/z (ESI): 228.4(M-l 第三步 MS m/z (ESI): 228.4 (M-l third step

4-(2,3-二氟-苯基) -1,3-二氢 -吲哚 -2-酮 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one

室温下，将 4-(2,3-二氟-苯基) -1H-吲哚 6c(744 mg， 3.25 mmol)搅拌下溶解于 12 ml乙醇中，依次加入 21 ml叔丁醇， 6.4 ml冰醋酸和三溴化吡啶鑰 (3.12 g， 9.7 namol), 加毕搅拌 3小时。再加入 16 ml冰醋酸和锌粉 (1.1 g， 16.25 mmol), 继续搅拌 1小时。反应液抽滤除去残渣，滤液减压浓缩后加入 30 ml乙酸乙酯，依次用 10 ml水， 10 ml饱和碳酸氢钠和 10 ml饱和氯化钠洗漆，用无水硫酸钠干燥，抽滤除去干燥剂，滤液减压浓縮。所得固体为标题产物 4-(2,3-二氟-苯基) -1,3-二氢 -吲哚 -2-酮 6d(780 mg, 白色固体)，产率： 97%。 4-(2,3-Difluoro-phenyl)-1H-indole 6c (744 mg, 3.25 mmol) was dissolved in 12 ml of ethanol with stirring at room temperature, followed by 21 ml of tert-butanol, 6.4 ml of ice. Acetic acid and tribromide pyridine (3.12 g, 9.7 namol) were added and stirred for 3 hours. Add 16 ml of glacial acetic acid and zinc powder (1.1 g, 16.25 mmol) and continue to stir for 1 hour. The residue was evaporated to dryness. The desiccant was removed and the filtrate was concentrated under reduced pressure. The obtained solid was the title product 4-(2,3-difluoro-phenyl)-1,3-dihydro-indole-2-one 6d (780 mg, white solid).

MS m/z (ESI): 246·6(Μ+1)。第四步 MS m/z (ESI): 246·6 (Μ +1). the fourth step

5-(2-二乙氨基-乙基) -2-[4-(2,3-二氟-苯基) -2-氧代 -1，2-二氢 -吲哚 -3-次甲基 ]-3-甲基 -5,6,7,8-四氢 -1Η-口比咯并 [3,2-c] 吖庚因 -4-酮 5-(2-diethylamino-ethyl)-2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indole-3-methine ]-3-methyl-5,6,7,8-tetrahydro-1 oxime-to-mouth ratio [3,2-c] azepin-4-one

重复本发明实施例 1第十步反应，不同的是使用实施例 1第九步中所得到的化合物 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1，4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 甲醛 lj和 4-(2,3-二氟-苯基) -1，3-二氢 -吲哚 -2-酮 6d作原料，得到标题产物 5-(2-二乙氨基 -乙基 )-2-[4-(2,3-二氟-苯基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-3-甲基 -5,6,7,8- 四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 6(43 mg，黄色固体)，产率： 61.4%。 The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used. ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-formaldehyde lj and 4-(2,3-difluoro-phenyl)-1,3- Dihydro-indol-2-one 6d was used as a starting material to give the title product 5-(2-diethylamino-ethyl)-2-[4-(2,3-difluoro-phenyl)-2-oxo -1,2-dihydro-indol-3-ylmethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4 - Ketone 6 (43 mg, yellow solid), Yield: 61.4%.

MS m/z (ESI): 519·6(Μ+1)。 MS m/z (ESI): 519·6 (Μ +1).

!ΗΝΜ (400 MHz, DMSO-d6) δ 13.53 l(s, 1Η,吡咯环 -NH)， 11.133(s, IH, 吲哚 -NH), 7.617~7.640(m, IH, -ArH), 7.429~7.442(m, IH, -ArH), 7.305~7.340(m, IH, -ArH), 7.232~7.270(m, IH, -ArH), 6.997~7.017(d, IH, -ArH), 6.874~6.893(d, IH, -ArH), 6.710(s， IH, -CH=C)， 3.445~3.478(t, 2H,七环内 -CH₂N)， 3.313(m, 2Ά,七环外接酰胺氮 -C¾)， 2.868~3.904(t, 2H,七环内 -CH₂C=C)， 2.465~2.542(m, 6H, 3 X -CH₂N) , 2.002~2.032(m, 2H, 七环内 - CH₂)， 1.794 (s， 3H, 吡咯环 -CH₃)， 0.930~0.965(t₅ 6H, 2X -CH 实施例 7 !ΗΝΜ (400 MHz, DMSO-d6) δ 13.53 l(s, 1Η, pyrrole ring-NH), 11.133(s, IH, 吲哚-NH), 7.617~7.640(m, IH, -ArH), 7.429~ 7.442(m, IH, -ArH), 7.305~7.340(m, IH, -ArH), 7.232~7.270(m, IH, -ArH), 6.997~7.017(d, IH, -ArH), 6.874~6.893( d, IH, -ArH), 6.710(s, IH, -CH=C), 3.445~3.478(t, 2H, hepta-CH ₂ N), 3.313 (m, 2Ά, heptacyclic external amide nitrogen-C3⁄4 ), 2.868~3.904(t, 2H, hepta-CH ₂ C=C), 2.465~2.542(m, 6H, 3 X -CH ₂ N) , 2.002~2.032(m, 2H, 7-ring - CH ₂ ), 1.794 (s, 3H, pyrrole ring-CH ₃ ), 0.930~0.965 (t ₅ 6H, 2X -CH Example 7

N-{3-[5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7，8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 亚 -5-氟 -²-氧代 -2，3-二氢 -1H-吲哚 -6-基}-2-甲氧基-乙酰胺 N-{3-[5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2 -c] 吖gyne-2-phenyl-5-fluoro- ² -oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide

第一步 First step

5-氟 -6-甲氧乙酰胺基 -2-吲哚酮 5-fluoro-6-methoxyacetamido-2-indanone

室温下，将 5-氟 -6-胺基 -2-吲哚酮 3d(2.028 g， 12.2 mmol)搅拌下溶解于 30 ml 四氢呋喃中，力口入 1.3 ml P比啶，用干冰 -乙醇浴使反应体系冷却至 -50°C左右。将甲氧乙酰氯 (1.35 g， 12.5 mmol)搅拌下溶解于 20 ml四氢呋喃中，滴加到上述反应体系中。加毕，撤去干冰-乙醇浴，使反应体系温度自然升至室温，搅拌过夜。点板跟踪至原料消失，停止反应。反应液过滤，所得固体用水洗涤 (10 ml X 3)，用甲醇重结晶，即得到标题产物 5-氟 -6-甲氧乙酰胺基 -2-吲哚酮 7a(1.18 g，灰色固体)，产率： 40.6%。 5-Fluoro-6-amino-2-indanone 3d (2.028 g, 12.2 mmol) was dissolved in 30 ml of tetrahydrofuran with stirring at room temperature, and 1.3 ml of P-pyridinium was added to the solution, using a dry ice-ethanol bath. The reaction system was cooled to about -50 °C. The methoxyacetyl chloride (1.35 g, 12.5 mmol) was dissolved in 20 ml of tetrahydrofuran with stirring and added dropwise to the above reaction system. After the addition, the dry ice-ethanol bath was removed, and the temperature of the reaction system was naturally raised to room temperature, and stirred overnight. The plate is tracked until the material disappears and the reaction is stopped. The reaction mixture was filtered, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Yield: 40.6%.

MS m/z (ESI): 239.3(M+1)。第二步 MS m/z (ESI): 239.3 (M + 1). Second step

N-{3-[5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5，6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 亚甲基 ]-5-氟 -2-氧代 -2，3-二氢 -1H-吲哚 -6-基}-2-甲氧基-乙酰胺 N-{3-[5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2 -c] 吖hine-2-methylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide

重复本发明实施例 1第十歩反应，不同的是使用实施例 1第九歩中所得到的化合物 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6，7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 甲醛 lj和 N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 _6 -基) -2-甲氧基-乙酰胺 7a作原料，得到标题产物 N-{3-[5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3，2-c] 吖庚因 -2-亚甲基 ]-5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基}-2-甲氧基-乙酰胺 7(37 mg, 褐色固体)，产率： 53.6%。 The tenth reaction of Example 1 of the present invention was repeated except that the compound obtained in the ninth example of Example 1 was used, 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1. ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-formaldehyde lj and N-(5-fluoro-2-oxo-2,3-dihydrogen -1H-吲哚_6-yl)-2-methoxy-acetamide 7a as a starting material to give the title product N-{3-[5-(2-diethylamino-ethyl)-3-methyl- 4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-methylene]-5-fluoro-2-oxo-2 ,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide 7 (37 mg, Brown solid), Yield: 53.6%.

MS m/z (ESI): 512.5(M+1)。 MS m/z (ESI): 512.5 (MI).

'HNMR(400 MHZ, DMSO-d6) δ 13.605(s, 1H，吡咯环 -NH)， 10.893(s, 1H,吲哚 -丽)， 9.320(s, 1H,酰胺 -NH)， 7.838~7.866(d, 1H, -ArH), 7.350(s, 1H, -CH=C), 7.540〜7.556(d, lH, -ArH)， 4.064(s, 2H, -C¾0)， 3.483-3.517(t, 2H,七环内 -C¾N)， 3.336~3.362(t, 2H,七环外接酰胺氮 -CH₂)， 3.314(s， 3H, -CH₃0)， 2.902~2.939(t, 2H, 七环内 -CH₂C=C), 2.530~2.562(m, 6H, 3 X -C¾N) , 2.444(s, 3H, 吡咯环 -CH₃)， 2.037~2.066(m, 2H,七环内 -CH₂)， 0.958-0.993 (t, 6H, 2 X -CH₃)。实施例 8 'HNMR (400 MHZ, DMSO-d6) δ 13.605 (s, 1H, pyrrole ring-NH), 10.893 (s, 1H, 吲哚-Li), 9.320 (s, 1H, amide-NH), 7.838~7.866 ( d, 1H, -ArH), 7.350(s, 1H, -CH=C), 7.540~7.556(d, lH, -ArH), 4.064(s, 2H, -C3⁄40), 3.483-3.517(t, 2H, Within the seven-ring -C3⁄4N), 3.336~3.362 (t, 2H, seven-ring external amide nitrogen-CH ₂ ), 3.314(s, 3H, -CH ₃ 0), 2.902~2.939 (t, 2H, seven-ring-CH ₂ C=C), 2.530~2.562(m, 6H, 3 X -C3⁄4N) , 2.444(s, 3H, pyrrole ring-CH ₃ ), 2.037~2.066 (m, 2H, hepta-CH ₂ ), 0.958 -0.993 (t, 6H, 2 X -CH ₃ ). Example 8

N-{3-[5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1 ,4,5，6,7,8-六氢-吡咯并[3,2-(；] 吖庚因 -2- 亚甲基 ]-5-氟 -2-氧代 -2,3- -1H-吲哚 -6-基 }-2-羟基-丙酰胺 N-{3-[5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2 -(;] 吖gyne-2-methylene]-5-fluoro-2-oxo-2,3- -1H-indol-6-yl}-2-hydroxy-propionamide

第一步 First step

乙酸 1-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-氨基甲酰基) -乙酯 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indole-6-carbamoyl)-ethyl acetate

室温下，将 5-氟 -6-胺基 -2-吲哚酮 3d(450 mg， 2.71 mmol)搅拌下溶解于 10 ml 四氢呋喃中，用干冰-丙酮浴冷却至 -45°C，加入 364 μ ΐ吡啶。将 2-乙酰氧基丙酰氯 (423 mg， 2.71 mmol)搅拌下溶解于 10 ml四氢呋喃中，滴加到上述反应液中，加毕撤去干冰-丙酮浴，让反应体系温度自然升至室温，搅拌过夜。点板监测反应至原料反应完全，停止反应。反应液过滤，滤饼用水洗涤，所得固体干燥后得到标题产物乙酸 1-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-氨基甲酰基) -乙酯 8a(840 mg，白色固体 )，直接进行下歩反应。 N2008/001352 5-Fluoro-6-amino-2-indanone 3d (450 mg, 2.71 mmol) was dissolved in 10 ml of tetrahydrofuran with stirring at room temperature, cooled to -45 ° C with dry ice-acetone bath, 364 μ Bismuth pyridine. 2-Acetoxypropionyl chloride (423 mg, 2.71 mmol) was dissolved in 10 ml of tetrahydrofuran with stirring, and added dropwise to the above reaction solution. After the addition, the dry ice-acetone bath was removed, and the temperature of the reaction system was naturally raised to room temperature. overnight. The plate was monitored until the reaction of the starting material was complete and the reaction was stopped. The reaction solution was filtered, and the filter cake was washed with water, and the obtained solid was dried to give the title product 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indole-6-carbamoyl)-ethyl acetate. 8a (840 mg, white solid), directly subjected to a sputum reaction. N2008/001352

MS m/z (ESI): 281·5(Μ+1)。第二歩 MS m/z (ESI): 281·5 (Μ +1). Second

N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基) -2-羟基-丙酰胺室温下，将乙酸 1-(5-氟 -2-氧代 -2,3-二氢 _1Η -吲哚 -6-氨基甲酰基) -乙酯 8a(1.86 g, 6.4 mmol)搅拌下溶解于 20 ml甲醇中，加入 10 ml水和 10 ml氢氧化钠溶液 (0.7 mol/L),搅拌 4小时，点板监测反应至原料反应完全，停止反应。反应液用 l mol/L 的盐酸中和后，减压蒸除溶剂，柱层析后干燥得到标题产物 N-(5-氟 -2-氧代 -2，3_二氢 -1H-吲哚 -6-基) -2-羟基-丙酰胺 8b(1.0 g，白色色固体)，产率： 70%。 N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide 1-(5-fluoro-2-oxoacetate) at room temperature 2,3-Dihydro_1Η-吲哚-6-carbamoyl)-ethyl ester 8a (1.86 g, 6.4 mmol) was dissolved in 20 ml of methanol with stirring, 10 ml of water and 10 ml of sodium hydroxide were added. The solution (0.7 mol/L) was stirred for 4 hours, and the reaction was monitored by spotting until the reaction of the starting material was complete, and the reaction was stopped. After the reaction mixture was neutralized with 1 mol/L hydrochloric acid, the solvent was evaporated under reduced pressure, and then purified by column chromatography to give the title product N-(5-fluoro-2-oxo-2,3-dihydro-1H-indole -6-yl)-2-hydroxy-propionamide 8b (1.0 g, white solid), Yield: 70%.

MS m/z (ESI): 239.6(M+1)。第三步 MS m/z (ESI): 239.6 (M + 1). third step

N-{3-[5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 亚甲基 ]-5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基}-2-羟基-丙酰胺 N-{3-[5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2 -c] 吖gyne-2-methylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-propionamide

重复本发明实施例 1第十步反应，不同的是使用实施例 1第九步中所得到的化合物 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6，7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 甲醛 lj和 N-(5-氟 -2-氧代 -2，3-二氢 -1H-吲哚 -6-基) -2-羟基-丙酰胺 8b作原料，得到标题产物 N-{3-[5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4，5,6，7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基}-2-轻基-丙酰胺 8(28 mg, 黄色固体)，产率： 40.8%。 The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used. ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-formaldehyde lj and N-(5-fluoro-2-oxo-2,3-dihydrogen -1H-indole-6-yl)-2-hydroxy-propionamide 8b as the starting material to give the title product N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4- Oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-methylene]-5-fluoro-2-oxo-2,3 -Dihydro-1H-indol-6-yl}-2-light-propionamide 8 (28 mg, yellow solid), Yield: 40.8%.

MS m/z (ESI): 512.4(M+1)。 MS m/z (ESI): 512.4 (MI).

¹HNMR(400 MHz, DMSO-d6) δ 13.594(s, 1H,吡咯环 -NH)， 10.902(s, 1H,吲哚 -NH)， 9.245(s, 1H,酰胺 -NH)， 7.856~7.884(d, 1H, -ArH), 7.725~7.741(d, 1H， -ArH), 7.663(s, 1H, -CH=C) , 6.057~6.070(d, 1H, -ArH) , 4.206~4.236(q, 1H, -CHO)， 3.480-3.514(t, 2H,七环内 -CH₂N)， 3.336-3.362 (t, 2H, 七环外接酰胺氮 -CH₂)， 2.902~2.939(t, 2H,七环内 -CH₂C=C)， 2.530~2.562(m, 6H, 3 X -CH₂N), 2.443(s, 3H, 吡咯环 -CH₃)， 2.037~2.066(m, 2H, 七环内 -CH₂)， 1.328-1.345(d, 3H， -CH₃) , 0.958-0.993 (t, 6H， 2 X -CH₃)。实施例 9 ¹ H NMR (400 MHz, DMSO-d6) δ 13.594 (s, 1H, pyrrole ring-NH), 10.902 (s, 1H, 吲哚-NH), 9.245 (s, 1H, amide-NH), 7.856~7.884 ( d, 1H, -ArH), 7.725~7.741(d, 1H, -ArH), 7.663(s, 1H, -CH=C), 6.057~6.070(d, 1H, -ArH), 4.206~4.236(q, 1H, -CHO), 3.480-3.514 (t, 2H, hepta-CH ₂ N), 3.336-3.362 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.902~2.939 (t, 2H, seven Within the ring -CH ₂ C=C), 2.530~2.562 (m, 6H, 3 X -CH ₂ N), 2.443 (s, 3H, pyrrole ring-CH ₃ ), 2.037~2.066 (m, 2H, within the seven-ring -CH ₂ ), 1.328-1.345 (d, 3H, -CH ₃ ), 0.958-0.993 (t, 6H, 2 X -CH ₃ ). Example 9

N-{3-[5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 亚甲基 ]-5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基}-2-羟基 -2-甲基-丙酰胺 N-{3-[5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2 -c] azepine-2-methylidene-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-2-methyl-propyl Amide

9 9

第一步 First step

乙酸 1-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-氨基甲酰基)小甲基 -乙酯室温下，将 5-氟 -6-胺基 -2-吲哚酮 3d(410 mg， 2.47 mmol)搅拌下溶解于 10 ml 四氢呋喃中，用干冰-丙酮浴冷却至 -45°C，加入 332 μ ΐ吡啶。将 2-乙酰氧基异丁酰氯 (423 mg， 2.71 mmol)搅拌下溶解于 10 ml四氢呋喃中，滴加到上述反应液中，加毕撤去干冰-丙酮浴，让反应体系温度自然升至室温，搅拌过夜。点板监测反应至原料反应完全，将反应液过滤，滤饼用水洗涤，所得固体干燥后得到标题产物乙酸 1-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-氨基甲酰基) -1-甲基 -乙酯 9a(792 mg, 白色固体)，直接进行下步反应。 1-(5-Fluoro-2-oxo-2,3-dihydro-1H-indole-6-carbamoyl)succinymethyl-ethyl acetate 5-fluoro-6-amino group at room temperature 2-nonanone 3d (410 mg, 2.47 mmol) was dissolved in 10 ml of tetrahydrofuran with stirring, cooled to -45 ° C with a dry ice-acetone bath, and 332 μ of pyridine was added. 2-Acetoxyisobutyryl chloride (423 mg, 2.71 mmol) was dissolved in 10 ml of tetrahydrofuran with stirring, and added dropwise to the above reaction solution. After the addition, the dry ice-acetone bath was removed, and the temperature of the reaction system was naturally raised to room temperature. Stir overnight. The reaction was monitored by spotting until the reaction of the starting material was complete. The reaction solution was filtered, and the filter cake was washed with water. The obtained solid was dried to give the title product 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indole. -6-carbamoyl)-1-methyl-ethyl ester 9a (792 mg, white solid) was taken directly to the next step.

MS m/z (ESI): 293.7(M-l)o 第二步 MS m/z (ESI): 293.7(M-l)o Step 2

N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基) -2_羟基-2-甲基-丙酰胺室温下，将乙酸 1-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-氨基甲酰基) -1-甲基 -乙酯 9a (2.035 g， 6.9 mmol)搅拌下溶解于 20 ml甲醇中，加入 20 ml氢氧化钠溶液 (0.7 mol L),搅拌 4小时，点板监测反应至原料反应完全，停止反应。反应液用 1 mol/L 的盐酸中和后，减压蒸除溶剂，柱层析后干燥得到标题产物 N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基) -2-羟基 -2-甲基-丙酰胺 9b(900 mg，白色固体)，产率： 59.2%。 MS m/z (ESI): 253.6(M+1)₀ 第三步 N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propanamide 1-(5- Fluoro-2-oxo-2,3-dihydro-1H-indole-6-carbamoyl)-1-methyl-ethyl ester 9a (2.035 g, 6.9 mmol) was dissolved in 20 ml of methanol with stirring. Add 20 ml of sodium hydroxide solution (0.7 mol L), stir for 4 hours, and monitor the reaction until the reaction of the starting material is complete, and stop the reaction. After the reaction mixture was neutralized with 1 mol/L hydrochloric acid, the solvent was evaporated under reduced pressure, and then purified by column chromatography to give the title product N-(5-fluoro-2-oxo-2,3-dihydro-1H-indole. -6-yl)-2-hydroxy-2-methyl-propionamide 9b (900 mg, white solid), yield: 59.2%. MS m/z (ESI): 253.6 (M+1) ₀ third step

重复本发明实施例 1第十步反应，不同的是使用实施例 1第九步中所得到的化合物 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢 -P比咯并 [3,2-c] 吖庚因 -2- 甲醛 lj和 N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基) -2-羟基 -2-甲基-丙酰胺 9b作原料，得到标题产物 N-{3-[5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7，8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基 }-2-轻基 -2-甲基 -丙酰胺 9(39 mg，土黄色固体)，产率： 62.4%。 The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used. ,4,5,6,7,8-hexahydro-P is more than [3,2-c] azepine-2-carbaldehyde lj and N-(5-fluoro-2-oxo-2,3- Dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propanamide 9b was used as the starting material to give the title product N-{3-[5-(2-diethylamino-ethyl)- 3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-methylene]-5-fluoro-2 -Oxo-2,3-dihydro-1H-indol-6-yl}-2-carbyl-2-methyl-propanamide 9 (39 mg, EtOAc).

MS m/z (ESI): 526.4(M+1)。 MS m/z (ESI): 526.4 (M + 1).

¹HNMR(400 MHz, DMSO-d6) δ 13.591(s, 1H，吡咯环 -NH)， 10.900(s, 1H,吲哚 -NH), 9.284(s, 1H,酰胺 -NH)， 7.862~7.890(d, 1H, -ArH), 7.774-7.79 l(d, 1H， -ArH), 7.661(s, 1H, -CH=C)， 6.052(s, 1H, -OH) , 3.480~3.514(t, 2H, 七环内 -CH₂N)， 3.334~3.361(t, 2H,七环外接酰胺氮 -CH₂)， 2.902-2.939(t, 2H,七环内 -CH₂C=C)， 2.530~2.562(m, 6H, 3 X-CH₂N), 2.443 (s, 3H,吡咯环 -C¾)， 2.037~2.066(m, 2H,七环内 -CH₂)， 1.377(s, 6H, 2 X - CH₃)， 0.958-0.993 (t, 6H, 2 X -CH₃)。实施例 10 ¹ H NMR (400 MHz, DMSO-d6) δ 13.591 (s, 1H, pyrrole ring-NH), 10.900 (s, 1H, 吲哚-NH), 9.284 (s, 1H, amide-NH), 7.862~7.890 ( d, 1H, -ArH), 7.774-7.79 l(d, 1H, -ArH), 7.661(s, 1H, -CH=C), 6.052(s, 1H, -OH) , 3.480~3.514(t, 2H , Hexacyclic-CH ₂ N), 3.334~3.361 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.902-2.939 (t, 2H, hepta-CH ₂ C=C), 2.530~2.562 (m, 6H, 3 X-CH ₂ N), 2.443 (s, 3H, pyrrole ring - C3⁄4), 2.037~2.066 (m, 2H, hepta-CH ₂ ), 1.377 (s, 6H, 2 X - CH ₃ ), 0.958-0.993 (t, 6H, 2 X -CH ₃ ). Example 10

2-(5-氯 -2-氧代 -1,2-二氢 - 哚 -3-次甲基 )-3-甲基 -5-(2-***啉 -4-基-乙基) -5,6，7,8-四氢 -1H-吡咯并 [3，2-c] 吖庚因 2-(5-Chloro-2-oxo-1,2-dihydro-indol-3-methylmethyl)-3-methyl-5-(2-morphinolin-4-yl-ethyl)-5 ,6,7,8-tetrahydro-1H-pyrrolo[3,2-c] azepine

第一歩

First

3-甲基 -5-[3-(2-***啉 -4-基-乙氨基) -丙基 ]-1Η-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯室温下，将本发明实施例 1第六步所得化合物 5-(3-甲磺酰氧-丙基) -3-甲基 -1H- 吡咯 -2，4-二羟酸 2-叔丁酯 4-乙酯 lg(5.812 g, 15 mmol)和 2-***啉 -4-基 -乙胺 (10.725 g, 82.5 mmol)于 30Ό水浴中搅拌至溶解，继续于室温下搅拌 5.5小时，点板表明原料反应完全，停止反应。向反应液中加入 100 ml乙酸乙酯和 100 ml饱和氯化钠，搅拌 5分钟后分层萃取。合并有机相，有机相用饱和氯化钠洗涤 (100 ml X 4)，无水硫酸镁干燥，抽滤除去千燥剂，滤液浓缩后柱层析得到标题产物 3-甲基 -5-[3-(2-***啉 -4-基-乙氨基) -丙基 ]-1Η-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 10a(2.238 g, 浅黄色油状物)，产率： 87 %。 3-methyl-5-[3-(2-morpholine-4-yl-ethylamino)-propyl]-1Η-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester at room temperature The compound obtained in the sixth step of the first embodiment of the present invention is 5-(3-methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-B. The ester lg (5.812 g, 15 mmol) and 2-morphinolin-4-yl-ethylamine (10.725 g, 82.5 mmol) were stirred in a 30 Torr water bath until dissolved, and the mixture was stirred at room temperature for 5.5 hours. , stop the reaction. 100 ml of ethyl acetate and 100 ml of saturated sodium chloride were added to the reaction mixture, and the mixture was stirred for 5 minutes and then extracted with a layer. The combined organic phases were washed with saturated sodium chloride (100 mL EtOAc) -(2-morpholine-4-yl-ethylamino)-propyl]-1Η-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 10a (2.238 g, pale yellow oil) Yield: 87%.

MS m/z (ESI): 424.9(M+1)。第, _~ "步 MS m/z (ESI): 424.9 (M + 1). First, _~ "step

3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1,4,5,6,7,8-六氢 -B比咯并 [3,2-c] 吖庚因 -2-羧酸叔丁酯 3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-B than s-[3,2- c] tert-butyl 2-carboxylic acid tert-butyl ester

氩气氛下，将 3-甲基 -5-[3-(2-***啉 -4-基 -乙氨基)-丙基] -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 10a(2.238 g， 5.29 mmol)搅拌下溶解于 50 ml甲苯中，缓慢加入三甲基铝的甲苯溶液 (3.9 ml， 2 mol/L, 7.9 rnmol)。反应体系于室温下搅拌 30分钟至瓶内不再有白烟，继续于油浴中回流 3小时。点板表明原料反应完全，撤去油浴，向反应液中加入少量水淬灭反应。反应液用稀氢氧化钠 (2 mol/L)调节 pH至 8〜10 左右，加入 50 ml饱和氯化钠，用乙酸乙酯萃取 (50 ml X 3)。合并有机相，用硅藻土抽滤，滤液减压浓缩得到标题产物 3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1,4,5，6,7，8-六氢-吡咯并[3,2-(；] 吖庚因 -2-羧酸叔丁酯 10b(1.218 g, 浅黄色固体)，产率： 61 %。 3-methyl-5-[3-(2-morphinolin-4-yl-ethylamino)-propyl]-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4 under argon atmosphere Ethyl ester 10a (2.238 g, 5.29 mmol) was dissolved in 50 ml of toluene with stirring, and a toluene solution of trimethylaluminum (3.9 ml, 2 mol/L, 7.9 rnmol) was slowly added. The reaction system was stirred at room temperature for 30 minutes until no more white smoke was present in the bottle, and the mixture was refluxed for 3 hours in an oil bath. The dot plate indicates that the starting material is completely reacted, the oil bath is removed, and a small amount of water is added to the reaction solution to quench the reaction. The reaction solution was adjusted to pH 8 to 10 with dilute sodium hydroxide (2 mol/L), 50 ml of saturated sodium chloride was added, and ethyl acetate (50 ml X 3 ) was applied. The combined organic phases were filtered with EtOAc EtOAc (EtOAc)EtOAc. 6,7,8-Hexahydro-pyrrolo[3,2-(;] azetidine-2-carboxylic acid tert-butyl ester 10b (1.218 g, pale yellow solid), yield: 61%.

MS m/z (ESI): 378.2(M+1)。第三步 ' MS m/z (ESI): 378.2 (M+1). third step'

3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]吖gyne-2-carbaldehyde

冰浴下，将 3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-羧酸叔丁酯 10b(725 mg， 1.92 mmol)搅拌下溶解于三氟醋酸 (2.6 ml, 34.2 mmol)中。反应体系于 4(TC水浴中搅拌 5分钟后再于冰浴中搅拌至温度降至 -5 °C，一次性加入甲酸三乙酯 (0.42 ml， 2.5 mmol), 搅拌 2分钟。撤去冰盐浴，反应液温度自然升至室温，反应液呈褐色，继续搅拌约 2小时。点板表明原料反应完全，向反应体系中加入少量水淬灭反应。反应液用稀氢氧化钠 (2 mol/L)调节 pH至 8左右，用二氯甲烷萃取 (50 mlX 3)，合并有机相，减压浓缩得到红褐色固体。固体柱层析得到标题产物 3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1,4,5,6,7,8-六氢 -P比咯并 [3,2-c] 吖庚因 -2-甲醛 10c(240 mg，浅黄色固体)，产率： 40%。 3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3] , 2-c] azepine-2-carboxylate tert-butyl ester 10b (725 mg, 1.92 mmol) was dissolved in trifluoroacetic acid (2.6 ml, 34.2 mmol). The reaction system was stirred in a 4 (TC water bath for 5 minutes and then stirred in an ice bath until the temperature dropped to -5 ° C. Triethyl formate (0.42 ml, 2.5 mmol) was added in one portion and stirred for 2 minutes. The temperature of the reaction solution naturally rises to room temperature, the reaction solution is brown, and stirring is continued for about 2 hours. The plate indicates that the reaction of the starting material is complete, and a small amount of water is added to the reaction system to quench the reaction. The reaction solution is diluted with sodium hydroxide (2 mol/L). The pH was adjusted to about 8 and extracted with dichloromethane (50 ml×3). 4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-P-pyrolo[3,2-c]azepine-2-carbaldehyde 10c (240 mg , pale yellow solid), Yield: 40%.

MS m/z (ESI): 306·3(Μ+1)。第四步 MS m/z (ESI): 306·3 (Μ +1). the fourth step

2-(5-氯 -2-氧代 -1，2-二氢 -吲哚 -3-次甲基 )-3-甲基 -5-(2-***啉 -4-基-乙基) -5,6,7，8-四氢 -1Η-吡咯并 [3,2-c] 吖庚因 -4-酮 2-(5-Chloro-2-oxo-1,2-dihydro-indol-3-methyl)-3-methyl-5-(2-morphinolin-4-yl-ethyl)- 5,6,7,8-tetrahydro-1Η-pyrrolo[3,2-c]azepine-4-one

室温下，将 3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 10c(53 mg， 0.174 mmol)和 5-氯 -1,3-二氢 -吲哚 -2-酮 (29 mg， 0.174 mmol)搅拌下溶解于 0.9 ml乙醇中。加入六氢吡啶 (0.1 ml, l.O mniol), 于油浴中加热回流 2小时。反应体系中有大量固体析出，撤去油浴，反应体系温度自然冷却至室温，抽滤，得到标题产物 2-(5-氯 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-3-甲基 -5-(2- ***啉基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 10(30 mg，红色固体)，产率： 38%。 3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3, at room temperature 2-c] azepine-2-carbaldehyde 10c (53 mg, 0.174 mmol) and 5-chloro-1,3-dihydro-indol-2-one (29 mg, 0.174 mmol) dissolved in 0.9 ml with stirring In ethanol. Hexahydropyridine (0.1 ml, 1.0 nmniol) was added and the mixture was heated to reflux for 2 hours in an oil bath. A large amount of solids precipitated in the reaction system, the oil bath was removed, the temperature of the reaction system was naturally cooled to room temperature, and suction filtered to give the title product 2-(5-chloro-2-oxo-1,2-dihydro-indole-3- Hypomethyl)-3-methyl-5-(2-morphinolinyl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4 - Ketone 10 (30 mg, red solid), Yield: 38%.

MS m/z (ESI): 455.2(M+1)。 MS m/z (ESI): 455.2 (M + 1).

¹HNMR(400 MHz, DMSO-d6) δ 13.682(s, 1H,吡咯环 -NH)， 11.009(s, 1H,吲哚 -NH)， 7.992~7.997(d, 1H, -ArH), 7.804(s, 1H, -CH=C), 7.138~7.164(dd, 1H, -ArH)， 6.873~6.894(d, 1H, -ArH) , 3.572~3.583(m, 6H, 七环接氮 -CH₂, 2 X -CH₂0) , 3.346~3.360(t, 2H,七环外接酰胺氮 -CH₂), 2.938~2.974(t, 2H, -CH₂C=C), 2.463 (s, 3H，吡咯环 -CH₃)， 2.438~2.510(m, 6H, 2 X -CH₂N), 2.054-2.083 (m, 2H,七环内 ¹ H NMR (400 MHz, DMSO-d6) δ 13.682 (s, 1H, pyrrole ring-NH), 11.009 (s, 1H, 吲哚-NH), 7.992-7.997 (d, 1H, -ArH), 7.804 (s , 1H, -CH=C), 7.138~7.164(dd, 1H, -ArH), 6.873~6.894(d, 1H, -ArH) , 3.572~3.583(m, 6H, seven-ring nitrogen-CH ₂ , 2 X -CH ₂ 0) , 3.346~3.360 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.938~2.974 (t, 2H, -CH ₂ C=C), 2.463 (s, 3H, pyrrole ring - CH ₃ ), 2.438~2.510(m, 6H, 2 X -CH ₂ N), 2.054-2.083 (m, 2H, seven rings

实施例 11 Example 11

2-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-3-甲基 -5-(2-***啉 -4-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 8 001352 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methylmethyl)-3-methyl-5-(2-morphinolin-4-yl-ethyl)- 5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one 8 001352

重复本发明实施例 10第四步反应，不同的是使用实施例 10第三步中所得到的化合物 3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1,4,5,6,7，8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 10c和 5-氟 -1,3-二氢 -Π引哚 -2-酮作原料，得到标题产物 2-(5-氟 -2-氧代 -1,2- 二氢 -吲哚 -3-次甲基 )-3-甲基 -5-(2-***啉 -4-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3，2-c] 吖庚因 -4-酮 11(29 mg，土黄色固体)，产率： 51.5 %。

The fourth step reaction of Example 10 of the present invention was repeated except that the compound obtained in the third step of Example 10 was used. 3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo Generation-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c and 5-fluoro-1,3-dihydro-indole- 2-ketone as starting material to give the title product 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methylmethyl)-3-methyl-5-(2-morpholine -4-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 11 (29 mg, yello solid), yield : 51.5 %.

MS m/z (ESI): 439.3(M+l MS m/z (ESI): 439.3 (M+l

¹HNMR(400 MHz, DMSO-d6) δ 13.727(s, 1H，吡咯环 -NH)， 10.908(s， IH,吲哚 -NH), 7.756~7.785(dd, IH, -ArH), 7.746(s, IH, -CH=C)， 6.917~6.968(m, IH, -ArH), 6.838~6.871(m, 1H， -ArH) , 3.571-3.600 (m, 6H, 七环接氮 -CH₂, 2 X -CH₂0)， 3.344-3.371 (t, 2H,七环外接酰胺氮 -CH₂)， 2.934~2.971(t, 2H, -CH₂C=C), 2.454(s, 3H,吡咯环 _C¾)， 2.438〜2.510(m, 6H, 2 X - CH₂N)， 2.053-2.082 (m, 2H,七环内 -CH 实施例 12 ¹ H NMR (400 MHz, DMSO-d6) δ 13.727 (s, 1H, pyrrole ring-NH), 10.908 (s, IH, 吲哚-NH), 7.756~7.785 (dd, IH, -ArH), 7.746(s , IH, -CH=C), 6.917~6.968(m, IH, -ArH), 6.838~6.871(m, 1H, -ArH) , 3.571-3.600 (m, 6H, heptacyclic nitrogen-CH ₂ , 2 X -CH ₂ 0), 3.344-3.371 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.934~2.971 (t, 2H, -CH ₂ C=C), 2.454 (s, 3H, pyrrole ring _ C3⁄4), 2.438~2.510 (m, 6H, 2 X - CH ₂ N), 2.053-2.082 (m, 2H, seven-ring-CH) Example 12

2-[4-(2,3-二氟-苯基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-3-甲基 -5-(2-***啉 -4-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3 2-[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-3-methyl-5-(2-morphine -Phenyl-4-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3

重复本发明实施例 10第四步反应，不同的是使用实施例 10第三步中所得到的化合物 3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1,4，5,6,7,8-六氢 -P比咯并 [3,2-c] 吖庚因 -2-甲醛 10c和本发明实施例 6第三步中所得到的化合物 4-(2,3-二氟-苯基) -1，3- 二氢 -吲哚 -2_酮 6d作原料，得到标题产物 2-[4-(2,3-二氟-苯基) -2-氧代 -1，2-二氢-吲哚 -3-次甲基 ]-3-甲基 -5-(2-***啉 -4-基-乙基) -5,6，7，8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-S 12(20 mg, 土黄色固体)，产率： 29%。 - MS m/z (ESI): 533.3(M+1)₀ T N2008/001352 iHNMRWOO MHz, DMSO-d6) δ 13.546(s, IH,吡咯环 -NH)， 11.135(s, IH, 吲哚 -NH)， 7.598~7.662(m, IH, -ArH), 7.409-7.46 l(m, 1H， -ArH), 7.306~7.343(m, IH, -ArH), 7.234~7.273(m, IH, -ArH), 6.700-7.019(d, IH, -ArH), 6.875~6.894(d, IH, -ArH), 6.712(s, IH, -CB C), 3.547~3.560(m, 6H, 七环接氮 -CH₂, 2 X -CH₂0), 3.295-3.310(t, 2H, 七环外接酰胺氮 -CH₂)， 2.897~2.933(t, 2H, -CH₂C=C)， 2.410~2.510(m, 6H, 2X-CH₂N), 1.999-2.061 (m, 2H_;七环内 - C¾)， 1.794(s, 3¾吡咯环 -CH₃)₀ 实施例 13

The fourth step reaction of Example 10 of the present invention was repeated except that the compound obtained in the third step of Example 10 was used. 3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo Generation-1,4,5,6,7,8-hexahydro-P-pyrolo[3,2-c]azepine-2-carbaldehyde 10c and the compound obtained in the third step of Example 6 of the present invention 4-(2,3-Difluoro-phenyl)-1,3-dihydro-indole-2-one 6d was used as the starting material to give the title product 2-[4-(2,3-difluoro-phenyl). -2-oxo-1,2-dihydro-indol-3-ylmethyl]-3-methyl-5-(2-morphinolin-4-yl-ethyl)-5,6,7, 8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-S 12 (20 mg, EtOAc). Yield: 29%. - MS m/z (ESI): 533.3(M+1) ₀ </ RTI></RTI></RTI><RTIgt; 7.46 l(m, 1H, -ArH), 7.306~7.343(m, IH, -ArH), 7.234~7.273(m, IH, -ArH), 6.700-7.019(d, IH, -ArH), 6.875~6.894 (d, IH, -ArH), 6.712(s, IH, -CB C), 3.547~3.560 (m, 6H, heptacyclic nitrogen-CH ₂ , 2 X -CH ₂ 0), 3.295-3.310 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.897~2.933(t, 2H, -CH ₂ C=C), 2.410~2.510(m, 6H, 2X-CH ₂ N), 1.999-2.061 (m, 2H _; inner heptacyclo - C¾), 1.794 (s, 3¾ pyrrole ring -CH ₃₎ ₀ Example 13

2-(4-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-5-(2-二乙氨基-乙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4- 2-(4-Bromo-2-oxo-1,2-dihydro-indol-3-methyl)-5-(2-diethylamino-ethyl)-3-methyl-5,6 ,7,8-tetrahydro-1H-pyrrolo[3,2-c] azepine-4-

重复本发明实施例 1第十步反应，不同的是使用实施例 1第九步中所得到的化合物 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 甲醛 lj和 4-溴 -1,3-二氢 -Π引哚 -2-酮作原料，得到标题产物 2-(4-溴 -2-氧代 -1,2-二氢- B引哚 -3-次甲基 )-5-(2-二乙氨基-乙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 13(30 mg, 桔黄色固体)，产率： 45.5%

The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used. ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-formaldehyde lj and 4-bromo-1,3-dihydro-indole-2-one As a starting material, the title product 2-(4-bromo-2-oxo-1,2-dihydro-B-indole-3-methylol)-5-(2-diethylamino-ethyl)-3 was obtained. -methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 13 (30 mg, orange solid), Yield: 45.5%

MS m/z (ESI): 585.1(M+1)。 MS m/z (ESI): 585.1 (M+1).

1HNMR(400 MHz, DMSO-d6) δ 13.634(s, IH,吡咯环 -NH)， 11.184(s, IH, 吲哚 -NH)， 8.589(s, IH, -CH=C), 7.220~7.240(d, IH, -ArH), 7.056~7.096(m, IH, -ArH), 6.938~6.957(d, IH，- ArH), 3.491~3.524(t, 2H,七环内 -CH₂N)， 3.346~3.373(t, 2H,七环外接酰胺氮 -CH₂)， 2.930~2.966(t, 2H,七环内 -CH₂C=C)， 2.508~2.569(m, 6H, 3 X -CH₂N)， 2.412(s, 3H, 吡咯环 -CH₃)， 2.030~2.095(m, 2H, 七环内 -CH₂)， 0.959~0.994(t, 6H, 2 X -CH₃)。实施例 14 1H NMR (400 MHz, DMSO-d6) δ 13.634 (s, IH, pyrrole ring-NH), 11.184 (s, IH, 吲哚-NH), 8.589 (s, IH, -CH=C), 7.220~7.240 ( d, IH, -ArH), 7.056~7.096(m, IH, -ArH), 6.938~6.957(d, IH,-ArH), 3.491~3.524(t, 2H, hepta-CH ₂ N), 3.346 ~3.373(t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.930~2.966 (t, 2H, hepta-CH ₂ C=C), 2.508~2.569 (m, 6H, 3 X -CH ₂ N ), 2.412 (s, 3H, pyrrole ring-CH ₃ ), 2.030 to 2.095 (m, 2H, hepta-CH ₂ ), 0.959 to 0.994 (t, 6H, 2 X -CH ₃ ). Example 14

2-(5-溴 -2-氧代 -1,2-二氢-吡咯并 [2,3-b]嘧啶 -3-次甲基 )-5-(2- -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因酮 2-(5-Bromo-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyrimidin-3-methyl)-5-(2- -5,6,7,8 -tetrahydro-1H-pyrrolo[3,2-c]azepine

重复本发明实施例 1第十步反应，不同的是使用实施例 1第九步中所得到的化合物 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢 -P比咯并 [3，2-c] 吖庚因 -2- 甲醛 lj和 5-溴 -1,3-二氢-吡咯并 [2,3-b]嘧啶 -2-酮作原料，得到标题产物 2-(5-溴 -2- 氧代 -1，2-二氢-吡咯并 [2,3-b]嘧啶 -3-次甲基 )-5-(2-二乙氨基-乙基) -3-甲基 -5，6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 14(23 mg，桔黄色固体)，产率： 33.8%。

The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used. , 4,5,6,7,8-hexahydro-P is more than [3,2-c] azepine-2-carbaldehyde lj and 5-bromo-1,3-dihydro-pyrrolo[2, 3-b]pyrimidin-2-one as starting material to give the title product 2-(5-bromo-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyrimidin-3-methylmethyl -5-(2-Diethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 14 (23 mg, orange solid), Yield: 33.8%.

MS m/z (ESI): 486·2(Μ+1)。 MS m/z (ESI): 486·2 (Μ +1).

^!HNMR(400 MHz, DMSO-d6) δ 13.472(s, 1H，吡咯环 -NH)， 11.636(s, IH, 吲哚 -NH), 8.487(s, 1H，吡啶环 -CH)， 8.116(s, IH, 吡啶环 -CH)， 7.889(s, IH, -CH=C), 3.505(t, 2H,七环内 -CH₂N)， 3.354(t, 2H,七环外接酖胺氮 -CH₂)， 2.930~2.966(t, 2H, 七环内 -CH₂C=C)， 2.508~2.569(m, 6H, 3 X -C¾N)， 2.472(s, 3H, 吡咯环 -CH₃)， 2.030~2.095(ra, 2H,七环内 -CH₂)， 0.959~0.994(t, 6H, 2 X -CH₃)。实施例 15 ^{! HNMR (400 MHz, DMSO-} d6) δ 13.472 (s, 1H, pyrrole ring -NH), 11.636 (s, IH , indole -NH), 8.487 (s, 1H , pyridine ring -CH), 8.116 (s , IH, pyridine ring-CH), 7.889 (s, IH, -CH=C), 3.505 (t, 2H, hepta-CH ₂ N), 3.354 (t, 2H, heptacyclic external guanamine nitrogen-CH ₂ ), 2.930~2.966(t, 2H, hepta-CH ₂ C=C), 2.508~2.569(m, 6H, 3 X -C3⁄4N), 2.472(s, 3H, pyrrole ring-CH ₃ ), 2.030 ~2.095 (ra, 2H, hepta-CH ₂ ), 0.959~0.994 (t, 6H, 2 X -CH ₃ ). Example 15

5-(2-二乙氨基 -乙基 )-2-(6-甲氧基 -2-氧代 -1 ,2-二氢-吲哚 -3-次甲基) -3-甲基 -5,6,7,8- 四氢 -1H-吡咯并 [3，2-c] 吖庚 -4-酮 5-(2-diethylamino-ethyl)-2-(6-methoxy-2-oxo-1,2-dihydro-indol-3-methyl)-3-methyl-5 ,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]pyridin-4-one

重复本发明实施例 1第十步反应，不同的是使用实施例 1第九步中所得到的化合物 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1，4,5,6,7，8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 甲醛 lj和 6-甲氧基 -1 ,3-二氢 -吲哚 -2-酮作原料，得到标题产物 5-(2-二乙氣基-乙基) -2-(6-甲氧基 -2-氧代 -1 ,2-二氢 -吲哚 -3-次甲基 )-3-甲基 -5，6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 15(31 mg，红色固体)，产率： 52.7%

The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used. ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-formaldehyde lj and 6-methoxy-1,3-dihydro-indole-2- The ketone was used as a starting material to give the title product 5-(2-diethyl-ethyl-ethyl)-2-(6-methoxy-2-oxo-1,2-dihydro-indole-3-methine )-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 15 (31 mg, red solid), Yield: 52.7%

MS m/z (ESI): 437.4(M+1)。 MS m/z (ESI): 437.4 (M + 1).

'HNMR(400 MHZ, DMSO-d6) δ 13.466(s, IH,吡咯环 -NH)， 10.852(s， IH,吲哚 -NH), 7.670-7.69 l(d, IH, -ArH), 7.496(s, IH, - CH=C)， 6.575~6.596(d, IH, -ArH), 6.463(s, IH, -ArH) , 3.769((s, 3H， -CH₃)， 3.477-3.510(t, 2H，七环内 -CH₂N)， 3.316-3.347(t, 2H,七环外接酰胺氮 -CH₂)， 2.888~2.924(t, 2H,七环内 -CH₂C=C)， 2.489~2.573(m, 6H, 3 X-CH₂N), 2.416(s, 3H,吡咯环 -CH₃)， 2.030~2.095(m, 2H,七环内 -CH₂)， 0.954~0.982(t, 6H, 2 X -CH₃)。实施例 16 'HNMR (400 MHZ, DMSO-d6) δ 13.466 (s, IH, pyrrole ring-NH), 10.852 (s, IH, 吲哚-NH), 7.670-7.69 l (d, IH, -ArH), 7.496 ( s, IH, - CH=C), 6.575~6.596(d, IH, -ArH), 6.463(s, IH, -ArH), 3.769((s, 3H, -CH ₃ ), 3.477-3.510(t, 2H, within the seven-ring -CH ₂ N), 3.316-3.347(t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.888~2.924 (t, 2H, hepta-CH ₂ C=C), 2.489~2.573 (m, 6H, 3 X-CH ₂ N), 2.416 (s, 3H, pyrrole ring-CH ₃ ), 2.030 to 2.095 (m, 2H, hepta-CH ₂ ), 0.954 to 0.982 (t, 6H, 2 X -CH ₃ ). Example 16

5-(2-二乙氨基-乙基) -3-甲基 -2-(4-甲基 -2-氧代 -1,2-二氢』引哚 -3-次甲基 )-5，6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 - -酮 5-(2-diethylamino-ethyl)-3-methyl-2-(4-methyl-2-oxo-1,2-dihydro)indol-3-ylmethyl)-5, 6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-ketone

重复本发明实施例 1第十步反应，不同的是使用实施例 1第九步中所得到的化合物 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5，6，7,8-六氢 -P比咯并 [3,2-c] 吖庚因 -2- 甲醛 lj和 4-甲基 -1,3-二氢 -吲哚 -2-酮作原料，得到标题产物 5-(2-二乙氨基-乙基) -3- 甲基 _2-(4-甲基 -2-氧代 -1,2-二氢 -H引哚 -3-次甲基 )-5,6,7，8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 16(25 mg，黄色固体)，产率： 44.1 %。

The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used. ,4,5,6,7,8-hexahydro-P-pyrolo[3,2-c]azepine-2-formaldehyde lj and 4-methyl-1,3-dihydro-indole-2 - Ketone as starting material to give the title product 5-(2-diethylamino-ethyl)-3-methyl-2-(4-methyl-2-oxo-1,2-dihydro-H-indole- 3-methine)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 16 (25 mg, yellow solid), Yield: 44.1 % .

MS m/z (ESI): 421.5(M+1)。 MS m/z (ESI): 421.5 (MI).

¹HNMR(400 MHz, DMSO-d6) δ 13.710(s, 1H，吡咯环 -NH)， 10.927(s, IH, 吲哚 -NH)， 7.566(s, IH, -CH=C), 7.034~7.072(m, IH, -ArH), 6.768~6.835(dd, 2H, -ArH), 3.483~3.517(t, 2H, 七环内 -CH₂N)， 3.339~3.366(t, 2H, 七环外接酰胺氮 -CH₂)， 2.909〜2.946(t, 2H，七环内 -CH₂C=C)， 2.489~2.573(m, 6H, 3 X -CH₂N), 2.590(s, 3H, 苯环 -CH₃)， 2.386(s, 3H, 吡咯环 -CH₃)， 2.041~2.069(m, 2H, 七环内 -CH₂)， 0.956-0.99 l(t, 6H, 2 X -CH₃) o 实施例 17 ¹ H NMR (400 MHz, DMSO-d6) δ 13.710 (s, 1H, pyrrole ring-NH), 10.927 (s, IH, 吲哚-NH), 7.566 (s, IH, -CH=C), 7.034~7.072 (m, IH, -ArH), 6.768~6.835(dd, 2H, -ArH), 3.483~3.517(t, 2H, hepta-CH ₂ N), 3.339~3.366(t, 2H, heptacyclic external amide Nitrogen-CH ₂ ), 2.909~2.946 (t, 2H, hepta-CH ₂ C=C), 2.489~2.573 (m, 6H, 3 X -CH ₂ N), 2.590 (s, 3H, benzene ring - CH ₃ ), 2.386 (s, 3H, pyrrole ring-CH ₃ ), 2.041~2.069 (m, 2H, hepta-CH ₂ ), 0.956-0.99 l(t, 6H, 2 X -CH ₃ ) o Example 17

5-(2-二乙氨基-乙基) -2-[4-(2-羟基-乙基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-3-甲基 -5,6，7,8-四氢 -1H-吡咯并 [3,2-c] -4-酮 5-(2-diethylamino-ethyl)-2-[4-(2-hydroxy-ethyl)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-3 -methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]-4-one

重复本发明实施例 1第十步反应，不同的是使用实施例 1第九步中所得到的化合物 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4，5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 甲醛 lj和 4-(2-羟基-乙基) -1,3-二氢 -吲哚 -2-酮作原料，得到标题产物 5-(2-二乙氨基 -乙基 )-2-[4-(2-羟基-乙基) -2-氧代 -1，2-二氢』引哚 -3-次甲基 ]-3-甲基 -5,6,7,8-四氢 -1H- 吡咯并 [3,2-c] 吖庚因 -4-酮 17(18 mg，黄色固体)，产率： 29.5 %。

The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used. ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-formaldehyde lj and 4-(2-hydroxy-ethyl)-1,3-dihydro- Indole-2-one was used as a starting material to give the title product 5-(2-diethylamino-ethyl)-2-[4-(2-hydroxy-ethyl)-2-oxo-1,2-dihydro哚-3-Methyl-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one 17 (18 mg, Yellow solid), Yield: 29.5 %.

MS m/z (ESI): 451.5(M+1)。 MS m/z (ESI): 451.5 (M+1).

^!ΗΝΜΚ(400 MHz, DMSO-d6) δ 13.722(s, 1H,吡咯环 -NH)， 10.924(s, 1H,吲哚 -NH), 7.652(s， 1H, -CH=C), 7.045~7.065(m, 1H, -ArH), 6.772~6.847(dd, 2H, -ArH), 4.871 (s, 1H, -OH), 3.726-3.739(1, 2H,七环外接酰胺氮 -CH₂0)， 3.486~3.502(t, 2H, 七环内 -CH₂N)， 3.342~3.556(t, 2H, -CH₂)， 3.095(t, 2H,苯环 -CH₂)， 2.910-2.946(t, 2H, 七环内 -CH₂C=C)， 2.504~2.566(m, 6H, 3 X -CH₂N), 2.398(s, 3H, 吡咯环 -CH₃)， 2.092(m, 2H,七环内 -CH₂)， 0.957~0.993(t, 6H, 2 X -CH₃)。实施例 18 ^{! ΗΝΜΚ (400 MHz, DMSO-} d6) δ 13.722 (s, 1H, pyrrole ring -NH), 10.924 (s, 1H , indole -NH), 7.652 (s, 1H , -CH = C), 7.045 ~ 7.065 (m, 1H, -ArH), 6.772~6.847(dd, 2H, -ArH), 4.871 (s, 1H, -OH), 3.726-3.739 (1, 2H, heptacyclic external amide nitrogen-CH ₂ 0), 3.486~3.502(t, 2H, hepta-CH ₂ N), 3.342~3.556(t, 2H, -CH ₂ ), 3.095(t, 2H, phenyl ring-CH ₂ ), 2.910-2.946(t, 2H , in the seven-ring, -CH ₂ C=C), 2.504~2.566 (m, 6H, 3 X -CH ₂ N), 2.398 (s, 3H, pyrrole ring -CH ₃ ), 2.092 (m, 2H, within the seven-ring -CH ₂ ), 0.957~0.993 (t, 6H, 2 X -CH ₃ ). Example 18

N-{5-氟 -3-[3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1,4,5,6,7,8-六氢 -P比咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2, -乙酰胺 N-{5-fluoro-3-[3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro -P is more than [3,2-c] azepine-2-methyl]-2-oxo-2, -acetamide

重复本发明实施例 10第四步反应，不同的是使用实施例 10第三步中所得到的化合物 3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 10c和本发明实施例 7第一步所得化合物 N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基) -2-甲氧-乙酰胺 7a作原料，得到标题产物 N-{5-氟 -3-[3-甲基 -5-(2-***啉 -4- 基-乙基) -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚- 6-基}-2-甲氧-乙酰胺 18(47 mg，棕黄色固体)，产率： 60%。

The fourth step reaction of Example 10 of the present invention was repeated except that the compound obtained in the third step of Example 10 was used. 3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo Generation-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c and the compound N-(5- obtained in the first step of Example 7 of the present invention fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide 7a as the starting material to give the title product N-{5-fluoro-3-[3- Methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c] 2-methylidene-2-oxo-2,3-dihydro-1H-indole-6-yl}-2-methoxy-acetamide 18 (47 mg, brown solid) : 60%.

MS m/z (ESI): 526.1(M+1)。 MS m/z (ESI): 526.1 (M+1).

1HNMR(400 MHz, DMSO-d6) δ 13.608(s, 1H，吡咯环 -NH)， 10.884(s, 1H, 吲哚 -NH), 9.308(s_; 1H, -NHCO), 7.827~7.854(d, 1H, -ArH), 7.659(s, 1H, -CH=C), 7.534〜7.550(d, 1H, -ArH), 4.056(s, 2H, -CH₂0) , 3.561~3.571(m, 6H,七环接氮 -CH₂, 2 X -CH₂0), 3.397(s, 3H, -CH₃0)， 3.331~3.345(t, 2H,七环外接酰胺氮 -CH₂)， 2.918~2.954(t, 2H, -CH₂C=C), 2.432(s, 3H, 吡咯环 -CH₃)， 2.431~2.500(m, 6H, 2 X-CH₂N), 2.040-2.067 (m, 2H,七环内 -CH₂)。 2008 001352 实施例 19 1H NMR (400 MHz, DMSO-d6) δ 13.608 (s, 1H, pyrrole ring-NH), 10.884 (s, 1H, 吲哚-NH), 9.308 (s _; 1H, -NHCO), 7.827~7.854 (d, 1H, -ArH), 7.659(s, 1H, -CH=C), 7.534~7.550(d, 1H, -ArH), 4.056(s, 2H, -CH ₂ 0) , 3.561~3.571(m, 6H, Hexacyclic nitrogen-CH ₂ , 2 X -CH ₂ 0), 3.397 (s, 3H, -CH ₃ 0), 3.331~3.345 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.918~2.954 ( t, 2H, -CH ₂ C=C), 2.432(s, 3H, pyrrole ring-CH ₃ ), 2.431~2.500(m, 6H, 2 X-CH ₂ N), 2.040-2.067 (m, 2H, seven Within the ring -CH ₂ ). 2008 001352 Example 19

2-[5-氟 -6-(4-氟-苄氨基) -2-氧代 -1,2-二氢』引哚 -3-次甲基 ]-3-甲基 -5-(2-***啉 -4-基- 乙基) -5，6,7,8-四氢 -1H-吡咯 2-[5-fluoro-6-(4-fluoro-benzylamino)-2-oxo-1,2-dihydroindol-3-indolyl-3-methyl-5-(2- Morpholino-4-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrole

重复本发明实施例 10第四歩反应，不同的是使用实施例 10第三步中所得到的化合物 3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 10c和本发明实施例 3第四步所得化合物 5-氟 -6-(4-氟- 氨基) -1,3-二氢- ^[哚 -2-酮 3e作原料，得到标题产物 2-[5-氟 -6-(4-氟-苄氨基) -2-氧代 -1，2-二氢 -吲哚 -3-次甲基 ]-3-甲基 -5-(2-***啉 -4-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3，2-c] 吖庚因 -4-S 19(57 mg, 深红色固体)，产率： 69%。

The fourth hydrazine reaction of Example 10 of the present invention was repeated except that the compound obtained in the third step of Example 10 was used. 3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo Generation-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 10c and compound 5-fluoro-6 obtained in the fourth step of Example 3 of the present invention -(4-Fluoro-amino)-1,3-dihydro-^[indol-2-one 3e as the starting material to give the title product 2-[5-fluoro-6-(4-fluoro-benzylamino)-2- Oxo-1,2-dihydro-indol-3-ylmethyl]-3-methyl-5-(2-morphinolin-4-yl-ethyl)-5,6,7,8-tetra Hydrogen-1H-pyrrolo[3,2-c]azepine-4-S 19 (57 mg, dark red solid), Yield: 69%.

MS m/z (ESI): 562.1(M+1)。 MS m/z (ESI): 5621. (M+1).

1HNMR(400 MHz, DMSO-d6) δ 13.423 (s, 1H,吡咯环 -NH)， 10.515(s, 1H,吲哚 -NH)， 7.565~7.595(d, 1H, -ArH), 7.359-7.394(m, 2H, -ArH), 7.343(s， 1H，- CH=C)， 7.134-7.177(m, 1H, -ArH) , 6.404(m, 1H, -NH) , 6.032~3.051(d, 1H, -ArH) , 4.399~4.353(d, 2H,苯胺 -CH₂)， 3.544-3.555 (m, 6H,七环接氮 -CH₂, 2 X - C¾0)， 3.310~3.326(t, 2H,七环外接酰胺氮 -CH₂)， 2.870~2.906(t, 2H, -CH₂C=C), 2.378(s, 3H,吡咯环 - CH₃)， 2.416~2.500(m, 6H, 2 X ~CH₂N), 2.014-2.041 (m, 2H,七环内 — CH₂ 实施例 20 1H NMR (400 MHz, DMSO-d6) δ 13.423 (s, 1H, pyrrole ring-NH), 10.515 (s, 1H, 吲哚-NH), 7.565~7.595 (d, 1H, -ArH), 7.359-7.394 ( m, 2H, -ArH), 7.343(s, 1H, -CH=C), 7.134-7.177(m, 1H, -ArH) , 6.404(m, 1H, -NH) , 6.032~3.051(d, 1H, -ArH) , 4.399~4.353(d, 2H, aniline-CH ₂ ), 3.544-3.555 (m, 6H, heptacyclic nitrogen-CH ₂ , 2 X - C3⁄40), 3.310~3.326(t, 2H, seven rings Externally amide nitrogen-CH ₂ ), 2.870~2.906(t, 2H, -CH ₂ C=C), 2.378(s, 3H, pyrrole ring-CH ₃ ), 2.416~2.500(m, 6H, 2 X ~CH ₂ N), 2.014-2.041 (m, 2H, seven-ring - CH ₂ Example 20

N-{5-氟 -3-[3-甲基 -5-(2-***啉 -4-基-乙基)- 4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3- 酰胺 N-{5-fluoro-3-[3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro -pyrrolo[3,2-c]azepine-2-methylene]-2-oxo-2,3-amide

第一步 First step

5-氟 -7-硝基 -2-吲哚酮 5-fluoro-7-nitro-2-indanone

-5°C下，将 5-氟 -2-吲哚酮 4a(5.0 g， 33 mmol)加入到 17.6 ml硫酸 (98%)中，控制温度不超过 0°C，搅拌下加入 2.1 ml硝酸 (65%— 68%), 加毕，室温搅拌 1小时，点板跟踪至原料消失。将反应液加入冰中，待冰融化后过滤，滤饼用水洗 3 次，所得固体重结晶。此固体即为标题产物 5-氟 -7-硝基 -2-吲哚酮 20a(4.0 g，橙色晶体)，产率： 62.5 %。 5-Fluoro-2-indanone 4a (5.0 g, 33 mmol) was added to 17.6 ml of sulfuric acid (98%) at -5 ° C, the temperature was controlled to not exceed 0 ° C, and 2.1 ml of nitric acid was added with stirring ( 65% - 68%), after adding, stirring at room temperature for 1 hour, the point plate is tracked until the raw materials disappear. The reaction solution was added to ice, and after the ice was melted, it was filtered, and the filter cake was washed three times with water, and the obtained solid was recrystallized. This solid was the title product 5-fluoro-7-nitro-2-indanone 20a (4.0 g, orange crystal), yield: 62.5 %.

MS ni/z (ESI): 196.3(M+1)。第二步 MS ni/z (ESI): 196.3 (M+1). Second step

5-氟 -7-胺基 -2-吲哚酮 5-fluoro-7-amino-2-indanone

室温下，将 5-氟- 7-硝基 -2-吲哚酮 20a(4.0 g， 20 mmol)溶解于 200 ml乙酸中，加入钯 /碳 (5 % , 1.0 g)抽去空气后边搅拌边向反应体系中充入氢气，点板跟踪至原料消失，停止反应。反应液过滤，滤液减压浓缩，得到标题产物 5-氟 -7-胺基 -2-吲哚酮 20b(3.2 g，白色固体)，产率： 97.5 %。 5-Fluoro-7-nitro-2-indanone 20a (4.0 g, 20 mmol) was dissolved in 200 ml of acetic acid at room temperature, and palladium/carbon (5 %, 1.0 g) was added to remove air and then stirred. Hydrogen gas was charged into the reaction system, and the spot was traced until the raw material disappeared, and the reaction was stopped. The reaction mixture was filtered, and the~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~

MS m/z (ESI): 167.4(M+l 第三步 MS m/z (ESI): 167.4 (M+l third step

5-氟 -7-甲酰胺基 -2-吲哚酮 5-fluoro-7-carboxamido-2-indanone

室温下，将 0.8 ml乙酸酐及 0.6 ml甲酸混合搅拌 1小时。将 5-氟 -7-胺基 -2-吲哚酮 20b(2.0 g， 12 mmol)搅拌下溶解于 30 ml四氢呋喃中，加入到上述混和液中，再加入 0.02 ml六氢吡啶，反应 3小时有固体析出，过滤得产品 1.95 g，此固体用甲醇重结晶，得到标题产物 5-氟 -7-甲酰胺基 -2-吲哚酮 20c(700 mg，白色固体)，产率： 30.4%。 0.8 ml of acetic anhydride and 0.6 ml of formic acid were mixed and stirred for 1 hour at room temperature. 5-Fluoro-7-amino-2-indanone 20b (2.0 g, 12 mmol) was dissolved in 30 ml of tetrahydrofuran with stirring, added to the above mixture, and then added with 0.02 ml of hexahydropyridine for 3 hours. A solid was precipitated, and 1.95 g of the product was obtained. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

MS m/z (ESI): 195·1(Μ+1)。第四步 MS m/z (ESI): 195·1 (Μ +1). the fourth step

N-{5-氟 -3-[3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1,4,5,6,7,8-六氢 -P比咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -7-基}-甲酰胺 N-{5-fluoro-3-[3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro -P is more than [3,2-c] azepine-2-methyl]-2-oxo-2,3-dihydro-1H-indol-7-yl}-carboxamide

重复本发明实施例 10第四步反应，不同的是使用实施例 10第三步中所得到的化合物 3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1,4,5,6,7，8-六氢 -P比咯并 [3,2-c] 吖庚因 -2-甲醛 10c和 N-(5-氟 -2-氧代 -2,3-二氢- 1H-吲哚 -7-基)-甲酰胺 20c作原料，得到标题产物 N- { 5-氟 -3-[3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1 ,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -7-基}-甲酰胺 20(37 mg，桔黄色固体)，产率： 52%。 The fourth step reaction of Example 10 of the present invention was repeated except that the compound obtained in the third step of Example 10 was used. 3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo Generation-1,4,5,6,7,8-hexahydro-P-pyrolo[3,2-c]azepine-2-carbaldehyde 10c and N-(5-fluoro-2-oxo-2 , 3-dihydro-1H-indol-7-yl)-carboxamide 20c as the starting material to give the title product N-{ 5-fluoro-3-[3-methyl-5-(2-morpholine-4- -ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-methylene]-2-oxo -2,3-Dihydro-1H-indol-7-yl}-carboxamide 20 (37 mg, orange solid). Yield: 52%.

MS m/z (ESI)_: 480.2(M-1)。 MS m/z (ESI) _: 480.2 (MI).

^!ΗΝΜΚ(400 MHz, DMSO-d6) δ 13.655 (s, 1H,吡咯环 -NH), 10.424(s, 1H,吲哚 -NH)， 9.801(s, 1H, -NHCO)， 8.330(s, 1H, -CHO)， 7.757(s, 1H, -CH=C) , 7.610~7.633(d, 1H, -ArH)， 7.428-7.46 l(dd, 1H, -ArH), 3.562-3.592 (m, 6H,七环接氮 -CH₂, 2 X -CH₂0), 3.331~3.345(t, 2H,七环外接酰胺氮 -CH₂)， 2.935-2.971 (t, 2H, -CH₂C=C), 2.45 l(s, 3H,吡咯环 -CH₃)， 2.431~2.500(m, 6H, 2 X - CH₂N)， 2.046-2.074 (m, 2H,七环内 -CH₂)。实施例 21 ^{! ΗΝΜΚ (400 MHz, DMSO-} d6) δ 13.655 (s, 1H, pyrrole ring -NH), 10.424 (s, 1H , indole -NH), 9.801 (s, 1H , -NHCO), 8.330 (s, 1H , -CHO), 7.757(s, 1H, -CH=C) , 7.610~7.633(d, 1H, -ArH), 7.428-7.46 l(dd, 1H, -ArH), 3.562-3.592 (m, 6H, Hexacyclic nitrogen-CH ₂ , 2 X -CH ₂ 0), 3.331~3.345 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.935-2.971 (t, 2H, -CH ₂ C=C), 2.45 l(s, 3H, pyrrole ring-CH ₃ ), 2.431 to 2.500 (m, 6H, 2 X - CH ₂ N), 2.046-2.074 (m, 2H, hepta-CH ₂ ). Example 21

N- { 5-氟 -3 -[3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 - 1 ,4,5,6,7，8-六氢 -吡咯并 [3 ,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2 -丙酰胺 N- { 5-fluoro-3 -[3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro -pyrrolo[3,2-c]azepine-2-methylene]-2-oxo-2-propanamide

重复本发明实施例 10第四步反应，不同的是使用实施例 10第三步中所得到的化合物 3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1,4,5，6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲酸 10c和本发明实施例 8第二步所得化合物 N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基) -2-羟基-丙酰胺 8b作原料,得到标题产物 N-{5-氟 -3-[3-甲基 -5-(2-***啉 -4- 基-乙基) -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -6-基}-2-羟基-丙酰胺 21(44 mg，桔黄色固体)，产率： 58 %。

The fourth step reaction of Example 10 of the present invention was repeated except that the compound obtained in the third step of Example 10 was used. 3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo Generation-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxylic acid 10c and the compound N-(5- obtained in the second step of Example 8 of the present invention fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide 8b as the starting material to give the title product N-{5-fluoro-3-[3- 5-(2-morpholine-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c] azepine -2-Methylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-propionamide 21 (44 mg, orange solid), Yield: 58 %.

MS m z (ESI): 526.1(M+1)。 MS m z (ESI): 526.1 (M+1).

1HNMR(400 MHz, D SO-d6) δ 13.599(s, 1H,吡咯环 -NH)， 10.895(s, 1H,吲哚 -NH)， 9.236(s, 1H, -NHCO)， 7.846~7.874(d, 1H, -ArH), 7.718~7.734(d, 1H， -ArH), 7.663(s, 1H， -CH=C)， 6.051~6.064(d, 1H， -OH) , 4.199~4.229(t, 1H, -CHO) , 3.560-3.586 (m, 6H,七环接氮 -C¾, 2 X- CH₂0)， 3.331~3.345(t, 2H,七环外接酰胺氮 -CH₂)， 2.918~2.954(t, 2H, -CH₂C=C)， 2.456(s, 3H, 卩比咯环 -CH₃)， 2.431〜2.500(m, 6H, 2 X- C¾N)， 2.048-2.077 (m, 2H,七环内 - C¾), 1.321~1.338(d, 2H, -CH₃)。实施例 22 1H NMR (400 MHz, D SO-d6) δ 13.599 (s, 1H, pyrrole ring-NH), 10.895 (s, 1H, 吲哚 -NH), 9.236(s, 1H, -NHCO), 7.846~7.874(d, 1H, -ArH), 7.718~7.734(d, 1H, -ArH), 7.663(s, 1H, -CH=C), 6.051~6.064(d, 1H, -OH) , 4.199~4.229(t, 1H, -CHO) , 3.560-3.586 (m, 6H, seven-ring nitrogen-C3⁄4, 2 X-CH ₂ 0), 3.331~3.345 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.918~2.954 (t, 2H, -CH ₂ C=C), 2.456 (s, 3H, deuterium ring-CH ₃ ), 2.431~2.500 ( m, 6H, 2 X- C3⁄4N), 2.048-2.077 (m, 2H, hepta- C3⁄4), 1.321~1.338 (d, 2H, -CH ₃ ). Example 22

2-(5-溴 -2-氧代 -1,2-二氢-吡咯并 [2,3-b]嘧啶 -3-次甲基 )-3-甲基 -5-(2-***啉 -4-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [ 2-(5-Bromo-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyrimidin-3-methyl)-3-methyl-5-(2-morpholine- 4-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[

重复本发明实施例 10第四步反应，不同的是使用实施例 10第三步中所得到的化合物 3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1,4,5，6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲酸 10c和 5-溴 -1,3-二氢-吡咯并 [2，3-b]嘧啶 -2-酮作原料，得到标题产物 2-(5- 溴 -2-氧代 -1，2-二氢-吡咯并 [2,3-b]嘧啶 -3-次甲基 )-3-甲基 -5-(2-***啉 -4-基-乙基) -5,6,7，8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 22(59 mg，桔黄色固体)，产率： 60 %。

The fourth step reaction of Example 10 of the present invention was repeated except that the compound obtained in the third step of Example 10 was used. 3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo Generation-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxylic acid 10c and 5-bromo-1,3-dihydro-pyrrolo[2 , 3-b]pyrimidin-2-one as a starting material to give the title product 2-(5-bromo-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyrimidine-3-sub. 3-methyl-5-(2-morphinolin-4-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c] azepine- 4-ketone 22 (59 mg, orange solid), Yield: 60%.

MS m/z (ESI): 500·0(Μ+1)。 MS m/z (ESI): 500·0 (Μ +1).

]HNMR(400 MHZ, DMSO-d6) δ 13.474(s, 1H,吡咯环 -NH)， 11.004(s, 1H, 吲哚 -NH)， 8.475(d, 1H, 吡啶 -CH)， 8.102-8.107(d, 1H,吡啶 -CH), 7.873(s, 1H₅ -CH=C), 3.560-3.591 (m, 6H,七环接氮 -CH₂, 2 X -C¾0)， 3.336~3.364(t, 2H,七环外接酰胺氮 -CH₂)， 2.946~2.983(t, 2H, -CH₂C=C)， 2.456(s, 3H, 吡咯环 -CH₃)， 2.425~2.500(m, 6H, 2 X -CH₂N), 2.048-2.077 (m, 2H,七环内 - CH₂)。实施例 23 HNMR (400 MHZ, DMSO-d6) δ 13.474 (s, 1H, pyrrole ring-NH), 11.004 (s, 1H, 吲哚-NH), 8.475 (d, 1H, pyridine-CH), 8.102-8.107 ( d, 1H, pyridine-CH), 7.873 (s, 1H ₅ -CH=C), 3.560-3.591 (m, 6H, heptacyclic nitrogen-CH ₂ , 2 X -C3⁄40), 3.336~3.364 (t, 2H , seven-ring external amide nitrogen-CH ₂ ), 2.946~2.983 (t, 2H, -CH ₂ C=C), 2.456 (s, 3H, pyrrole ring-CH ₃ ), 2.425~2.500 (m, 6H, 2 X -CH ₂ N), 2.048-2.077 (m, 2H, hepta-CH ₂ ). Example 23

2-(5-氯 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-5-(2-二甲基氨基-乙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 2-(5-Chloro-2-oxo-1,2-dihydro-indol-3-methyl)-5-(2-dimethylamino-ethyl)-3-methyl-5, 6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one

第一步

first step

5-[3-(2-二甲基氨基-乙氨基) -丙基 ]-3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯室温下将本发明实施例 1第六步所得化合物 5-(3-甲磺酰氧-丙基) -3-甲基 -1H- 吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 lg(11.964 g， 25.7 mmol)搅拌下溶解于 Ν,Ν-二甲基乙二胺 (12 ml， 97 mmol)中并继续搅拌 5小时。点板表明原料反应完全，停止反应。反应液中加入 80 ml乙酸乙酯和 80 ml饱和氯化钠，搅拌 5 min后分层萃取。合并有机相，用饱和氯化钠洗涤 (80 mlx4)除去 Ν,Ν-二甲基乙二胺，无水硫酸镁干燥，抽滤除去干燥剂，滤液浓缩得到黄褐色油状物。油状物柱层析得到标题产物 5-[3-(2-二甲基氨基 -乙氨基)-丙基] -3-甲基 -1Η-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 23a(5.85 g, 黄色油状物)，产率： 45.9%。 5-[3-(2-Dimethylamino-ethylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester Inventive Example 1 Compound obtained in the sixth step: 5-(3-methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester lg ( 11.964 g, 25.7 mmol) was dissolved in hydrazine, hydrazine-dimethylethylenediamine (12 ml, 97 mmol) and stirring was continued for 5 h. The dot plate indicates that the raw material reaction is complete and the reaction is stopped. 80 ml of ethyl acetate and 80 ml of saturated sodium chloride were added to the reaction mixture, and the mixture was stirred for 5 min and then extracted with a layer. The combined organic phases were washed with EtOAc (EtOAc m. Oil column chromatography gave the title product 5-[3-(2-dimethylamino-ethylamino)-propyl]-3-methyl-1 oxime-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-Ethyl ester 23a (5.85 g, yellow oil), Yield: 45.9%.

MS m/z (ESI): 382.2(M+1)。第二步 MS m/z (ESI): 382.2 (M + 1). Second step

5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7，8-六氢-吡咯并 [3,2-c] 吖庚因 -2-羧酸叔丁酯 5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c] Tert-butyl 2-carboxylate

氩气氛下，将 5-[3-(2-二甲基氨基-乙氨基) -丙基 ]-3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 23a (5.85 g, 13.8 mmol)搅拌下溶解于 130 ml甲苯中，缓慢加入三甲基铝的甲苯溶液 (12 ml， 2 mol/L, 24 mmol), 加毕，于室温下搅拌 10分钟至瓶内不再有白烟。反应液于油浴中加热回流 3 小时，点板表明原料基本消失，加冰淬灭反应。待反应体系温度自然降至室温后，加入 50 ml盐酸 (2 mol/L)搅拌 10分钟。混合液用氢氧化钠溶液 (2 mol/L)调节 pH至 9左右，用二氯甲垸萃取 (50 ml X 4)，合并有机相，有机相用无水硫酸镁干燥，抽滤除去干燥剂，滤液减压浓縮得到标题产物 5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1，4,5,6,7，8-六氢 -P比咯并 [3,2-c] 吖庚因 -2-羧酸叔丁酯 23b(3.3 g，黄色固体)，产率： 71.4%。 5-[3-(2-Dimethylamino-ethylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-B under argon Ester 23a (5.85 g, 13.8 mmol) was dissolved in 130 ml of toluene with stirring, and a solution of trimethylaluminum in toluene (12 ml, 2 mol/L, 24 mmol) was slowly added, and the mixture was stirred at room temperature for 10 minutes. There is no longer any white smoke in the bottle. The reaction solution was heated to reflux in an oil bath for 3 hours, and the plate indicated that the material was substantially disappeared and quenched with ice. After the temperature of the reaction system naturally dropped to room temperature, 50 ml of hydrochloric acid (2 mol/L) was added and stirred for 10 minutes. The mixture was adjusted to pH 9 with sodium hydroxide solution (2 mol/L) and extracted with dichloromethane (50 ml X). 4), the organic phase was combined, and the organic layer was dried over anhydrous magnesium sulfate. -oxo-1,4,5,6,7,8-hexahydro-P-pyrolo[3,2-c]azepine-2-carboxylic acid tert-butyl ester 23b (3.3 g, yellow solid), Yield: 71.4%.

MS m/z (ESI): 336.2(M+1)。弟二少 MS m/z (ESI): 336.2 (M + 1). Two younger brothers

5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c] 2-carbaldehyde

氩气氛下，将 5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-羧酸叔丁酯 23b (774 mg, 2.3 mmol)搅拌下溶解于三氟醋酸 (3.1 ml, 20 mmol)中，并于 40Ό油浴中反应 5分钟，再于冰盐浴中搅拌至温度降至 -5 °C，加入原甲酸三乙酯 (0.5 ml, 3.0 mmol), 继续搅拌 2分钟。撤去冰盐浴，反应液温度自然升至室温，继续搅拌约 1 小时。点板表明原料反应完全，停止反应。向反应体系中加入 3 ml冰水和 10 ml二氯甲烷，再用氢氧化钠溶液 (2 mol/L)调节 pH至 11左右，用二氯甲烷萃取 (10 mlx3)混合液。合并有机相，有机相用无水硫酸镁干燥，抽滤除去干燥剂，滤液减压浓缩得到红褐色油状物。油状物经柱层析得到标题产物 5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4，5,6,7,8-六氢-吡咯并 [3,2-c;] 吖庚因 -2-甲醛 23c(223 mg，黄色油状物)，产率： 37%。 5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2 under argon atmosphere -c] azepine-tert-butyl 2-carboxylate 23b (774 mg, 2.3 mmol) was dissolved in trifluoroacetic acid (3.1 ml, 20 mmol) with stirring, and reacted in a 40 Ό oil bath for 5 min. Stir in the ice salt bath until the temperature dropped to -5 °C, and add triethyl orthoformate (0.5 ml, 3.0 mmol) and continue stirring for 2 min. The ice salt bath was removed, the temperature of the reaction was naturally raised to room temperature, and stirring was continued for about 1 hour. The dot plate indicates that the starting material is completely reacted and the reaction is stopped. 3 ml of ice water and 10 ml of dichloromethane were added to the reaction system, and the pH was adjusted to about 11 with a sodium hydroxide solution (2 mol/L), and a mixture of 10 ml x 3 was extracted with dichloromethane. The combined organic layers were dried with EtOAc EtOAc. The oil was subjected to column chromatography to give the title product 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrole. [3,2-c;] azepine-2-carbaldehyde 23c (223 mg, yellow oil), yield: 37%.

MS m/z (ESI): 264.2(M+1)。第四步 MS m/z (ESI): 264.2 (M+1). the fourth step

2-(5-氯 -2-氧代 -1，2-二氢 -吲哚 -3-次甲基 )-5-(2-二甲基氨基-乙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 2-(5-Chloro-2-oxo-1,2-dihydro-indol-3-methyl)-5-(2-dimethylamino-ethyl)-3-methyl-5, 6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one

室温下，将 5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 23c(53 mg, 0.2 mmol)搅拌下溶解于 1 ml甲醇中，加入 5-氯 -1,3-二氢 -吲哚 -2-酮 (34 mg， 0.2 mmol)和 0.1 ml哌啶，加毕，避光搅拌均匀。反应液加热回流 2小时，有大量固体析出，点板表明原料反应完全，停止反应。反应液自然冷却至室温，抽滤，滤饼用乙醇洗涤后千燥，得到标题产物 2-(5-氯 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-5-(2-二甲基氨基-乙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 23(62 mg，橙黄色粉末)，产率： 75 %。 5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2- at room temperature c] azepine-2-carbaldehyde 23c (53 mg, 0.2 mmol) was dissolved in 1 ml of methanol with stirring, and added 5-chloro-1,3-dihydro-indol-2-one (34 mg, 0.2 mmol) ) and 0.1 ml piperidine, add, and mix well in the dark. The reaction solution was heated to reflux for 2 hours, and a large amount of solid was precipitated, which indicated that the starting material was completely reacted and the reaction was stopped. The reaction solution was naturally cooled to room temperature, suction filtered, and the filter cake was washed with ethanol and dried to give the title product 2-(5-chloro-2-oxo-1,2-dihydro-indole-3-methyl) 5-(2-dimethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 23 (62 mg, orange-yellow powder), Yield: 75 %.

MS m/z (ESI): 413.1(M+1)。 MS m/z (ESI): 41:21.

'HNMR(400 MHZ, DMSO-d6) δ 13.667(s, 1H,吡咯环 -NH)， 11.004(s, 1H, 吲哚 -NH), 7.990(s, 1H, -ArH) , 7.799(s, 1H, -CH=C), 7.134^7.159(m, 1H, -ArH) , 6.869〜6.890(m, 1H, -ArH), 3.533-3.567 (t, 2H, 七环接氮 -CH₂)，， 3.336~3.364(t, 2H, 七环外接酰胺氮 -CH₂)， 2.909〜2.945(t, 2H, -CH₂O=C)， 2.463(s, 3H,吡咯环 -CH₃)， 2.401~2.434(t, 2H, -CH₂N)， 2.204(s, 6H, 2X -CH₃N), 2.035-2.079 (m, 2H,七环内实施例 24 'HNMR (400 MHZ, DMSO-d6) δ 13.667 (s, 1H, pyrrole ring-NH), 11.004 (s, 1H, 吲哚-NH), 7.990 (s, 1H, -ArH), 7.799 (s, 1H) , -CH=C), 7.134^7.159(m, 1H, -ArH), 6.869~6.890(m, 1H, -ArH), 3.533-3.567 (t, 2H, heptacyclic nitrogen-CH ₂ ),, 3.336 ~3.364(t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.909~2.945 (t, 2H, -CH ₂ O=C), 2.463 (s, 3H, pyrrole ring-CH ₃ ), 2.401~2.434 ( t, 2H, -CH ₂ N), 2.204(s, 6H, 2X -CH ₃ N), 2.035-2.079 (m, 2H, within the seven-ring Example 24

2-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-5-(2-二甲基氨基-乙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 - -酮 2-(5-Bromo-2-oxo-1,2-dihydro-indol-3-methyl)-5-(2-dimethylamino-ethyl)-3-methyl-5, 6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-ketone

重复本发明实施例 23第四步反应，不同的是使用实施例 23第三步中所得到的化合物 5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4，5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 23c和 5-溴 -1,3-二氢』引哚 -2-酮作原料，得到标题产物 2-(5-溴 -2-氧代 -1,2- 二氢 -吲哚 -3-次甲基 )-5-(2-二甲基氨基-乙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 24(71 mg，红色固体)，产率： 77%。

The fourth step reaction of Example 23 of the present invention was repeated except that the compound 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo obtained in the third step of Example 23 was used. 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxaldehyde 23c and 5-bromo-1,3-dihydroindol-2-one As a starting material, the title product 2-(5-bromo-2-oxo-1,2-dihydro-indol-3-methyl)-5-(2-dimethylamino-ethyl)-3 was obtained. Methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 24 (71 mg, red solid), yield: 77%.

MS m/z (ESI): 457·0(Μ+1)。 MS m/z (ESI): 457·0 (Μ +1).

¹HNMR(400 MHz, DMSO-d6) δ 13.663(s, 1H，吡咯环 -NH)， 11.011(s, 1H,吲哚 -NH)， 8.118(s, 1H, -ArH)， 7.804(s, 1H, -CH=C)， 7.262~7.287(m, 1H, -ArH), 6.826~6.847(m, 1H, -ArH), 3.533-3.567 (t, 2H,七环接氮 -CH₂)， 3.336~3.364(t, 2H, 七环外接酰胺氮 -CH₂)， 2.909~2.945(t, 2H, -CH₂C=C), 2.465(s, 3H,吡咯环 -CH₃)， 2.401~2.434(t, 2H, -CH₂N), 2.204(s, 6H, 2 X -CH₃N), 2.035-2.079 (m, 2H,七环内 - CH₂)。实施例 25 ¹ H NMR (400 MHz, DMSO-d6) δ 13.663 (s, 1H, pyrrole ring-NH), 11.011 (s, 1H, 吲哚-NH), 8.118 (s, 1H, -ArH), 7.804 (s, 1H) , -CH=C), 7.262~7.287(m, 1H, -ArH), 6.826~6.847(m, 1H, -ArH), 3.533-3.567 (t, 2H, heptacyclic nitrogen-CH ₂ ), 3.336~ 3.364(t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.909~2.945(t, 2H, -CH ₂ C=C), 2.465(s, 3H, pyrrole ring-CH ₃ ), 2.401~2.434(t , 2H, -CH ₂ N), 2.204 (s, 6H, 2 X -CH ₃ N), 2.035-2.079 (m, 2H, hepta-CH ₂ ). Example 25

2-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-5-(2-二甲基氨基-乙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 - -酮 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methyl)-5-(2-dimethylamino-ethyl)-3-methyl-5, 6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-ketone

重复本发明实施例 23第四步反应，不同的是使用实施例 23第三歩中所得到的化合物 5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4，5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲酪 23c和 5-氟 -1,3-二氢 -吲哚 -2-酮作原料，得到标题产物 2-(5-氟 -2-氧代 -1,2- 二氢 - 哚 - 3-次甲基 )-5-(2-二甲基氨基-乙基) -3-甲基 -5,6,7,8-四氢 -IH-吡咯并 [3,2-c] 吖庚因斗酮 25(205 mg，红色固体)，产率： 68 %。

The fourth step of the reaction of Example 23 of the present invention was repeated except that the compound 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo obtained in the third hydrazine of Example 23 was used. 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-methylbenzoate 23c and 5-fluoro-1,3-dihydro-indole-2- The ketone was used as a starting material to give the title product 2-(5-fluoro-2-oxo-1,2- Dihydro-indole-3-hydroxymethyl)-5-(2-dimethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-IH-pyrrolo[3,2 -c] 吖gone ketone 25 (205 mg, red solid), Yield: 68%.

MS m/z (ESI): 397.0(M+1)。 MS m/z (ESI): 397.0 (M+1).

1HNMR(400 MHz, DMSO-d6) δ 13.714(s, 1H,吡咯环 -NH)， 10.904(s, 1H,吲哚 -NH), 7.760-7.783 (m, 1H, -ArH), 7.744(s, 1H, -CH=C)， 6.915~6.943(m, 1H, -ArH), 6.836~6.868(m, 1H, -ArH), 3.533~3.567(t, 2H,七环接氮 -CH₂)，3.336~3.364(t， 2H, 七环外接酰胺氮 -CH₂)， 2.909~2.945(t, 2H， -CH₂C=C) , 2.457(s, 3H, 吡咯环 -CH₃), 2.401〜2.434(t, 2H, -CH₂N), 2.204(s, 6H, 2 X - C¾N)， 2.035-2.079 (m, 2H,七环内 - C¾)。实施例 26 1H NMR (400 MHz, DMSO-d6) δ 13.714 (s, 1H, pyrrole ring-NH), 10.904 (s, 1H, 吲哚-NH), 7.760-7.783 (m, 1H, -ArH), 7.744 (s, 1H, -CH=C), 6.915~6.943(m, 1H, -ArH), 6.836~6.868(m, 1H, -ArH), 3.533~3.567(t, 2H, heptacyclic nitrogen-CH ₂ ), 3.336 ~3.364(t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.909~2.945 (t, 2H, -CH ₂ C=C), 2.457 (s, 3H, pyrrole ring-CH ₃ ), 2.401~2.434 ( t, 2H, -CH ₂ N), 2.204(s, 6H, 2 X - C3⁄4N), 2.035-2.079 (m, 2H, hepta-C3⁄4). Example 26

N-{3-[5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢 -B比咯并 [3,2-c] 吖庚因 -2-亚甲基 ]- 5-氟 -2-氧代 -2,3-二 -1H-吲哚 -7-基}-甲酰胺 N-{3-[5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-B ratio 3,2-c] azepine-2-methyl]- 5-fluoro-2-oxo-2,3-di-1H-indol-7-yl}-carboxamide

重复本发明实施例 23第四步反应，不同的是使用实施例 23第三步中所得到的化合物 5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1，4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 23c和本发明实施例 20第三步反应中所得 N-(5-氟 -2-氧代 -2,3-二氢 -1H- 吲哚 -7-基) -甲酰胺 20c作原料，得到标题产物 N-{3-[5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢 -P比咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-5-氟 -2-氧代 -2,3-二氢 -1H- 引哚 -7-基}-甲酰胺 26(71 mg，橙红色固体)，产率： 79%。

The fourth step of the reaction of Example 23 of the present invention was repeated except that the compound 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo obtained in the third step of Example 23 was used. 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c and N-(5-fluoride) obtained in the third step reaction of Example 20 of the present invention 2-Oxo-2,3-dihydro-1H-indol-7-yl)-carboxamide 20c as the starting material to give the title product N-{3-[5-(2-dimethylamino-ethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-P than s-[3,2-c]azepine-2-methylene]-5 -Fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl}-carboxamide 26 (71 mg, orange- red solid), Yield: 79%.

MS m/z (ESI): 440舉+1)。 MS m/z (ESI): 440 +1).

iHNMR OO MHz, DMSO-d6) δ 13.653(s, 1Η,吡咯环 -NH)， 10.437(s, IH,吲哚 -NH) , 9.814(s, 1H， -NHCO)， 8.339(s, IH, -CH=0) , 7.768(s, IH, -CH=C) , 7.621~7.649(m, IH, -ArH), 7.440-7.473 (m, IH, -ArH), 3.533-3.567 (t, 2H,七环接氮 -CH₂)， 3.336~3.364(t, 2H, 七环外接酰胺氮 -CH₂)， 2.919~2.955(t, 2H, -CH₂C=C), 2.463(s, 3H,吡咯环 -CH₃)， 2.403~2.436(t, 2H, -CH₂N), 2.204(s, 6H, 2 X -CH₃N), 2.035-2.079 (m, 2H,七环内一 CH₂)。实施例 27 iHNMR OO MHz, DMSO-d6) δ 13.653 (s, 1 Η, pyrrole ring-NH), 10.437 (s, IH, 吲哚-NH), 9.814 (s, 1H, -NHCO), 8.339 (s, IH, - CH=0), 7.768(s, IH, -CH=C), 7.621~7.649(m, IH, -ArH), 7.440-7.473 (m, IH, -ArH), 3.533-3.567 (t, 2H, seven Ring nitrogen-CH ₂ ), 3.336~3.364 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.919~2.955(t, 2H, -CH ₂ C=C), 2.463(s, 3H, pyrrole ring _{-CH 3), 2.403 ~ 2.436 (} t, 2H, -CH 2 N), 2.204 (s, 6H, 2 X -CH 3 N), 2.035-2.079 (m, inner 2H, a heptacyclo CH _2). Example 27

N-{3-[5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 - -亚甲基 ]-5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基 }-2-羟基-乙酰胺 N-{3-[5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3, 2-c] 吖庚因 - -methylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide

第一步

first step

乙酸（5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-氨基甲酰基) -甲酯室温下，将 5-氟 -6-胺基 -2-吲哚酮 3d(500 mg, 3.0 mmol)搅拌下溶解于 10 ml 四氢呋喃中，加入 0.4 ml吡啶，搅拌均匀后用干冰 -丙酮浴使反应体系冷却至 -40 °C左右。将乙酰氧基乙酰氯 (420 mg， 3.0 mmol)加入到 10 ml四氢呋喃中，溶解后滴加到已冷却好的反应体系中，加毕撤去干冰 -丙酮浴，使反应体系自然升温至室温，搅拌过液。点板跟踪至原料消失，过滤，所得固体用水洗 3 次后干燥即得到标题产物乙酸（5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-氨基甲酰基) -甲酯 27a(562 mg，灰色固体)，产率： 70.4% 5-fluoro-6-amino-2-indanone at room temperature, acetic acid (5-fluoro-2-oxo-2,3-dihydro-1H-indole-6-carbamoyl)-methyl ester 3d (500 mg, 3.0 mmol) was dissolved in 10 ml of tetrahydrofuran with stirring, 0.4 ml of pyridine was added, and the mixture was stirred well, and the reaction system was cooled to about -40 °C with a dry ice-acetone bath. Add acetoxyacetyl chloride (420 mg, 3.0 mmol) to 10 ml of tetrahydrofuran, dissolve it and add it to the cooled reaction system. After removing the dry ice-acetone bath, the reaction system is naturally warmed to room temperature and stirred. Over liquid. The spot plate was traced until the disappearance of the starting material, and the obtained solid was washed three times with water and dried to give the title product (5-fluoro-2-oxo-2,3-dihydro-1H-indole-6-carbamoyl). -Methyl ester 27a (562 mg, grey solid), Yield: 70.4%

MS: 265.3(M-1)。第二步 MS: 265.3 (M-1). Second step

N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基) -2-羟基-乙酰胺室温下，将乙酸（5-氟 -2-氧代 -2，3-二氢 -1H-吲哚 -6-氨基甲酰基) -甲酯 27a(58 mg, 0.22 mmol)搅拌下溶解于 1 ml甲醇中，加入 1 ml水和氢氧化钠 (15 mg, 0.375 mmol), 加毕，继续搅拌 1小时。点板跟踪至原料消失，停止反应。反应液过滤，所得固体用水洗 3次，干燥即得到标题产物 N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6- 基) -2-羟基-乙酰胺 27b(46 mg，灰白色固体)，产率： 93.8%。 N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide, acetic acid (5-fluoro-2-oxo-) 2,3-Dihydro-1H-indole-6-carbamoyl)-methyl ester 27a (58 mg, 0.22 mmol) was dissolved in 1 ml of methanol with stirring, and 1 ml of water and sodium hydroxide (15 mg, 0.375 mmol), after the addition, continue to stir for 1 hour. The plate is tracked until the material disappears and the reaction is stopped. The reaction solution was filtered, and the obtained solid was washed three times with water and dried to give the title product N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-B Amide 27b (46 mg, off white solid), yield: 93.8%.

第三步

third step

N-{3-[5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 , -2-亚甲基 ]-5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基}-2-轻基-乙酰胺 N-{3-[5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3, 2-c] azepine, -2-methylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-light-acetamide

重复本发明实施例 23第四步反应，不同的是使用实施例 23第三步中所得到的化合物 5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7，8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 23c和 N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基) -2-羟基-乙酰胺 27b作原料，得到标题产物 N-{3-[5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4,5，6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基}-2-轻基-乙酰胺 27(80 mg, 橙黄色固体)，产率： 83.4%。 The fourth step reaction of Example 23 of the present invention was repeated except that the compound 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo obtained in the third step of Example 23 was used. 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c and N-(5-fluoro-2-oxo-2,3-di Hydrogen-1H-indol-6-yl)-2-hydroxy-acetamide 27b was used as the starting material to give the title product N-{3-[5-(2-dimethylamino-ethyl)-3-methyl- 4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-methylene]-5-fluoro-2-oxo-2 , 3-dihydro-1H-indol-6-yl}-2-carbyl-acetamide 27 (80 mg, orange-yellow solid), Yield: 83.4%.

MS m/z (ESI): 470.1(M+1)。 MS m/z (ESI): 470.1 (M + 1).

MHz, DMSO-d6) δ 13.599(s, 1H,吡咯环 -NH)， 10.893(s, 1H，吲哚 -NH), 9.233(s, 1H, -NHCO), 7.854~7.879(m, 1H, -ArH)， 7.725(s, 1H, -CH=C), 7.663~7.688(m, 1H, -ArH), 5.950(s, 1H, -OH), 4.053(s, 2H, -CH₂0), 3.544 (t, 2H,七环接氮 -CH₂)， 3.315~3.340(t, 2H,七环外接酰胺氮 -C )， 2.924(t, 2H, -CH₂C=C)， 2.464(t, 2H, -CH₂N), 2.442(s, 3H, 吡咯环 -CH₃)， 2.199(s， 6H, 2 X - C¾N)， 2.044 (m, 2H,七环内- CH₂)。实施例 28

MHz, DMSO-d6) δ 13.599 (s, 1H, pyrrole ring-NH), 10.893 (s, 1H, 吲哚-NH), 9.233 (s, 1H, -NHCO), 7.854~7.879 (m, 1H, - ArH), 7.725(s, 1H, -CH=C), 7.663~7.688(m, 1H, -ArH), 5.950(s, 1H, -OH), 4.053(s, 2H, -CH ₂ 0), 3.544 (t, 2H, heptacyclic nitrogen-CH ₂ ), 3.315~3.340 (t, 2H, heptacyclic external amide nitrogen-C), 2.924(t, 2H, -CH ₂ C=C), 2.464(t, 2H , -CH ₂ N), 2.442 (s, 3H, pyrrole ring-CH ₃ ), 2.199 (s, 6H, 2 X - C 3⁄4N), 2.044 (m, 2H, hepta-CH ₂ ). Example 28

2—[4-(2,3-二氟-苯基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-3-甲基 -5-(2-吡咯烷小基-乙基) - -四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 2-[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-3-methyl-5-(2-pyrrole Alkenyl-ethyl)--tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one

第一步

first step

3-甲基 -5-[3-(2-吡咯烷 -1-基-乙氨基) -丙基] -1Η-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 3-methyl-5-[3-(2-pyrrolidin-1-yl-ethylamino)-propyl]-1Η-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester

室温下，将 5-(3-甲磺酰氧-丙基) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 lg(8.462 g， 21.75 mmol)搅拌下溶解于 2-吡咯烷 -1-基 -乙胺 (6.3 ml, 49.79 mmol), 搅拌过夜，点板表明原料反应完全，停止反应。向反应液中加入 200 ml乙酸乙酯，再加入少量甲醇至反应液变澄清。反应液用水洗涤 (30 mlX 3)，有机层用饱和氯化钠洗涤 (40 mi x 2), 减压浓缩得到浅褐色油状物，油状物经柱层析得到标题产物 3-甲基 -5-[3-(2-吡咯垸 -1-基-乙氨基) -丙基] -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 28a(4.488 g, 黄色油状物)，产率： 63.5 %。 5-(3-Methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester lg (8.462 g, 21.75 mmol) Dissolved in 2-pyrrolidin-1-yl-ethylamine (6.3 ml, 49.79 mmol) with stirring, and stirred overnight. 200 ml of ethyl acetate was added to the reaction mixture, and a small amount of methanol was added until the reaction mixture became clear. The reaction mixture was washed with water (3 ml EtOAc) [3-(2-Pyrrolidin-1-yl-ethylamino)-propyl]-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 28a (4.488 g, yellow oil) , Yield: 63.5 %.

MS m/z (ESI): 406.5(M-1)。第二步 MS m/z (ESI): 406.5 (M-1). Second step

₃_甲基 _4-氧代 -5-(2-吡咯烷 -1-基-乙基) -1，4,5，6，7，8-六氢 -P比咯并 [3,2-c] 吖庚因 -2-羧酸叔丁酯 ₃ _methyl_4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-P ratio oct[3,2- c] tert-butyl 2-carboxylic acid tert-butyl ester

氩气氛下，将 3-甲基 -5-[3-(2-吡咯垸 -1-基-乙氨基) -丙基] -1H-吡咯 -2,4-二羟酸 3-methyl-5-[3-(2-pyrrole-1-yl-ethylamino)-propyl]-1H-pyrrole-2,4-dihydroxy acid under argon atmosphere

2-叔丁酯 4-乙酯 28a (6.754 g， 16.6 mmol)搅拌下溶解于 150 ml甲苯中，缓慢加入三甲基铝的甲苯溶液 (16.6 ml， 2 mol/L, 33.2 mmol)。反应体系于室温下搅拌 20分钟至瓶内不再有白烟，继续于油浴中回流 3.5小时。点板表明原料反应完全，撤去油浴，向反应液中加入少量 95 %乙醇淬灭反应。反应液中加入 100 ml乙酸乙酯，硅藻土抽滤，滤液减压浓缩后柱层析得到标题产物 3-甲基 -4-氧代 -5-(2-吡咯烷 - 1- 基-乙基) -1,4,5，6,7，8-六氢 -P比咯并 [3,2-c] 吖庚因 -2-羧酸叔丁酯 28b(3.894 g，黄色油状物)，产率: 65 %。 . 2-tert-Butyl ester 4-ethyl ester 28a (6.754 g, 16.6 mmol) was dissolved in 150 ml of toluene with stirring, and a toluene solution of trimethylaluminum (16.6 ml, 2 mol/L, 33.2 mmol) was slowly added. The reaction system was stirred at room temperature for 20 minutes until no more white smoke was present in the bottle, and the mixture was refluxed for 3.5 hours in an oil bath. The dot plate indicates that the starting material is completely reacted, the oil bath is removed, and a small amount of 95% ethanol is added to the reaction solution to quench the reaction. 100 ml of ethyl acetate was added to the reaction mixture, and the mixture was filtered over Celite. -1,4,5,6,7,8-hexahydro-P-pyrolo[3,2-c] azet-butyl-2-carboxylate tert-butyl ester 28b (3.894 g, yellow oil) Yield: 65 %. .

MS m/z (ESI): 362.2(M+1)。第三步 MS m/z (ESI): 362.2 (M + 1). third step

3-甲基 -4-氧代 -5-(2-吡咯烷小基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 3-methyl-4-oxo-5-(2-pyrrolidinyl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c] 2-carbaldehyde

室温下，将 3-甲基 -4-氧代 -5-(2-吡咯烷 -1-基-乙基)- 1，4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-羧酸叔丁酯 28b (3.562 g， 9.87 mmol)搅拌下溶解于 50 ml二氯甲烷中，加入三氟醋酸 (19.7 ml， 260 mmol), 加毕，反应体系于油浴中加热回流 30分钟。点板表明原料反应完全，停止反应。反应体系于冰盐浴中降温至 -5°C，一次性加入甲酸三乙酯 (2.96 ml， 14.8 mmol), 加毕，于 -5°C下搅拌 5分钟，继续于室温下搅拌 1小时，向反应体系中加入 25 ml水。反应液用稀氢氧化钠溶液 (2 mol/L)调节 pH 至 11左右，用二氯甲烷萃取 (100 ml X 3)，合并有机相，减压浓缩得到红褐色油状物。油状物经柱层析得到标题产物 3-甲基 -4-氧代 -5-(2-吡咯垸 -1-基-乙基) -1,4，5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 28c(l.ll6 g，黄色固体)，产率： 49%。 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3, at room temperature 2-c] azepine-tert-butyl 2-carboxylate 28b (3.562 g, 9.87 mmol) was dissolved in 50 ml of dichloromethane with stirring, and then added trifluoroacetic acid (19.7 ml, 260 mmol). The system was heated to reflux in an oil bath for 30 minutes. The dot plate indicates that the starting material is completely reacted and the reaction is stopped. The reaction system was cooled to -5 ° C in an ice salt bath, and triethyl formate (2.96 ml, 14.8 mmol) was added in one portion, and the mixture was stirred at -5 ° C for 5 minutes, and then stirred at room temperature for 1 hour. 25 ml of water was added to the reaction system. The reaction mixture was adjusted to pH EtOAc (EtOAc) (EtOAc) The oil was subjected to column chromatography to give the title product 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro- Pyrrolo[3,2-c]azepine-2-carbaldehyde 28c (1.ll6 g, yellow solid), yield: 49%.

MS m/z (ESI): 290.2(M+l 第四步 MS m/z (ESI): 290.2 (M+l step 4)

2-[4-(2,3-二氟-苯基) -2-氧代 -1,2-二氯 -吲哚 -3-次甲基 ]-3-甲基 -5-(2-吡咯垸 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 2-[4-(2,3-Difluoro-phenyl)-2-oxo-1,2-dichloro-indol-3-ylmethyl]-3-methyl-5-(2-pyrrole垸-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one

室温下，将 3-甲基 -4-氧代 -5-(2-吡咯烷 -1-基-乙基) -1 ,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 28c (40mg, 0.134 mmol)和本发明实施例 6第三步所得化合物 4-(2,3- 二氟-苯基) -1,3-二氢 -吲哚 -2-酮 6d(31 mg, 0.127 mmol)搅拌下溶解于 0.3 ml乙醇中。加入六氢吡啶 (0.03 ml， 0.3 mmol), 加毕，室温搅拌过夜。点板监测反应至原料反应完全，停止反应。反应液减压抽滤,得到标题产物 2-[4-(2，3-二氟-苯基) -2-氧代 -1,2- 二氢 -吲哚 -3-次甲基 ]-3-甲基 -5-(2-吡咯烷 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 28(40 mg，黄色固体)，产率： 57%。 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3, at room temperature 2-c] azepine-2-carbaldehyde 28c (40 mg, 0.134 mmol) and the compound obtained in the third step of Example 6 of the present invention 4-(2,3-difluoro-phenyl)-1,3-dihydro- Indole-2-one 6d (31 mg, 0.127 mmol) was dissolved in 0.3 ml of ethanol with stirring. Hexahydropyridine (0.03 ml, 0.3 mmol) was added, added, and stirred at room temperature overnight. The plate was monitored until the reaction of the starting material was complete and the reaction was stopped. The reaction solution was suction filtered under reduced pressure to give the title product 2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indole-3-methylmethyl]-3 -methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 28 (40 mg, yellow solid), Yield: 57%.

MS m/z (ESI): 517.2(M+l MS m/z (ESI): 517.2 (M+l

1HNMR(400 MHz, DMSO-d6) δ 13.532(s, IH,吡咯环 -NH)， 11.132(s, IH, 吲哚 -NH)， 7.598~7.620(m, IH, -ArH), 7.421~7.434(m, IH, -ArH), 7.307~7.323(m, 1H， -ArH), 7.232-7.27 l(m, IH, -ArH), 7.001~7.021(d, IH, , -ArH), 6.865~6.884(d, IH, -ArH) , 6.698(s, 1H， -CH=C)， 3.499~3.533(t, 2H, 七环外接酰胺氮 -C¾)， 3.273~3.302(t, 2H,七环接氮 -CH₂)， 2.854~2.891(t, 2H， -CH₂C=C), 2.536〜2.570(t， 2H, -CH₂N), 2.498-2.515(m, 4H,五环 -CH₂N)， 1.982~2.012(m, 2H,七环 -CH₂)， 1.777(s, 3H,吡咯环 -CH₃)， 1.657(m, 4H,五环 -CH₂)。实施例 29 1H NMR (400 MHz, DMSO-d6) δ 13.532 (s, IH, pyrrole ring-NH), 11.132 (s, IH, 吲哚-NH), 7.598~7.620 (m, IH, -ArH), 7.421~7.434 ( m, IH, -ArH), 7.307~7.323(m, 1H, -ArH), 7.232-7.27 l(m, IH, -ArH), 7.001~7.021(d, IH, , -ArH), 6.865~6.884( d, IH, -ArH), 6.698(s, 1H, -CH=C), 3.499~3.533(t, 2H, heptacyclic external amide nitrogen-C3⁄4), 3.273~3.302 (t, 2H, seven-ring nitrogen- CH ₂ ), 2.854~2.891 (t, 2H, -CH ₂ C=C), 2.536~2.570(t, 2H, -CH ₂ N), 2.498-2.515 (m, 4H, penta-CH ₂ N), 1.982~2.012 (m, 2H, hepta-CH ₂ ), 1.777 (s, 3H, pyrrole ring-CH ₃ ), 1.657 (m, 4H, penta-CH ₂ ). Example 29

N-{5-氟 -3-[3-甲基 -4-氧代 -5-(2-吡咯垸小基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3- -1H-吲哚 -7- 酰胺 N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidinyl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrole And [3,2-c] azepine-2-methyl]-2-oxo-2,3- -1H-indole-7-amide

重复本发明实施例 28第四步反应，不同的是使用实施例 28第三歩所得化合物 3-甲基 -4-氧代 -5-(2-吡咯垸 -1-基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 28c和本发明实施例 20第三步中所得到的化合物 N-(5-氟 -2-氧代 -2,3-二氢 -1H- 吲哚 -7-基) -甲酰胺 20c作原料，得到标题产物 N-{5-氟 -3-[3-甲基 -4-氧代 -5-(2-吡咯垸小基 -乙基 )-1,4,5,6,7,8-六氢-吡咯并 [3，2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2，3-二氢 -1H-吲哚 -7-基甲酰胺 29(59 mg，黄色固体)，产率： 95 %。

The fourth step of the reaction of Example 28 of the present invention was repeated except that the compound obtained in the third example of Example 28 was used. 3-methyl-4-oxo-5-(2-pyrrole-1-yl-ethyl)-1 , 4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c and the compound N-(5- obtained in the third step of Example 20 of the present invention fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-carboxamide 20c was used as the starting material to give the title product N-{5-fluoro-3-[3-methyl-4- Oxo-5-(2-pyrrole Indole-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-methylene]-2-oxo-2, 3-Dihydro-1H-indol-7-ylcarboxamide 29 (59 mg, yellow solid), yield: 95%.

MS m/z (ESI): 466.2(M+1)。 MS m/z (ESI): 466.2 (M + 1).

¹HNMR(400 MHz, DMSO-d6) δ 13.679(s, 1H，吡咯环 -NH)， 10.868(s, 1H,吲哚 -NH)， 8.324(s, 1H, -HCO)， 7.796(s, 1H, -ArH) , 7.747(s, 1H, -CH=C), 7.601~7.629( dd, 1H, -ArH), 7.424~7.454(dd, 1H, -ArH), 3.543~3.577(t, 2H，七环外接酰胺氮 -CH₂)， 3.330〜3.357(t， 2H,七环接氮 -CH₂)， 2.907~2.944(t, 2H, -C¾C=C), 2.576~2.610(t, 2H, -CH₂N) , 2.498-2.515(m, 4H, 五环 -CH₂N)， 2.449(s, 3H, 吡咯环 -CH₃)， 2.026~2.055(m, 2H,七环 -C¾)1.679(m, 4H,五环 -CH₂)。实施例 30 ¹ H NMR (400 MHz, DMSO-d6) δ 13.679 (s, 1H, pyrrole ring-NH), 10.868 (s, 1H, 吲哚-NH), 8.324 (s, 1H, -HCO), 7.796 (s, 1H) , -ArH) , 7.747(s, 1H, -CH=C), 7.601~7.629( dd, 1H, -ArH), 7.424~7.454(dd, 1H, -ArH), 3.543~3.577(t, 2H,7 The ring is externally amide nitrogen-CH ₂ ), 3.330~3.357 (t, 2H, heptacyclic nitrogen-CH ₂ ), 2.907~2.944 (t, 2H, -C3⁄4C=C), 2.576~2.610(t, 2H, -CH _{2 N), 2.498-2.515 (m,} 4H, rings _{-CH 2 N), 2.449 (s} , 3H, pyrrole _{-CH 3), 2.026 ~ 2.055 (} m, 2H, heptacyclo -C¾) 1.679 (m, 4H, pentacyclic-CH ₂ ). Example 30

N-{3-[3-甲基 -4-氧代 -5-(2-吡咯烷 -1-基-乙基)- 1,4，5,6,7,8-六氢_吡咯并 [3,2-c] 吖庚因 - -亚甲基 ]-2-氧代 -2,3-二氢 -111』引哚-5-基}-乙酰胺 N-{3-[3-Methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[ 3,2-c] azepine--methylene]-2-oxo-2,3-dihydro-111"pyridin-5-yl}-acetamide

5-硝基 -2-吲哚酮 5-nitro-2-indanone

冰浴下，将 2-吲哚酮 30a(20.0 g， 150 nimol)搅拌下溶解于 100 ml硫酸 (98%) 中，滴加 10 ml硝酸 (65%— 68%)并控制温度低于 0°C，加毕继续于 0°C下搅拌 1小时。点板跟踪至原料消失，停止反应。向反应液中加入冰，待冰融化后过滤，滤饼用水洗涤 (20 mi x 3),所得固体重结晶得到标题产物 5-硝基 -2-吲哚酮 30b(25.3 g' 橙色晶体)，产率： 92.4%。 Under ice bath, 2-nonanone 30a (20.0 g, 150 nimol) was dissolved in 100 ml of sulfuric acid (98%) with stirring, 10 ml of nitric acid (65% - 68%) was added dropwise and the temperature was controlled below 0 ° C, the addition was continued at 0 ° C for 1 hour. The plate is tracked until the material disappears and the reaction is stopped. Ice was added to the reaction mixture, and the mixture was filtered, washed with water (20 mi x 3), and the obtained solid was recrystallized to give the title product 5-nitro-2-indolone 30b (25.3 g of orange crystal). Yield: 92.4%.

MS m/z (ESI): 177.3(M-l)o P T/CN2008/001352 MS m/z (ESI): 177.3 (Ml)o PT/CN2008/001352

第二步 Second step

5-氨基 -2-吲哚酮 5-amino-2-indanone

室温下，将 5-硝基 -2-吲哚酮 30b(3.56 g， 20 mmol)搅拌下溶解于 200 ml乙酸中，加入钯 /碳 (5 %， 1.0 g), 抽去空气后边搅拌边向反应体系中充入氢气，点板跟踪至原料消失，停止反应。过滤，滤液减压浓缩，得到标题产物 5-氨基 -2-吲哚酮 30c(2.04g, 白色固体)，产率： 68.9%。 5-Nitro-2-indanone 30b (3.56 g, 20 mmol) was dissolved in 200 ml of acetic acid with stirring at room temperature, palladium/carbon (5 %, 1.0 g) was added, and the air was removed and stirred. The reaction system was filled with hydrogen gas, and the spot plate was traced until the raw material disappeared, and the reaction was stopped. Filtration, and the filtrate was concentrated under reduced pressure to give the title product, 5-amino-2-indoleone 30c (2.04 g, white solid), yield: 68.9%.

MS m/z (ESI): 149.4(M+1)。第三步 MS m/z (ESI): 149.4 (M + 1). third step

N-(2-氧代 -2,3-二氢 -1H-吲哚 -5-基) -乙酰胺室温下，将 5-氨基 -2-吲哚酮 30c(3.5 g， 23.6 mmol)搅拌下溶解于 20 ml四氢呋喃中，加入三乙基胺 (3.6 ml， 26 mmol), 加毕，反应体系于干冰-丙酮浴中冷却至 -30°C。将乙酰氯 (1.8 ml, 24.8 mmol)缓慢加入反应体系，并控制反应体系温度低于 -20°C，加毕，撤去干冰-丙酮浴，反应体系温度自然升至室温，搅拌 20分钟。点板监测反应至原料反应完全，停止反应。向反应体系中加入 20 ml乙酸乙酯，有灰色固体生成，过滤，滤饼用水洗涤 (70 mix 3)，得到 2.5 g固体。滤液用乙酸乙酯萃取 (200 ml X 3), 合并有机相，有机相减压浓缩所得固体与上述固体合并，干燥得到标题产物 N-(2-氧代 -2,3-二氢 -1H-吲哚- 5-基)-乙酰胺 30d(4.0 g，灰色固体)，产率： 89%。 N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide, stirring 5-amino-2-indanone 30c (3.5 g, 23.6 mmol) at room temperature Dissolved in 20 ml of tetrahydrofuran, added triethylamine (3.6 ml, 26 mmol), and the reaction was cooled to -30 ° C in a dry ice-acetone bath. Acetyl chloride (1.8 ml, 24.8 mmol) was slowly added to the reaction system, and the temperature of the reaction system was controlled to be lower than -20 ° C. After the addition, the dry ice-acetone bath was removed, and the temperature of the reaction system was naturally raised to room temperature and stirred for 20 minutes. The plate was monitored until the reaction of the starting material was complete and the reaction was stopped. 20 ml of ethyl acetate was added to the reaction system, a gray solid was formed, filtered, and the filter cake was washed with water (70 mix 3) to obtain 2.5 g of a solid. The filtrate was extracted with EtOAc (EtOAc (EtOAc) (EtOAcjjjjjjj吲哚-5-yl)-acetamide 30d (4.0 g, m.p.), Yield: 89%.

MS m/z (ESI)： 191.2(M+1 )。第四步 MS m/z (ESI): 1921. (M+1). the fourth step

N-{3-[3-甲基 -4-氧代 -5-(2-吡咯嫁 -1-基-乙基) -1,4，5,6,7,8-六氢-吡咯并 [3,2-_C] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -5-基}-乙酰胺 N-{3-[3-Methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[ 3,2- _C ] azepine-2-methylidene-2-oxo-2,3-dihydro-1H-indol-5-yl}-acetamide

重复本发明实施例 28第四步反应，不同的是使用实施例 28第三步所得化合物 3-甲基 -4-氧代 -5-(2-吡咯垸 -1-基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3，2-c] 吖庚因 -2-甲醛 28c和 N-(2-氧代 -2,3-二氢 -1H-吲哚 -5-基) -乙酰胺 30d作原料，得到标题产物 N-{3-[3-甲基 -4-氧代 -5-(2-吡咯烷 -1-基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3，2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -5-基}-乙酰胺 30(50 mg，黄色固体)，产率. · 80 %。 The fourth step reaction of Example 28 of the present invention was repeated except that the compound obtained in the third step of Example 28 was used. 3-methyl-4-oxo-5-(2-pyrrole-1-yl-ethyl)-1 ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c and N-(2-oxo-2,3-dihydro-1H-indole哚-5-yl)-acetamide 30d was used as the starting material to give the title product N-{3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1. 4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-methylene]-2-oxo-2,3-dihydro-1H-indole- 5-yl}-acetamide 30 (50 mg, yellow solid), yield. 80%.

MS m/z (ESI): 462.2(M+1)。 MS m/z (ESI): 4621.

1HNMR(400 MHz, DMS0-d6) δ 13.679(s, 1H,吡咯环 -NH)， 10.868(s， 1H，吲哚 -NH)， 9.806(s, 1H, -NHCO), 7.796(s, 1H, -ArH) , 7.447(s₅ 1H, -CH=C)， 1H NMR (400 MHz, DMS0-d6) δ 13.679 (s, 1H, pyrrole ring-NH), 10.868 (s, 1H, 吲哚-NH), 9.806 (s, 1H, -NHCO), 7.796 (s, 1H, -ArH) , 7.447(s ₅ 1H, -CH=C),

7.231~7.256( dd， 1H, -ArH), 6.789-6.710(s, 1H, -ArH), 3.513-3.547 (t, 2H,七环外接酰胺氮 -CH₂)， 3.303~3.330(t, 2H,七环接氮 -CH₂), 2.866~2.903(t, 2H, -CH₂C=C), N2008/001352 7.231~7.256( dd, 1H, -ArH), 6.789-6.710(s, 1H, -ArH), 3.513-3.547 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 3.303~3.330(t, 2H, Seven-ring nitrogen-CH ₂ ), 2.866~2.903 (t, 2H, -CH ₂ C=C), N2008/001352

2.540〜2.574(t, 2H，- CH₂N)， 2.461-2.513(m, 4H,五环 -CH₂N)， 2.388(s, 3H,吡咯环 -CH₃)， 2.002~2.024(m, 2H,七环 -CH₂)， 2.024(s, 3H, -CH₃), 1.648(m, 4H,五环 -CH₂)。实施例 31 2.540~2.574(t, 2H,-CH ₂ N), 2.461-2.513(m, 4H, pentacyclic-CH ₂ N), 2.388(s, 3H, pyrrole ring-CH ₃ ), 2.002~2.024(m, 2H , hepta-CH ₂ ), 2.024 (s, 3H, -CH ₃ ), 1.648 (m, 4H, penta-CH ₂ ). Example 31

N-{5-氟 -3-[3-甲基 -4-氧代 -5-(2-吡咯烷 -1-基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3- -1H-吲哚 -6-基}-2- -乙酰胺 N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro -pyrrolo[3,2-c]azepine-2-methylene]-2-oxo-2,3- -1H-indol-6-yl}-2-acetamide

重复本发明实施例 28第四步反应，不同的是使用实施例 28第三步所得化合物

The fourth step reaction of Example 28 of the present invention was repeated except that the compound obtained in the third step of Example 28 was used.

3-甲基 -4-氧代 -5-(2-吡咯烷 -1-基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3，2-c] 吖庚因 -2-甲醛 28c和本发明实施例 27第二步中所得到的化合物 N-(5-氟 -2-氧代 -2,3-二氢 -1H- 吲哚 -6-基) -2-羟基-乙酰胺 27b作原料，得到标题产物 N-{5-氟 -3-[3-甲基 -4-氧代 -5-(2-吡咯焼小基-乙基) -1,4,5,6，7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3-二氢- 1H-吲哚 -6-基}-2-羟基-乙酰胺 31(50 mg，黄色固体)，产率： 76%。 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c] Indole-2-carbaldehyde 28c and the compound N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl) obtained in the second step of Example 27 of the present invention 2-hydroxy-acetamide 27b was used as the starting material to give the title product N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidinyl-ethyl)-1. 4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-methylene]-2-oxo-2,3-dihydro-1H-indole- 6-yl}-2-hydroxy-acetamide 31 (50 mg, yellow solid), yield: 76%.

MS m/z (ESI): 496.2(M+l)o MS m/z (ESI): 496.2 (M+l) o

¹HNMR(400 MHz, DMSO-d6) δ 13.658(s, 1H,吡咯环 -NH)， 10.857(s, 1H,吲哚 -NH)， 9.426(s, 1H, -NHCO), 7.826~7.854(d, 1H, -ArH), 7.694~7.710(d, 1H, -ArH), 7.640(s, 1H, -CH=C)， 5.717(s, 1H, -HO), 4.035(d, 2H, -CH₂0)， 3.536〜3.570(t， 2H, 七环接氮 -CH₂)， 3.339(t, 2H, 七环外接酰胺氮 -CH₂)， 2.889~2.926(t, 2H, -CH₂C=C), 2.562~2.596(t, 2H, -CH₂N), 2.483~2.513(m, 4H,五环 -CH₂N)， 2.427(s, 3H，吡咯环 -CH₃)， 2.034(m, 2H,七环 -CH₂)， 1.673(m, 4H,五环 -CH₂)。实施例 32 ¹ H NMR (400 MHz, DMSO-d6) δ 13.658 (s, 1H, pyrrole ring-NH), 10.857 (s, 1H, 吲哚-NH), 9.426 (s, 1H, -NHCO), 7.826~7.854 (d , 1H, -ArH), 7.694~7.710(d, 1H, -ArH), 7.640(s, 1H, -CH=C), 5.717(s, 1H, -HO), 4.035(d, 2H, -CH ₂ 0), 3.536~3.570(t, 2H, heptacyclic nitrogen-CH ₂ ), 3.339(t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.889~2.926(t, 2H, -CH ₂ C=C ), 2.562~2.596(t, 2H, -CH ₂ N), 2.483~2.513(m, 4H, pentacyclic-CH ₂ N), 2.427(s, 3H, pyrrole ring-CH ₃ ), 2.034(m, 2H , heptacyclic-CH ₂ ), 1.673 (m, 4H, pentacyclic-CH ₂ ). Example 32

2-(5-氟 -2-氧代 -1,2-二氢』引哚 -3-次甲基 )-3-甲基 -5-(2-哌啶小基-乙基) -5，6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 2-(5-fluoro-2-oxo-1,2-dihydro)indol-3-ylmethyl)-3-methyl-5-(2-piperidinyl-ethyl)-5, 6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one

第一步

first step

3-甲基 -5-[3-(2-哌啶 -1-基-乙氨基) -丙基] -1Η-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 3-methyl-5-[3-(2-piperidin-1-yl-ethylamino)-propyl]-1Η-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester

室温下，将 5-(3-甲磺酰氧-丙基) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 lg(10.64 g, 27.3 mmol)搅拌下溶解于 2-哌啶 -1-基 -乙胺（7 ml， 49.2 mmol)中，搅拌过夜，点板表明原料反应完全，停止反应。向反应液中加入 200 ml乙酸乙酯，再加入少量甲醇至反应液变澄清。反应液用水洗涤 (30 πύΧ 3)，有机层用饱和氯化钠洗涤 (40 ml X2), 有机相减压浓缩得到油状物，油状物经柱层析得到标题产物 3- 甲基 -5-[3-(2-哌啶 -1-基-乙氨基) -丙基 ]-1Η-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 32a(5.35 g, 黄色油状物)，产率： 46.5%。 5-(3-Methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester lg (10.64 g, 27.3 mmol) Dissolved in 2-piperidin-1-yl-ethylamine (7 ml, 49.2 mmol) with stirring and stirring overnight. 200 ml of ethyl acetate was added to the reaction mixture, and a small amount of methanol was added until the reaction mixture became clear. The reaction mixture was washed with water (30 π EtOAc). 3-(2-piperidin-1-yl-ethylamino)-propyl]-1Η-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 32a (5.35 g, yellow oil) Yield: 46.5%.

MS m/z (ESI): 422.3(M+ 1)。第二步 MS m/z (ESI): 422.3 (M + 1). Second step

3-甲基 -4-氧代 -5-(2-哌啶小基-乙基) -1，4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-羧酸叔丁酯 3-methyl-4-oxo-5-(2-piperidinyl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c] Tert-butyl 2-carboxylate

氩气氛下，将 3-甲基 -5-[3-(2-哌啶小基-乙氨基) -丙基 ]-1Η-吡咯 -2,4-二羟酸 2- 叔丁酯 4-乙酯 32a (225 mg, 0.534 mmol)搅拌下溶解于 5 ml甲苯 (干燥)中，加毕，反应体系于冰浴中冷却，缓慢加入三甲基铝的甲苯溶液 (0.534 ml, 2 mol/L, 1.07 mmol)₀ 加毕，反应体系于室温下搅拌 20分钟至瓶内不再有白烟，继续于油浴中回流 3小时。点板表明原料反应完全，撤去油浴，向反应液中加入 10 ml饱和氯化钠溶液和 20 ml乙酸乙酯，加毕，混合液于室温搅拌 15分钟。混合物过滤，滤饼用乙酸乙酯洗涤 (10 ml X 3)，滤液用乙酸乙酯萃取 (10 ml X2)，合并有机相，有机相用饱和氯化钠洗涤 (10 ml X2)，无水硫酸镁干燥，抽滤除去干燥剂，滤液减压浓缩得到标题产物 3-甲基 -4-氧代 -5-(2-哌啶 -1-基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-羧酸叔丁酯 32b(105 mg，无色油状物)，直接进行下步反应。 3-methyl-5-[3-(2-piperidinyl-ethylamino)-propyl]-1Η-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-B under argon Ester 32a (225 mg, 0.534 mmol) was dissolved in 5 ml of toluene (dry) with stirring. After the addition, the reaction system was cooled in an ice bath, and a solution of trimethylaluminum in toluene (0.534 ml, 2 mol/L, was slowly added. 1.07 mmol) After the addition of ₀ , the reaction system was stirred at room temperature for 20 minutes until there was no more white smoke in the bottle, and the mixture was refluxed for 3 hours in an oil bath. The dot plate indicated that the starting material was completely reacted, the oil bath was removed, 10 ml of a saturated sodium chloride solution and 20 ml of ethyl acetate were added to the reaction mixture, and the mixture was added, and the mixture was stirred at room temperature for 15 minutes. The mixture was filtered, and the filter cake was washed with EtOAc (EtOAc (EtOAc) (EtOAc) The magnesium was dried, and the desiccant was removed by suction filtration, and the filtrate was concentrated under reduced pressure to give the title product, 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6, 7,8-Hexahydro-pyrrolo[3,2-c]azepine-2-carboxylic acid tert-butyl ester 32b (105 mg, colorless oil) was taken directly to the next step.

MS m/z (ESI): 376·2(Μ+1)。第三步 MS m/z (ESI): 376·2 (Μ +1). third step

3-甲基 -5-(2-哌啶 -1-基-乙基) -5,6，7，8-四氢 -1H-吡咯并 [3，2-c] 吖庚因 -4-酮氩气氛下，将 3-甲基 -4-氧代 -5-(2-哌啶 -1-基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3，2-c] 吖庚因 -2-羧酸叔丁酯 32b (953 mg， 2.54 mmol)搅拌下溶解于 3 ml乙醇中，冰浴冷却，滴加 3.2 1111盐酸(12_∞01/1^，加毕，撤去冰浴，反应体系于 60Ό油浴中反应 1 小时。点板表明原料反应完全，停止反应。反应液用氢氧化钠溶液 (10 mol/L)调节 pH至 7左右，混合物减压下蒸除乙醇，再用氢氧化钠溶液 (10 mol/L)调节混合物的 pH至 10，二氯甲垸萃取 (20 ml X 3)，合并有机相，有机相用饱和氯化钠溶液洗涤 (20 ml X I), 无水硫酸镁干燥，抽滤除去干燥剂，滤液减压浓缩后柱层析得到标题产物 3-甲基 -5-(2-哌啶 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3，2-c] 吖庚因 -4-酮 32c(395 mg, 白色固体)，产率： 57%。 3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 3-Methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3] under argon ,2-c] azepine-tert-butyl 2-carboxylate 32b (953 mg, 2.54 mmol) was dissolved in 3 ml of ethanol with stirring, cooled in an ice bath, and added dropwise with 3.2 1111 hydrochloric acid (12 _∞ 01/1^, After the addition, the ice bath was removed, and the reaction system was reacted in a 60-inch oil bath for 1 hour. The plate indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was adjusted to a pH of about 7 with a sodium hydroxide solution (10 mol/L), and the mixture was decompressed. Evaporate the ethanol, adjust the pH of the mixture to 10 with sodium hydroxide solution (10 mol/L), dichloromethane extract (20 ml X 3), combine the organic phases, and wash the organic phase with saturated sodium chloride solution ( 20 ml of XI), dried over anhydrous magnesium sulfate, and filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to give the title product 3-methyl-5-(2-piperidin-1-yl-ethyl) -5 , 6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 32c (395 mg, white solid), yield: 57%.

MS m/z (ESI)： 276.1 (M+l)。第四步 MS m/z (ESI): 276.1 (M+l). the fourth step

3-甲基 -4-氧代 -5-(2-哌啶 -1-基-乙基) -1,4,5，6,7，8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛氩气氛下，将二氯甲烷 (36 ml, 559 mmol)和 N， N-二甲基甲酰胺 (1.637 ml, 20.9 mmol)于 -15°C冰盐中搅拌 5分钟，滴加三氯氧磷 (1.07 ml， 11.5 mmol)，控制反应体系温度在 -10°C搅拌 15分钟。将 3-甲基 -5-(2-哌啶 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 32c(L26 g， 4.58 mmol)搅拌下溶解于 10 ml二氯甲烷中，滴加到上述反应体系中，加毕，撤去冰盐浴，反应体系于室温下搅拌 3 小时。点板监测反应至原料反应完全，加冰淬灭反应。反应液用氢氧化钠溶液 (10 mol/L)调节 pH至 10左右，继续搅拌 30分钟，混合物用二氯甲烷萃取 (30 ml X 3)，合并有机相，有机相用饱和氯化钠溶液洗涤 (30 mi x 1)，用无水硫酸镁干燥，抽滤除去干燥剂，滤液减压浓缩后柱层析得到标题产物 3-甲基 -4-氧代 -5-(2-哌啶 -1-基- 乙基) -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 32d(993 mg，浅黄色固体)，产率： 71.4% 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c] Acetone (2-3 ml, 559 mmol) and N,N-dimethylformamide (1.637 ml, 20.9 mmol) were stirred in ice salt at -15 ° C for 5 min. Phosphorus oxychloride (1.07 ml, 11.5 mmol) was added dropwise, and the temperature of the reaction system was controlled to stir at -10 ° C for 15 minutes. 3-Methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4- The ketone 32c (L26 g, 4.58 mmol) was dissolved in 10 ml of dichloromethane with stirring, and added dropwise to the above reaction system. After the addition, the ice salt bath was removed, and the reaction system was stirred at room temperature for 3 hours. The reaction was monitored by spotting until the reaction of the starting material was complete, and the reaction was quenched with ice. The reaction solution was adjusted to pH 10 with sodium hydroxide solution (10 mol/L), stirring was continued for 30 minutes, the mixture was extracted with dichloromethane (30 ml X 3), and the organic phase was combined. The organic phase was washed with saturated sodium chloride solution. (30 mi x 1), dried over anhydrous magnesium sulfate, filtered, filtered, evaporated, evaporated, evaporated. -yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d (993 mg, pale yellow solid), yield : 71.4%

MS m/z (ESI): 304.1(M+1)。第五步 MS m/z (ESI): 304.1 (MI). the fifth step

2-(5-氟 -2-氧代 -1,2-二氢』引哚 -3-次甲基 )-3-甲基 -5-(2-呃啶小基-乙基) -5,6,7,8-四氢2-(5-fluoro-2-oxo-1,2-dihydroindol-3-pyridyl-3-methyl)-3-methyl-5-(2-acridine-yl-ethyl)-5, 6,7,8-tetrahydrogen

-1H-吡咯并 [3,2-c] 吖庚因 -4-酮 -1H-pyrrolo[3,2-c] azepine-4-ketone

室温下，将 3-甲基 -4-氧代 -5-(2-哌啶小基-乙基) -1,4,5，6,7，8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 32d (50mg, 0.165 mmol)和 5-氟 -1,3-二氢-卩引哚 -2-酮 (22.4 mg, 0.15 mmol)搅拌下溶解于 0.3 ml乙醇中。加入六氢吡啶 (0.05 ml, 0.5 mmol), 加毕，于 40~50°C油浴中反应 5小时。点板监测反应至原料反应完全，停止反应。反应液减压抽滤得到黄色固体，此固体中加入 2 ml乙醇，加热回流 30分钟，混合物冷却至

'(¾ -¾ε¾8εοτ〜6θοτ '(N¾D— x 'He ¾^i£-£~68re '(Μ¾Ο- ^;^ ¾s 'ι)9ες·ε〜ί ^·ε '(Ο=ΗΟ- ¾Ϊ ^)6QL9 '(HW-3-methyl-4-oxo-5-(2-piperidinyl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2- at room temperature c] azepine-2-carbaldehyde 32d (50mg, 0.165 mmol) and 5-fluoro-1,3-dihydro-indole-2-one (22.4 mg, 0.15 mmol) dissolved in 0.3 ml of ethanol with stirring . Hexahydropyridine (0.05 ml, 0.5 mmol) was added, and the reaction was carried out for 5 hours in an oil bath at 40-50 °C. The plate was monitored until the reaction of the starting material was complete and the reaction was stopped. The reaction solution was filtered under reduced pressure to give a yellow solid.

'(3⁄4 -3⁄4ε3⁄48εοτ~6θοτ '(N3⁄4D— x 'He 3⁄4^i£-£~68re '(Μ3⁄4Ο- ^;^ 3⁄4s 'ι)9ες·ε~ί ^·ε '(Ο=ΗΟ- 3⁄4Ϊ ^) 6QL9 '(HW-

¾Ι 'Ρ)ε68·9~1^8·9 '(PPV- ¾Ι ^cp)AI0-L~866'9 'Ηΐ ^XLZL-ZiTL '(HPV-3⁄4Ι 'Ρ) ε68·9~1^8·9 '(PPV- 3⁄4Ι ^c p)AI0-L~866'9 'Ηΐ ^XLZL-ZiTL '(HPV-

¾ΐ '^)09£- L-90^C L '(W - ¾1 ^e^)l9VL-6ZVL '(WV- ¾ΐ ^OWL^WL '(ΗΝ- 'Ηΐ 's)0£rU '(ΗΝ-^Ι¾ΐ¾ϋ 'HI '^s)0^-£l 9 (9P"OS^a ¾JW Οθ ^^ΝΗ^

3⁄4ΐ '^)09£- L-90 ^C L '(W - 3⁄41 ^e ^)l9VL-6ZVL '(WV- 3⁄4ΐ ^OWL^WL '(ΗΝ- 'Ηΐ 's)0£rU '(ΗΝ-^Ι3⁄4ΐ3⁄4ϋ 'HI ' ^s )0^-£l 9 (9P"OS^a 3⁄4JW Οθ ^^ΝΗ^

°%6'08 '(棚 '^Sm κ)εε醒 -1/-Ξ¾αϋ [3-ζ'ε]#¾ ϋ-Ηΐ-霄 -8 '9'£-(¾2- -ΐ-¾1τζ - - -ε- [愛

i 本 ¾ ρζε °%6'08 '(shed ' ^Sm κ)εε醒-1/-Ξ3⁄4αϋ [3-ζ'ε]#3⁄4 ϋ-Ηΐ-霄-8 '9'£-(3⁄42- -ΐ-3⁄41τζ - - - Ε- [love

i 本3⁄4 ρζε

2-¾十¾¾- - -¾由-£-[¾由^-£-¾1&1-¾二-2'1-^¾- -(¾¾ -鹭二 -ε¾寸 2-3⁄4 十3⁄43⁄4 - -3⁄4 by -£-[3⁄4 by ^-£-3⁄41&1-3⁄4二-2'1-^3⁄4- - (3⁄43⁄4 - 鹭二-ε3⁄4 inch

' (¾D- M

' (N¾D- X £ ¾9 ¾ i 乙〜 98£·ζ ' (¾ _ ^_:¾ΐ¾ϋ ¾£ ^ZWZ '(D=D^ZUD-^^ 'IK ¾8S6 ~S26'2 '(¾ -¾K繊缉 ^ ^ ¾Z ¾^5 -£~93 '£ '(Κ¾0- Ε^ 'HZ ¾ S'£~6£S'£ '(iPV- ¾l 'Ρ)乙 98'9〜7£89 '(HJV- 'HI '∞)£96·9~ 6'9 '( =ΗΟ_ ¾ΐ ^)0^ L '(IPV. 'Ηΐ ^CVV)6L L~6H' L '(HN_ ¾ΐ|έϋ ¾ΐ 's)006'0l '(ΗΝ-4ϊ¾ί ϋ 'HI

' (3⁄4D- M

'(N3⁄4D- X £ 3⁄49 3⁄4 i B ~ 98£·ζ ' (3⁄4 _ ^ _: 3⁄4ΐ3⁄4ϋ 3⁄4£ ^ZWZ '(D=D ^Z UD-^^ 'IK 3⁄48S6 ~S26'2 '(3⁄4 -3⁄4K繊缉^ ^ 3⁄4Z 3⁄4^5 -£~93 '£ '(Κ3⁄40- Ε^ 'HZ 3⁄4 S'£~6£S'£ '(iPV- 3⁄4l 'Ρ) B 98'9~7£89 '(HJV- 'HI '∞) £96·9~ 6'9 '( =ΗΟ_ 3⁄4ΐ ^)0^ L '(IPV. 'Ηΐ ^C VV)6L L~6H' L '(HN_ 3⁄4ΐ|έϋ 3⁄4ΐ 's)006' 0l '(ΗΝ-4ϊ3⁄4ί ϋ 'HI

°(Ι+Μ)ΓΑ£17 ⁵(ISH)Z∞S1A[ °(Ι+Μ)ΓΑ£17 ⁵ (ISH)Z∞S1A[

¾Τΰ-3)-5-¾-ώ-ε-(¾ώ^-ε-¾ιΐ^-¾--ε'ΐ-¾->¾-^- -5Η ^ m mm^ 3⁄4Τΰ-3)-5-3⁄4-ώ-ε-(3⁄4ώ^-ε-3⁄4ιΐ^-3⁄4--ε'ΐ-3⁄4->3⁄4-^- -5Η ^ m mm^

ZSei00800ZN3X3d Z£Z8Cl/800Z OAV 实施例 34 ZSei00800ZN3X3d Z£Z8Cl/800Z OAV Example 34

2_[₅_(4-甲氧基 -苯基 )-₂_氧代 _1,2-二氢 -吲哚 -3-次甲基 ]-3-甲基 -5-(2-哌啶 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3 -c] 吖庚因 -4-酮 2_ _[5 _ (4-methoxy - phenyl) - _2-oxo _1,2- _ dihydro - indol-3-methylene] -3-methyl-5- (2-piperidin - 1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3 -c]azepin-4-one

重复本发明实施例 32第五步反应，不同的是使用实施例 32第四步所得化合物 3-甲基 -4-氧代 -5-(2-哌啶 -1-基-乙基) -1,4，5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 32d和 5-(4-甲氧基 -苯基 )-1,3-二氢 -吲哚 -2-酮作原料，得到标题产物 2-[5-(4-甲氧基 -苯基 )-2-氧代 -1,2-二氢 -Π引哚 -3-次甲基 ]-3-甲基 -5-(2-哌啶 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 34(68 mg，黄色固体)，产率： 68.7%。

The fifth step reaction of Example 32 of the present invention was repeated except that the compound obtained in the fourth step of Example 32 was used. 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1 ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d and 5-(4-methoxy-phenyl)-1,3-di Hydrogen-inden-2-one was used as a starting material to give the title product 2-[5-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indole-3-indol. 3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c] azepine- 4-ketone 34 (68 mg, yellow solid), Yield: 68.7%.

MS m/z (ESI): 525.2(M+1)。 MS m/z (ESI): 525.2 (M+1).

iHNMR OO MHz, DMSO-d6) δ 13.653(s, 1H, 吡咯环 -NH)， 11.003(s, 1H, 吲哚 -NH), 7.930~7.850(d, 1H, -ArH)， 7.668(s, 1H , -CH=C), 7.583~7.605(d, 2H, -ArH), 7.251~7.274(d, 1H, -ArH) , 7.017-7.07 l(m, 3H, -ArH) , 3.804(s, 3H, -CH₃0)， 3.541~3.574(t, 2H, 七环内 -CH₂N)， 3.343(t, 2H, 七环外接酰胺氮 -CH₂)， 2.926~2.962(t, 2H,七环内 -CH₂C=C)， 2.386~2.449(m, 9H,吡咯环 -C¾, 3 X - C¾N)， 2.062(m, 2H，七环内 -CH₂)， 1.475-1.487(m, 4H,六环 2 X - CH₂)， 1.379-1.391 (m, 2H, 六环 -CHy。实施例 35 iHNMR OO MHz, DMSO-d6) δ 13.653 (s, 1H, pyrrole ring-NH), 11.003 (s, 1H, 吲哚-NH), 7.930~7.850 (d, 1H, -ArH), 7.668(s, 1H , -CH=C), 7.583~7.605(d, 2H, -ArH), 7.251~7.274(d, 1H, -ArH) , 7.017-7.07 l(m, 3H, -ArH) , 3.804(s, 3H, -CH ₃ 0), 3.541~3.574(t, 2H, hepta-CH ₂ N), 3.343(t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.926~2.962(t, 2H, 7-ring -CH ₂ C=C), 2.386~2.449 (m, 9H, pyrrole ring-C3⁄4, 3 X - C3⁄4N), 2.062 (m, 2H, hepta-CH ₂ ), 1.475-1.487 (m, 4H, Ring 2 X - CH ₂ ), 1.379-1.391 (m, 2H, hexa-CHy. Example 35

₂_₍₅_氯 _₂_氧代 _1 ,2-二氢 -B引哚 -3-次甲基) -3-甲基 -5-(2-哌啶 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 - -酮 ₂ _ _{(_} ₂ _ ₅ _ chloro-oxo _1, 2-dihydro-indol -3- -B methine) -3-methyl-5- (2-piperidin-1-yl-ethyl) - -5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-ketone

重复本发明实施例 32第五歩反应，不同的是使用实施例 32第四步所得化合物 ₃_甲基 _₄_氧代 _5-(2-哌啶 -1-基-乙基) -1，4,5,6,7,8-六氯-吡咯并 [3,2-c] 吖庚因 -2-甲醛 32d和 5-氯 -1,3-二氢 -吲哚 -2-酮作原料，得到标题产物 2-(5-氯 -2-氧代 -1,2-二氢-吲哚 -3-次甲基 )-3-甲基 -5-(2-哌啶 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 35(44 mg, 黄色固体)，产率： 64.8%。

The fifth oxime reaction of Example 32 of the present invention was repeated except that the compound ₃ _methyl- ₄ oxo-5-(2-piperidin-1-yl-ethyl)-1 obtained in the fourth step of Example 32 was used. ,4,5,6,7,8-hexachloro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d and 5-chloro-1,3-dihydro-indol-2-one Starting material, the title product 2-(5-chloro-2-oxo-1,2-dihydro-indol-3-methyl)-3-methyl-5-(2-piperidin-1-yl) -ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c] azepine 4-ketone 35 (44 mg, yellow solid), Yield: 64.8%.

MS m/z (ESI)： 453.2(M+1)。 MS m/z (ESI): 453.2 (M + 1).

¹HNMR(400 MHz, DMSO-d6) δ 13.674(s, IH,吡咯环 -NH)， 11.003(s, IH,吲哚 -NH)， 7.989(s, IH, -ArH), 7.799(s, IH, -CH=C), 7.135〜7.155(d, IH, -ArH) , 6869~6.890(d, IH, -ArH), 3.545~3.576(t, 2H,七环内 - CH₂N)， 3.313-3.342(t, 2H,七环外接酰胺氮 -CH₂)， 2.925~2.962(t, 2H,七环内 -CH₂C=C)， 2.399~2.459(m, 9H, 吡咯环 -CH₃, 3 X- CH₂N)， 2.047~2.074(t, 2H,七环内 -CH₂)， 1.490(m, 4H,六环 2 X -CH₂), 1.385(m, 2H,六环 -CH₂)。实施例 36 ¹ H NMR (400 MHz, DMSO-d6) δ 13.674 (s, IH, pyrrole ring-NH), 11.003 (s, IH, 吲哚-NH), 7.989 (s, IH, -ArH), 7.799 (s, IH) , -CH=C), 7.135~7.155(d, IH, -ArH), 6869~6.890(d, IH, -ArH), 3.545~3.576(t, 2H, seven-ring-CH ₂ N), 3.313- 3.342(t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.925~2.962 (t, 2H, hepta-CH ₂ C=C), 2.399~2.459 (m, 9H, pyrrole ring-CH ₃ , 3 X-CH ₂ N), 2.047~2.074 (t, 2H, hepta-CH ₂ ), 1.490 (m, 4H, 6-ring 2 X -CH ₂ ), 1.385 (m, 2H, hexa-CH ₂ ) . Example 36

2-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-3-甲基 -5-(2-哌啶 -1-基 -乙基 )-5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 2-(5-Bromo-2-oxo-1,2-dihydro-indol-3-methyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)- 5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one

重复本发明实施例 32第五步反应，不同的是使用实施例 32第四步所得化合物

The fifth step reaction of Example 32 of the present invention was repeated except that the compound obtained in the fourth step of Example 32 was used.

3-甲基 -4-氧代 -5-(2-哌啶 -1-基-乙基) -1,4，5，6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 32d和 5-溴 -1,3-二氢 -吲哚 -2-酮作原料，得到标题产物 2-(5-溴 -2-氧代 -1,2-二氢』引哚 -3-次甲基 )-3-甲基 -5-(2-哌啶 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-K 36(43 mg, 黄色固体)，产率： 57.6%。 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c] The desired product 2-(5-bromo-2-oxo-1,2-dihydrogen) was obtained as a starting material from aq. 』哚哚-3-Methyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3, 2-c] azepine-4-K 36 (43 mg, yellow solid), yield: 57.6%.

MS m/z (ESI): 497.2(M+1)。 MS m/z (ESI): 497.2 (M+1).

¹HNMR(400 MHz, DMSO-d6) δ 13.670(s, IH,吡咯环 -NH)， 11.010(s, IH, 吲哚 -NH)， 8.114(s, IH, -ArH), 7.802(s, IH, -CH=C), 7.262~7.283(d, IH, -ArH), 6.826~6.846(d, IH, -ArH), 3.542~3.574(t, 2H,七环内 -CH₂N)， 3.315~3.339(t, 2H,七环外接酰胺氮 -CH₂)， 2.924~2.960(t, 2H,七环内 -CH₂C=C)， 2.389~2.460(m, 9H,吡咯环 -CH₃, 3 X - CH₂N)， 2.045~2.074(t, 2H,七环内 -CH₂)， 1.476-1.489(m, 4H,六环 2 X-CH₂), 1.381(m, 2H,六环 -CH₂)。实施例 37 ¹ H NMR (400 MHz, DMSO-d6) δ 13.670 (s, IH, pyrrole ring-NH), 11.010 (s, IH, 吲哚-NH), 8.114 (s, IH, -ArH), 7.802 (s, IH) , -CH = C), 7.262 ~ 7.283 (d, IH, -ArH), 6.826 ~ 6.846 (d, IH, -ArH), 3.542 ~ 3.574 (t, inner 2H, heptacyclo -CH ₂ N), 3.315 ~ 3.339(t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.924~2.960 (t, 2H, hepta-CH ₂ C=C), 2.389~2.460 (m, 9H, pyrrole ring-CH ₃ , 3 X - CH ₂ N), 2.045~2.074 (t, 2H, hepta-CH ₂ ), 1.476-1.489 (m, 4H, Hexa 2 X-CH ₂ ), 1.381 (m, 2H, Hexa-CH ₂ ). Example 37

N-{5-氟 -3-[3-甲基 -4-氧代 -5-(2-哌啶 -1-基-乙基) -1,4，5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -6-基}-2-甲氧基-乙酰胺 001352 N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro -pyrrolo[3,2-c]azepine-2-methylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-B Amide 001352

重复本发明实施例 32第五步反应，不同的是使用实施例 32第四步所得化合物 3-甲基 -4-氧代 -5-(2-哌啶 -1-基-乙基) -1,4,5，6,7，8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 32d和本发明实施例 7第一步所得化合物 N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基) -2- 甲氧基-乙酰胺 7a作原料，得到标题产物 N-{5-氟 -3-[3-甲基 -4-氧代 -5-(2-哌啶 -1-基 -乙基 )-1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -6-基 2-甲氧基-乙酰胺 37(59 mg，黄色固体)，产率: 75%。

The fifth step reaction of Example 32 of the present invention was repeated except that the compound obtained in the fourth step of Example 32 was used. 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1 , 4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d and the compound N-(5-fluoro-2) obtained in the first step of the present invention -Oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide 7a as the starting material to give the title product N-{5-fluoro-3-[3-methyl 4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c] azepine- 2-Methylene]-2-oxo-2,3-dihydro-1H-indol-6-yl 2-methoxy-acetamide 37 (59 mg, yellow solid), yield: 75%.

MS m/z (ESI): 524.2(M+1)。MS m/z (ESI): 524.2 (M + 1).

MHz, DMSO-d6 ) δ 13.613(s, 1H, 吡咯环 -NH)， 10.890(s, 1H，吲哚 -NH)， 9.316(s, 1H, -NHCO), 7.835~7.863(d, 1H, -ArH)， 7.668(s, 1H, -CH=C)， 7.542~7.558(d, 1H， -ArH), 4.064(s, 2H, -CH₂0)， 3.540~3.572(t, 2H,七环内 -CH₂N), 3.406(s, 3H, CH₃0), 3.315-3.340(t, 2H,七环外接酰胺氮 -CH₂)， 2.918~2.954(t, 2H, 七环内 -CH₂C=C), 2.390~2.467(m, 9H,吡咯环 -CH₃, 3 X_CH₂N)， 2.043~2.072(t， 2H, 七环内 -CH₂)， 1.478-1.490(m, 4H,六环 2 X- CH₂)， 1.382-1.393(m, 2H,六环 -CH₂)。实施例 38

MHz, DMSO-d6) δ 13.613(s, 1H, pyrrole ring-NH), 10.890(s, 1H, 吲哚-NH), 9.316(s, 1H, -NHCO), 7.835~7.863(d, 1H, - ArH), 7.668(s, 1H, -CH=C), 7.542~7.558(d, 1H, -ArH), 4.064(s, 2H, -CH ₂ 0), 3.540~3.572(t, 2H, 7-ring -CH ₂ N), 3.406 (s, 3H, CH ₃ 0), 3.315-3.340 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.918~2.954 (t, 2H, hepta-CH ₂ C =C), 2.390~2.467 (m, 9H, pyrrole ring-CH ₃ , 3 X_CH ₂ N), 2.043~2.072 (t, 2H, hepta-CH ₂ ), 1.478-1.490 (m, 4H, 6 ring 2 X-CH ₂ ), 1.382-1.393 (m, 2H, hexa-CH ₂ ). Example 38

N-{5-氟 -3-[3-甲基 -4-氧代 -5-(2-哌啶 -1-基-乙基) -1,4,5,6，7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3-二 -1H-吲哚 -6-基 }-2-羟基-丙酰胺 N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro -pyrrolo[3,2-c]azepine-2-methylene]-2-oxo-2,3-di-1H-indol-6-yl}-2-hydroxy-propionamide

重复本发明实施例 32第五步反应，不同的是使用实施例 32第四步所得化合物 3-甲基 -4-氧代 -5-(2-哌啶 -1-基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 32d和本发明实施例 8第二步所得化合物 N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基) -2- 羟基-丙酰胺 8b作原料，得到标题产物 N-{5-氟 -3-[3-甲基 -4-氧代 -5-(2-哌啶 -1-基- 乙基) -1,4,5,6,7,8-六氣 -B比咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -6- 基}-2-羟基-丙酰胺 38(49 mg，黄色固体)，产率： 62.5 %。 MS m/z (ESI): 524.2(M+1)。

The fifth step reaction of Example 32 of the present invention was repeated except that the compound obtained in the fourth step of Example 32 was used. 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1 , 4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d and the compound N-(5-fluoro-2) obtained in the second step of Example 8 of the present invention -Oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide 8b as a starting material to give the title product N-{5-fluoro-3-[3-methyl-4 -oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexa-B ratio [3,2-c] azepine- 2-Methylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-propionamide 38 (49 mg, yellow solid), yield: 62.5 %. MS m/z (ESI): 524.2 (M + 1).

¹HNMR(400 MHz, DMSO-d6) δ 13.603(s, 1H,吡咯环 -NH)， 10.900(s, 1H, 吲哚 -NH), 9.246(s, 1H, -NH)， 7.853~7.881(d, 1H, -ArH), 7.726~7.743(d, 1H, -ArH), 7.659(s, 1H, -CH=C), 6.058~6.070(d, 1H, -OH), 4.207~4.237(m, 1H, -CHO), 3.541~3.573(t, 2H, 七环内 -CH₂N)， 3.326~3.354(t, 2H, 七环外接酰胺氮 -CH₂)， 2.917〜2.954(t， 2H,七环内 -CH₂C=C)， 2.392〜2.440(m, 9H,吡咯环 -CH₃, 3 X - CH₂N)， 2.025~2.089(t, 2H,七环内 -C¾)， 1.478-1.490(m, 4H,六环 2 X - CH₂)， 1.383 (m, 2H, 六环 -CH₂)， 1.330-1.347(d, 3H， CH₃0)。实施例 39 ¹ H NMR (400 MHz, DMSO-d6) δ 13.603 (s, 1H, pyrrole ring-NH), 10.900 (s, 1H, 吲哚-NH), 9.246 (s, 1H, -NH), 7.853~7.881 (d , 1H, -ArH), 7.726~7.743(d, 1H, -ArH), 7.659(s, 1H, -CH=C), 6.058~6.070(d, 1H, -OH), 4.207~4.237(m, 1H , -CHO), 3.541~3.573(t, 2H, hepta-CH ₂ N), 3.326~3.354(t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.917~2.954(t, 2H, seven rings -CH ₂ C=C), 2.392~2.440 (m, 9H, pyrrole ring-CH ₃ , 3 X - CH ₂ N), 2.025~2.089 (t, 2H, hepta-C3⁄4), 1.478-1.490 ( m, 4H, Hexa 2 X - CH ₂ ), 1.383 (m, 2H, Hexa-CH ₂ ), 1.330-1.347 (d, 3H, CH ₃ 0). Example 39

N-{3-[5-(2-二甲氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 亚甲基 ]-5-氟 -2-氧代 -2,3-二氢 - -吲哚 -6-基}-2-甲氧基-乙酰胺 N-{3-[5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2 -c] azepine-2-methylidene-5-fluoro-2-oxo-2,3-dihydro-indol-6-yl}-2-methoxy-acetamide

重复本发明实施例 23第四步反应，不同的是使用实施例 23第三步所得化合物

The fourth step reaction of Example 23 of the present invention was repeated except that the compound obtained in the third step of Example 23 was used.

5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 23c和本发明实施例 7第一步中所得到的化合物 N-(5-氟 -2-氧代 -2,3-二氧 -1H-吲哚 -6-基) -2-甲氧基-乙酰胺 7a作原料，得到标题产物 N-{3-[5-(2-二甲氨基-乙基) -3- 甲基斗氧代 -1,4，5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基 }-2-甲氧基-乙酰胺 39(75 mg，黄褐色固体)，产率： 76.5 %。 5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c] The compound N-(5-fluoro-2-oxo-2,3-dioxo-1H-indol-6-yl)-2 obtained from 2-carbaldehyde 23c and the first step of Example 7 of the present invention -Methoxy-acetamide 7a as a starting material to give the title product N-{3-[5-(2-dimethylamino-ethyl)-3-methylindole-1,4,5,6,7 ,8-hexahydro-pyrrolo[3,2-c]azepine-2-methylene]-5-fluoro-2-oxo-2,3-dihydro-1H-purin-6-yl }-2-methoxy-acetamide 39 (75 mg, tan solid), Yield: 76.5 %.

MS m/z (ESI): 484.1(M+1)。 MS m/z (ESI): 484.1 (MI).

'HNMR OO MHz, DMSO-d6) δ 13.607(s, 1H,吡咯环 -NH)， 10.894(s, 1H, 吲哚 -NH), 9.320(s, 1H， -NHCO), 7.840~7.868(d, 1H, -ArH), 7.673(s, 1H, -CH=C)， 7.540〜7.557(d, 1H, -ArH), 4.064(s, 2H, -CH₂0)， 3.531-3.564 (t, 2H,七环接氮 -CH₂)， 3.406(s, 3H， -CH₃0)， 3.333~3.359(t, 2H, 七环外接酰胺氮 -CH₂)， 2.904-2.941 (t, 2H, -CH₂C=C) , 2.445(s, 3H, 吡咯环 _CH₃)， 2.404~2.420(t, 2H, -CH₂N)， 2.206(s, 6H, 2 X -CH₃N), 2.029~2.057 (m, 2H,七环内 - CH₂)。实施例 40 'HNMR OO MHz, DMSO-d6) δ 13.607 (s, 1H, pyrrole ring-NH), 10.894 (s, 1H, 吲哚-NH), 9.320 (s, 1H, -NHCO), 7.840~7.868 (d, 1H, -ArH), 7.673(s, 1H, -CH=C), 7.540~7.557(d, 1H, -ArH), 4.064(s, 2H, -CH ₂ 0), 3.531-3.564 (t, 2H, Hexacyclic nitrogen-CH ₂ ), 3.406 (s, 3H, -CH ₃ 0), 3.333~3.359 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.904-2.941 (t, 2H, -CH ₂ C=C), 2.445(s, 3H, pyrrole ring_CH ₃ ), 2.404~2.420(t, 2H, -CH ₂ N), 2.206(s, 6H, 2 X -CH ₃ N), 2.029~2.057 ( m, 2H, within the seven-ring - CH ₂ ). Example 40

2-[4-(2,6-二氟-苯基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-5-(2-二甲氨基-乙基) -3-甲基 -5,6，7，8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮

重复本发明实施例 23第四步反应，不同的是使用实施例 23第三步所得化合物 5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6，7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 23c和 4-(2,6-二氟-苯基) -1,3-二氢 -B引哚 -2-酮作原料，得到标题产物 2-[4-(2,6-二氟-苯基) -2-氧代 -1,2-二氢』引哚 -3-次甲基 ]-5-(2-二甲氨基-乙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 40(36 mg，橙黄色固体)，产率： 36.4%。 2-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-5-(2-dimethylamino-ethyl -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one

The fourth step reaction of Example 23 of the present invention was repeated except that the compound obtained in the third step of Example 23 was used. 5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4 ,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c and 4-(2,6-difluoro-phenyl)-1,3-dihydrogen -B-anthracene-2-one was used as a starting material to obtain the title product 2-[4-(2,6-difluoro-phenyl)-2-oxo-1,2-dihydro] 哚-3-次甲5-(2-dimethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 40 (36 mg, orange solid), Yield: 36.4%.

MS m/z (ESI): 491·1(Μ+1)。 MS m/z (ESI): 491·1 (Μ +1).

^XHNMR(400 MHz, DMSO-d6) δ 13.552(s, IH,吡咯环 -NH)， 11.075(s, IH, 吲哚 -NH)， 7.66 l(m, IH, -ArH), 7.338~7.378(m, 2H, -ArH), 7.238~7.277(m, 1H， -ArH), 7.008~7.027(m, IH, -ArH) , 6.895~6.914(d, IH, -ArH) , 6.652(s, IH, -CH=C) , 3.488~3.522(t, 2H, 七环接氮 -CH₂)， 3.280-3.316(t, 2H, 七环外接酰胺氮 -C¾)， 2.868~2.904(t, 2H, -CH₂C=C)， 2.355~2.388(t, 2H, -C¾N)， 2.171(s, 6H, 2 X-CH₃N), 1.992-2.021 (m, 2H,七环内 - CH₂)， 1.764(s, 3H,吡咯环 -C¾)。实施例 41 ^X H NMR (400 MHz, DMSO-d6) δ 13.552 (s, IH, pyrrole ring-NH), 11.075 (s, IH, 吲哚-NH), 7.66 l (m, IH, -ArH), 7.338~7.378 ( m, 2H, -ArH), 7.238~7.277(m, 1H, -ArH), 7.008~7.027(m, IH, -ArH), 6.895~6.914(d, IH, -ArH) , 6.652(s, IH, -CH=C) , 3.488~3.522(t, 2H, heptacyclic nitrogen-CH ₂ ), 3.280-3.316(t, 2H, heptacyclic external amide nitrogen-C3⁄4), 2.868~2.904(t, 2H, -CH ₂ C=C), 2.355~2.388(t, 2H, -C3⁄4N), 2.171(s, 6H, 2 X-CH ₃ N), 1.992-2.021 (m, 2H, hepta-CH ₂ ), 1.764 ( s, 3H, pyrrole ring-C3⁄4). Example 41

5-(2-二甲氨基 -乙基 )-2-[4-(3-氟-苯基) -2-氧代 -1,2-二氢-吲哚 -3-次甲基] -3-甲基 -5,6,7,8-四氢 -IH-吡咯并 [3，2-c] -4-酮 5-(2-Dimethylamino-ethyl)-2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-methylol]-3 -methyl-5,6,7,8-tetrahydro-IH-pyrrolo[3,2-c]-4-one

重复本发明实施例 23第四步反应，不同的是使用实施例 23第三步所得化合物 5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 23c和 4-(3-氟-苯基) -1,3-二氢 -B引哚 -2-酮作原料，得到标题产物 5-(2-二甲氨基- 乙基) _₂_[₄_₍₃_氟 -苯基〉_₂_氧代 _1，2-二氢 -吲哚 -3-次甲基 ]-3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 41(37 mg，黄色固体)，产率： 38.9%。

The fourth step reaction of Example 23 of the present invention was repeated except that the compound obtained in the third step of Example 23 was used. 5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4 ,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c and 4-(3-fluoro-phenyl)-1,3-dihydro-B The indole-2-one was used as a starting material to give the title product 5-(2-dimethylamino-ethyl) _ ₂ _[ ₄ _ ₍₃ _fluoro-phenyl>_ ₂ _oxo-1,2-dihydro- Indole-3-methyl-methyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 41 (37 mg, yellow Solid), Yield: 38.9%.

MS m/z (ESI): 473.2(M+1)。 MS m/z (ESI): 473.2 (M + 1).

'HNMR(400 MHZ, DMSO-d6) δ 13.533(s, IH,吡咯环 -NH) , 11.075(s, IH,吲哚 -NH)， 7.595~7.610(m, IH, -ArH), 7.286~7.343(m, 3H, -ArH), 7.191~7.229(m, IH, -ArH), 6.942~6.962(d, IH, -ArH), 6.830~6.844(d, 1H， -ArH), 6.811(s, IH, -CH=C), 3.488~3.521(t, 2H, 七环接氮 -CH₂)， 3.277-3.315(t, 2H, 七环外接酰胺氮 -C¾)， 2.859~2.896(t, 2H, -CH₂C=C)， 2.361~2.394(t, 2H, -CH₂N), 2.176(s, 6H, 2 X- CH₃N)， 1.989〜2.018(m, 2H,七环内 - CH₂)， 1.774(s, 3H,吡咯环 -CH₃)。实施例 42 'HNMR (400 MHZ, DMSO-d6) δ 13.533 (s, IH, pyrrole ring-NH), 11.075 (s, IH, 吲哚-NH), 7.595~7.610 (m, IH, -ArH), 7.286~7.343 (m, 3H, -ArH), 7.191~7.229 (m, IH, -ArH), 6.942~6.962(d, IH, -ArH), 6.830~6.844(d, 1H, -ArH), 6.811(s, IH, -CH=C), 3.488~3.521(t, 2H, 7-ring Nitrogen-CH ₂ ), 3.277-3.315 (t, 2H, heptacyclic external amide nitrogen-C3⁄4), 2.859~2.896 (t, 2H, -CH ₂ C=C), 2.361~2.394(t, 2H, -CH ₂ N), 2.176(s, 6H, 2 X-CH ₃ N), 1.989~2.018 (m, 2H, hepta-CH ₂ ), 1.774 (s, 3H, pyrrole ring -CH ₃ ). Example 42

2-[4-(2,3-二氟-苯基) -2-氧代 -1,2-二氢』引哚 -3-次甲基 ]-5-(2-二甲氨基-乙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] -4-酮 2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro"indol-3-ylmethyl]-5-(2-dimethylamino-ethyl -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]-4-one

重复本发明实施例 23第四步反应，不同的是使用实施例 23第三步所得化合物 5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 23c和本发明实施例 6第三步中所得到的化合物 4-(2,3-二氟-苯基) -1,3-二氢 -吲哚 -2-酮 6d作原料，得到标题产物 2-[4-(2,3-二氟-苯基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基] -5-(2-二甲氨基-乙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 42(25 mg，黄色固体)，产率： 25.2%。

The fourth step reaction of Example 23 of the present invention was repeated except that the compound obtained in the third step of Example 23 was used. 5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4 , 5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxaldehyde 23c and the compound 4-(2,3-) obtained in the third step of Example 6 of the present invention Difluoro-phenyl)-1,3-dihydro-indol-2-one 6d was used as the starting material to give the title product 2-[4-(2,3-difluoro-phenyl)-2-oxo-1 ,2-dihydro-indol-3-methylol]-5-(2-dimethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[ 3,2-c] azepin-4-one 42 (25 mg, yellow solid), yield: 25.2%.

MS m/z (ESI): 491.2(M+1)。 MS m/z (ESI): 4921. (M+1).

tHNMR OO MHz, DMSO-d6) δ 13.532(s, IH,吡咯环 -NH), 11.132(s, IH, 吲哚 -NH), 7.618~7.640(m, IH, -ArH), 7.429~7.442(m, IH, -ArH), 7.306~7.340(m, IH, -ArH), 7.232-7.27 l(m, IH, -ArH), 6.998-7.017(d, IH, -ArH), 6.874~6.893(d, IH, -ArH), 6.712(s, 1H, -CH=C)， 3.491~3.525(t, 2H,七环接氮 -CH₂)， 3.292-3.315(t, 2H, 七环外接酰胺氮 -C¾)， 2.869~2.905(t, 2H, -CH₂C=C), 2.362~2.395(t, 2H, -CH₂N), 2.176(s, 6H, 2 X -CH₃N), 1.993-2.018(m, 2H,七环内 - CH₂)， 1.795(s, 3H₅吡咯环 _CH₃)。实施例 43 tHNMR OO MHz, DMSO-d6) δ 13.532 (s, IH, pyrrole ring-NH), 11.132 (s, IH, 吲哚-NH), 7.618~7.640 (m, IH, -ArH), 7.429~7.442 (m , IH, -ArH), 7.306~7.340(m, IH, -ArH), 7.232-7.27 l(m, IH, -ArH), 6.998-7.017(d, IH, -ArH), 6.874~6.893(d, IH, -ArH), 6.712(s, 1H, -CH=C), 3.491~3.525(t, 2H, heptacyclic nitrogen-CH ₂ ), 3.292-3.315(t, 2H, heptacyclic external amide nitrogen-C3⁄4 ), 2.869~2.905(t, 2H, -CH ₂ C=C), 2.362~2.395(t, 2H, -CH ₂ N), 2.176(s, 6H, 2 X -CH ₃ N), 1.993-2.018( m, 2H, heptacyclic-CH ₂ ), 1.795 (s, 3H ₅ pyrrole ring _CH ₃ ). Example 43

5-(2-二甲氨基-乙基) -2-[5-氟 -6-(4-氟-苄氨基) -2-氧代 -1,2-二氢』引哚 -3-次甲基 ]-3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮

重复本发明实施例 23第四步反应，不同的是使用实施例 23第三步所得化合物 5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 甲醛 23c和本发明实施例 3第四步所得化合物 5-氟 -6-(4-氟-苄氨基) -1，3-二氢 -吲哚 -2-酮 3e作原料，得到标题产物 5-(2-二甲氨基-乙基) -2-[5-氟 -6-(4-氟-节氣基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 43(50 mg, 红色固体)，产率： 43.7%。 5-(2-dimethylamino-ethyl)-2-[5-fluoro-6-(4-fluoro-benzylamino)-2-oxo-1,2-dihydroindol-3-pyrene 3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one

The fourth step of the reaction of Example 23 of the present invention was repeated, except that the compound obtained in the third step of Example 23 was used. 5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4 , 5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c and the compound obtained in the fourth step of the present invention, 5-fluoro-6-(4-fluoro -Benzylamino)-1,3-dihydro-indol-2-one 3e as a starting material to give the title product 5-(2-dimethylamino-ethyl)-2-[5-fluoro-6-(4- Fluorine-rhodium-based)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[ 3,2-c] azepin-4-one 43 (50 mg, red solid), yield: 43.7%.

MS m/z (ESI): 520·1(Μ+1)。 MS m/z (ESI): 520·1 (Μ +1).

!ΗΝΜΚ(400 MHz, DMSO-d6) δ 13.421(s, IH,吡咯环 -NH)， 10.523(s, 1H，吲哚 -NH)， 7.574~7.603(d, IH, -ArH), 7.367~7.402(m, 2H, -ArH), 7.513(s, IH, -CH=C), 7.142-7.186(m, 2H, -ArH) , 6.4 l(t, IH, -NH)， 6.041~6.059(d, IH, -ArH)， 4.348~4.362(d, 2H, 苯胺 -C¾)， 3.982~3.996(d, 2H, -C¾0)， 3.531-3.564 (t, 2H, 七环接氮 -CH₂)， 3.316-3.344(t, 2H, 七环外接酰胺氮 -CH₂)， 2.856~2.893(t, 2H, -CH₂C=C), 2.398-2.415(t, 2H, -CH₂N), 2.390(s, 3H,吡咯环 -CH₃)， 2.192(s, 6H, 2 X -CH₃N), 2.002~2.030(m, 2H,七环内 CH₂)。实施例 44 ΗΝΜΚ (400 MHz, DMSO-d6) δ 13.421 (s, IH, pyrrole ring-NH), 10.523 (s, 1H, 吲哚-NH), 7.574~7.603 (d, IH, -ArH), 7.367~7.402 (m, 2H, -ArH), 7.513(s, IH, -CH=C), 7.142-7.186(m, 2H, -ArH), 6.4 l(t, IH, -NH), 6.041~6.059(d, IH, -ArH), 4.348~4.362(d, 2H, aniline-C3⁄4), 3.982~3.996(d, 2H, -C3⁄40), 3.531-3.564 (t, 2H, heptacyclic nitrogen-CH ₂ ), 3.316- 3.344(t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.856~2.893(t, 2H, -CH ₂ C=C), 2.398-2.415(t, 2H, -CH ₂ N), 2.390(s, 3H, pyrrole ring-CH ₃ ), 2.192 (s, 6H, 2 X -CH ₃ N), 2.002~2.030 (m, 2H, CH _{2 in the} hepta). Example 44

N-{3-[5-(2-二甲氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 亚甲基 ]-2- -2,3-二氢 -1H-吲哚 -5-基 2-羟基-乙酰胺 N-{3-[5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2 -c] 吖gyne-2-methylene]-2- 2,3-dihydro-1H-indol-5-yl 2-hydroxy-acetamide

第一步

first step

乙酸（2-氧代 -2,3-二氢- 1H-吲哚 -5-氨基甲酰基)-甲酯室温下，将 5-氨基 -2-吲哚酮 30c(500 mg， 3.38 mmol)搅拌下溶解于 10 ml二氯甲垸中，用干冰-丙酮浴将溶液冷却至 -40°C，加入吡啶 (470 μ 1， 5 mmol)搅拌均匀。将乙酰氧基乙酰氯 (473 mg, 3.48 mmol)搅拌下溶解于 10 ml二氯甲烷中，缓慢滴加到上述反应液中，加毕，撤去干冰-丙酮浴，反应体系温度自然升至室温，搅拌过夜。点板监测反应至原料反应完全，停止反应。反应液过滤，滤饼用水洗漆 (10 ml X 3)后重结晶，得到标题产物乙酸（2-氧代 -2,3-二氢 -1H-吲哚 -5-氨基甲酰基) -甲酯 44a(510 mg，黄色固体)，产率： 60.7 %。 Stirring 5-amino-2-indanone 30c (500 mg, 3.38 mmol) at room temperature with (2-oxo-2,3-dihydro-1H-indol-5-carbamoyl)-methyl acetate The solution was dissolved in 10 ml of dichloromethane, the solution was cooled to -40 ° C with a dry ice-acetone bath, and pyridine (470 μl, 5 mmol) was added and stirred. Acetoxyacetyl chloride (473 mg, 3.48 mmol) was dissolved in 10 ml of dichloromethane with stirring, and slowly added dropwise to the above reaction solution. After the addition, the dry ice-acetone bath was removed, and the temperature of the reaction system was naturally raised to room temperature. Stir overnight. The plate was monitored until the reaction of the starting material was complete and the reaction was stopped. The reaction mixture was filtered, and the filter cake was washed with water (10 ml X 3) and then recrystallized to give the title product (2-oxo-2,3-dihydro-1H-indole-5-carbamoyl)-methyl ester 44a (510 mg, yellow solid), Yield: 60.7 %.

MS m/z (ESI): 247.7(M-l)c 笛一丄!^ MS m/z (ESI): 247.7(M-l)c Flute! ^

一少 One less

2-羟基 -N-(2-氧代 -2,3-二氢 -1H-吲哚 -5-基)-乙酰胺 2-hydroxy-N-(2-oxo-2,3-dihydro-1H-indole-5-yl)-acetamide

室温下，将乙酸（2-氧代 -2，3-二氢 -1H-吲哚 -5-氨基甲酰基) -甲酯 44a(2.43 g， 10 mmol)搅拌下溶解于 60 ml甲醇中，加入 20 ml氢氧化钠溶液 (2 mol/L)，搅拌过夜。点板监测反应至原料反应完全，停止反应。反应液于冰浴下用盐酸 (6 mol/L)中和，减压蒸除溶剂，所得固体柱层析后得到标题产物 2-羟基 -N-(2-氧代 -2,3-二氢 -1H-吲哚 -5-基) -乙酰胺 44b(402 mg，黄色固体)，产率- 19.5 %。 Ethyl acetate (2-oxo-2,3-dihydro-1H-indole-5-carbamoyl)-methyl ester 44a (2.43 g, 10 mmol) was dissolved in 60 ml of methanol with stirring at room temperature. 20 ml of sodium hydroxide solution (2 mol/L), stir overnight. The plate was monitored until the reaction of the starting material was complete and the reaction was stopped. The reaction solution was neutralized with hydrochloric acid (6 mol/L), and the solvent was evaporated under reduced pressure. -1H-indol-5-yl)-acetamide 44b (402 mg, yellow solid), yield - 19.5%.

MS m/z (ESI): 205·3(Μ-1)。第三步 MS m/z (ESI): 205·3 (Μ-1). third step

Ν-{3-[5-(2-二甲氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 亚甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -5-基}-2-羟基-乙酰胺 Ν-{3-[5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2 -c] azepine-2-methyl]-2-oxo-2,3-dihydro-1H-indol-5-yl}-2-hydroxy-acetamide

重复本发明实施例 23第四步反应，不同的是使用实施例 23第三步所得化合物 5-(2-二甲基氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3，2-c] 吖庚因 -2- 甲醛 23c和 2-羟基 -N-(2-氧代 -2,3-二氢 -1H-吲哚 -5-基) -乙酰胺 44b作原料，得到标题产物 N-{3-[5-(2-二甲氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢 -P比咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -5-基}-2-羟基-乙酰胺 44(52 mg，橙黄色固体)，产率： 50.5 %。 The fourth step of the reaction of Example 23 of the present invention was repeated, except that the compound obtained in the third step of Example 23 was used. 5-(2-Dimethylamino-ethyl)-3-methyl-4-oxo-1,4 ,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c and 2-hydroxy-N-(2-oxo-2,3-dihydro-1H - 吲哚-5-yl)-acetamide 44b as a starting material to give the title product N-{3-[5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4 ,5,6,7,8-hexahydro-P-pyrolo[3,2-c]azepine-2-methylene]-2-oxo-2,3-dihydro-1H-indole -5-yl}-2-hydroxy-acetamide 44 (52 mg, orange-yellow solid), Yield: 50.5 %.

MS m/z (ESI): 452.1(M+1)。 MS m/z (ESI): 4521. (M+1).

1HNMR(400 MHz, DMSO-d6) δ 13.658(s, IH,吡咯环 -NH)， 10.857(s, IH, 吲哚 -NH)， 9.426(s, IH，- NHCO), 7.939~7.942(d, IH, -ArH)， 7.513(s, IH, -CH=C), 7.485~7.489(d, IH, _ArH)， 6.820~6.841(d,lH ArH), 5.717(s, IH, -HO), 3.982~3.996(d, 2H, -CH₂0), 3.531-3.564 (t, 2H,七环接氮 -CH₂)， 3.337~3.365(t, 2H,七环外接酰胺氮 -CH₂)， 2.908~2.944(t, 2H， -CH₂C=C), 2.433(s, 3H,吡咯环 -CH₃)， 2.394-2.41 l(t, 2H, -CH₂N), 2.199(s, 6H, 2 X-CH₃N), 2.03 l~2.059(m, 2H,七环内—CH₂)。实施例 45 1H NMR (400 MHz, DMSO-d6) δ 13.658 (s, IH, pyrrole ring-NH), 10.857 (s, IH, 吲哚-NH), 9.426 (s, IH, -NHCO), 7.939~7.942 (d, IH, -ArH), 7.513(s, IH, -CH=C), 7.485~7.489(d, IH, _ArH), 6.820~6.841(d,lH ArH), 5.717(s, IH, -HO), 3.982 ~3.996(d, 2H, -CH ₂ 0), 3.531-3.564 (t, 2H, heptacyclic nitrogen-CH ₂ ), 3.337~3.365 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.908~ 2.944(t, 2H, -CH ₂ C=C), 2.433(s, 3H, pyrrole ring-CH ₃ ), 2.394-2.41 l(t, 2H, -CH ₂ N), 2.199(s, 6H, 2 X -CH ₃ N), 2.03 l~2.059 (m, 2H, seven-ring-CH ₂ ). Example 45

2-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-3-甲基 -5-(2-吡咯垸 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4- 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methyl)-3-methyl-5-(2-pyrrole-1-yl-ethyl)- 5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-

重复本发明实施例 28第四步反应，不同的是使用实施例 28第三步所得化合物 3—甲基 _4-氧代 -5-(2-吡咯烷小基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3，2-c] 吖庚因 -2-甲醛 28c和 5-氟 -1，3-二氢 -吲哚 -2-酮作原料，得到标题产物 2-(5-氟 -2-氧代 -1,2-二氢- 吲哚 -3-次甲基 )-3-甲基 -5-(2-吡咯烷 -1 -基-乙基) -5,6,7，8-四氢 -1H-吡咯并 [3,2-c] 吖庚因—4-酮 45(61 mg, 橙黄色固体)，产率： 80.8 %。

The fourth step reaction of Example 28 of the present invention was repeated except that the compound obtained in the third step of Example 28 was used. 3-methyl-4-oxo-5-(2-pyrrolidinyl-ethyl)-1,4 , 5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c and 5-fluoro-1,3-dihydro-indol-2-one as raw materials, The title product 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methylmethyl)-3-methyl-5-(2-pyrrolidin-1-yl-B -5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine- 4-keto 45 (61 mg, orange-yellow solid), Yield: 80.8 %.

MS m/z (ESI): 423.1(M+l) c MS m/z (ESI): 423.1 (M+l) c

¹HNMR(400 MHz, DMSO-d6) δ 13.715(s, 1H,吡咯环 -NH)， 10.902(s, 1H, 吲哚 -NH)， 7.752~7.782(m, 1H, -ArH), 7.743(s, 1H, -CH=C), 6.937~6.965(m, 1H, -ArH), 6.835~6.867(d, 1H, -ArH), 3.548~3.582(t, 2H,七环内 -C¾N)， 3.337~3.365(t, 2H,七环外接酰胺氮 -CH₂)， 3.314(m, 4H，五环 2 X - CH₂N)， 2.990-3.027(t, 2H,七环内 -CH₂C=C)， 2.573-2.607(t, 2H, -CH₂N), 2.473(s, 3H,吡咯环 -CH₃)， 2.101~2.129(m, 2H,七环内 - C¾)， 1.751(m, 4H, 五环 -CH₂)。实施例 46 ¹ H NMR (400 MHz, DMSO-d6) δ 13.715 (s, 1H, pyrrole ring-NH), 10.902 (s, 1H, 吲哚-NH), 7.752~7.782 (m, 1H, -ArH), 7.743(s , 1H, -CH=C), 6.937~6.965(m, 1H, -ArH), 6.835~6.867(d, 1H, -ArH), 3.548~3.582(t, 2H, 7-ring-C3⁄4N), 3.337~ 3.365 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 3.314 (m, 4H, pentacyclic 2 X - CH ₂ N), 2.990-3.027 (t, 2H, hepta-CH ₂ C=C) , 2.573-2.607(t, 2H, -CH ₂ N), 2.473(s, 3H, pyrrole ring-CH ₃ ), 2.101~2.129 (m, 2H, hepta-C3⁄4), 1.751(m, 4H, 5 Ring-CH ₂ ). Example 46

2-(5-溴 -2-氧代 -1,2-二氢』引哚 -3-次甲基 )-3-甲基 -5-(2-吡咯垸 -1-基-乙基) -5,6,7，8-四氢 -1H-吡咯并 [3，2-c] 吖庚因 -4- 2-(5-bromo-2-oxo-1,2-dihydroindol-3-pyridyl-3-methyl)-3-methyl-5-(2-pyrrole-1-yl-ethyl)- 5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-

重复本发明实施例 28第四步反应，不同的是使用实施例 28第三步所得化合物 3-甲基 -4-氧代 -5-(2-吡咯烷小基-乙基) -1,4,5,6,7，8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 28c和 5-溴 -1,3-二氢 -吲哚 -2-酮作原料，得到标题产物 2-(5-溴 -2-氧代 -1,2-二氢- 吲哚 -3-次甲基 )-3-甲基 -5-(2-吡咯垸 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 46(61 mg，黄色固体)，产率： 70.4%。

The fourth step reaction of Example 28 of the present invention was repeated except that the compound obtained in the third step of Example 28 was used. 3-methyl-4-oxo-5-(2-pyrrolidinyl-ethyl)-1,4 , 5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c and 5-bromo-1,3-dihydro-indol-2-one as raw materials, The title product 2-(5-bromo-2-oxo-1,2-dihydro-indol-3-methylmethyl)-3-methyl-5-(2-pyrrole-1-yl-B -5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c] In 4-ketone 46 (61 mg, yellow solid), Yield: 70.4%.

MS m/z (ESI)_: 485.1(M+1)。 MS m/z (ESI) _: 485.1 (M+1).

^]ΗΝΜΚ(400 MHz, DMSO-d6) δ 13.664(s, IH,吡咯环 -NH)， 11.007(s, IH,吲哚 -NH)， 8.113~8.114(d, IH, -ArH), 7.803(s, IH, -CH=C)， 7.261〜7.286(m, IH, -ArH), 6.825~6.846(d, IH, -ArH), 3.548~3.582(t, 2H,七环内 -C¾N)， 3.337~3.364(t, 2H,七环外接酰胺氮 -CH₂)， 3.312(m, 4H,五环 2 X - CH₂N)， 2.905~2.942(t, 2H,七环内 -CH₂C=C), 2.573~2.606(t, 2H, -CH₂N), 2.462(s, 3H,吡咯环 -CH₃)， 2.028~2.057(m, 2H,七环- CH₂)， 1.751(m, 4H,五环 -CH₂)。实施例 47 ^{] ΗΝΜΚ (400 MHz, DMSO-} d6) δ 13.664 (s, IH, pyrrole ring -NH), 11.007 (s, IH , indole -NH), 8.113 ~ 8.114 (d , IH, -ArH), 7.803 (s , IH, -CH=C), 7.261~7.286(m, IH, -ArH), 6.825~6.846(d, IH, -ArH), 3.548~3.582(t, 2H, 7-ring-C3⁄4N), 3.337~ 3.364(t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 3.312 (m, 4H, pentacyclic 2 X - CH ₂ N), 2.905~2.942 (t, 2H, hepta-CH ₂ C=C) , 2.573~2.606(t, 2H, -CH ₂ N), 2.462(s, 3H, pyrrole ring-CH ₃ ), 2.028~2.057(m, 2H, hepta-CH ₂ ), 1.751(m, 4H, 5 ring -CH _2). Example 47

2-(5-氯 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-3-甲基 -5-(2-吡咯垸 -1-基-乙基) -5，6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4- 2-(5-Chloro-2-oxo-1,2-dihydro-indol-3-methyl)-3-methyl-5-(2-pyrrole-1-yl-ethyl)- 5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-

3-甲基 _4-氧代 -5-(2-吡咯烷 -1-基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3，2-c] 吖庚因 -2-甲醛 28c和 5-氯 -1,3-二氢 -Π引哚 -2-酮作原料，得到标题产物 2-(5-氯 -2-氧代 -1,2-二氢- 吲哚 -3-次甲基 3-甲基 -5-(2-吡咯垸 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 47(61 mg，黄色固体)，产率： 77.7%。 3-methyl_4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]吖hine-2-carbaldehyde 28c and 5-chloro-1,3-dihydro-indole-2-one are used as starting materials to obtain the title product 2-(5-chloro-2-oxo-1,2-di Hydrogen - indole-3-methylmethyl 3-methyl-5-(2-pyrrole-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2 -c] azepin-4-one 47 (61 mg, yellow solid), yield: 77.7%.

MS m/z (ESI): 439.2(M+1)。 MS m/z (ESI): 439.2 (M+1).

^HNMR^OO MHz, DMSO-d6) δ 13.714(s, IH,吡咯环 -NH)， 11.046(s, IH,吲哚 -NH), 8.038(s, IH, -CH=C), 7.838~7.845(d, IH, -ArH), 7.179~7.205(dd, IH, -ArH), 6.915~6.935(d, IH, -ArH), 3.612~3.629(t， 2H,七环内 -C¾N)， 3.384~3.412(t, 2H, 七环外接酰胺氮 -CH₂)， 3.337~3.384(m, 4H,五环 2 X - CH₂N)， 2.990-3.027(t, 2H,七环内 -CH₂C=C)， 2.650~2.684(t, 2H, -CH₂N)， 2.473(s, 3H, 吡咯环 -CH₃) , 2.101~2.129(m, 2H,七环内 - CH₂)， 1.751(m, 4H,五环 -CH₂)。实施例 48 ^HNMR^OO MHz, DMSO-d6) δ 13.714 (s, IH, pyrrole ring-NH), 11.046 (s, IH, 吲哚-NH), 8.038 (s, IH, -CH=C), 7.838~7.845 (d, IH, -ArH), 7.179~7.205(dd, IH, -ArH), 6.915~6.935(d, IH, -ArH), 3.612~3.629(t, 2H, seven-ring-C3⁄4N), 3.384~ 3.412 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 3.337~3.384 (m, 4H, pentacyclic 2 X - CH ₂ N), 2.990-3.027 (t, 2H, heptacyclic-CH ₂ C= C), 2.650~2.684(t, 2H, -CH ₂ N), 2.473(s, 3H, pyrrole ring-CH ₃ ), 2.101~2.129 (m, 2H, hepta-CH ₂ ), 1.751(m, 4H, pentacyclic-CH ₂ ). Example 48

3-甲基 -2-(2-氧代 -5-苯基 -1,2-二氢 -吲哚 -3-次甲基 )-5-(2-吡咯垸 -1-基-乙基) -SA^- 四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮

重复本发明实施例 28第四歩反应，不同的是使用实施例 28第三步所得化合物 3-甲基 -4-氧代 -5-(2-吡咯烷小基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 28c和 5-苯基 -1,3-二氢^ 1哚 -2-酮作原料，得到标题产物 3-甲基 -2-(2-氧代 -5-苯基 -1,2-二氢 -吲哚 -3-次甲基 )-5-(2-吡咯烷 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 48(41 mg，黄色固体)，产率： 62.3 %。 3-methyl-2-(2-oxo-5-phenyl-1,2-dihydro-indol-3-methyl)-5-(2-pyrrole-1-yl-ethyl) -SA^-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one

The fourth hydrazine reaction of Example 28 of the present invention was repeated except that the compound obtained in the third step of Example 28 was used. 3-methyl-4-oxo-5-(2-pyrrolidinyl-ethyl)-1,4 ,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxaldehyde 28c and 5-phenyl-1,3-dihydro^1哚-2-one as raw materials , the title product 3-methyl-2-(2-oxo-5-phenyl-1,2-dihydro-indol-3-methyl)-5-(2-pyrrolidin-1-yl) -ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 48 (41 mg, yellow solid), yield: 62.3 %.

MS m/z (ESI)_: 481·2(Μ+1)。 MS m/z (ESI) _: 481. 2 (Μ +1).

¹HNMR(400 MHz, DMSO-d6) δ 13.706(s, 1H,吡咯环 -NH)， 10.070(s, 1H,吲哚 -NH)， 8.174(s, 1H, -CH=C) , 7.843(s, 1H, -ArH) , 7.722-7.74 l(d, 2H, -ArH) , 7.443~7.480(m, 3H, -ArH), 7.314-7.35 l(t, 1H， -ArH), 6.961~6.981(d, 1H， -ArH), 3.554~3.588(t, 2H,七环内 -CH₂N)， 3.362~3.376(t, 2H, 七环外接酰胺氮 -CH₂)， 3.289~3.347(m, 4H, 五环 2 X - CH₂N)， 2.990-3.027(t, 2H, 七环内 -CH₂C=C)， 2.650~2.684(t, 2H, -CH₂N)， 2.473(s, 3H,吡咯环—C¾)， 2.101-2.129(m, 2H,七环内- CH₂)， 1.751(m，4H,五环 2 X -C¾)。实施例 49 ¹ H NMR (400 MHz, DMSO-d6) δ 13.706 (s, 1H, pyrrole ring-NH), 10.070 (s, 1H, 吲哚-NH), 8.174 (s, 1H, -CH=C), 7.843 (s , 1H, -ArH) , 7.722-7.74 l(d, 2H, -ArH) , 7.443~7.480(m, 3H, -ArH), 7.314-7.35 l(t, 1H, -ArH), 6.961~6.981(d , 1H, -ArH), 3.554~3.588 (t, 2H, hepta-CH ₂ N), 3.362~3.376 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 3.289~3.347 (m, 4H, Pentacyclic 2 X - CH ₂ N), 2.990-3.027 (t, 2H, hepta-CH ₂ C=C), 2.650~2.684 (t, 2H, -CH ₂ N), 2.473 (s, 3H, pyrrole Ring—C3⁄4), 2.101-2.129 (m, 2H, hepta-CH ₂ ), 1.751 (m, 4H, penta ring 2 X -C3⁄4). Example 49

2-(4-溴 -2-氧代 -1 ,2-二氢-吲哚 -3-次甲基) -3-甲基 -5-(2-吡咯烷小基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3，2-c] 吖庚因 -4- 2-(4-Bromo-2-oxo-1,2-dihydro-indol-3-methylmethyl)-3-methyl-5-(2-pyrrolidinyl-ethyl)-5, 6,7,8-tetrahydro-1H-pyrrolo[3,2-c] azepine-4-

重复本发明实施例 28第四步反应，不同的是使用实施例 28第三步所得化合物 3-甲基 _4-氧代 -5-(2-吡咯垸 -1-基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 28c和 4-溴 -1,3-二氢 -吲哚 -2-酮作原料，得到标题产物 2-(4-溴 -2-氧代 -1,2-二氢- 哚 -3-次甲基 )-3-甲基- 5-(2-吡咯烧 -1-基-乙基) -5,6,7，8-四氢 -1H-吡咯并 [3，2-c] 吖庚因 -4-酮 49(40 mg，黄色固体)，产率： 60.5 %。

The fourth step reaction of Example 28 of the present invention was repeated except that the compound obtained in the third step of Example 28 was used. 3-methyl-4-oxo-5-(2-pyrrole-1-yl-ethyl)-1 ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c and 4-bromo-1,3-dihydro-indol-2-one Starting material, the title product 2-(4-bromo-2-oxo-1,2-dihydro-indol-3-methylmethyl)-3-methyl-5-(2-pyrrole-1-yl- Ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 49 (40 mg, yellow solid), yield: 60.5 %.

MS m/z (ESI): 483·2(Μ-1)。 ^!iiNMR(400 MHz, DMSO-d6) δ 13.697(s, 1H，吡咯环 -NH)， 11.244(s, 1H,吲哚 -NH), 8.650(s, 1H, -CH=C), 7.281-7.301(d, 1H, -ArH), 7.118~7.158(m, 1H, -ArH), 7.000-7.190(d, 1H, -ArH), 3.618-3.652 (t, 2H,七环内 -CH₂N)， 3.410~3.438(t, 2H, 七环外接酰胺氮 -CH₂)， 3.356~3.378(m, 4H,五环 2X - CH₂N)， 2.990-3.027(t, 2H, 七环内 -CH₂C=C)， 2.650~2.684(t, 2H, -CH₂N) , 2.473(s, 3H, 吡咯环 -CH₃)， 2.101~2.129(m, 2H,七环内 _CH₂), 1.751(m, 4H,五环 -CH₂)。实施例 50 MS m/z (ESI): 483·2 (Μ-1). ^{! IiNMR (400 MHz, DMSO-} d6) δ 13.697 (s, 1H, pyrrole ring -NH), 11.244 (s, 1H , indole -NH), 8.650 (s, 1H , -CH = C), 7.281-7.301 (d, 1H, -ArH), 7.118~7.158(m, 1H, -ArH), 7.000-7.190(d, 1H, -ArH), 3.618-3.652 (t, 2H, hepta-CH ₂ N), 3.410~3.438(t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 3.356~3.378(m, 4H, pentacyclic 2X - CH ₂ N), 2.990-3.027(t, 2H, heptacyclic-CH ₂ C =C), 2.650~2.684(t, 2H, -CH ₂ N), 2.473(s, 3H, pyrrole ring-CH ₃ ), 2.101~2.129 (m, 2H, heptacyclic_CH ₂ ), 1.751(m , 4H, pentacyclic-CH ₂ ). Example 50

2-(7-溴 -5-氟 -2-氧代 -1,2-二氢-吲哚 -3-次甲基 )-3-甲基 -5-(2-吡咯烷 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3, -c] 吖庚因 -4-酮 2-(7-Bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-methyl)-3-methyl-5-(2-pyrrolidin-1-yl- Ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo[3, -c] azepine-4-one

重复本发明实施例 28第四步反应，不同的是使用实施例 28第三步所得化合物 3-甲基 -4-氧代 -5-(2-吡咯烷小基-乙基) -1，4，5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 28c和本发明实施例 4第一步所得化合物 7-溴 -5-氟 -1,3-二氢 -吲哚 -2-酮 4b作原料，得到标题产物 2-(7-溴 -5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-3-甲基 -5-(2-吡咯烷 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3，2-c] 吖庚因 -4-酮 50(51 mg，橙黄色固体)，产率： 73.2%

The fourth step reaction of Example 28 of the present invention was repeated except that the compound obtained in the third step of Example 28 was used. 3-methyl-4-oxo-5-(2-pyrrolidinyl-ethyl)-1,4 , 5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c and the compound 7-bromo-5-fluoro-1 obtained in the first step of Example 4 of the present invention, 3-Dihydro-indol-2-one 4b as a starting material to give the title product 2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indole-3-methyl) 3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4- Ketone 50 (51 mg, orange solid), Yield: 73.2%

MS m/z (ESI): 501.1 (M+ l)。 MS m/z (ESI): 501.1 (M + l).

!ΗΝΜΚ(400 MHz, DMSO-d6) δ 13.660(s, 1H,吡咯环 -NH)， 11.177(s, 1H,吲哚 -NH), 7.857~7.875(d, 1H， -ArH), 7.798(s, 1H， -CH=C), 7.251~7.269(d, 1H， -ArH), 3.556~3.590(t, 2H, 七环内 -CH₂N) , 3.317~3.359(t, 2H, 七环外接酰胺氮 -CH₂)， 3.294~3.359(m, 4H, 五环 2 X - CH₂N)， 2.935-2.97 l(t, 2H, 七环内 -CH₂C=C)， 2.587~2.620(t, 2H, -CH₂N), 2.473(s, 3H,吡咯环 - CH₃), 2.059(m, 2H,七环内 - CH₂), 1.751(m，4H,五环 -CH₂)。实施例 51 ΗΝΜΚ (400 MHz, DMSO-d6) δ 13.660 (s, 1H, pyrrole ring-NH), 11.177 (s, 1H, 吲哚-NH), 7.857~7.875 (d, 1H, -ArH), 7.798(s , 1H, -CH=C), 7.251~7.269(d, 1H, -ArH), 3.556~3.590(t, 2H, hepta-CH ₂ N), 3.317~3.359(t, 2H, heptacyclic external amide Nitrogen-CH ₂ ), 3.294~3.359 (m, 4H, pentacyclic 2 X - CH ₂ N), 2.935-2.97 l(t, 2H, hepta-CH ₂ C=C), 2.587~2.620 (t, 2H, -CH ₂ N), 2.473 (s, 3H, pyrrole ring - CH ₃ ), 2.059 (m, 2H, hepta-CH ₂ ), 1.751 (m, 4H, penta-CH ₂ ). Example 51

N-{3-[5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1，4,5,6,7,8-六氢-吡咯并 [3，2-c] 吖庚因 -2- 亚甲基 ]-2-氧代 -2，3-二氢 -1H-吲哚 -5-基}-乙酰胺

重复本发明实施例 1第十步反应，不同的是使用实施例 1第九步中所得到的化合物 5-(2-二乙氨基 -乙基 )-3-甲基 -4-氧代 -1,4，5,6，7，8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 甲醛 lj和本发明实施例 30第三步反应所得化合物 N-(2-氧代 -2,3-二氢 -1H-吲哚 -5- 基)-乙酰胺 30d作原料，得到标题产物 N-{3-[5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4，5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -5-基} - 乙酰胺 51(12 mg，桔黄色固体)，产率： 18.9%。 N-{3-[5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2 -c] azepine-2-methyl]-2-oxo-2,3-dihydro-1H-indol-5-yl}-acetamide

The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used. , 4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde lj and the compound N-(2-oxo) obtained in the third step reaction of Example 30 of the present invention -2,3-Dihydro-1H-indol-5-yl)-acetamide 30d as a starting material to give the title product N-{3-[5-(2-diethylamino-ethyl)-3-methyl 4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-methylene]-2-oxo-2,3- Dihydro-1H-indol-5-yl}-acetamide 51 (12 mg, orange solid), Yield: 18.9%.

MS m/z (ESI): 464.2(M+1)。 MS m/z (ESI): 464.2 (M + 1).

!ΗΝΜΚ(400 MHz, DMSO-d6) δ 13.679(s, 1H,吡咯环 -NH)， 10.868(s, 1H, 吲哚 -NH)， 9.806(s, 1H, 酰胺 -NH)， 7.841(s, 1H, -ArH) , 7.472(s, 1H, -CH=C)， 7.251~7.256(d, 1H, -ArH), 6.806~6.827(s, 1H, -ArH), 3.499(t, 2H,七环内 -C¾N)， 3.322~3.347(t， 2H,七环外接酰胺氮 -CH₂)， 2.902-2.939(t, 2H,七环内 -CH₂C=C)， 2.530〜2.562(m, 6H, 3 X -CH₂N)， 2.423(s, 3H,吡咯环 -C¾)， 2.029-2.051 (m, 2H,七环内 -CH₂)， 2.029(s, 3H, -CH₃CO), 0.958~0.993 (t, 6H, 2 X -CH₃)。实施例 52 ΗΝΜΚ (400 MHz, DMSO-d6) δ 13.679 (s, 1H, pyrrole ring-NH), 10.868 (s, 1H, 吲哚-NH), 9.806 (s, 1H, amide-NH), 7.841 (s, 1H, -ArH), 7.472(s, 1H, -CH=C), 7.251~7.256(d, 1H, -ArH), 6.806~6.827(s, 1H, -ArH), 3.499(t, 2H, 7-ring -C3⁄4N), 3.322~3.347(t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.902-2.939 (t, 2H, hepta-CH ₂ C=C), 2.530~2.562 (m, 6H, 3 X -CH ₂ N), 2.423 (s, 3H, pyrrole ring - C3⁄4), 2.029-2.051 (m, 2H, hepta-CH ₂ ), 2.029 (s, 3H, -CH ₃ CO), 0.958~ 0.993 (t, 6H, 2 X -CH ₃ ). Example 52

N-{5-氟 -3-[3-甲基 -4-氧代 -5-(2-吡咯烷 -1-基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3- -1H-吲哚 -6-基}-2-甲氧基-乙酰胺 N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro -pyrrolo[3,2-c]azepine-2-methylene]-2-oxo-2,3- -1H-indol-6-yl}-2-methoxy-acetamide

重复本发明实施例 28第四步反应，不同的是使用实施例 28窠三步所得化合物 3-甲基 -4-氧代 -5-(2-吡咯浣 -1-基-乙基) -1,4,5,6,7,8-六氢 -P比咯并 [3,2-c] 吖庚因 -2-甲醛 28c和本发明实施例 7第一步所得化合物 5-氟 -6-甲氧乙酰胺基 -2-吲哚酮 7a作原料，得到标题产物 N-{5-氟 -3-[3-甲基 -4-氧代 -5-(2-吡咯垸 -1-基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-亚甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -6-基}-2-甲氧基 -乙酰胺 52(45 mg，土黄色固体)，产率： 63.7%。

The fourth step reaction of Example 28 of the present invention was repeated except that the compound obtained in Example 28, Step 3, 3-methyl-4-oxo-5-(2-pyrrole-1-yl-ethyl)-1 was used. , 4,5,6,7,8-hexahydro-P-pyrolo[3,2-c]azepine-2-carbaldehyde 28c and the compound obtained in the first step of Example 7 of the present invention 5-fluoro-6- Methoxyacetamido-2-indanone 7a was used as the starting material to give the title product N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl- Ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-methylene]-2-oxo-2,3-dihydro -1H-indol-6-yl}-2-methoxy-acetamide 52 (45 mg, EtOAc).

MS m/z (ESI): 510.1 (M+ l)。 ^]HNMR(400 MHz, DMSO-d6) δ 13.652(s, 1H,吡咯环 -NH)， 10.936(s, 1H,吲哚 -NH), 9.362(s, 1H, -NHCO), 7.882~7.910(d, 1H₅ -ArH), 7.714(s, 1H, -CH=C), 7.582~7.598(d, 1H, -ArH), 4.110(s, 2H, -CH₂0)， 3.597-3.63 l(t, 2H，七环内 -CH₂N)， 3.447(s, 3H, -C¾0)， 3.381~3.408(t, 2H,七环外接酰胺氮 -CH₂)， 3.331~3.355(m, 4H, 五环 2 X - C¾N)， 2.945-2.98 l(t, 2H, 七环内 -C¾D=C)， 2.660(m, 2H, -CH₂N), 2.489(s, 3H, 吡咯环 -CH₃), 2.069~2.099(m, 2H，七环内 - C¾)， 1.731(m, 4H,五环 -C¾)。实施例 53 MS m/z (ESI): 510.1 (M + l). ^{] HNMR (400 MHz, DMSO-} d6) δ 13.652 (s, 1H, pyrrole ring -NH), 10.936 (s, 1H , indole -NH), 9.362 (s, 1H , -NHCO), 7.882 ~ 7.910 (d , 1H ₅ -ArH), 7.714(s, 1H, -CH=C), 7.582~7.598(d, 1H, -ArH), 4.110(s, 2H, -CH ₂ 0), 3.597-3.63 l(t, 2H, hepta-CH ₂ N), 3.447 (s, 3H, -C3⁄40), 3.381~3.408 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 3.331~3.355 (m, 4H, five ring 2 X - C3⁄4N), 2.945-2.98 l(t, 2H, hepta-C3⁄4D=C), 2.660(m, 2H, -CH ₂ N), 2.489(s, 3H, pyrrole ring-CH ₃ ), 2.069~ 2.099 (m, 2H, seven-ring - C3⁄4), 1.731 (m, 4H, five-ring - C3⁄4). Example 53

2-(5-氟 -2-氧代 -1，2-二氢 -吲哚 -3-次甲基 )-5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -5,6,7,8- -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methylmethyl)-5-(2-hydroxy-3-morphinolin-4-yl-propyl)-3 -methyl-5,6,7,8- -1H-pyrrolo[3,2-c]azepine-4-one

第三步third step

53a 53b 53c 53a 53b 53c

第一步

first step

4-环氧乙垸基甲基-***啉 4-epoxyethylidenemethyl-morpholine

室温下，将***啉 53a(8.712 ml, 0.1 mol)搅拌下溶解于 4.5 ml叔丁醇中，用冰浴冷却至 0°C后，缓慢滴加 (R)-(-)-环氧氯丙烷 (8.05 ml, 0.1 mol),加毕撤去冰浴，反应体系温度自然升至室温，继续搅拌 24小时。点板监测反应至原料基本消失。边用冰浴控制反应体系温度低于 10°C边滴加叔丁醇钾的四氢呋喃溶液 (60 ml, 1.67 mol/L, 100 mmol), 反应液由浅黄色逐渐变成白色混浊液，加毕继续搅拌 30 min。点板监测反应至原料基本消失，停止反应。反应混合物减压蒸除溶剂，加入 50 ml 水，用二氯甲垸萃取 (100 mlx2)，合并有机相，有机相用饱和氯化钠溶液洗漆 (100 mlxl), 无水硫酸镜干燥，抽滤除去干燥剂，滤液浓缩得到标题产物 4-环氧乙烷基甲基-***啉 53b(12.7 g，黄色油状物)，产率： 88.8%。 The morpholine 53a (8.712 ml, 0.1 mol) was dissolved in 4.5 ml of tert-butanol with stirring at room temperature. After cooling to 0 ° C in an ice bath, (R)-(-)-epichlorohydrin (8.05 ml, 0.1 mol) was slowly added dropwise. After the addition, the ice bath was removed, the temperature of the reaction system was naturally raised to room temperature, and stirring was continued for 24 hours. . The plate was monitored for reaction until the starting material disappeared. While maintaining the temperature of the reaction system below 10 ° C with ice bath, a solution of potassium t-butoxide in tetrahydrofuran (60 ml, 1.67 mol/L, 100 mmol) was added dropwise, and the reaction mixture gradually changed from pale yellow to white turbid. Stirring was continued for 30 min. The plate was monitored for reaction until the starting material disappeared and the reaction was stopped. The reaction mixture was evaporated to dryness under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAcjjjjjjjjj The desiccant was removed by filtration, and the filtrate was concentrated to give the title product 4- ethethaneethyl- morpholine 53b (12.7 g, yellow oil), yield: 88.8%.

MS m/z (ESI): 144.4(M+1)。第二步 MS m/z (ESI): 144.4 (M+1). Second step

1-氨基 -3-***啉 -4-基-异丙醇 1-amino-3-morpholine-4-yl-isopropanol

冰浴下，控制温度低于 0Ό，将 4-环氧乙烷基甲基-***啉 53b(6.3 g， 44 mmol) 缓慢滴入 450 ml氨水 (25%， 6.6 mol)中，加毕，反应体系温度自然升至室温，继续搅拌 18小时。点板监测反应至原料基本消失，停止反应。反应液减压下蒸除溶剂，得到标题产物 1-氨基 -3-***啉 -4-基-异丙醇 53c(7 g，白色固体)，产率： 99%。 MS m/z (ESI): 161.1(M+1)。第三步 Under ice bath, the temperature was below 0 控制, and 4-oxiranylmethyl-morpholine 53b (6.3 g, 44 mmol) was slowly dropped into 450 ml of ammonia water (25%, 6.6 mol), and the reaction was completed. The temperature of the system naturally rose to room temperature and stirring was continued for 18 hours. The plate was monitored for reaction until the starting material disappeared and the reaction was stopped. The solvent was evaporated under reduced pressure to give crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal MS m/z (ESI): 161.1 (M + 1). third step

5-[3-(2-羟基 -3-***啉 -4-基-丙氨基) -丙基 ]-3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4- 乙酯 5-[3-(2-Hydroxy-3-morphinolin-4-yl-propylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4- Ethyl ester

室温下，将 5-(3-甲磺酰氧-丙基) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 l_g(1.13 g， 2.9 mmol)搅拌下溶解于 5.6 ml二氯甲烷中，加入 1-氨基 -3-***啉 -4-基 -异丙醇 53c(0.93 g， 5.8 mmol), 加毕，室温搅拌过夜，再于 45°C油浴中加热反应 14小时，点板监测反应至原料反应完全，停止反应。向反应液中加入 15 ml饱和氯化钠溶液，用二氯甲垸萃取 (20 mi x 3)，合并有机相，有机相减压下蒸除溶剂后柱层析得到标题产物 5-[3-(2-羟基 -3-***啉 -4-基-丙氨基) -丙基 ]-3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 53d(600 mg，无色油状物)，产率： 72.5%。 5-(3-Methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 1 _g (1.13 g, 2.9) Ment) dissolved in 5.6 ml of dichloromethane with stirring, add 1-amino-3-morphinolin-4-yl-isopropanol 53c (0.93 g, 5.8 mmol), add, stir at room temperature overnight, then at 45 ° The reaction was heated in a C oil bath for 14 hours, and the reaction was monitored by spotting until the reaction of the starting material was complete, and the reaction was stopped. 15 ml of a saturated sodium chloride solution was added to the reaction mixture, and the mixture was extracted with methylene chloride (20 mi x 3), and the organic phase was combined. (2-Hydroxy-3-morpholine-4-yl-propylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 53d (600 Mg, colorless oil), Yield: 72.5%.

MS m/z (ESI): 454.2(M+1)。第四步 MS m/z (ESI): 454.2 (M + 1). the fourth step

5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮氩气氛下，将 5-[3-(2-羟基 -3-***啉 -4-基-丙氨基) -丙基 ]-3-甲基 -1H-吡咯 -2,4- 二羟酸 2-叔丁酯 4-乙酯 53d(580 mg， 1.28 mmol)搅拌下溶解于 6 ml甲苯中，边用冰浴冷却边滴加三甲基铝的甲苯溶液 (1.9 ml, 2 mol/L, 3.84 mmol), 加毕，撤去冰浴，反应液加热回流 24小时。点板监测反应至原料反应完全，停止反应。反应液减压下蒸除溶剂，加入 20 _∞1盐酸(6 111₀1/1，室温搅拌 20分钟，再于冰浴中用氢氧化钠溶液 (12 mol/L)调节 pH至 12左右，用二氯甲烷萃取 (50 ml X 2)，合并有机相，有机相减压蒸除溶剂后柱层析得到标题产物 5-(2-轻基 -3-***啉 -4-基-丙基) -3- 甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 53e(300 mg，白色固体)，产率- 57.6 %。 5-(2-hydroxy-3-morpholine-4-yl-propyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c] azepine 5-[3-(2-hydroxy-3-morphinolin-4-yl-propylamino)-propyl]-3-methyl-1H-pyrrole-2,4-di 2-tert-Butyl hydroxy 4-carboxylate 53d (580 mg, 1.28 mmol) was dissolved in 6 ml of toluene with stirring, and a solution of trimethylaluminum in toluene (1.9 ml, 2 mol/) was added dropwise while cooling in an ice bath. L, 3.84 mmol), after the addition, the ice bath was removed and the reaction was heated to reflux for 24 hours. The plate was monitored until the reaction of the starting material was complete and the reaction was stopped. The reaction solution Evaporate the solvent under reduced pressure, add 20 _∞ 1 hydrochloric acid (6 111 ₀ 1 /1, stir at room temperature for 20 minutes, then adjust the pH to about 12 with sodium hydroxide solution (12 mol / L) in an ice bath, with dichloro Methane extraction (50 ml of X 2 ), EtOAc (EtOAc) Methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 53e (300 mg, white solid), yield - 57.6 %.

MS m/z (ESI): 308.2(M+1)。第五歩 MS m/z (ESI): 308.2 (M+1). Fifth

5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -4-氧代 -1,4,5,6，7,8-六氢-吡咯并[3，2-(；] 吖庚因 -2-甲醛 5-(2-hydroxy-3-morphinolin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3, 2-(;] azepine-2-carbaldehyde

氩气氛下，将氯亚甲基二甲基氯化胺 (130 mg, 0.977 mmol)搅拌下溶解于 3 ml 二氯甲烷中，冰浴冷却至 0°C。将 5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -5,6,7，8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 53e(300 mg, 0.977 mmol)搅拌下溶解于 2 ml二氯甲垸中，缓慢滴加到上述溶液中并控制反应液温度在 0Ό以下。加毕室温搅拌 20 分钟，点板监测反应至原料反应完全，向反应液中加入氢氧化钠溶液 (12 mol/L)淬灭反应。向反应液中加入 10 ml饱和氯化钠溶液，用二氯甲烷和甲醇的混合溶液 (V:V=10:1)萃取 (100 ml X 3)，合并有机相，有机相用饱和氯化钠溶液洗涤 (100 ml X I), 无水硫酸镁千燥，抽滤除去干燥剂，滤液浓缩后柱层析得到标题产物 5-(2- 羟基 -3-***啉 -4-基-丙基) -3-甲基 -4-氧代 -1,4，5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 甲醛 53f(200 mg，白色固体)，产率： 61 %。 Under an argon atmosphere, chloromethylene dimethylamine chloride (130 mg, 0.977 mmol) was dissolved in 3 ml of dichloromethane with stirring and cooled to 0 ° C in an ice bath. 5-(2-Hydroxy-3-morphinolin-4-yl-propyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c] It was dissolved in 2 ml of dichloromethane by stirring with 4-ketone 53e (300 mg, 0.977 mmol), and slowly added dropwise to the above solution to control the temperature of the reaction solution below 0 Torr. After stirring at room temperature for 20 minutes, the reaction was monitored by spotting until the reaction of the starting material was complete, and a sodium hydroxide solution (12 mol/L) was added to the reaction solution to quench the reaction. 10 ml of a saturated sodium chloride solution was added to the reaction solution, and a mixture of dichloromethane and methanol (V: V = 10:1) was extracted (100 ml of X 3 ), and the organic phase was combined, and the organic phase was saturated sodium chloride. The solution was washed (100 ml XI), dried over anhydrous magnesium sulfate, and filtered to remove the desiccant, and the filtrate was concentrated to give the title product 5-(2-hydroxy-3-morphinolin-4-yl-propyl). 3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 53f (200 mg, white solid) Yield: 61%.

MS m/z (ESI): 336.2(M+1)。第六步 MS m/z (ESI): 336.2 (M + 1). Step 6

2-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -5,6,7，8-四氢 -1H-口比咯并 [3,2-c] 吖庚因 -4-酮 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methylmethyl)-5-(2-hydroxy-3-morphinolin-4-yl-propyl)-3 -methyl-5,6,7,8-tetrahydro-1H-portpyrolo[3,2-c]azepin-4-one

室温下，将 5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢 -P比咯并 [3,2-c] 吖庚因 -2-甲醛 53f(50 mg, 0.149 mmol)搅拌下溶解于 261 μ ΐ乙醇中，加入 5-氟 -1,3-二氢』引哚 -2-酮 (20.28 mg, 0.134 mmol)和哌啶 (7.3 μ 1, 0.074 mmol), 加毕，于 80Ό油浴中避光搅拌 2小时。点板监测反应至原料反应完全，停止反应。撤去油浴，反应体系温度自然降至室温，反应液经抽滤并干燥得到标题产物 2-(5- 氟 _2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -5,6,7,8- 四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 53(40 mg，黄色固体)，产率： 57%。 5-(2-Hydroxy-3-morpholine-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-P at room temperature比并 [3,2-c] azepine-2-carbaldehyde 53f (50 mg, 0.149 mmol) was dissolved in 261 μ ΐ ethanol and stirred with 5-fluoro-1,3-dihydro hydrazine - 2-ketone (20.28 mg, 0.134 mmol) and piperidine (7.3 μl, 0.074 mmol) were added, and the mixture was stirred in an 80 hr oil bath for 2 hours. The plate was monitored until the reaction of the starting material was complete and the reaction was stopped. The oil bath was removed, the temperature of the reaction system was naturally lowered to room temperature, and the reaction mixture was suction filtered and dried to give the title product 2-(5-fluoro-2-oxo-1,2-dihydro-indole-3-methyl) -5-(2-hydroxy-3-morphinolin-4-yl-propyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c] In 4-keto 53 (40 mg, yellow solid), Yield: 57%.

MS m/z (ESI): 469·2(Μ+1)。 MS m/z (ESI): 469·2 (Μ +1).

^!HNMR(400 MHz, DMSO-d6) δ 13.725(s, 1H，吡咯环 -NH)， 10.907(s, 1H,吲哚 -NH), 7.760-7.783 (m, 1H, -ArH)， 7.747(s, 1H, -CH=C), 6.914-6.939 (m, 1H, -ArH), 6.835~6.867(m, 1H, -ArH) , 4.719-4.73 l(d, 1H, -OH) , 3.897(m, 1H, -CHO) , 3.749〜3.792(dd, IH, 七环外接酰胺氮 -CH₂)， 3.570~3.592(t, 4H, ***啉环 2 X -CH₂0)， 3.384~3.351(t, 2H,七环接氮 -CH₂)， 3.138~3.191(dd, IH,七环外接酰胺氮 -CH₂), 2.917~2.953(t, 2H, -C¾C-C)， 2.457(s, 3H,吡咯环 -CH₃)， 2.418~2.507(ra, 4H, -C¾N, ***啉环 -C¾N)， 2.289〜2.313(t, 2H, ***啉环 -CH₂N)， 2.076(m, 2H, 七环 -C¾)。实施例 54 ^{! HNMR (400 MHz, DMSO-} d6) δ 13.725 (s, 1H, pyrrole ring -NH), 10.907 (s, 1H , indole -NH), 7.760-7.783 (m, 1H , -ArH), 7.747 (s , 1H, -CH=C), 6.914-6.939 (m, 1H, -ArH), 6.835~6.867 (m, 1H, -ArH), 4.719-4.73 l(d, 1H, -OH) , 3.897(m, 1H, -CHO) , 3.749~3.792 (dd, IH, heptacyclic external amide nitrogen-CH ₂ ), 3.570~3.592 (t, 4H, morpholine ring 2 X -CH ₂ 0), 3.384~3.351 (t, 2H, seven-ring nitrogen- CH ₂ ), 3.138~3.191 (dd, IH, heptacyclic external amide nitrogen-CH ₂ ), 2.917~2.953(t, 2H, -C3⁄4C-C), 2.457(s, 3H, pyrrole ring-CH ₃ ), 2.418 ~ 2.507 (ra, 4H, -C3⁄4N, morpholine ring - C3⁄4N), 2.289~2.313 (t, 2H, morpholine ring -CH ₂ N), 2.076 (m, 2H, hepta-C3⁄4). Example 54

3-甲基 -2-(2-氧代 -4-吡啶 -4-基 -1 ,2-二氢-吲哚 -3-次甲基 )-5-(2-哌啶小基-乙基) -5,6，7,8-四氢 -1H-吡咯并 [3,2-c -4-酮 3-methyl-2-(2-oxo-4-pyridin-4-yl-1,2-dihydro-indol-3-methyl)-5-(2-piperidinyl-ethyl -5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c-4-ketone

重复本发明实施例 32第五步反应，不同的是使用本发明实施例 32第四步所得化合物 3-甲基 -4-氧代 -5-(2-哌啶 -1-基-乙基) -1，4,5,6，7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 32d和 4-吡啶 -4-基 -1,3-二氢 -吲哚 -2-酮作原料，得到标题产物 3-甲基 -2-(2- 氧代 -4-吡啶 -4-基 -1,2-二氢 -吲哚 -3-次甲基 )-5-(2-哌啶 -1-基-乙基) -5,6,7，8-四氢 -1H- 吡咯并 [3,2-c] 吖庚因 -4-酮 54(40 mg，黄色固体)，产率： 54%。

The fifth step reaction of Example 32 of the present invention was repeated except that the compound obtained in the fourth step of Example 32 of the present invention was used. 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d and 4-pyridin-4-yl-1,3-dihydro-indole The indole-2-one was used as the starting material to give the title product 3-methyl-2-(2-oxo-4-pyridin-4-yl-1,2-dihydro-indol-3-methylmethyl)-5 -(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 54 (40 mg, yellow Solid), Yield: 54%.

MS m/z (ESI): 496.2(M+l)o MS m/z (ESI): 496.2 (M+l) o

¹HNMR(400 MHz, DMSO-d6) δ 13.530(s, IH,吡咯环 -NH)， 11.115(s, IH, 吲哚 -NH)， 8.738~8.753(d, 2H, -CH=N), 7.498(s, 2H,吡啶 -CH=C), 7.219-7.258(m, IH, -ArH), 6.976~6.996(d, IH, -ArH), 6.808~6.830(d, IH, -ArH)， 6.808(s, IH, -CH=C), 3.499~3.532(t, 2H, 七环内 -C¾N)， 3.270~3.298(t, 2H, 七环外接酰胺氮- CH₂)， 2.879~2.916(t, 2H,七环内 -CH₂C=C)， 2.361~2.413(m, 6H, 3 X— CH₂N)， 2.055〜2.084(t, 2H,七环内 -CH₂)， 1.732(s, 3H,吡咯环 -CH₃)， 1.453-1.478(m, 4H,六环 2 X - CH₂)， 1.365-1.377(m, 2H,六环 -CH₂)。实施例 55 ¹ H NMR (400 MHz, DMSO-d6) δ 13.530 (s, IH, pyrrole ring-NH), 11.115 (s, IH, 吲哚-NH), 8.738~8.753 (d, 2H, -CH=N), 7.498 (s, 2H, pyridine-CH=C), 7.219-7.258 (m, IH, -ArH), 6.976~6.996 (d, IH, -ArH), 6.808~6.830 (d, IH, -ArH), 6.808( s, IH, -CH=C), 3.499~3.532(t, 2H, hepta-C3⁄4N), 3.270~3.298(t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.879~2.916(t, 2H , seven rings -CH ₂ C=C), 2.361~2.413 (m, 6H, 3 X-CH ₂ N), 2.055~2.084 (t, 2H, hepta-CH ₂ ), 1.732 (s, 3H, Pyrrole ring-CH ₃ ), 1.453-1.478 (m, 4H, hexa 2X-CH ₂ ), 1.365-1.377 (m, 2H, hexa-CH ₂ ). Example 55

2-[5-氟 -6-(4-氟-苄氨基) -2-氧代 -1,2-二氢 - 哚 -3-次甲基 ]-3-甲基 -5-(2-哌啶 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮

重复本发明实施例 32第五步反应，不同的是使用本发明实施例 32第四步所得化合物 3-甲基 -4-氧代 -5-(2-哌啶 -1-基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 32d和本发明实施例 3第四步 5-氟 -6-(4-氟-苄氨基) -1,3-二氢 -B引哚 -2-酮 3e 作原料，得到标题产物 2-[5-氟 -6-(4-氟-苄氨基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-3- 甲基 -5-(2-哌啶小基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 55(77 mg，黄色固体)，产率： 90.8 %。 2-[5-fluoro-6-(4-fluoro-benzylamino)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-3-methyl-5-(2-piperidin Pyridin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one

The fifth step reaction of Example 32 of the present invention was repeated except that the compound obtained in the fourth step of Example 32 of the present invention was used. 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d and inventive Example 3 fourth step 5-fluoro-6-(4 -Fluoro-benzylamino)-1,3-dihydro-B-indol-2-one 3e as a starting material to give the title product 2-[5-fluoro-6-(4-fluoro-benzylamino)-2-oxo -1,2-dihydro-indol-3-methylmethyl]-3-methyl-5-(2-piperidinyl-ethyl)-5,6,7,8-tetrahydro-1H- Pyrrolo[3,2-c]azepin-4-one 55 (77 mg, yellow solid), Yield: 90.8 %.

MS m/z (ESI): 560.1(M+1)。 MS m/z (ESI): 560.1 (M + 1).

'HNMR(400 MHZ, DMSO-d6) δ 13.425(s, 1H,吡咯环 -NH)， 10.520(s, 1H, - NH)， 7.572~7.602(d, 1H, -ArH) , 7.349(s, 1H, -CH=C) , 7.367~7.402(m, 2H, -ArH) , 7.141~7.186(m, 2H, -ArH), 6.398~6.422(m, 1H, -NH)， 6.040~6.059(m, 1H, -ArH), 4.347~4.361(d, 2H,苯胺 -CH₂)， 3.524~3.557(t, 2H,七环内 -CH₂N)， 3.314~3.337(t, 2H, 七环外接酰胺氮 -CH₂)，2.869〜2.906(t，2H,七环内 -CH₂C=C)，2.390~2.467(m, 9H,吡咯环 -CH₃, 3 X - CH₂N)， 1.999~2.063(t, 2H,七环内 -CH₂)， 1.476~1.489(m, 4H,六环 2 X - C¾)， 1.383-1.393(m, 2H,六环 -CH₂)。实施例 56 'HNMR (400 MHZ, DMSO-d6) δ 13.425 (s, 1H, pyrrole ring-NH), 10.520 (s, 1H, -NH), 7.572~7.602 (d, 1H, -ArH), 7.349(s, 1H , -CH=C), 7.367~7.402(m, 2H, -ArH), 7.141~7.186(m, 2H, -ArH), 6.398~6.422(m, 1H, -NH), 6.040~6.059(m, 1H , -ArH), 4.347~4.361(d, 2H, aniline-CH ₂ ), 3.524~3.557 (t, 2H, hepta-CH ₂ N), 3.314~3.337 (t, 2H, heptacyclic external amide nitrogen - CH ₂ ), 2.869~2.906 (t, 2H, hepta-CH ₂ C=C), 2.390~2.467 (m, 9H, pyrrole ring-CH ₃ , 3 X - CH ₂ N), 1.999~2.063(t , 2H, hepta-CH ₂ ), 1.476~1.489 (m, 4H, 6-ring 2 X - C3⁄4), 1.383-1.393 (m, 2H, hexa-CH ₂ ). Example 56

2-(7-溴 -5-氟 -2-氧代 -1,2-二氢 -Π引哚 -3-次甲基 )-3-甲基 -5-(2-哌啶 -1-基-乙基) -5,6,7,8- 四氢 -1H-吡咯并 [3,2-c] 吖庚因 - -酮 2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indole 哚-3-methylol)-3-methyl-5-(2-piperidin-1-yl -ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-ketone

重复本发明实施例 32第五步反应，不同的是使用本发明实施例 32第四步所得化合物 3-甲基 -4-氧代 -5-(2-哌啶 -1-基-乙基) -1,4,5,6，7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 32d和本发明实施例 4第一步 7-溴 -5-氟 -1，3-二氢 -吲哚 -2-酮 4b作原料，得到标题产物 2-(7-溴 -5-氟 -2-氧代 -1，2-二氢 -吲哚 -3-次甲基 )-3-甲基 -5-(2-哌啶 -1-基-乙基) -5，6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 56(63 mg, 黄色固体)，产率： 76.44 MS m/z (ESI): 515.1(M+1)。

The fifth step reaction of Example 32 of the present invention was repeated except that the compound obtained in the fourth step of Example 32 of the present invention was used. 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d and the first step of the present invention 4 7-bromo-5-fluoro- 1,3-Dihydro-indol-2-one 4b was used as a starting material to give the title product 2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indole-3-indole 3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c] azepine- 4-ketone 56 (63 mg, yellow solid), Yield: 76.44 MS m/z (ESI): 515.1 (M+1).

iHNMRWOO MHz, DMSO-d6) δ 13.661(s, 1H,吡咯环 -NH)， 11.184(s, 1H，吲哚 -NH) , 7.848~7.876(dd, 1H, -ArH)， 7.794(s, 1H, -CH = C), 7.242~7.240(dd, 1H, -ArH), 3.545~3.571(t, 2H,七环内接酰胺氮 -C¾)， 3.331~3.358(t, 2H，七环外接酰胺氮 -CH₂)， 2.950~2.986(t, 2H,七环内 -CH₂C=C)， 2.390~2.467(m, 9H,吡咯环 -CH₃, 3 X-CH₂N), 2.055~2.084(t, 2H,七环内 -CH₂)， 1.476~1.489(m, 4H₅六环 2 X— CH₂)， 1.383-1.393(m, 2H,六环 -CH₂)。实施例 57 iHNMRWOO MHz, DMSO-d6) δ 13.661 (s, 1H, pyrrole ring-NH), 11.184 (s, 1H, 吲哚-NH), 7.848~7.876 (dd, 1H, -ArH), 7.794(s, 1H, -CH = C), 7.242~7.240(dd, 1H, -ArH), 3.545~3.571 (t, 2H, heptacyclic amide nitrogen-C3⁄4), 3.331~3.358 (t, 2H, heptacyclic external amide nitrogen - CH ₂ ), 2.950~2.986 (t, 2H, hepta-CH ₂ C=C), 2.390~2.467 (m, 9H, pyrrole ring-CH ₃ , 3 X-CH ₂ N), 2.055~2.084(t , 2H, hepta-CH ₂ ), 1.476~1.489 (m, 4H ₅ Hexa 2 X-CH ₂ ), 1.383-1.393 (m, 2H, hexa-CH ₂ ). Example 57

2-(4-溴- 2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-3-甲基 -5-(2-哌啶 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 2-(4-Bromo-2-oxo-1,2-dihydro-indol-3-methyl)-3-methyl-5-(2-piperidin-1-yl-ethyl)- 5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one

重复本发明实施例 32第五步反应，不同的是使用本发明实施例 32第四歩所得化合物 3-甲基 -4-氧代 -5-(2-哌啶小基-乙基) -1,4,5，6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 32d和 4-溴 -1,3-二氢 -吲哚 -2-酮作原料，得到标题产物 2-(4-溴 -2-氧代 -1,2- 二氢 -吲哚 -3-次甲基 )-3-甲基 -5-(2-哌啶 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 57(68 mg，黄色固体)，产率： 91.2%。

The fifth step reaction of Example 32 of the present invention was repeated except that the compound obtained in the fourth step of Example 32 of the present invention was used. 3-methyl-4-oxo-5-(2-piperidinyl-ethyl)-1 ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d and 4-bromo-1,3-dihydro-indol-2-one Starting material, the title product 2-(4-bromo-2-oxo-1,2-dihydro-indol-3-methylmethyl)-3-methyl-5-(2-piperidin-1-yl) -ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 57 (68 mg, yellow solid), yield: 91.2%.

MS m/z (ESI): 499·1(Μ+1)。 MS m/z (ESI): 499·1 (Μ +1).

'H MR(400 MHZ, DMSO-d6) δ 13.682(s, 1H, 吡咯环 -NH)， 11.232(s, 1H, 吲哚 -NH), 8.634(s, 1H， -CH=C)， 7.267~7.287(m, 1H， -ArH), 105~7.144(m, 1H, -ArH), 6.988~7.007(d, 1H, -ArH), 3.595~3.627(t, 2H,七环内 -CH₂N)， 3.402(t, 2H,七环外接酰胺氮 -CH₂)， 2.991~3.028(t, 2H,七环内 -CH₂C=C)， 2.454~2.556(m, 9H, 吡咯环 -C¾, 3 X _CH₂N)， 2.102~2.131(t, 2H,七环内 -C¾)， 1.523~1.550(m, 4H,六环 2 X-CH₂), 1.429-1.44 l(m, 2H,六环 -CH₂)。实施例 58 'H MR(400 MHZ, DMSO-d6) δ 13.682(s, 1H, pyrrole ring-NH), 11.232(s, 1H, 吲哚-NH), 8.634(s, 1H, -CH=C), 7.267~ 7.287(m, 1H, -ArH), 105~7.144(m, 1H, -ArH), 6.988~7.007(d, 1H, -ArH), 3.595~3.627(t, 2H, hepta-CH ₂ N) , 3.402 (t, 2H, amide N seven external ring _{-CH 2), 2.991 ~ 3.028 (} t, inner 2H, heptacyclo _{-CH 2 C = C), 2.454} ~ 2.556 (m, 9H, pyrrole ring -C¾, 3 X _CH ₂ N), 2.102~2.131 (t, 2H, hepta-C3⁄4), 1.523~1.550 (m, 4H, 6-ring 2 X-CH ₂ ), 1.429-1.44 l(m, 2H, 6-ring - CH ₂ ). Example 58

3_甲基 _₂_₍₄_甲基 _₂_氧代 _1,₂_二氢 -吲哚 -₃_次甲基 )_₅_(2-哌啶 -1-基-乙基) -5，6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 _ ₂ _ 3_ methyl _(meth _ ₄ _ ₂ _ oxo _1, _{_-dihydro-2} - indol _--3 methine _) _ ₅ _ (2-piperidin-1-yl-ethyl) - -5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one

重复本发明实施例 32第五步反应，不同的是使用本发明实施例 32第四步所得化合物 3-甲基 -4-氧代 -5-(2-哌啶 -1-基-乙基) -1,4,5,6,7,8-六氢-吡咯并 [3，2-c] 吖庚因 -2-甲酸 32d和 4-甲基 -1,3-二氢 -吲哚 -2-酮作原料，得到标题产物 3-甲基 -2-(4-甲基 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-5-(2-哌啶小基-乙基) -5,6,7,8-四氢 -1H-吡咯并

The fifth step reaction of Example 32 of the present invention was repeated except that the compound obtained in the fourth step of Example 32 of the present invention was used. 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxylic acid 32d and 4-methyl-1,3-dihydro-indole-2 - Ketone as starting material, the title product 3-methyl-2-(4-methyl-2-oxo-1,2-dihydro-indol-3-methylmethyl)-5-(2-piperidine) was obtained. Small base-ethyl)-5,6,7,8-tetrahydro-1H-pyrrole

[3,2-c] 吖庚因 -4-酮 58(46 mg，黄色固体)，产率： 70.9%。 [3,2-c] azepine-4-ketone 58 (46 mg, yellow solid), yield: 70.9%.

MS m/z (ESI): 433.2(M+1)。 MS m/z (ESI): 433.2 (M+1).

¹HNMR(400 MHz, DMSO-d6) δ 13.703(s, 1H, 吡咯环 -NH)， 10.926(s, 1H, 吲哚 - NH)， 7.567(s, 1H, -CH=C), 7.035~7.074(m, 1H, -ArH)， 6.769-6.838(dd, 2H, -ArH)， 3.544~3.576(t, 2H, 七环内 -C¾N)， 3.331~3.359(t, 2H, 七环外接酰胺氮 -CH₂)， 2.926~2.962(t, 2H，七环内 -CH₂C=C)， 2.591(s, 3H, 苯环 -CH₃)， 2.383~2.437(m, 9H, 吡咯环 -CH₃, 3 X - CH₂N)， 2.030~2.092(t, 2H,七环内 -CH₂)， 1.479-1.49 l(m, 4H,六环 2 X - CH₂)， 1.383-1.394(m, 2H,六环 -CH₂)。实施例 59 ¹ H NMR (400 MHz, DMSO-d6) δ 13.703 (s, 1H, pyrrole ring-NH), 10.926 (s, 1H, 吲哚-NH), 7.567 (s, 1H, -CH=C), 7.035~7.074 (m, 1H, -ArH), 6.769-6.838 (dd, 2H, -ArH), 3.544~3.576 (t, 2H, hepta-C3⁄4N), 3.331~3.359 (t, 2H, heptacyclic external amide nitrogen - CH ₂ ), 2.926~2.962 (t, 2H, hepta-CH ₂ C=C), 2.591 (s, 3H, benzene ring-CH ₃ ), 2.383~2.437 (m, 9H, pyrrole ring-CH ₃ , 3 X - CH ₂ N), 2.030~2.092 (t, 2H, hepta-CH ₂ ), 1.479-1.49 l (m, 4H, 6-ring 2 X - CH ₂ ), 1.383-1.394 (m, 2H, Hexacyclic-CH ₂ ). Example 59

2-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3 -c] 吖庚因 -4-酮 2-(5-Bromo-2-oxo-1,2-dihydro-indol-3-methyl)-5-(2-hydroxy-3-morphinolin-4-yl-propyl)-3 -methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3 -c]azepine-4-one

重复本发明实施例 53第六步反应，不同的是使用本发明实施例 53第五步所得化合物 5-(2-轻基 -3-***啉 -4-基-丙基) -3-甲基 -4-氧代 -1,4,5，6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 53f和 5-溴 -1,3-二氢 -吲哚 -2-酮作原料，得到标题产物 2-(5-溴 -2-氧代 -1,2-二氢 -Π引哚 -3-次甲基 )-5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -5,6,7，8-四氢 -1H- 吡咯并 [3,2-c] 吖庚因 -4-酮 59(30 mg，黄色固体)，产率： 63 %。

The sixth step reaction of Example 53 of the present invention was repeated except that the compound obtained in the fifth step of Example 53 of the present invention was used, 5-(2-light-methyl-3-morpholine-4-yl-propyl)-3-methyl 4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 53f and 5-bromo-1,3-dihydro- Indole-2-one was used as a starting material to give the title product 2-(5-bromo-2-oxo-1,2-dihydro-indole-3-indolyl-3-methyl)-5-(2-hydroxy-3) -morpholine-4-yl-propyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 59 (30 mg , yellow solid), Yield: 63%.

MS m/z (ESI): 529.1(M+1)。 'HNMR^OO MHz, DMSO-d6) δ 13.674(s, IH,吡咯环 -NH)， 11.014(s, IH, 吲哚 -NH), 8.116~8.120(d, IH, -ArH), 7.807(s, IH, -CH=C)， 7.262~7.287(dd, IH, -ArH), 6.826~6.846(d, 1H， -ArH)， 4.719-4.73 l(d, IH, -OH) , 3.897(m, IH, -CHO) , 3.748~3.758(dd, IH, 七环外接酰胺氮 -CH₂)， 3.570~3.593(t, 4H, ***啉环 2 X -CH₂0)， 3.433(t, 2H，七环接氮 -CH₂)， 3.159(dd, IH, 七环外接酰胺氮 -C¾)， 2.917~2.954(t， 2H, -CH₂C=C), 2.465(s, 3H,吡咯环 -CH₃)， 2. 418~2.465(m, 4H, -CH₂N, ***啉环 -CH₂N)， 2.290-2.314(t, 2H, ***啉环 -CH₂N)， 2.061~2.092(m, 2H, 七环 -C¾)。实施例 60 MS m/z (ESI): 529.1 (M+1). 'HNMR^OO MHz, DMSO-d6) δ 13.674 (s, IH, pyrrole ring-NH), 11.014 (s, IH, 吲哚-NH), 8.116~8.120 (d, IH, -ArH), 7.807(s , IH, -CH=C), 7.262~7.287(dd, IH, -ArH), 6.826~6.846(d, 1H, -ArH), 4.719-4.73 l(d, IH, -OH) , 3.897(m, IH, -CHO), 3.748~3.758 (dd, IH, heptacyclic external amide nitrogen-CH ₂ ), 3.570~3.593 (t, 4H, morpholine ring 2 X -CH ₂ 0), 3.433(t, 2H, seven Ring nitrogen-CH ₂ ), 3.159 (dd, IH, heptacyclic external amide nitrogen-C3⁄4), 2.917~2.954 (t, 2H, -CH ₂ C=C), 2.465 (s, 3H, pyrrole ring-CH ₃ ), 2. 418~2.465 (m, 4H, -CH ₂ N, morpholine ring -CH ₂ N), 2.290-2.314 (t, 2H, morpholine ring -CH ₂ N), 2.061~2.092 (m, 2H) , seven rings - C3⁄4). Example 60

5-(2-二乙基氨基-乙基) -2-(5-氟 -2-氧代 -1,2-二氢』引哚 -3-次甲基 )-3-甲基 -6,7,8，9-四氢 -1 -4-酮 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro)indol-3-ylmethyl)-3-methyl-6, 7,8,9-tetrahydro-1 -4- ketone

第一；

the first;

5- (环丙基-羟基-甲基) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯氩气氛下，将 15 ml溴化环丙基镁 (0.5 mol/L)用冰盐浴冷却至 -10°C。将 5-甲酰 352 基 -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 lb(1.26 g, 4.5 mmol)搅拌下溶解于 10 ml四氢呋喃中，滴加到上述溶液中，并控制温度在 -10°C左右。加毕，撤去冰盐浴，继续于室温下搅拌 1 小时，点板跟踪至原料反应完全，加水淬灭反应。向反应液中加入 20 ml硫酸溶液 (10%)继续搅拌 30分钟，用乙酸乙酯萃取 (50 ml X 3)，合并有机相，有机相用饱和氯化钠洗涤 (50 mlxl)，无水硫酸镁干燥，抽滤除去干燥剂，滤液浓缩后柱层析得到标题产物 5- (环丙基-羟基-甲基) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 60a(576 mg，白色固体)，产率： 39.6% , 5-(cyclopropyl-hydroxy-methyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 15 ml of brominated cyclopropyl group under argon atmosphere Magnesium (0.5 mol/L) was cooled to -10 °C with an ice salt bath. 5-formyl 352 -3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester lb (1.26 g, 4.5 mmol) was dissolved in 10 ml of tetrahydrofuran with stirring and added dropwise to the above solution. Medium, and control the temperature at around -10 °C. After the addition, the ice salt bath was removed, and stirring was continued at room temperature for 1 hour. The plate was traced until the reaction of the starting material was complete, and the reaction was quenched by adding water. 20 ml of sulfuric acid solution (10%) was added to the reaction solution, and the mixture was stirred for 30 minutes, extracted with ethyl acetate (50 ml X 3 ), and the organic phase was combined and washed with saturated sodium chloride (50 ml×l) The magnesium is dried, filtered to remove the desiccant, and the filtrate is concentrated to give the title product 5-(cyclopropyl-hydroxy-methyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-unclear. Butyl 4-ethyl ester 60a (576 mg, white solid), Yield: 39.6%,

MS mix (ESI).- 322.2(M-1)。第二步 MS mix (ESI).- 322.2 (M-1). Second step

5- (4-溴 -丁基 -1-烯) -3-甲基 -1Η-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯室温下，将 5- (环丙基-羟基-甲基) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 60a(323 mg， 1 mmol)搅拌下溶解于 4 ml甲醇中，加入 2.8 ml氢溴酸 (40%)，搅拌 30分钟。点板监测反应至原料反应完全，停止反应。反应液用乙酸乙酯萃取 (10 mlx5), 合并有机相，有机相用饱和氯化钠洗涤 (15 mlxl), 无水硫酸镁干燥，抽滤除去干燥剂，滤液浓缩后柱层析得到标题产物 5-(4-溴 -丁醇 -1-烯) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 60b(345 mg，白色固体)，产率： 89.5 %。 5-(4-Bromo-butyl-1-ene)-3-methyl-1Η-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 5-(cyclopropyl) at room temperature -hydroxy-methyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 60a (323 mg, 1 mmol) was dissolved in 4 ml of methanol with stirring, 2.8 ml of hydrobromic acid (40%), stir for 30 minutes. The plate was monitored until the reaction of the starting material was complete and the reaction was stopped. The reaction mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. 5-(4-bromo-butan-1-ene)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 60b (345 mg, white solid) Rate: 89.5 %.

MS m/z (ESI): 329.4(M+ 1)。第三步 MS m/z (ESI): 329.4 (M + 1). third step

5-(4-溴-丁基) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯室温下，将 5-(4-溴 -丁醇 -1-烯) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 60b(30 mg, 0.08 mmol)搅拌下溶解于 3 mi乙醇中，加入钯 /碳 (5 %， 6 mg), 氢气氛下搅拌 45分钟，点板监测反应至原料反应完全，停止反应。反应液过滤，滤液减压下浓缩得到标题产物 5-(4-溴-丁基) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 60c(21 mg, 无色油状物)，产率： 70%。 5-(4-Bromo-butyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 5-(4-bromo-butanol- 1-ene)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 60b (30 mg, 0.08 mmol) was dissolved in 3 mi of ethanol with stirring, palladium / Carbon (5 %, 6 mg) was stirred under a hydrogen atmosphere for 45 minutes, and the reaction was monitored by spotting until the reaction of the starting material was complete, and the reaction was stopped. The reaction solution was filtered, and the filtrate was evaporated to dryness crystals crystals crystalssssssssssssssssss 21 mg, colorless oil), Yield: 70%.

MS m/z (ESI): 388·0(Μ+ 1)。第四歩 MS m/z (ESI): 388·0 (Μ + 1). Fourth

5-[4-(3-乙基 -戊基氨基) -丁基 ]-3-甲基 -1Η-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯室温下，将 5-(4-溴-丁基) -3-甲基 -1Η-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 60c(220 mg, 0.57 mmol)搅拌下溶解于 5 ml二氯甲垸中，加入 Ν,Ν-二乙基乙二胺 (164 μ 1， 1.13 mmol), 于油浴中回流 30 min，反应液减压下蒸除大部分溶剂，继续于油浴中回流 1 小时。点板监测反应至原料反应完全，停止反应。反应液减压浓缩后柱层析得到标题产物 5-[4-(3-乙基 -戊基氨基) -丁基 ]-3-甲基 -1H-吡咯 -2，4-二羟酸 2-叔丁酯 4-乙酯 60d(187 mg，白色固体)，产率： 78 %。 MS m/z (ESI)_: 424.3(M+ l)o 第五步 5-[4-(3-ethyl-pentylamino)-butyl]-3-methyl-1Η-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester at room temperature, 5 -(4-Bromo-butyl)-3-methyl-1Η-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 60c (220 mg, 0.57 mmol) dissolved in 5 ml of 2 To the chloroformamone, hydrazine, hydrazine-diethylethylenediamine (164 μl, 1.13 mmol) was added, and the mixture was refluxed for 30 min in an oil bath. The solvent was evaporated under reduced pressure and the solvent was evaporated. 1 hour. The plate was monitored until the reaction of the starting material was complete and the reaction was stopped. The reaction mixture was concentrated under reduced pressure and purified tolululululululululu tert-Butyl 4-ethyl ester 60d (187 mg, white solid), Yield: 78%. MS m/z (ESI) _: 424.3(M+ l)o Step 5

5-(2_二乙基氨基-乙基) -3-甲基 -4-氧代 -4,5,6,7,8，9-六氢 -lH-1,5-二氮-环戊二烯并环系四烯 -2-甲酸 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7,8,9-hexahydro-lH-1,5-diaza-cyclopentyl Diene ring tetraene-2-carboxylic acid

室温下，将 489 μ ΐ三甲基铝 (2 mol/L)搅拌下溶解于 3 ml甲苯中。将 5-[4-(3- 乙基 -戊基氨基) -丁基 ]-3-甲基 -1H-吡咯 -2，4-二羟酸 2-叔丁酯 4-乙酯 60d(345 mg, 0.82 mmol)搅拌下溶解于 6 ml甲苯中，加入到上述溶液中。加毕，室温搅拌 30分钟，于油浴中回流 2小时，补加 900 μ 1三甲基铝 (2 mol/L)继续回流 7小时，点板监测反应至原料基本消失，加水淬灭反应。反应液中加入 1 ml盐酸 (2 mol/L)，室温搅拌 30分钟。反应液用氢氧化钠溶液 (10%)调节 pH值至 10左右，用乙酸乙酯萃取 (25 ml X 3), 合并有机相，有机相用饱和氯化钠洗涤 (25 mlxl), 无水硫酸镁干燥，抽滤除去干燥剂，滤液浓缩后柱层析得到标题产物 5-(2-二乙基氨基-乙基) -3- 甲基 -4-氧代 -4，5,6,7,8,9-六氢 -1H-1，5-二氮-环戊二烯并环系四烯 -2-甲醛 60e(60 mg, 白色固体)，产率： 26.7%。 489 μM trimethylaluminum (2 mol/L) was dissolved in 3 ml of toluene with stirring at room temperature. 5-[4-(3-Ethyl-pentylamino)-butyl]-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 60d (345 mg , 0.82 mmol) was dissolved in 6 ml of toluene with stirring and added to the above solution. After the addition, the mixture was stirred at room temperature for 30 minutes, refluxed in an oil bath for 2 hours, and further added with 900 μl of trimethylaluminum (2 mol/L) for 7 hours. The reaction was monitored until the starting material disappeared, and the reaction was quenched with water. 1 ml of hydrochloric acid (2 mol/L) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was adjusted to pH 10 with sodium hydroxide solution (10%), extracted with ethyl acetate (25 ml X 3), and the organic phase was combined and washed with saturated sodium chloride (25 ml×l) The magnesium is dried, and the desiccant is removed by suction filtration. The filtrate is concentrated and purified by column chromatography to give the title product 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7, 8,9-Hexahydro-1H-1,5-diaza-cyclopentacyclotetradec-2-carbaldehyde 60e (60 mg, white solid), Yield: 26.7%.

MS m/z (ESI): 278.2(M+ 1)。第六步 MS m/z (ESI): 278.2 (M + 1). Step 6

5-(2-二乙基氨基-乙基) -2-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基) -3-甲基 -6,7,8,9-四氢 -1H,5H-1，5-二氮-环戊二烯并环系四烯 -4-酮 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methyl)-3-methyl-6, 7,8,9-tetrahydro-1H,5H-1,5-diaza-cyclopentadienyltetradec-4-one

室温下，将 5-(2-二乙基氨基-乙基) -3-甲基 -4-氧代 -4,5,6,7,8,9-六氢 -1H-1, 5-二氮 5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7,8,9-hexahydro-1H-1, 5-di nitrogen

-环戊二烯并环系四烯 -2-甲醛 60e(20 mg, 0.066mmol)搅拌下溶解于 1 ml乙醇中，加入 5-氟 -1,3-二氢』引哚 -2-酮 (9.9 mg， 0.066mmol), 避光搅拌至溶解，加入 0.1 ml 哌啶，加热回流 2小时。点板表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤得到标题产物 5-(2-二乙基氨基-乙基) -2-(5-氟 -2-氧代 -1,2-二氢 -η引哚- cyclopentadienyltetradecene-2-carbaldehyde 60e (20 mg, 0.066 mmol) was dissolved in 1 ml of ethanol with stirring, and 5-fluoro-1,3-dihydroindol-2-one was added. 9.9 mg, 0.066 mmol), stir to dissolve in the dark, add 0.1 ml of piperidine, and heat to reflux for 2 hours. The dot plate indicates that the starting material is completely reacted and the reaction is stopped. The reaction solution was naturally cooled to room temperature and filtered under reduced pressure to give the title product 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-?

-3-次甲基 )-3-甲基 -6,7,8,9-四氢 -1Η,5Η-1,5-二氮-环戊二烯并环系四烯 -4-酮 60(14 mg, 黄色固体)，产率： 48.8 %。 3-Methylmethyl)-3-methyl-6,7,8,9-tetrahydro-1Η,5Η-1,5-diaza-cyclopentacyclotetradec-4-one 60 ( 14 mg, yellow solid), Yield: 48.8 %.

MS m/z (ESI): 439·2(Μ+ 1)。 MS m/z (ESI): 439·2 (Μ + 1).

¹HNMR(400MHz, DMSO-d6) δ 13.462(s， 1H, 吡咯环 -NH)， 10.874(s, 1H，吲哚 -NH)， 7.739~7.758(d, 1H, -ArH), 7.715(s, 1H, -CH=C), 6.832~6.933(m, 2H, -ArH), 3.406(m, 4H, 2 X - C¾NCO)， 2.874(t, 2H, -CH₂C=C), 2.597~2.630(t, 2H, -CH₂N)， 2.486~2.538(q, 4H, 乙基 2 X - CH₂N)， 2.322(s, 3H,吡咯环 -CH₃)， 1.733(m, 4H,八环内 2 X— CH₂)， 0.963~0.968(t, 6H, 2 X— CH₃)。实施例 61 ¹ H NMR (400MHz, DMSO-d6) δ 13.462 (s, 1H, pyrrole ring-NH), 10.874 (s, 1H, 吲哚-NH), 7.739~7.758 (d, 1H, -ArH), 7.715 (s, 1H, -CH=C), 6.832~6.933(m, 2H, -ArH), 3.406(m, 4H, 2 X - C3⁄4NCO), 2.874(t, 2H, -CH ₂ C=C), 2.597~2.630 ( t, 2H, -CH ₂ N), 2.486~2.538 (q, 4H, ethyl 2 X - CH ₂ N), 2.322 (s, 3H, pyrrole ring -CH ₃ ), 1.733 (m, 4H, within 2 X—CH ₂ ), 0.963~0.968 (t, 6H, 2 X—CH ₃ ). Example 61

5-(2-二乙基氨基-乙基) -2-(5-溴 -2-氧代 -1,2-二氢』引哚 -3-次甲基 )-3-甲基 -6,7,8,9-四氢 -1H,5H-1,5-二氮-环戊二烯并 -4-酮 5-(2-diethylamino-ethyl)-2-(5-bromo-2-oxo-1,2-dihydro)indol-3-ylmethyl)-3-methyl-6, 7,8,9-four Hydrogen-1H,5H-1,5-diaza-cyclopentadien-4-one

重复本发明实施例 60第六步反应，不同的是使用实施例 60第五步中所得到的化合物 5-(2-二乙基氨基-乙基) -3-甲基 -4-氧代 -4,5，6，7,8,9-六氢 -1H-1,5-二氮-环戊二烯并环系四烯 -2-甲醛 60e和 5-漠 -1,3-二氢 -吲哚 -2-酮作原料，得到标题产物 5-(2- 二乙基氨基-乙基) -2-(5-溴 -2-氧代 -1,2-二氢』引哚 -3-次甲基 )-3-甲基 -6,7,8,9-四氢 -1H,5H-1,5-二氮-环戊二烯并环系四烯 -4-酮 61(16 mg，黄色固体)，产率： 68%。 MS m/z (ESI): 499.2(M+l)o

The sixth step reaction of Example 60 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo obtained in the fifth step of Example 60 was used. 4,5,6,7,8,9-hexahydro-1H-1,5-diaza-cyclopentadienyltetraene-2-carbaldehyde 60e and 5-di-1,3-dihydro- The indole-2-one was used as a starting material to give the title product 5-(2-diethylamino-ethyl)-2-(5-bromo-2-oxo-1,2-dihydro) hydrazine-3- Hypomethyl)-3-methyl-6,7,8,9-tetrahydro-1H,5H-1,5-diaza-cyclopentacyclotetradec-4-one 61 (16 mg, Yellow solid), Yield: 68%. MS m/z (ESI): 499.2 (M+l) o

'HNMR(400 MHZ, DMSO-d6) δ 13.660(s, 1H, 吡咯环 -NH)， 11.008(s, 1H, 吲哚 -NH), 8.113~8.117(d, 1H， -ArH)， 7.803(s, 1H, -CH=C), 7.260~7.286(dd, 1H, -ArH), 6.825~6.845(d, 1H, -ArH), 3.406(m, 4H， 2X -CH₂NCO), 2.874(t, 2H, -C¾C=C)， 2.597~2.630(t, 2H, -CH₂N)， 2.486-2.538(q, 4H, 乙基 2 X _CH₂N)， 2.322(s, 3H，吡咯环 -C¾)， 1.733(m, 4H, 八环内 2 X - C¾)， 0.963~0.968(t,6H,2 X - CH₃)。实施例 62 'HNMR (400 MHZ, DMSO-d6) δ 13.660 (s, 1H, pyrrole ring-NH), 11.008 (s, 1H, 吲哚-NH), 8.113~8.117 (d, 1H, -ArH), 7.803(s , 1H, -CH=C), 7.260~7.286(dd, 1H, -ArH), 6.825~6.845(d, 1H, -ArH), 3.406(m, 4H, 2X -CH ₂ NCO), 2.874(t, 2H, -C3⁄4C=C), 2.597~2.630(t, 2H, -CH ₂ N), 2.486-2.538(q, 4H, ethyl 2 X _CH ₂ N), 2.322(s, 3H, pyrrole ring-C3⁄4) , 1.733 (m, 4H, 2 X - C3⁄4 in the eight rings), 0.963~0.968 (t, 6H, 2 X - CH ₃ ). Example 62

5-(2-乙氨基 -乙基 )-2-(5-氟 -2-氧代 -1 ,2-二氢 -吲哚 -3-次甲基 )-3-甲基 -5,6，7,8-四氢 - 1H- 吡咯并 [3，2-c] 吖庚因 -4-酮 5-(2-ethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methylmethyl)-3-methyl-5,6, 7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one

第一步

first step

5-[2-(2-乙酰氨基 -乙基氨基甲酰基) -乙基 ]-3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4- 乙酯 5-[2-(2-Acetylamino-ethylcarbamoyl)-ethyl]-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester

室温下，将本发明实施例 1第四步所得化合物 5-(2-羧基-乙基) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 le(9.85 g， 30.3 mmol)搅拌下溶解于 50 ml乙腈中，加入 1-羟基苯并*** (8.2 g, 60.6 mmol)和 N-乙基 -N，- (二甲氨基丙基) -碳二亚胺 (11.6 g， 60.6 mmol), 加毕，室温搅拌过夜。点板表明原料反应完全，停止反应。反应液减压浓缩后加入 200 ml水，乙酸乙酯萃取 (200 mi x 4)，合并有机相，有机相用饱和氯化钠溶液洗涤 (100 mi x 1)，无水硫酸镁干燥，抽滤除去干燥剂，滤液减压浓缩后柱层析得到标题产物 5-[2-(2-乙酰氨基 -乙基氨基甲酰基) -乙基 ]-3-甲基 -1H- 吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 62a(8 g，白色晶体)，产率： 65 %。 The compound obtained in the fourth step of the first embodiment of the present invention is 5-(2-carboxy-ethyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester obtained at room temperature. Le (9.85 g, 30.3 mmol) was dissolved in 50 ml of acetonitrile with stirring, and 1-hydroxybenzotriazole (8.2 g, 60.6 mmol) and N-ethyl-N,-(dimethylaminopropyl)-carbon were added. Diimine (11.6 g, 60.6 mmol), added, and stirred at room temperature overnight. The dot plate indicates that the starting material is completely reacted and the reaction is stopped. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAcjjjjjj The desiccant was removed, and the filtrate was concentrated under reduced pressure. 2-tert-Butyl dicarboxylate 4-ethyl ester 62a (8 g, white crystal), Yield: 65 %.

MS m/z (ESI): 410.1(M+1)。第二步 MS m/z (ESI): 410.1 (M + 1). Second step

2-[2-(2-乙酰氨基 -乙基氨基甲酰基) -乙基 ]-4-甲基 -1H-吡咯 -3-羧酸乙酯室温下，将 5-[2-(2-乙酰氨基 -乙基氨基甲酰基) -乙基 ]-3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 62a(818 mg， 2 mmol)搅拌下溶解于 5 ml乙醇中，加入 5 ml浓盐酸 (12 mol/L)，加毕，于 60°C油浴中反应 2小时。点板监测反应至原料消失，停止反应。反应液减压下蒸除乙醇，用氢氧化钠溶液 (10%)调节 pH至 12左右，用乙酸乙酯萃取 (20 mi x 3)，合并有机相，有机相用无水硫酸镆千燥，抽滤除去干燥剂，滤液减压浓缩得到标题产物 2-[2-(2-乙酰氨基 -乙基氨基甲酰基) -乙基 ]-4-甲基 -1H- 吡咯 -3-羧酸乙酯 62b(600 mg，白色固体)，产率： 97%。 MS m/z (ESI): 310.1(M+1) = 第三步 Ethyl 2-[2-(2-acetamido-ethylcarbamoyl)-ethyl]-4-methyl-1H-pyrrole-3-carboxylate 5-[2-(2-acetyl) at room temperature Amino-ethylcarbamoyl)-ethyl]-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester 62a (818 mg, 2 mmol) dissolved in stirring 5 ml of concentrated hydrochloric acid (12 mol/L) was added to 5 ml of ethanol, and the reaction was carried out for 2 hours in an oil bath at 60 °C. The plate was monitored for reaction until the starting material disappeared and the reaction was stopped. The reaction solution was evaporated to dryness under reduced pressure, and the mixture was adjusted to pH 12 with sodium hydroxide solution (10%), and extracted with ethyl acetate (20 mi x 3). The organic phase was combined and the organic phase was dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, and the filtrate was concentrated under reduced pressure to give ethyl 2-[2-(2-acetylamino-ethylcarbamoyl)-ethyl]-4-methyl-1H-pyrrole-3-carboxylate. 62b (600 mg, white solid), Yield: 97%. MS m/z (ESI): 310.1 (M+1) = step 3

2-[3-(2-乙氨基-乙氨基) -丙基 ]-4-甲基- 1H-吡咯 -3-羧酸乙酯氩气氛下，将 2-[2-(2-乙酰氨基 -乙基氨基甲酰基) -乙基 ]-4-甲基 -1H-吡咯 -3-羧酸乙酯 62b(600 mg， 1.94 mmol)搅拌下溶解于 4 ml四氢呋喃中，冰浴冷却，缓慢滴加硼烷的四氢呋喃溶液 (7.79 ml, 1 mol/L, 7.79 mmol), 加毕，加热回流 2小时，点板监测反应至原料反应完全，用盐酸淬灭反应。反应液继续于室温下搅拌 30分钟，用氢氧化钠溶液 (10%)调节 pH至 12左右，乙酸乙酯萃取 (30 ml X 3)。合并有机相，有机相用饱和氯化钠溶液洗涤 (30 ml X 1)，无水硫酸镁干燥，抽滤除去干燥剂，滤液减压浓縮后柱层析得到标题产物 2-[3-(2-乙氨基-乙氨基) -丙基 ]-4-甲基 -1H- 吡咯 -3-羧酸乙酯 62c(170 mg，白色固体），产率： 31 %。 Ethyl 2-[3-(2-ethylamino-ethylamino)-propyl]-4-methyl-1H-pyrrole-3-carboxylate 2-[2-(2-acetylamino-) Ethyl ethyl carbamoyl)-ethyl]-4-methyl-1H-pyrrole-3-carboxylate 62b (600 mg, 1.94 mmol) was dissolved in 4 ml of tetrahydrofuran with stirring, cooled in ice bath, slowly added dropwise A solution of borane in tetrahydrofuran (7.79 ml, 1 mol/L, 7.79 mmol) was added, and the mixture was heated under reflux for 2 hours. The reaction was monitored by spotting until the reaction was completed and quenched with hydrochloric acid. The reaction solution was further stirred at room temperature for 30 minutes, and the pH was adjusted to about 12 with a sodium hydroxide solution (10%), and ethyl acetate (30 ml X 3 ). The organic phase was combined, and the organic phase was washed with saturated aqueous sodium chloride (30 ml), dried over anhydrous magnesium sulfate. Ethyl 2-ethylamino-ethylamino)-propyl]-4-methyl-1H-pyrrole-3-carboxylate 62c (170 mg, white solid).

MS m/z (ESI): 282.2(M+1)。第四步 MS m/z (ESI): 282.2 (M + 1). the fourth step

5-(2-乙氨基 -乙基 )-3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮室温下，将 2-[3-(2-乙氨基-乙氨基) -丙基 ]-4-甲基 -1H-吡咯 -3-羧酸乙酯 62c(350 mg, 1.245 mmol)和三甲基铝 (1.25 ml， 2.49 mmol)搅拌下溶解于 75ml甲苯中，于 140Ό油浴中回流 24小时，点板监测反应至原料反应完全，停止反应。反应液减压蒸除溶剂，用盐酸 (6 mol/L)调节 pH至 3左右，搅拌 30分钟，再用氢氧化钠溶液 (12 mol/L)调节 pH至 14, 二氯甲烷萃取 (100 ml X 4)。合并有机相，有机相用饱和氯化钠溶液洗漆 (150 ml X 1)，无水硫酸镜干燥，抽滤除去干燥剂，滤液减压浓缩得到标题产物 5-(2-乙氨基 -乙基 )-3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-M 62d(450 mg, 黄色油状物），直接进行下歩反应。 5-(2-ethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one at room temperature, 2-[3-(2-Ethylamino-ethylamino)-propyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 62c (350 mg, 1.245 mmol) and trimethylaluminum (1.25 ml) , 2.49 mmol) was dissolved in 75 ml of toluene with stirring, and refluxed for 24 hours in a 140 Torr oil bath. The reaction was monitored by spotting until the reaction of the starting material was complete, and the reaction was stopped. The reaction solution was evaporated under reduced pressure. The pH was adjusted to about 3 with hydrochloric acid (6 mol/L), stirred for 30 minutes, and then adjusted to pH 14 with sodium hydroxide solution (12 mol/L), and extracted with dichloromethane (100 ml) X 4). The organic phase was combined, and the organic phase was washed with a saturated sodium chloride solution (150 ml X 1), dried over anhydrous sulfate, and filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to give the title product 5-(2-ethylamino-ethyl )-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-M 62d (450 mg, yellow oil), directly squat reaction.

MS m/z (ESI): 236.0(M+1)。第五步 MS m/z (ESI): 23:21. the fifth step

乙基 -[2-(3-甲基 -4-氧代 -4,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -5-基) -乙基] -氨基甲酸叔丁酯 Ethyl-[2-(3-methyl-4-oxo-4,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-5-yl)-ethyl ]-tert-butyl carbamate

室温下，将 5-(2-乙氨基 -乙基 )-3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4- 酮 62d(450 mg， 1.91 mmol)搅拌下溶解于 20 ml二氯甲烷中，加入二碳酸二叔丁酯 (834 mg, 3.83 mmol), 碳酸钾 (528 mg， 3.83 mmol)和 30 ml四氢呋喃，加毕室温搅拌过夜。点板监测反应至原料反应完全，停止反应。反应液中加入 50 ml水，用乙酸乙酯萃取 (50 ml X 3)。合并有机相，有机相用饱和氯化钠溶液洗涤 (50 ml X 1)，无水硫酸镁干燥，抽滤除去干燥剂，滤液减压浓缩后柱层析得到标题产物乙基 -[2-(3-甲基 -4-氧代 -4,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -5-基) -乙基] -氨基甲酸叔丁酯 62e(40 mg，黄色固体)，产率： 6%。 5-(2-Ethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one at room temperature 62d (450 mg, 1.91 mmol) was dissolved in 20 ml of dichloromethane with stirring, and di-tert-butyl dicarbonate (834 mg, 3.83 mmol), potassium carbonate (528 mg, 3.83 mmol) and 30 ml of tetrahydrofuran were added. Stir at room temperature overnight. The plate was monitored until the reaction of the starting material was complete and the reaction was stopped. 50 ml of water was added to the reaction mixture, and extracted with ethyl acetate (50 ml X 3). The organic phase was combined, and the organic phase was washed with saturated sodium chloride (50 ml EtOAc). 3-methyl-4-oxo-4,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-5-yl)-ethyl]-carbamic acid Butyrate 62e (40 mg, yellow solid), Yield: 6%.

MS m/z (ESI): 336·2(Μ+1)。第六步 MS m/z (ESI): 336·2 (Μ +1). Step 6

乙基 -[2-(2-甲酰基 -3-甲基 -4-氧代 -4,6,7,8-四氢 -1Η-吡咯并 [3,2-c] 吖庚因 -5-基) -乙基] -氨基甲酸叔丁酯 Ethyl-[2-(2-formyl-3-methyl-4-oxo-4,6,7,8-tetrahydro-1Η-pyrrolo[3,2-c] azepine-5- -ethyl]-tert-butyl carbamate

室温下，将乙基 -[2-(3-甲基 -4-氧代 -4,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -5- 基)-乙基] -氨基甲酸叔丁酯 62e(40 mg, 0.119 mmol)搅拌下溶解于 25 ml二氯甲垸中，加入氯亚甲基二甲基氯化胺 (15.92 mg， 0.12 mmol), 加毕室温搅拌 10分钟。点板监测反应至原料反应完全，用氢氧化钠溶液 (12 mol/L)淬灭反应，反应液继续于室温下搅拌 15分钟，二氯甲烷萃取 (20 ml X 3)。合并有机相，有机相用饱和氯化钠洗涤 (20 mi x 1)，无水硫酸镁干燥，抽滤除去干燥剂，滤液减压浓缩得到标题产物乙基 -[2-(2-甲酰基 -3-甲基 -4-氧代 -4,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -5-基) - 乙基] -氨基甲酸叔丁酯 62f(54 mg，黄色固体)，直接进行下步反应。 Ethyl-[2-(3-methyl-4-oxo-4,6,7,8-tetrahydro-1H-pyrrolo[3,2-c] azepine-5-yl group at room temperature -ethyl]-tert-butyl carbamate 62e (40 mg, 0.119 mmol) was dissolved in 25 ml of dichloromethane and stirred with chloromethylene dimethylamine (15.92 mg, 0.12 mmol). Stir at room temperature for 10 minutes. The reaction was monitored by spotting until the reaction of the starting material was complete. The reaction was quenched with sodium hydroxide solution (12 mol/L). The reaction mixture was stirred at room temperature for 15 minutes and extracted with dichloromethane (20 ml X 3). The organic phase was combined, and the organic layer was washed with EtOAc EtOAcjjjjjjjjjjjj 3-methyl-4-oxo-4,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-5-yl)-ethyl]-carbamic acid tert-butyl ester 62f (54 mg, yellow solid), directly to the next step.

MS m/z (ESI): 364.1(M+1)。第七步 MS m/z (ESI): 364.1 (M + 1). Seventh step

5-(2-乙氨基 -乙基 )-3-甲基 -4-氧代 -1，4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛冰浴下，将乙基 -[2-(2-甲酰基 -3-甲基 -4-氧代 -4,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -5-基) -乙基] -氨基甲酸叔丁酯 62f(43 mg, 0.118 mmol)搅拌下溶解于 10 ml二氯甲烷中，加入三氟醋酸 (272 μ ΐ, 3.55 mmol), 搅拌 15分钟，点板监测反应至原料反应完全，停止反应。反应液减压浓缩得到标题产物 5-(2-乙氨基 -乙基 )-3-甲基 -4- 氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 62j直接进行下一步反应。 5-(2-ethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c] azepine- Ethyl-[2-(2-formyl-3-methyl-4-oxo-4,6,7,8-tetrahydro-1H-pyrrolo[3,2-] in 2-formaldehyde ice bath c] 吖gine-5-yl)-ethyl]-carbamic acid tert-butyl ester 62f (43 mg, 0.118 mmol) was dissolved in 10 ml of dichloromethane with stirring, and added trifluoroacetic acid (272 μ ΐ, 3.55 mmol) The mixture was stirred for 15 minutes, and the reaction was monitored by spotting until the reaction of the starting material was complete, and the reaction was stopped. The reaction mixture was concentrated under reduced pressure to give the title product 5-(2-ethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3, 2-c] Azepine-2-carbaldehyde 62j directly proceeds to the next reaction.

MS m/z (ESI): 264.1(M+1)。第八步 MS m/z (ESI): 264.1 (M + 1). Eighth step

5-(2-乙氨基 -乙基 )-2-(5-氟 -2-氧代 -1,2-二氢 -Π引哚 -3-次甲基 )-3-甲基 -5,6,7,8-四氢 -1H- 吡咯并 [3,2-c] 吖庚因 -4-酮 5-(2-ethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indole 哚-3-methylol)-3-methyl-5,6 ,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one

氩气氛下，将 5-(2-乙氨基 -乙基 )-3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 62j(45 mg, 0.118 mmol)搅拌下溶解于 5 ml乙醇中，加入 5-氟 -1,3- 二氢 -吲哚 -2-酮 (16 mg， 0.106 mmol)和哌啶 (0.15 ml, 1.49 mmol), 加毕于 90°C油浴中回流 1小时，点板监测反应至原料反应完全，停止反应。反应液减压蒸除溶剂，加入少量乙醇，得到标题产物 5-(2-乙氨基 -乙基 )-2-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3- 次甲基 )-3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 62(34 mg，黄色固体)，产率： 76%。 5-(2-Ethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c under argon atmosphere ] aglycone-2-formaldehyde 62j (45 mg, 0.118 mmol) was dissolved in 5 ml of ethanol with stirring, and 5-fluoro-1,3-dihydro-indol-2-one (16 mg, 0.106 mmol) was added. Piperidine (0.15 ml, 1.49 mmol) was added to a 90 ° C oil bath for 1 hour, and the reaction was monitored by spotting until the reaction of the starting material was complete and the reaction was stopped. The reaction mixture was evaporated under reduced pressure and the mixture was evaporated to ethylamine (ethylamine) - methine)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 62 (34 mg, yellow solid), Rate: 76%.

MS m/z (ESI): 397·1(Μ+1)。 1H N R ( 400 MHz, DMSO-d6 ) δ 13.748(s,lH, 吡咯环 -NH),10.920(s,lH, 吲哚 -NH),7.781~7.788(d,lH,-ArH),7.759(s,lH,-CH=C),6.925~6.976(td,lH,-ArH),6.845~6. 877(dd,lH,-ArH),3.637-3.688(t,2H, 七环接氮 -CH₂),3.371~3.398(t，2H, 七环外接酰胺氮 -CH₂)，2.959~3.026(m,4H, -CH₂C=C,-CH₂N), 2.864~2.918(q,2H,乙基 -CH₂)2.488 (s，3H,吡咯环 - C ) , 2.056~2.083(m,2H,七环 -CH₂),1.136~1.172(t，3H,乙基- CH₃)。实施例 63 MS m/z (ESI): 397·1 (Μ +1). 1H NR ( 400 MHz, DMSO-d6 ) δ 13.748 (s, lH, pyrrole ring-NH), 10.920 (s, lH, 吲哚-NH), 7.78 to 7.788 (d, lH, -ArH), 7.759 (s , lH, -CH=C), 6.925~6.976(td,lH,-ArH), 6.845~6. 877(dd,lH,-ArH),3.637-3.688(t,2H, seven-ring nitrogen-CH ₂ ), 3.371~3.398 (t, 2H, seven-ring external amide nitrogen-CH ₂ ), 2.995~3.026 (m, 4H, -CH ₂ C=C, -CH ₂ N), 2.864~2.918 (q, 2H, B) Base -CH ₂ ) 2.488 (s, 3H, pyrrole ring - C ), 2.056 to 2.083 (m, 2H, hepta-CH ₂ ), 1.136 to 1.172 (t, 3H, ethyl-CH ₃ ). Example 63

5-(2-二乙氨基-乙基) -2-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-3-甲基 -3a,5，6,7,8，8a- 六氢 -1H-吡咯 [3,2-c] 吖 -4-酮苹果酸盐 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methylmethyl)-3-methyl-3a,5 ,6,7,8,8a-hexahydro-1H-pyrrole[3,2-c]indole-4-one malate

室温下，将本发明实施例 1所得化合物 5-(2-二乙氨基-乙基) -2-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-3-甲基 -3a，5,6,7,8,8a-六氢 -1H-吡咯 [3,2-c] 吖庚因 -4-酮 1(2.01 g， 4.75 mmol)搅拌下溶解于 279 ml甲醇中，一次性加入 2-羟基-丁二酸 (0.953 g， 7.11 mmol), 得到桔黄色澄清溶液，将此溶液减压蒸除溶剂，加入 45 ml乙腈，于油浴中加热回流 30分钟，撤去油浴，反应体系温度自然降至室温，反应混合物抽滤后干燥得到标题产物 5-(2-二乙氨基-乙基) -2-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基) -3-甲基 -3a,5,6,7,8,8a-六氢 -1H-吡咯 [3,2-c] 吖庚因 -4-酮苹果酸盐 63(2.02 g,橙黄色固体)，产率： 76.2%。

The compound obtained in Example 1 of the present invention is 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indole-3-indolyl) at room temperature. 3-methyl-3a,5,6,7,8,8a-hexahydro-1H-pyrrole[3,2-c] azepin-4-one 1 (2.01 g, 4.75 mmol) with stirring Dissolve in 279 ml of methanol, add 2-hydroxy-succinic acid (0.953 g, 7.11 mmol) in one time to obtain a clear orange solution. Evaporate the solvent under reduced pressure, add 45 ml of acetonitrile, and heat in an oil bath. After refluxing for 30 minutes, the oil bath was removed, the temperature of the reaction system was naturally lowered to room temperature, and the reaction mixture was filtered and dried to give the title product 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo- 1,2-dihydro-indol-3-methylol)-3-methyl-3a,5,6,7,8,8a-hexahydro-1H-pyrrole[3,2-c] azepine 4-keto malate 63 (2.02 g, orange-yellow solid), Yield: 76.2%.

MS m/z (ESI): 425.1(M+1)。 MS m/z (ESI): 425.1 (M+1).

¹HNMR(400 MHz, DMSO-d6) δ 13.742(s, 1H,吡咯环 -NH)， 10.925(s, 1H, 吲哚 -NH), 7.784~7.790(dd, 1H, -ArH), 7.755(s, 1H, -CH=C), 6.922-6.95 l(m, 1H, -ArH), 6.840~6.873(m, 1H, -ArH), 3.631~3.665(t, 2H,七环内 -CH₂N)， 3.374 3.401 (t, 2H,七环外接酰胺氮 -CH₂)， 2.911~2.958(t, 2H,七环内 -C¾C=C)， 2.536~2.575(m, 6H, 3X -CH₂N)， 2.471(s, 3H, 吡咯环 -CH₃)， 2.053~2.079(m, 2H，七环内 CH₂)， 1.137(t, 6H, 2X-CH₃) o 实施例 64 ¹ H NMR (400 MHz, DMSO-d6) δ 13.742 (s, 1H, pyrrole ring-NH), 10.925 (s, 1H, 吲哚-NH), 7.784~7.790 (dd, 1H, -ArH), 7.755 (s , 1H, -CH=C), 6.922-6.95 l(m, 1H, -ArH), 6.840~6.873(m, 1H, -ArH), 3.631~3.665(t, 2H, hepta-CH ₂ N) , 3.374 3.401 (t, 2H, heptacyclic external amide nitrogen-CH ₂ ), 2.911~2.958 (t, 2H, hepta-C3⁄4C=C), 2.536~2.575 (m, 6H, 3X -CH ₂ N), 2.471 (s, 3H, pyrrole ring-CH ₃ ), 2.053 to 2.079 (m, 2H, CH _{2 in the} hepta), 1.137 (t, 6H, 2X-CH ₃ ) o Example 64

(Z)-2-((5-(2,6-二氯苄磺酰基 )-2-吲哚酮 -3-亚基）甲基 )-3-甲基 -5-(2-吗啉乙基) -5,6,7,8-四氢吡咯并 [3，2-c] 吖庚因 -4(1H)-酮 (Z)-2-((5-(2,6-dichlorobenzylsulfonyl)-2-indolone-3-ylidene)methyl)-3-methyl-5-(2-morpholine B -5,6,7,8-tetrahydropyrrolo[3,2-c]azepine-4(1H)-one

第一步

first step

5-氯磺酰基 -2-吲哚酮 5-chlorosulfonyl-2-indanone

冰浴下，向 2-吲哚酮 64a (13.3 g， lOOmmol)中缓慢加入氯磺酸 (26.6 ml, 400 mmol), 加毕于冰浴中搅拌 1小时，继续室温搅拌 1小时，升温至 68°C后继续搅拌 1小时。反应液冷却至室温后缓慢加入 400 ml水中搅拌，有黄色固体析出，室温静置 1小时后减压抽滤，滤饼用水洗涤 (20 mi x 4)后干燥得到标题产物 5-氯磺酰基 -2-吲哚酮 64b(15.0 g，黄色固体)，产率： 65 %。 Under ice bath, chlorosulfonic acid (26.6 ml, 400 mmol) was slowly added to 2-nonanone 64a (13.3 g, 100 mmol), and the mixture was stirred for 1 hour in an ice bath, and the mixture was stirred at room temperature for 1 hour, and the temperature was raised to 68. Stirring was continued for 1 hour after °C. After the reaction mixture was cooled to room temperature, it was slowly added to 400 ml of water and stirred, and a yellow solid was precipitated. After standing at room temperature for 1 hour, it was filtered under reduced pressure. The filter cake was washed with water (20 mi x 4) and dried to give the title product 5-chlorosulfonyl- 2-nonanone 64b (15.0 g, yellow solid), Yield: 65 %.

参考文献： Acta Pharmacol Sin,; 2007, 28(1), 140-152. 第二步 References: Acta Pharmacol Sin,; 2007, 28(1), 140-152. Step 2

5-(2,6-二氯苄磺酰基)吲哚 -2-酮 5-(2,6-dichlorobenzylsulfonyl)indole-2-one

室温下，将十二水合磷酸一氢钠（142 g, 1.0 mol)和亚硫酸钠（252 g, 2.0 mol) 溶解于 2L水中后加热至 30 °C，再加入 5-氯磺酰基 -2-吲哚酮 64b (232 g, 1.0 mol), 加毕，混合物于 60 °C下搅拌 16小时。将 2,6-二氯苄基溴（240 g, 1.0 mol)溶解于 1.8L丙酮后加入上述反应液中，继续于 60 °C下搅拌 1小时，补加 200 ml丙酮后继续搅拌 2小时。反应液加入到 5L水中淬灭反应，混合物继续于室温下搅拌 1小时后减压抽滤，再用水 (1LX 1)和丙酮 (1L X 1)洗涤，真空干燥后得到标题产物 5-(2,6- 二氯苄磺酰基)吲哚 -2-酮 64c(314 g，白色固体)，产率： 88%。 Dissolve sodium monohydrogen monohydrate (142 g, 1.0 mol) and sodium sulfite (252 g, 2.0 mol) in 2 L of water at room temperature, then heat to 30 °C, then add 5-chlorosulfonyl-2-indole Ketone 64b (232 g, 1.0 mol) was added, and the mixture was stirred at 60 ° C for 16 hours. 2,6-Dichlorobenzyl bromide (240 g, 1.0 mol) was dissolved in 1.8 L of acetone and added to the above reaction mixture, and the mixture was further stirred at 60 ° C for 1 hour, and further stirred for 2 hours after adding 200 ml of acetone. The reaction mixture was quenched by the addition of 5 L of water, and the mixture was stirred at room temperature for 1 hour, then filtered under reduced pressure, washed with water (1L.sub.1) and acetone (1L X1). 6-Dichlorobenzylsulfonyl)indol-2-one 64c (314 g, white solid), Yield: 88%.

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

'HNMR(400 MHZ, DMSO-d6) δ 10.90(s， 1H, 吲哚- NH)， 7.56(m, 4H, -ArH), 7.43(m， 1H, -ArH), 6.99(d, 1H, -ArH), 4.59(s, 2H, -ArCH₂) 'HNMR (400 MHZ, DMSO-d6) δ 10.90 (s, 1H, 吲哚-NH), 7.56 (m, 4H, -ArH), 7.43 (m, 1H, -ArH), 6.99(d, 1H, -ArH), 4.59(s, 2H, -ArCH ₂ )

参考文献： Organic Process Research & Development,; 2003, 7, 313-317. 第三步 References: Organic Process Research &Development,; 2003, 7, 313-317.

(Z)-2-((5-(2,6-二氯苄磺酰基）-2-吲哚酮 -3-亚基）甲基 )-3-甲基 -5-(2-吗啉乙基) -5,6,7,8-四氢吡咯并 [3,2-c] 吖庚因 -4(1H)-酮 (Z)-2-((5-(2,6-dichlorobenzylsulfonyl)-2-indolone-3-ylidene)methyl)-3-methyl-5-(2-morpholine B -5,6,7,8-tetrahydropyrrolo[3,2-c]azepine-4(1H)-one

室温下，将 3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1,4，5,6，7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 10c (100 mg， 0.325 mmol)和 5-(2,6-二氯苄磺酰基)吲哚 -2-酮 64c(104 mg, 0.293 mmol)加入到 3 ml乙醇中，再加入 52μ1哌啶，加毕加热回流 2小时。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗涤 (3 ml X 2), 千燥后得到标题产物 (Z)-2-((5-(2,6-二氯苄磺酰基 )-2- 吲哚酮 -3-亚基）甲基) -3-甲基 -5-(2-吗啉乙基) -5,6,7,8-四氢吡咯并 [3,2-c] 吖庚因 3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3, at room temperature 2-c] azepine-2-carbaldehyde 10c (100 mg, 0.325 mmol) and 5-(2,6-dichlorobenzylsulfonyl)indol-2-one 64c (104 mg, 0.293 mmol) were added to 3 In ml ethanol, 52 μl of piperidine was further added, and the mixture was heated under reflux for 2 hours. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was naturally cooled to room temperature, filtered under reduced pressure, and filtered, washed with anhydrous ethyl ether (3 ml, EtOAc). Sulfonyl)-2-indolone-3-ylidene)methyl)-3-methyl-5-(2-morpholinylethyl)-5,6,7,8-tetrahydropyrrolo[3, 2-c] 吖庚因

-4(1H)-酮 64(166 mg, 桔黄色固体)，产率： 88 %。 -4(1H)-one 64 (166 mg, orange solid), Yield: 88%.

MS m/z (ESI): 643.3(M+1)。 MS m/z (ESI): 643.3 (M+1).

MHz, DMSO-d6) δ 13.63(s, 1H,吡咯环 -NH), 11.42(s, 1H,吲哚 -NH)，

MHz, DMSO-d6) δ 13.63 (s, 1H, pyrrole ring-NH), 11.42 (s, 1H, 吲哚-NH),

8.28 (s， 1H， -ArH), 7.90(s, 1H, -ArH), 7.5 l(m, 3H, -ArH), 7.42(s, 1H, -CH=C), 7.06(m,8.28 (s, 1H, -ArH), 7.90(s, 1H, -ArH), 7.5 l(m, 3H, -ArH), 7.42(s, 1H, -CH=C), 7.06(m,

1H, -ArH), 4.88(s, 2H, -ArCH₂), 3.58~2.08(m, 18H,脂肪族 H), 2.44(s， 3H，吡咯环1H, -ArH), 4.88(s, 2H, -ArCH ₂ ), 3.58~2.08(m, 18H, aliphatic H), 2.44(s, 3H, pyrrole ring

-CH₃) 实施例 65 -CH ₃ ) Example 65

2-[5-(4-氟-苄磺酰基 )-2-氧代 -1,2-二氢』引哚 -3-亚甲基 ]-3-甲基 -5-(2-吡咯烷 -1-基-乙 -5，6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 2-[5-(4-Fluoro-benzylsulfonyl)-2-oxo-1,2-dihydro]pyridinium-3-methylene]-3-methyl-5-(2-pyrrolidine- 1-yl-ethyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one

第一歩

First

5-(4-氟- 磺酰基 )-1,3-二氢』引哚 -2-酮 5-(4-fluoro-sulfonyl)-1,3-dihydroindol-2-one

室温下，将十二水合磷酸一氢钠（3.58 g， 10 mmol)和亚硫酸钠（2.52 g, 20 mmol) 溶解于 20 ml水中后加热至 30。C，再加入 5-氯磺酰基 -2-吲哚酮 64b(2.32 g, 10 mmol), 加毕，混合物于 60 °C下搅拌 16小时。将 4-氟苄基溴 (1.9 g, 10 mmol)溶解于 18 ml丙酮后缓慢加入到上述反应液中，继续于 60 °C下搅拌 2小时。反应液加入到 50 mi水中淬灭反应，反应液中有大量固体析出，混合物继续于室温下搅拌 1小时后减压抽滤，再用 20 ml水和丙酮的混合溶剂 (V:V=1 :1)洗涤，真空干燥后得到标题产物 5-(4-氟-苄磺酰基 )-1,3-二氢 -吲哚 -2-酮 65a(1.8 g，淡黄色固体)，产率： 59 %。 Sodium monohydrogen monohydrate (3.58 g, 10 mmol) and sodium sulfite (2.52 g, 20 mmol) at room temperature Heat to 30 after dissolving in 20 ml of water. Further, 5-chlorosulfonyl-2-indanone 64b (2.32 g, 10 mmol) was added, and the mixture was stirred at 60 ° C for 16 hours. 4-Fluorobenzyl bromide (1.9 g, 10 mmol) was dissolved in 18 ml of acetone, and then slowly added to the above reaction mixture, and stirring was continued at 60 ° C for 2 hours. The reaction solution was quenched by adding to 50 ml of water, and a large amount of solid was precipitated in the reaction mixture. The mixture was further stirred at room temperature for 1 hour, and then filtered under reduced pressure, and then mixed with 20 ml of water and acetone (V:V = 1: 1) Washing and drying in vacuo gave the title product 5-(4-fluoro-benzylsulfonyl)-1,3-dihydro-indol-2-one 65a (1.8 g, pale yellow solid), yield: 59 % .

MS m/z (ESI): 304.1(M-1)。 MS m/z (ESI): 304.1 (MI).

^!HNMR(400 MHz, DMSO-d6) δ 10.85(s, 1H,吲哚 -NH)， 7.42(m, 2H, -ArH), 7.21 (m, 3H, -ArH), 6.95(d₅ 1H, -ArH), 4.59(s, 2H, -ArCH₂) ^{! HNMR (400 MHz, DMSO-} d6) δ 10.85 (s, 1H, indole -NH), 7.42 (m, 2H , -ArH), 7.21 (m, 3H, -ArH), 6.95 (d 5 1H, - ArH), 4.59(s, 2H, -ArCH ₂ )

参考文献： Organic Process Research & Development,; 2003, 7, 313-317. 第二步 References: Organic Process Research &Development,; 2003, 7, 313-317. Step 2

2-[5-(4-氟-苄磺酰基 )-2-氧代 -1,2-二氢』引哚 -3-亚甲基 ]-3-甲基 -5-(2-吡咯烷 -1-基-乙基) -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 2-[5-(4-Fluoro-benzylsulfonyl)-2-oxo-1,2-dihydro]pyridinium-3-methylene]-3-methyl-5-(2-pyrrolidine- 1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one

室温下，将 3-甲基 -4-氧代 -5-(2-吡咯烷 -1-基-乙基) -1 ,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 28c (60.2 mg， 0.21 mmol)和 5-(4-氟-苄磺酰基 )-1 ,3-二氢 -B引哚 -2-酮 65a (57.6 mg, 0.19 mmol)加入到 2 ml乙醇中，再加入 50μ1哌啶，加毕加热回流 3 小时。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗涤 (3 mi x 2)，千燥后得到标题产物 2-[5-(4-氟-苄磺酰基 )-2- 氧代 -1,2-二氢 -吲哚 -3-亚甲基 ]-3-甲基 -5-(2-吡咯烷 -1-基-乙基) -5，6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 65(90 mg，桔黄色固体)，产率： 81.8 %。 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3, at room temperature 2-c] azepine-2-carbaldehyde 28c (60.2 mg, 0.21 mmol) and 5-(4-fluoro-benzylsulfonyl)-1,3-dihydro-B-indol-2-one 65a (57.6 mg , 0.19 mmol) was added to 2 ml of ethanol, 50 μl of piperidine was added, and the mixture was heated under reflux for 3 hours. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was naturally cooled to room temperature, filtered under reduced pressure, and filtered, washed with anhydrous ethanol (3 <RTI ID=0.0></RTI> </RTI> <RTIgt; -1,2-dihydro-indole-3-methylene]-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-5,6,7,8-tetrahydro -1H-pyrrolo[3,2-c]azepin-4-one 65 (90 mg, orange solid), Yield: 8.18%.

MS m/z (ESI): 577.3(M+1)。 MS m/z (ESI): 577.3 (MI).

¹HNMR(400 MHz, DMSO-d6) δ 12.133(s, 1H, 吲哚 -NH)， 8.99(s, 1H, -ArH), 8.61(s, 1H, -ArH), 7.88(s, 1H, -CH=C), 8.14〜7.76(m, 4H, -ArH) , 7.75(d, 1H, -ArH), 5.39(s, 2H， -ArCH₂), 4.33(m, 2H, -NCH₂), 4.11~3.25(m, 12H,脂肪族 H), 3.70(m, 2H, -NCH₂)， 2.8 l(m, 2H， -NCH₂), 2.46(s, 3H, 吡咯环 -C¾) 实施例 66 ¹ H NMR (400 MHz, DMSO-d6) δ 12.133 (s, 1H, 吲哚-NH), 8.99 (s, 1H, -ArH), 8.61 (s, 1H, -ArH), 7.88 (s, 1H, - CH=C), 8.14~7.76(m, 4H, -ArH), 7.75(d, 1H, -ArH), 5.39(s, 2H, -ArCH ₂ ), 4.33(m, 2H, -NCH ₂ ), 4.11 ~ 3.25 (m, 12H, aliphatic H), 3.70 (m, 2H, -NCH ₂ ), 2.8 l (m, 2H, -NCH ₂ ), 2.46 (s, 3H, pyrrole ring - C3⁄4) Example 66

(Z)-2-((5-(2,6-二氯苄磺酰基 )-2』引哚酮 -3-亚基)甲基) -3-甲基 -5-(2- (吡咯烷 -1-基)乙基) -5,6,7,8-四氢吡咯并 [3,2-c] 吖庚因 -4(1H)-酮 (Z)-2-((5-(2,6-dichlorobenzylsulfonyl)-2"indolone-3-ylidene)methyl)-3-methyl-5-(2-(pyrrolidine) -1-yl)ethyl)-5,6,7,8-tetrahydropyrrolo[3,2-c]azepine-4(1H)-one

室温下，将 3-甲基 -4-氧代 -5-(2-吡咯垸小基-乙基) -^，^，^-六氢-吡咯并 ^- 吖庚因 -2-甲醛 28c (75 mg, 0.262 mmol)和 5-(2,6-二氯苄磺酰基)吲哚 -2-酮 64c (84 mg, 0.236 mmol)加入到 2.5 ml乙醇中，再加入 42μ1哌啶，加毕加热回流 3小时。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗涤 (3 ml X 2), 干燥后得到标题产物 (Z)-2-((5-(2，6-二氯节磺酰基 )-2- 吲哚酮 -3-亚基)甲基) -3-甲基 -5-(2- (；吡咯垸 -1-基)乙基) -5，6，7,8-四氢吡咯并 [3,2-c] 吖庚因 -4(1H)-酮 66(117 mg，桔黄色固体)，产率： 79.6%。

3-methyl-4-oxo-5-(2-pyrroleinyl-ethyl)-^,^,^-hexahydro-pyrrolo--azepine-2-carbaldehyde 28c (at room temperature) 75 mg, 0.262 mmol) and 5-(2,6-dichlorobenzylsulfonyl)indol-2-one 64c (84 mg, 0.236 mmol) were added to 2.5 ml of ethanol, then 42 μl of piperidine was added and heated. Reflux for 3 hours. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was naturally cooled to room temperature, suction filtered under reduced pressure, and filtered, washed with anhydrous ethyl ether (3 ml of EtOAc) to give the title product (Z)-2-((5-(2,6-dichlorosulfonate) Acyl)-2-indolone-3-ylidene)methyl)-3-methyl-5-(2-(;pyrrole-1-yl)ethyl)-5,6,7,8-tetra Hydropyrrolo[3,2-c]azepine-4(1H)-one 66 (117 mg, orange solid), Yield: 79.6%.

MS m/z (ESI): 627.3(M+1)。 MS m/z (ESI): 627.3 (M + 1).

^!ΗΝΜΚ(400 MHz, DMSO-d6) δ 12.18(s, 1H, 吲哚 -NH)， 9.04(s, 1H， -ArH)， 8.66(s, 1H, -ArH), 8.25(s, 1H, -CH=C), 8.23〜8.16(m, 3H, -ArH) , 7.99(d, 1H， -ArH), 5.64(s, 2H, -ArCH₂), 4.34(m, 2H, -NCH₂), 4.12〜3.26(m, 12H,脂肪族 H)， 3.70(m, 2H, -NCH₂), 2.8 l(m, 2H, -NCH₂), 2.46(s, 3H,吡咯环 -CH₃) 实施例 67 ^{! ΗΝΜΚ (400 MHz, DMSO-} d6) δ 12.18 (s, 1H, indole -NH), 9.04 (s, 1H , -ArH), 8.66 (s, 1H, -ArH), 8.25 (s, 1H, - CH=C), 8.23~8.16(m, 3H, -ArH), 7.99(d, 1H, -ArH), 5.64(s, 2H, -ArCH ₂ ), 4.34(m, 2H, -NCH ₂ ), 4.12 ~ 3.26 (m, 12H, aliphatic H), 3.70 (m, 2H, -NCH ₂ ), 2.8 l (m, 2H, -NCH ₂ ), 2.46 (s, 3H, pyrrole ring -CH ₃ ) Example 67

(Z)-2-((5-(4-氟苄磺酰基 )-2-吲哚酮 -3-亚基）甲基) -3-甲基 -5-(2-(哌啶 - 1 -基）乙基) -5,6,7,8-四氢卩比咯 -c] 吖庚因 -4(1H)-酮 (Z)-2-((5-(4-fluorobenzylsulfonyl)-2-indolone-3-ylidene)methyl)-3-methyl-5-(2-(piperidine- 1 - Ethyl)ethyl,5,6,7,8-tetrahydroindole-c] azepine-4(1H)-one

室温下，将 3-甲基 -4-氧代 -5-(2-哌啶 -1 -基-乙基) -1 ,4,5，6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 32d (57.6 mg, 0.21 mmol)和 5-(4-氟-苄磺酰基 )-1,3-二氢』引哚 -2-酮 65a (57.6 mg, 0.19 mmol)加入到 2 ml乙醇中，再加入 42μ1哌啶，加毕加热回流 3 小时。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗涤 (3 ml X 2), 干燥后得到标题产物 (Z)-2- ((5-(4-氟苄磺酰基) -2- 哚酮 -3-亚基)甲基) -3-甲基- 5-(2- (哌啶 - 1 -基)乙基) -5,6,7,8-四氢吡咯并 [3，2-c] 吖庚因 -4(1H)-酮 67(84 mg，桔黄色固体)，产率： 76%。 MS m/z (ESI): 591.3(M+1)。

3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3, at room temperature 2-c] azepine-2-carbaldehyde 32d (57.6 mg, 0.21 mmol) and 5-(4-fluoro-benzylsulfonyl)-1,3-dihydroindol-2-one 65a (57.6 mg, 0.19 mmol) was added to 2 ml of ethanol, 42 μl of piperidine was added, and the mixture was heated under reflux for 3 hours. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was cooled to room temperature, and filtered under reduced pressure. The filtered cake was washed with anhydrous ethyl alcohol (3 ml EtOAc) and dried to give the title product (Z)-2-((5-(4-fluorobenzylsulfonyl)- 2-nonanone-3-ylidenemethyl)-3-methyl-5-(2-(piperidin-1-yl)ethyl)-5,6,7,8-tetrahydropyrrolo[3 , 2-c] azepine-4(1H)-one 67 (84 mg, orange solid), Yield: 76%. MS m/z (ESI): 591.3 (M + 1).

^!ΗΝΜΚ(400 MHz, DMSO-d6) δ 13.61(s, 1H, 吡咯环 -NH)， 11.39(s, 1H, 吲哚 -NH)， 8.24(s, IH, -HCO), 7.86(s, 1H, -ArH), 7.17(s, 1H, -CH=C), 7.39〜7.13(m, 4H, -ArH) , 6.99(d, IH, -ArH), 4.64(s, 2H, -ArCH₂)， 3.58(m, 2H, -NCH₂), 3.29~2.40(m, 11H,脂肪族 H), 2.97(m, 2H, - NCH₂), 2.08(m, 2H, -NC¾), 1.49(s, 3H,吡咯环 -C¾) 实施例 68 ^{! ΗΝΜΚ (400 MHz, DMSO-} d6) δ 13.61 (s, 1H, pyrrole ring -NH), 11.39 (s, 1H , indole -NH), 8.24 (s, IH , -HCO), 7.86 (s, 1H , -ArH), 7.17(s, 1H, -CH=C), 7.39~7.13(m, 4H, -ArH), 6.99(d, IH, -ArH), 4.64(s, 2H, -ArCH ₂ ), 3.58(m, 2H, -NCH ₂ ), 3.29~2.40 (m, 11H, aliphatic H), 2.97(m, 2H, - NCH ₂ ), 2.08(m, 2H, -NC3⁄4), 1.49(s, 3H , pyrrole ring-C3⁄4) Example 68

(Z)-2-((⁵-(²,6-二氯苄磺酰基 )-²-Π引哚酮 _³-亚基）甲基) _³-甲基 -5-(²_ (哌啶 -1-基）乙基) -5,6,7,8-四氢吡咯并 -c] 吖庚因 -4(1H)-酮 ^{(Z) -2 - ((5} - (2, 6- dichlorobenzyl-sulfonyl) - ² -Π primer _ indolinone ³ - ylidene) methyl) _ ³ - methyl-5- ⁽² _ (l Pyridin-1-yl)ethyl)-5,6,7,8-tetrahydropyrrolo-c]azepine-4(1H)-one

室温下，将 3-甲基 -4-氧代 -5-(2-哌啶 -1-基-乙基) -1,4,5,6,7,8-六氢 -B比咯并 [3,2-c] 吖庚因 -2-甲醛 32d (57.6 mg, 0.21 mmol)和 5-(2,6-二氯苄磺酰基)吲哚 -2-酮 64c (67.2 mg， 0.19 mmol)加入到 2.5 ml乙醇中，再加入 42μ1哌啶，加毕加热回流 3小时。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗涤 (3 ml X 2), 干燥后得到标题产物 (Z)-2-((5-(2,6-二氯苄磺酰基 )-2- 吲哚酮 -3-亚基)甲基) -3-甲基 -5-(2- (哌啶 -1-基)乙基) -5,6,7,8-四氢吡咯并 [3，2-c] 吖庚因 -4(1H)-酮 68(93 mg，桔黄色固体)，产率： 77.5 %。

3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-B is conjugated at room temperature [ 3,2-c] azepine-2-carbaldehyde 32d (57.6 mg, 0.21 mmol) and 5-(2,6-dichlorobenzylsulfonyl)indol-2-one 64c (67.2 mg, 0.19 mmol) To 2.5 ml of ethanol, 42 μl of piperidine was further added, and the mixture was heated under reflux for 3 hours. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was naturally cooled to room temperature, filtered under reduced pressure, and filtered, washed with anhydrous ethyl ether (3 ml, EtOAc). Acyl)-2-indolone-3-ylidene)methyl)-3-methyl-5-(2-(piperidin-1-yl)ethyl)-5,6,7,8-tetrahydro Pyrrolo[3,2-c]azepine-4(1H)-one 68 (93 mg, orange solid), Yield: 77.5 %.

MS m/z (ESI): 641.2(M+1)。 MS m/z (ESI): 641.2 (M + 1).

^HNMRWOO MHz, DMS0-d6) δ 8.79(s, IH, -ArH), 7.90(s, IH, -CH=C), 7.51〜 7.41 (m, 3H, -ArH) , 7.05(d, IH, -ArH), 4.89(m, 2H, -ArCH₂), 3.57(m, 2H, -NCH₂), 3.35(m, 2H， -NCH₂)， 2.97(m, 2H, -NCH₂), 3.31~2.39(m, 15H,脂肪族 H), 2.07(m, 2H, -NCH₂) o 实施例 69 ^HNMRWOO MHz, DMS0-d6) δ 8.79(s, IH, -ArH), 7.90(s, IH, -CH=C), 7.51~ 7.41 (m, 3H, -ArH) , 7.05(d, IH, - ArH), 4.89(m, 2H, -ArCH ₂ ), 3.57(m, 2H, -NCH ₂ ), 3.35(m, 2H, -NCH ₂ ), 2.97(m, 2H, -NCH ₂ ), 3.31~2.39 (m, 15H, aliphatic H), 2.07 (m, 2H, -NCH ₂ ) o Example 69

(Z)-2-((5-(4-氟苄磺酰基) -2』引哚酮 -3-亚基）甲基) -3-甲基 -5- (2-吗啉乙基) -5,6,7，8-四氢吡咯并 [3,2-c] 吖庚因 -4(1H)-酮 (Z)-2-((5-(4-fluorobenzylsulfonyl)-2"indolone-3-ylidene)methyl)-3-methyl-5-(2-morpholinethyl)- 5,6,7,8-tetrahydropyrrolo[3,2-c]azepine-4(1H)-one

室温下，将 3-甲基 -5-(2-***啉 -4-基-乙基) -4-氧代 -1,4,5,6,7，8-六氢-吡咯并[3,2-( 吖庚因 -2-甲醛 10c (80 mg， 0.26醒 ol)和 5-(4-氟-苄磺酰基 )-1,3-二氢』引哚 -2-酮 65a (72 mg， 0.24 mmol)加入到 2.5 ml乙醇中，再加入 42μ1哌啶，加毕加热回流 3小时。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗涤 (3 ml X 2)，干燥后得到标题产物 (Z)-2-((5_(4-氟苄磺酰基) -2- 吲哚酮 -3-亚基）甲基 )-3-甲基 -5-(2-吗啉乙基) -5,6,7,8-四氢吡咯并 [3,2-c] 吖庚因 -4(1H)-酮 69(120 mg，桔黄色固体)，产率： 85.7%。

3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3, at room temperature 2-(azepine-2-carbaldehyde 10c (80 mg, 0.26 awake ol) and 5-(4-fluoro-benzylsulfonyl)-1,3-dihydroindol-2-one 65a (72 mg, 0.24 mmol) was added to 2.5 ml of ethanol, then 42 μl of piperidine was added, and the mixture was heated and refluxed for 3 hours. The spot plate monitoring showed that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was naturally cooled to room temperature, filtered under reduced pressure, and filtered cake was used. Wash with water (3 ml of X2) and dry to give the title product (Z)-2-((5-(4-fluorobenzylsulfonyl)-2-indolone-3-ylidene)methyl)-3- Methyl-5-(2-morpholinethyl)-5,6,7,8-tetrahydropyrrolo[3,2-c]azepine-4(1H)-one 69 (120 mg, orange Solid), Yield: 85.7%.

MS m/z (ESI): 593·5(Μ+1)。 MS m/z (ESI): 593·5 (Μ +1).

¹HNMR(400 MHz, DMSO-d6) δ 13.61(s, IH,吡咯环 -NH)， 11.39(s, IH,吲哚 -NH)， 8.24(s, IH, -ArH), 7.86(s, IH, -ArH), 7.40(m, IH, -ArH), 7.24(m, 3H, 3 X -ArH), 7.2 l(s, IH, -CH=C), 7.01(d, IH, -ArH),4.64(s, 2H, -ArCH₂), 3.58~2.07(m, 18H,脂肪族 H), 2.44(s, 3H,吡咯环 -C¾) 实施例 70 ¹ H NMR (400 MHz, DMSO-d6) δ 13.61 (s, IH, pyrrole ring-NH), 11.39 (s, IH, 吲哚-NH), 8.24 (s, IH, -ArH), 7.86 (s, IH) , -ArH), 7.40(m, IH, -ArH), 7.24(m, 3H, 3 X -ArH), 7.2 l(s, IH, -CH=C), 7.01(d, IH, -ArH), 4.64(s, 2H, -ArCH ₂ ), 3.58~2.07 (m, 18H, aliphatic H), 2.44 (s, 3H, pyrrole ring-C3⁄4) Example 70

(Z)-2-((5-(2,6-二氯苄磺酰基 )-2-吲哚酮 -3-亚基)甲基) -5-(2- (二乙氨基)乙基) -3-甲基 - -四氢吡咯并 [3,2-c] 吖庚因 -4(1H)-酮 (Z)-2-((5-(2,6-Dichlorobenzylsulfonyl)-2-indolone-3-ylidene)methyl)-5-(2-(diethylamino)ethyl) -3-methyl--tetrahydropyrrolo[3,2-c]azepine-4(1H)-one

室温下，将 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 lj (60 mg， 0.21 mmol)和 5_(2，6-二氯苄磺酰基)吲哚 -2-酮 64c(67 mg, 0.19 mmol)加入到 3 ml乙醇中，再加入 52μ1哌啶，加毕加热回流 2小时。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗漆 (3 ml Χ 2)，干燥后得到标题产物 (Ζ)-2-((5-(2,6-二氯苄磺酰基 )-2 哚酮 -3-亚基）甲基) -5-(2- (二乙氨基）乙基) -3-甲基 -5,6,7,8-四氢吡咯并 [3，2-c] 吖庚因 -4(1H)-酮 70(95 mg，桔黄色固体)，产率： 79 %。 MS m/z (ESI): 629.3(M+l)c

5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c at room temperature Aglycone-2-formaldehyde lj (60 mg, 0.21 mmol) and 5-(2,6-dichlorobenzylsulfonyl)indol-2-one 64c (67 mg, 0.19 mmol) were added to 3 ml of ethanol. Further, 52 μl of piperidine was added, and the mixture was heated under reflux for 2 hours. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was naturally cooled to room temperature, suction filtered under reduced pressure, and the filter cake was washed with anhydrous ethanol (3 ml Χ 2), and dried to give the title product (?)-2-((5-(2,6-dichlorobenzyl) Sulfonyl)-2 fluorenone-3-ylidenemethyl)-5-(2-(diethylamino)ethyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3 , 2-c] azepine-4(1H)-one 70 (95 mg, orange solid), Yield: 79%. MS m/z (ESI): 629.3 (M+l).

^!ΗΝΜΚ(400 MHz, DMSO-d6) δ 13.62(s, 1H，吡咯环 -NH)， 11.42(s, 1H,吲哚 -NH)， 8.29(s, 1H, -ArH), 7.90(s, 1H, -ArH), 7.49(s, 1H, -CH=C), 7.52(m, 2H, -NCH₂), 7.06(s, 1H, -ArH), 4.89(s, 2H, -ArCH₂), 3.52~2.07(m, 14H,脂肪族 H), 2.50(s, 3H,吡咯环 -CH₃)， 1.00(m，6H, 2 X -C¾) 实施例 71 ^{! ΗΝΜΚ (400 MHz, DMSO-} d6) δ 13.62 (s, 1H, pyrrole ring -NH), 11.42 (s, 1H , indole -NH), 8.29 (s, 1H , -ArH), 7.90 (s, 1H , -ArH), 7.49(s, 1H, -CH=C), 7.52(m, 2H, -NCH ₂ ), 7.06(s, 1H, -ArH), 4.89(s, 2H, -ArCH ₂ ), 3.52 ~2.07 (m, 14H, aliphatic H), 2.50 (s, 3H, pyrrole ring-CH ₃ ), 1.00 (m, 6H, 2 X - C3⁄4) Example 71

(Z)-2-((5-(4-氟苄磺酰基) -2-吲哚酮 -³-亚基）甲基) -5-(2- (二乙氨基）乙基) -3-甲基 -5,6,7,8-四氢吡咯并 [3， -c] 吖庚因 -4(1H)-酮 (Z)-2-((5-(4-fluorobenzylsulfonyl)-2-indolone- ³ -yl)methyl)-5-(2-(diethylamino)ethyl)-3- Methyl-5,6,7,8-tetrahydropyrrolo[3, -c] azepine-4(1H)-one

室温下，将 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 lj (60 mg， 0.21 mmol)和 5-(4-氟-苄磺酰基 )-1，3-二氢 -吲哚 -2-酮 65a (58 mg, 0.19 mmol)加入到 2 ml乙醇中，再加入 34μ1哌啶，加毕加热回流 3小时。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗涤 (3 ml X 2),干燥后得到标题产物 (Z)-2-((5-(4-氟苄磺酰基) -2-吲哚酮 -3-亚基）甲基 5-(2- (二乙氨基）乙基) -3-甲基 -5,6,7,8-四氢吡咯并 [3,2-c] 吖庚因 -4(1H)-酮 71(73 mg，桔黄色固体)，产率： 66%。

5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c at room temperature Aglycone-2-formaldehyde lj (60 mg, 0.21 mmol) and 5-(4-fluoro-benzylsulfonyl)-1,3-dihydro-indol-2-one 65a (58 mg, 0.19 mmol) After adding to 2 ml of ethanol, 34 μl of piperidine was added, and the mixture was heated under reflux for 3 hours. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction mixture was cooled to room temperature, and filtered under reduced pressure. The filtered cake was washed with anhydrous ethyl alcohol (3 ml of EtOAc) to afford the title product (Z)-2-((5-(4-fluorobenzylsulfonyl)- 2-indolone-3-ylidene)methyl 5-(2-(diethylamino)ethyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c ]glycine-4(1H)-one 71 (73 mg, orange solid), Yield: 66%.

MS m/z (ESI): 579.3(M+1)。 MS m/z (ESI): 579.3 (M+1).

iHNMRWOO MHz, DMSO-d6) δ 13.59(s, 1H，吡咯环 -NH)， 11.39(s, 1H,吲哚 -NH)， 8.24(s, 1H, -ArH), 7.86(s, 1H, -ArH), 7.2 l(s, 1H, -CH=C), 7.24~7.13(m, 3H, -ArH), 7.01 (d, 1H, -ArH), 4.64(s, 2H， -ArCH₂), 3.52~2.06(m, 14H,脂肪族 H), 2.50(s, 3H,吡咯环 -CH₃)， 1.00(m, 6H, 2 X -CH₃) 实施例 72 iHNMRWOO MHz, DMSO-d6) δ 13.59 (s, 1H, pyrrole ring-NH), 11.39 (s, 1H, 吲哚-NH), 8.24 (s, 1H, -ArH), 7.86 (s, 1H, -ArH) ), 7.2 l(s, 1H, -CH=C), 7.24~7.13(m, 3H, -ArH), 7.01 (d, 1H, -ArH), 4.64(s, 2H, -ArCH ₂ ), 3.52~ 2.06 (m, 14H, aliphatic H), 2.50 (s, 3H, pyrrole ring-CH ₃ ), 1.00 (m, 6H, 2 X -CH ₃ ) Example 72

(R,Z)-2-((5-(2,6-二氯苄磺酰基 )-2-吲哚酮 -3-亚基)甲基) -5-(2-羟基 -3-***啉丙基) -3- 甲基 -5,6,7,8-四氢吡咯并 [3,2-c] 吖庚因 -4(1Η)-酮

室温下，将 5-(2_羟基-3-***啉 -4-基-丙基) -3-甲基 -4-氧代 -1，4,5,6，7,8-六氢- P比咯并 [3,2-c] 吖庚因 -2-甲醛 53f (80 mg, 0.24 mmol)和 5-(2,6-二氯节磺酰基 ) !哚 -2-酮 64c(75 mg， 0.21 mmol)加入到 3 ml乙醇中，再加入 30μ1哌啶，加毕预搅拌 4分钟后于 12CTC下微波反应 5分钟，反应液呈桔黄色浑浊液。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗搽 (2 ml X 2)，干燥后得到标题产物 (R,Z)-2-((5-(2,6-二氯苄磺酰基 2-吲哚酮 -3-亚基）甲基) -5-(2-羟基 -3-***啉丙基) -3-甲基 -5,6,7,8-四氢吡咯并 [3,2-c] 吖庚因 -4(1H)-酮 72(120 mg, 黄色固体)，产率： 85 %。 (R,Z)-2-((5-(2,6-dichlorobenzylsulfonyl)-2-indolone-3-ylidene)methyl)-5-(2-hydroxy-3-morpholine Propyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepine-4(1Η)-one

5-(2-Hydroxy-3-morpholine-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-P at room temperature Bis-[3,2-c] azepine-2-carbaldehyde 53f (80 mg, 0.24 mmol) and 5-(2,6-dichlorosulfonyl)-indol-2-one 64c (75 mg, 0.21 mmol) was added to 3 ml of ethanol, and 30 μl of piperidine was added thereto. After the addition, the mixture was stirred for 4 minutes, and then microwave-reacted at 12 CTC for 5 minutes. The reaction solution was orange turbid. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was naturally cooled to room temperature, suction filtered under reduced pressure, and then filtered, and then filtered and evaporated to dryness (2 ml X 2) to give the title product (R,Z)-2-((5-(2,6-II) Chlorobenzylsulfonyl 2-indolone-3-ylidene)methyl)-5-(2-hydroxy-3-morphinorylpropyl)-3-methyl-5,6,7,8-tetrahydropyrrole And [3,2-c] azepine-4(1H)-one 72 (120 mg, yellow solid), yield: 85 %.

MS m/z (ESI): 673.2(M+1)。 MS m/z (ESI): 67:21.

¹HNMR(400 MHz, DMSO-d6) δ 13.63(s, 1H, 吡咯环 -NH)， 11.42(s, 1H, 吲哚 -·ΝΗ)， 8.29(d, 1H, -ArH), 7.90(s, 1H, -ArH), 7.52(m, 4H， -ArH), 7.42(s, 1H, -CH=C)， 7.06(d, 1H, -ArH)， 4.89(s, 2H, -ArCH₂), 4.74(m, 1H, -CHO), 3.92~2.33(m, 18H,脂肪族 H), 2.44(s, 3H,吡咯环 -CH₃) 实施例 73 ¹ H NMR (400 MHz, DMSO-d6) δ 13.63 (s, 1H, pyrrole ring-NH), 11.42 (s, 1H, 吲哚-·ΝΗ), 8.29 (d, 1H, -ArH), 7.90 (s, 1H, -ArH), 7.52(m, 4H, -ArH), 7.42(s, 1H, -CH=C), 7.06(d, 1H, -ArH), 4.89(s, 2H, -ArCH ₂ ), 4.74 (m, 1H, -CHO), 3.92~2.33 (m, 18H, aliphatic H), 2.44 (s, 3H, pyrrole ring-CH ₃ ) Example 73

(R,Z)-2-((5-(4-氟苄磺酰基) -2-吲哚酮 -3-亚基)甲基) -5-(2-羟基 -3-***啉丙基) -3-甲基 - -四氢吡咯并 [3,2-c] 吖庚因 -4(1H)-酮 (R,Z)-2-((5-(4-fluorobenzylsulfonyl)-2-indanone-3-ylidene)methyl)-5-(2-hydroxy-3-morphinylpropyl) -3-methyl--tetrahydropyrrolo[3,2-c]azepine-4(1H)-one

室温下，将 5-(2- 基-3-***啉 -4-基-丙基) -3-甲基 -4-氧代 -1，4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 53f (80 mg, 0.24 mmol)和 5-(4-氟-节磺酰基 )-1,3-二氢』引哚 -2-S 65a (64 mg, 0.21 mmol)加入到 3 ml乙醇中，再加入 30μ1呢啶，加毕预搅拌 4分钟后于 120°C下微波反应 5分钟，反应液呈桔黄色浑浊液。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗涤 (2 mi x 2) , 干燥后得到标题产物 (R，Z)-2-((5-(4-氟苄磺酰基) -2-吲哚酮 -3-亚基）甲基) -5-(2-羟基 -3-***啉丙基) -3-甲基 -5,6,7,8-四氢吡咯并 [3,2-c] 吖庚因 -4(1Η)-酮 73(100 mg, 黄色固体)，产率： 76%。

5-(2-yl-3-morpholine-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrole at room temperature And [3,2-c] azepine-2-carbaldehyde 53f (80 mg, 0.24 mmol) and 5-(4-fluoro-sulfonyl)-1,3-dihydroindol-2-S 65a (64 mg, 0.21 mmol) was added to 3 ml of ethanol, and then 30 μl of pyridine was added. After the addition, the mixture was stirred for 4 minutes, and then microwaved at 120 ° C for 5 minutes. The reaction solution was orange turbid. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was cooled to room temperature, filtered under reduced pressure, and filtered (EtOAc) -2-indolone-3-ylidenemethyl)-5-(2-hydroxy-3-morphinorylpropyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[ 3,2-c] aglycone-4(1Η)-ketone 73 (100 mg, yellow solid), Yield: 76%.

MS m/z (ESI): 621.3(M-l) o MS m/z (ESI): 621.3 (M-l) o

^!HNMR(400 MHz, DMSO-d6) δ 13.61(s, IH, 吡咯环 -NH)， 11.38(s, IH, 吲哚 -NH)， 8.24(d, IH, -ArH), 7.86(s, IH, -ArH), 7.40(m, IH, -ArH), 7.24(m, 1H， -ArH), 7.17(m, IH, -ArH), 7.13(s, IH, -CH=C), 7.01(d, IH, -ArH), 4.74(m, IH, -CHO), 4.64(s, 2H, -ArC¾), 3.92~2.32(m, 18H,脂肪族 H), 2.44(s, 3H,吡咯环 -CH₃) 实施例 74 ^{! HNMR (400 MHz, DMSO-} d6) δ 13.61 (s, IH, pyrrole ring -NH), 11.38 (s, IH , indole -NH), 8.24 (d, IH , -ArH), 7.86 (s, IH , -ArH), 7.40(m, IH, -ArH), 7.24(m, 1H, -ArH), 7.17(m, IH, -ArH), 7.13(s, IH, -CH=C), 7.01(d , IH, -ArH), 4.74(m, IH, -CHO), 4.64(s, 2H, -ArC3⁄4), 3.92~2.32 (m, 18H, aliphatic H), 2.44(s, 3H, pyrrole ring-CH ₃ ) Example 74

(Z)-5-(2- (二乙氨基)乙基) -2-((4-(2,3-二氟苯基) -5-氟 -²-氧代吲哚 -3-亚基)甲基) -3-甲基 -5, -四氢吡咯并 [3,2-c] 吖庚因 -4(1H)-酮 (Z)-5-(2-(Diethylamino)ethyl)-2-((4-(2,3-difluorophenyl)-5-fluoro- ² -oxoindole-3-ylidene )methyl)-3-methyl-5,-tetrahydropyrrolo[3,2-c]azepine-4(1H)-one

第一歩

First

1-碘 -2-甲基 -3-硝基-苯 1-iodo-2-methyl-3-nitro-benzene

冰浴下，将 2-甲基 -3-硝基苯胺 74a(21.28 g， 0.14 mol)溶解于 70 ml浓盐酸中，加入 40 π 水后搅拌并控制混合物温度在 0〜5°C。反应液中出现黄绿色固体，向反应液中滴加 40 ml亚硝酸钠溶液 (3.6 M)继续搅拌 15分钟，反应液过滤，滤液在 0〜5°C下滴加到 280 ml碘化钾溶液 (5.25 M)中，加毕混合物继续搅拌 1小时，点板表明原料反应完全，停止反应。反应液减压抽滤，滤饼用乙酸乙酯溶解后经 10% 氢氧化钠溶液、水、 5 %硫代硫酸钠溶液、饱和氯化钠溶液洗涤，有机相经无水硫酸钠干燥后得到 34.4 g褐色油状物。粗品经柱层析得到标题产物 1-碘 -2-甲基 -3-硝基-苯 74b(30.1 g，类白色固体)，产率： 81.7%。第二步 2-Methyl-3-nitroaniline 74a (21.28 g, 0.14 mol) was dissolved in 70 ml of concentrated hydrochloric acid under ice-cooling, stirred under 40 π water, and the mixture was stirred at 0 to 5 °C. a yellow-green solid appears in the reaction solution, 40 ml of sodium nitrite solution (3.6 M) was added dropwise to the reaction solution, stirring was continued for 15 minutes, the reaction solution was filtered, and the filtrate was added dropwise to 280 ml of potassium iodide solution (5.25 M) at 0 to 5 ° C, and the mixture was continuously stirred. After 1 hour, the plate indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was filtered under reduced pressure. The filter cake was dissolved in ethyl acetate and washed with 10% sodium hydroxide solution, water, 5% sodium thiosulfate solution, and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. 34.4 g of brown oil. The crude product was purified by EtOAcjjjjjjjj Second step

3-(2-碘 -6-硝基 -苯) -2-氧代 -丙酸 3-(2-iodo-6-nitro-benzene)-2-oxo-propionic acid

氮气氛下，向冰浴冷却下的乙醇钠溶液 (35 ml， 44 mmol)中滴加 1-碘 -2-甲基 1-iodo-2-methyl was added dropwise to a sodium ethoxide solution (35 ml, 44 mmol) cooled in an ice bath under a nitrogen atmosphere

-3-硝基-苯 74b的乙醇溶液 (35 ml, 40 mmol), 加毕，反应液搅拌至有大量棕色固体生成，向反应液中一次性加入草酸二乙酯 (6 ml, 44 mmol),加毕，反应液于 10(TC 油浴中回流 0.5小时，向反应液中加入 70 ml水，继续回流 1小时，停止反应。反应液减压蒸除乙醇，在碱性条件下用乙酸乙酯洗涤 (50 ml X 1)除去未反应的原料，用 1M的盐酸调节水相 pH至 3，再用乙酸乙酯萃取 (30 mlX 3)，合并有机相，用饱和氯化钠洗涤 (30 mix 1)，无水硫酸钠干燥后减压浓缩得到标题产物 3-(2-碘 -6-硝基 -苯) -2-氧代 -丙酸 74c(2.94 g，褐色油状物)，直接进行下步反应。 A solution of -3-nitro-benzene 74b in ethanol (35 ml, 40 mmol) was added, and the reaction mixture was stirred until a large amount of brown solid was formed, and diethyl oxalate (6 ml, 44 mmol) was added in one portion to the reaction mixture. After the addition, the reaction solution was refluxed for 10 hours in a 10 (TC oil bath), 70 ml of water was added to the reaction solution, and refluxing was continued for 1 hour to stop the reaction. The reaction liquid was evaporated under reduced pressure to give ethanol under basic conditions. The ester was washed (50 ml X 1) to remove the unreacted starting material, the pH of the aqueous phase was adjusted to 3 with 1M hydrochloric acid, and extracted with ethyl acetate (30 ml×3). The organic phase was combined and washed with saturated sodium chloride (30 1) Drying with anhydrous sodium sulfate and concentrating under reduced pressure to give the title product 3-(2-iodo-6-nitro-benzene)-2-oxo-propionic acid 74c (2.94 g, brown oil) Step reaction.

MS: 334軍-1)。第三步 MS: 334 Army-1). third step

(₂_碘 -6-硝基 -苯) -乙酸 ( ₂ iodine-6-nitro-benzene)-acetic acid

室温下，将 3-(2-碘 -6-硝基 -苯) -2-氧代 -丙酸 74c(2.086 g， 6.2 mmol)搅拌下溶解于 6 ml甲醇中，加入 20 ml水和 7 ml双氧水，加毕室温搅拌 1小时。点板表明原料反应完全，停止反应。反应液过滤，滤液用乙酸乙酯萃取 (20 mix 2)，有机相减压浓縮后和滤饼合并，干燥后得到标题产物 (2-碘 -6-硝基 -苯) -乙酸 74d(1.77 g，棕色固体)，产率： 70%。第四步 3-(2-Iodo-6-nitro-phenyl)-2-oxo-propionic acid 74c (2.086 g, 6.2 mmol) was dissolved in 6 ml of methanol with stirring at room temperature, 20 ml of water and 7 ml Hydrogen peroxide was added and stirred at room temperature for 1 hour. The dot plate indicates that the raw material reacts completely and stops the reaction. The reaction mixture was filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj g, brown solid), Yield: 70%. the fourth step

1_羟基 _₄_碘 _1,₃_二氢噪 _₂ -酮 1_hydroxy_ ₄ _iodo_1, ₃ _ dihydrogen _ ₂ - ketone

室温下，将 (2-碘 -6-硝基 -苯) -乙酸 74d(0.91 g， 3 mmol)搅拌下溶解于 30 ml乙醇 (95%)中，加入钯 /碳 (30 mg， 3 %), 加毕，向反应瓶中充入氢气，并在氢气氛下搅拌反应液 2小时。点板表明原料反应完全，停止反应。反应液抽滤，滤液减压浓缩后柱层析得到标题产物 1-轻基 -4-碘 -1,3-二氢 -吲哚 -2-酮 74e(516 mg,类白色固体)，产率： 63.4%。 (2-Iodo-6-nitro-benzene)-acetic acid 74d (0.91 g, 3 mmol) was dissolved in 30 ml of ethanol (95%) with stirring at room temperature, palladium on carbon (30 mg, 3 %) After the addition, hydrogen was charged into the reaction flask, and the reaction solution was stirred under a hydrogen atmosphere for 2 hours. The dot plate indicates that the starting material is completely reacted and the reaction is stopped. The reaction solution was suction filtered, and the filtrate was evaporated, evaporated,jjjjjjjjj : 63.4%.

MS: 274.1(M-1)。第五步 5-氟 _4-碘 -1 ,3-二氢-吲哚 -2-酮 MS: 274.1 (M-1). the fifth step 5-fluoro-4-iodo-1,3-dihydro-indol-2-one

干冰 -丙酮浴下，将 1-羟基 -4-碘 -1,3-二氢 -吲哚 -2-酮 74e(326 mg, 1.19 mmol) 加入到 24 ml二氯甲烷中，加毕，边向混合物中缓慢滴加二乙氨基三氟化硫 (0.16 ml, 1.19 mmol)边控制温度在 -25Ό , 滴加完毕，反应液继续在 -25 °C条件下搅拌 15 分钟至反应液变澄清。点板表明原料反应完全，用饱和碳酸氢钠溶液淬灭反应。向反应液中加入 30 ml饱和氯化钠溶液，用二氯甲垸萃取 (30 mi x 3)，合并有机相，用饱和氯化钠溶液洗涤 (30 ml X I), 无水硫酸钠干燥得到 284 mg土黄色固体，粗产品经柱层析得到标题产物 5-氟 -4-碘 -1 ,3-二氢 -吲哚 -2-酮 74f(114 mg, 类白色固体)，产率： 34.7 %。 1-hydroxy-4-iodo-1,3-dihydro-indol-2-one 74e (326 mg, 1.19 mmol) was added to 24 ml of dichloromethane under dry ice-acetone bath. The mixture was slowly added dropwise with diethylaminosulfur trifluoride (0.16 ml, 1.19 mmol) while the temperature was controlled at -25 Torr. After the dropwise addition was completed, the reaction mixture was further stirred at -25 °C for 15 minutes until the reaction solution became clear. The dot plate indicated that the starting material was completely reacted and the reaction was quenched with saturated sodium bicarbonate solution. 30 ml of a saturated sodium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane (30 mi x 3). The organic phase was combined, washed with saturated sodium chloride solution (30 ml XI), dried over anhydrous sodium sulfate Mp yello solid, crude product was purified by column chromatography to give the title product 5-fluoro-4-iodo-1,3-dihydro-indol-2-one 74f (114 mg, white solid), yield: 34.7 % .

MS : 276.6(M-1)。第六步 MS: 276.6 (M-1). Step 6

4-(2,6-二氟-苯基) -5-氟 -1，3-二氢 -吲哚 -2-酮 4-(2,6-difluoro-phenyl)-5-fluoro-1,3-dihydro-indol-2-one

氩气氛下，将 5-氟 -4-碘 -U-二氢』引哚 -2-酮 74f(277 mg, 1 匪 ol)加入到 10 mlN,N-二甲基甲酰胺中，向混合物中加入 2,3-二氟苯基硼酸 (158 mg， 1 mmol)、碳酸氢钠 (168 mg, 2 mmol)和 10 ml水，加毕搅拌均匀后再加入四 (三苯基膦)钯 (109 mg, 0.15 mmol) , 加热回流过夜。点板表明原料反应完全，停止反应，反应液减压蒸除1^二甲基甲酰胺后加入1(^11盐酸(1 ]^)，乙酸乙酯萃取 (10 ml X 3)，合并有机相，有机相用无水硫酸镁干燥后柱层析得到标题产物 4-(2，6-二氟-苯基) -5- 氟 -1,3-二氢 -吲哚 -2-酮 74_g(42 mg，灰白色固体)，产率： 16 %。 Add 5-fluoro-4-iodo-U-dihydro"pyridin-2-one 74f (277 mg, 1 匪ol) to 10 ml of N,N-dimethylformamide under argon atmosphere. Add 2,3-difluorophenylboronic acid (158 mg, 1 mmol), sodium bicarbonate (168 mg, 2 mmol) and 10 ml of water, add evenly and then add tetrakis(triphenylphosphine)palladium (109). Mg, 0.15 mmol), heated to reflux overnight. The plate indicates that the reaction of the starting material is complete, the reaction is stopped, the reaction solution is evaporated under reduced pressure of 1 dimethylformamide, and then 1 (^11 hydrochloric acid (1)^) is added, ethyl acetate is extracted (10 ml X 3 ), and the organic phase is combined. after the organic phase was dried over anhydrous magnesium sulfate column chromatography to give the title product 4- (2,6-difluoro - phenyl) -5-fluoro-1,3-dihydro - indol-2-one 74 _g ( 42 mg, off-white solid), Yield: 16%.

MS : 262.0(M+ 1)。第七步 MS: 262.0 (M+ 1). Seventh step

(Z)-5-(2- (二乙氨基)乙基) -2-((4-(2,3-二氟苯基) -5-氟 -2-氧代吲哚 -3-亚基)甲基) -3-甲基 -5,6,7,8-四氢口比咯并 [3,2-c] 吖庚因 -4(1H 酮 (Z)-5-(2-(Diethylamino)ethyl)-2-((4-(2,3-difluorophenyl)-5-fluoro-2-oxoindole-3-ylidene )methyl)-3-methyl-5,6,7,8-tetrahydroperylpyrolo[3,2-c]azepine-4 (1H ketone)

室温下，将 5-(2-二乙氨基-乙基) -3-甲基 -4-氧代 -1,4,5,6，7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 lj (73 mg, 0.25醒 ol)和 4-(2，6-二氟-苯基) -5-氟 -1,3-二氢 -吲哚 -2-酮 74g (60 mg, 0.23 mmol)加入到 2 ml乙醇中，再加入 35μ1呃啶，加毕加热回流 2 小时。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗涤 (3 mi x 2), 干燥后得到标题产物 (Z)-5-(2- (二乙氨基)乙基) -2-((4-(2,3-二氟苯基) -5-氟 -2-氧代吲哚 -3-亚基)甲基) -3-甲基 -5,6,7,8-四氢吡咯并 [3,2-c] 吖庚因 -4(1H)-酮 74(23 mg，桔黄色固体)，产率： 19 %。 5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c at room temperature ] 吖gyne-2-formaldehyde lj (73 mg, 0.25 awake ol) and 4-(2,6-difluoro-phenyl)-5-fluoro-1,3-dihydro-indol-2-one 74g (60 mg, 0.23 mmol) was added to 2 ml of ethanol, 35 μl of acridine was added, and the mixture was heated under reflux for 2 hours. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was naturally cooled to room temperature, filtered under reduced pressure, and filtered, washed with anhydrous ethyl alcohol (3 <RTI ID=0.0> -((4-(2,3-difluorophenyl)-5-fluoro-2-oxoindole-3-ylidene)methyl)-3-methyl-5,6,7,8-tetra Hydropyrrolo[3,2-c]azepine-4(1H)-one 74 (23 mg, orange solid), Yield: 19%.

MS m/z (ESI): 537·2(Μ+1)。 MS m/z (ESI): 537. 2 (Μ +1).

¹HNMR(400 MHz, DMSO-d6) δ 13.58(s, 1H,吡咯环 -NH)， 11.178(s, 1H, 吲哚 -NH), 8.24(s, 1H， -HCO), 7.70〜6.998(m, 5H, -Ai'H) , 6.65(s, 1H, -CH=C), 4.36(m, 2H, -NCH₂), 2.9 l(m, 2H， -NC¾), 2.54(s, 3H,吡咯环 -C¾)， 1.2~3.4(m, 14H,脂肪族 H), 2.20(m, 2H, -NCH₂)。实施例 75 ¹ H NMR (400 MHz, DMSO-d6) δ 13.58 (s, 1H, pyrrole ring-NH), 11.178 (s, 1H, 吲哚-NH), 8.24 (s, 1H, -HCO), 7.70~6.998 (m) , 5H, -Ai'H) , 6.65(s, 1H, -CH=C), 4.36(m, 2H, -NCH ₂ ), 2.9 l(m, 2H, -NC3⁄4), 2.54(s, 3H, pyrrole Ring-C3⁄4), 1.2~3.4 (m, 14H, aliphatic H), 2.20 (m, 2H, -NCH ₂ ). Example 75

2-((Z)-(4-(2,3-二氟苯基) -5-氟 -2-氧代吲哚 -3-亚基)甲基) -5-((R)-2-羟基 -3-***啉丙基) -3-甲基 -5,6,7,8-四氢 -c] 吖庚因 -4(1H)-酮' 2-((Z)-(4-(2,3-difluorophenyl)-5-fluoro-2-oxoindole-3-ylidene)methyl)-5-((R)-2- Hydroxy-3-morpholinepropyl)-3-methyl-5,6,7,8-tetrahydro-c]azepine-4(1H)-one

室温下，将 5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -4-氧代 -1,4,5,6 7 8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲醛 53f (84 mg 0.25 ol)和 4-(2,6-二氟-苯基) -5-氟 -1,3-二氢 -吲哚 -2-酮 74g (60 mg 0.23 mniol)加入到 2 ml乙醇中，再加入 35μ1哌啶，加毕加热回流 2小时。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗涤 (3 ml Χ2)，干燥后得到 2-((Ζ)-(4-(2,3-二氟苯基) -5- 氟 -2-氧代吲哚 -3-亚基)甲基) -5-((R)-2-羟基 -3-***啉丙基) -3-甲基 -5,6,7,8-四氢吡咯并 [3,2-c] 吖庚因 -4(1H)-酮 75(100 mg，桔红色固体)，产率： 78%

5-(2-Hydroxy-3-morpholine-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6 7 8-hexahydro-pyrrolo[ 3,2-c] azepine-2-carbaldehyde 53f (84 mg 0.25 ol) and 4-(2,6-difluoro-phenyl)-5-fluoro-1,3-dihydro-indole-2 - Ketone 74g (60 mg 0.23 mniol) was added to 2 ml of ethanol, 35 μl of piperidine was added thereto, and the mixture was heated under reflux for 2 hours. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was naturally cooled to room temperature, suction filtered under reduced pressure, and the filter cake was washed with anhydrous ethanol (3 ml Χ2), and dried to give 2-((()-(4-(2,3-difluorophenyl)-5) - fluoro-2-oxoindole-3-ylidene)methyl)-5-((R)-2-hydroxy-3-morphinan propyl)-3-methyl-5,6,7,8 -tetrahydropyrrolo[3,2-c]azepine-4(1H)-one 75 (100 mg, orange solid), Yield: 78%

MS m/z (ESI): 581.3(M+1)。 MS m/z (ESI): 581.3 (M + 1).

iHNMR OO MHz, DMSO-d6) δ 13.57(s, 1H,吡咯环 -NH 11.12(s, 1H,吲哚 -NH 7.704 6.98(m, 5H, -ArH) , 6.65(s, 1H, -CH=C), 4.69(m, 1H, -CHOH), 3.86(m, 2H -NCH₂), 2.89(m, 2H, -NC¾), 2.33(m, 2H, -NCH₂), 3.86~2.28(m, 12H,脂肪族 H)。实施例 76 iHNMR OO MHz, DMSO-d6) δ 13.57 (s, 1H, pyrrole ring-NH 11.12 (s, 1H, 吲哚-NH 7.704 6.98 (m, 5H, -ArH), 6.65 (s, 1H, -CH=C ), 4.69(m, 1H, -CHOH), 3.86(m, 2H -NCH ₂ ), 2.89(m, 2H, -NC3⁄4), 2.33(m, 2H, -NCH ₂ ), 3.86~2.28(m, 12H , aliphatic H). Example 76

(R,Z)-5-(2-羟基 -3-***啉丙基) -3-甲基 -2-((4-甲基 -2-氧代吲哚 -3-亚基)甲基) -5,6,7,8- 四氢吡咯并 [3,2-c] 吖庚因 - -酮 . (R,Z)-5-(2-hydroxy-3-morpholinepropyl)-3-methyl-2-((4-methyl-2-oxoindole-3-ylidene)methyl) -5,6,7,8-tetrahydropyrrolo[3,2-c] azepine-ketone.

室温下，将 5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3 2-c] 吖庚因 -2-甲醛 53f (30 mg 0.09 mmol)和 4-甲基 -1,3-二氢 -吲哚 -2-酮 (12 mg, 0.08 mniol)加入到 156 μΐ乙醇中，再加入 4.4μ1哌啶，加毕 45°C搅拌 16小时。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗涤 (1 ml X 2), 千燥后得到 (R,Z)-5-(2-羟基 -3-***啉丙基) -3-甲基 _2-((4-甲基 -2-氧代吲哚 -3-亚基)甲基) -5,6,7,8-四氢吡咯并 [3,2-c] 吖庚因 -4(1Η)-酮 76(12 mg, 桔红色固体)，产率： 30%。

5-(2-Hydroxy-3-morpholine-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrole at room temperature And [3 2-c] azepine-2-carbaldehyde 53f (30 mg 0.09 mmol) and 4-methyl-1,3-dihydro-indol-2-one (12 mg, 0.08 mniol) were added to 156 In μΐ ethanol, 4.4 μl of piperidine was further added, and the mixture was stirred at 45 ° C for 16 hours. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was naturally cooled to room temperature, suction filtered under reduced pressure, and the filter cake was washed with anhydrous ethanol (1 ml X 2) and dried to give (R,Z)-5-(2-hydroxy-3-morpholinepropyl) -3-methyl_2-((4-methyl-2-oxoindole-3-ylidene)methyl)-5,6,7,8-tetrahydropyrrolo[3,2-c] Indole-4(1Η)-ketone 76 (12 mg, orange solid), Yield: 30%.

MS m/z (ESI): 465.2(M+1)。 MS m/z (ESI): 465.2 (M + 1).

¹HNMR(400 MHz, DMSO-d6) δ 13.71(s, IH, 吡咯环 -NH), 10.92 (s, IH, 吲哚 -NH)， 7.57(s, IH, -CH=C), 7.07〜6.77(m, 3H， -ArH) , 4.72(d, IH, -OH), 3.90(m, IH, -CHOH), 3.78(dd, IH, 七环外接酰胺 -NCH₂)， 3.58(t, 4H, 吗啉环内 2 X -CH₂0), 3.40(m, 2H,七环接 -NC¾), 3.17(dd, IH,七环外接酰胺 -NCH₂), 2.94(t, 2H,吡咯环 -CH₂), 2.59(s, 3H，苄甲基)， 2.44(m, 4H, 吗啉环内 2 X CH2N) , 2.39(s, 3H,吡咯 -CH₃), 2.29(m, 2H, 吗啉环外 -NCH₂), 2.08(m, 2H,七环 CH₂-CH₂-CH₂)。实施例 77 ¹ H NMR (400 MHz, DMSO-d6) δ 13.71 (s, IH, pyrrole ring-NH), 10.92 (s, IH, 吲哚-NH), 7.57 (s, IH, -CH=C), 7.07~6.77 (m, 3H, -ArH), 4.72(d, IH, -OH), 3.90 (m, IH, -CHOH), 3.78 (dd, IH, heptacyclic external amide-NCH ₂ ), 3.58 (t, 4H, Morpholine ring 2 X -CH ₂ 0), 3.40 (m, 2H, heptacyclo-NC3⁄4), 3.17 (dd, IH, heptacyclic external amide-NCH ₂ ), 2.94 (t, 2H, pyrrole ring-CH ₂ ), 2.59(s, 3H,benzylidene), 2.44 (m, 4H, morpholine 2X CH2N), 2.39 (s, 3H, pyrrole-CH ₃ ), 2.29 (m, 2H, morpholine ring Exo-NCH ₂ ), 2.08 (m, 2H, heptacyclic CH ₂ -CH ₂ -CH ₂ ). Example 77

(R,Z)-5-(2-羟基 -3-***啉丙基) -2-((6-甲氧基 -2-氧代吲哚 -3-亚基）甲基) -3-甲基 -5,6,7,8-四氢吡咯并 [3,2- c -4(1H)-酮 (R,Z)-5-(2-hydroxy-3-morphinorylpropyl)-2-((6-methoxy-2-oxoindole-3-ylidene)methyl)-3-methyl 5-,6,7,8-tetrahydropyrrolo[3,2-c-4(1H)-one

室温下，将 5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -4-氧代 -1,4，5,6，7,8-六氢 -吡咯并 [3,2-c] 吖庚因 -2-甲醛 53f (30 mg， 0,09 mmol)和 6-甲氧基 -1，3-二氢 -吲哚 -2-酮 (13 mg, 0.08 mmol)加入到 156 μΐ乙醇中，再加入 4.4μ1哌啶，加毕 45°C搅拌 16小时。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗涤 (1 mi x 2),干燥后得到 (R,Z)-5-(2-羟基 -3-***啉丙基) -2-((6-甲氧基 _₂_氧代吲哚 _3-亚基）甲基) -3-甲基 -5,6,7,8-四氢吡咯并 [3,2-c] 吖庚因 -4(1H)-酮 77(22 mg, 黄色固体)，产率： 51 %。

5-(2-Hydroxy-3-morpholine-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrole at room temperature And [3,2-c] azepine-2-carbaldehyde 53f (30 mg, 0,09 mmol) and 6-methoxy-1,3-dihydro-indol-2-one (13 mg, 0.08 Methyl) was added to 156 μl of ethanol, then 4.4 μl of piperidine was added, and the mixture was stirred at 45 ° C for 16 hours. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was naturally cooled to room temperature, suction filtered under reduced pressure, and the filter cake was washed with anhydrous ethanol (1 mi x 2) and dried to give (R,Z)-5-(2-hydroxy-3-morpholinepropyl) 2-((6-Methoxy- ₂ )-oxoindole-3-ylidenemethyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c] Indole-4(1H)-one 77 (22 mg, yellow solid), Yield: 51%.

MS m/z (ESI): 481.2(M+1)。 MS m/z (ESI): 481.2 (MI).

¹H MR(400 MHz, DMSO-d6) δ 13.47(s, IH, 吡咯环 -NH)， 10.94 (s, IH, 吲哚 -NH), 7.68(d, IH, -ArH), 7.40(s, IH, -CH=C), 6.60(d, IH, -ArH), 6.46(s, IH, -ArH), 4.70(d, IH, -OH), 3.89(m, IH, -CHOH), 3.77(dd, IH,七环外接酰胺 -NCH₂), 3.58(t, 4H, 吗啉环内 2 X -CH₂0), 3.41(m₅ 2H,七环接 -NCH₂), 3.17(dd, IH, 七环外接酰胺 -NCH₂)， 2.93 (t, 2H,吡咯环 -CH₂), 2.41(s, 3H,吡咯环 -CH₃), 2.34(m, 4H，吗啉环内 2 , X -CH₂N), 2.29(m, 2H, 吗啉环外 -NCH₂), 2.07(m, 2H,七环 C¾-CH₂-C¾)。实施例 78 ¹ H MR (400 MHz, DMSO-d6) δ 13.47 (s, IH, pyrrole ring-NH), 10.94 (s, IH, 吲哚-NH), 7.68 (d, IH, -ArH), 7.40 (s, IH, -CH=C), 6.60(d, IH, -ArH), 6.46(s, IH, -ArH), 4.70(d, IH, -OH), 3.89(m, IH, -CHOH), 3.77( Dd, IH, heptacyclic external amide-NCH ₂ ), 3.58 (t, 4H, morpholine ring 2 X -CH ₂ 0), 3.41 (m ₅ 2H, heptacyclo-NCH ₂ ), 3.17 (dd, IH , heptacyclic external amide-NCH ₂ ), 2.93 (t, 2H, pyrrole ring-CH ₂ ), 2.41 (s, 3H, pyrrole ring-CH ₃ ), 2.34 (m, 4H, morpholine ring 2 , X - CH ₂ N), 2.29 outer (m, 2H, morpholine ring _{-NCH 2), 2.07 (m,} 2H, heptacyclo C¾-CH ₂ -C¾). Example 78

(S,Z)-2-((5-氟 -2-氧代吲哚 -3-亚基)甲基) -5-(2-羟基 -3-***啉丙基) -3-甲基 -5,6,7,8-四氢吡 -c] 吖庚因 -4(1H)-酮 (S,Z)-2-((5-fluoro-2-oxoindole-3-ylidene)methyl)-5-(2-hydroxy-3-morphinanylpropyl)-3-methyl- 5,6,7,8-tetrahydropyridin-c] azepine-4(1H)-one

第一步

first step

(S)-4-环氧乙垸基甲基-***啉 (S)-4-epoxyethylidenemethyl-morpholine

室温下，将***啉 78a(4.356 ml, 50 mmol)搅拌下溶解于 2.5 ml叔丁醇中，用冰浴冷却至 0°C后，缓慢滴加 (S)-(+)-环氧氯丙烷 (4.02 ml， 50 mmol), 加毕反应体系温度自然升至室温，搅拌过夜。点板监测反应至原料基本消失。边用冰浴控制反应体系温度低于 10°C边滴加叔丁醇钾的四氢呋喃溶液 (30 ml, 1.67 mol/L, 50 mmol), 反应液由浅黄色逐渐变成白色混浊液，加毕继续搅拌 30 min。点板监测反应至原料基本消失，停止反应。反应混合物减压下蒸除溶剂，加入 20 ml水，用二氯甲垸萃取 (100 mlx3), 有机相用饱和氯化钠洗涤 (100 mlxl), 无水硫酸镁干燥，抽滤除去干燥剂，滤液浓缩得到标题产物 (S)-4-环氧乙烷基甲基-***啉 78b(5.52 g，黄色油状物)，产率： 77.2 %。 The morphine 78a (4.356 ml, 50 mmol) was dissolved in 2.5 ml of tert-butanol with stirring at room temperature, and after cooling to 0 ° C with an ice bath, (S)-(+)-epichlorohydrin was slowly added dropwise. (4.02 ml, 50 mmol), the reaction mixture was warmed to room temperature and stirred overnight. The plate was monitored for reaction until the starting material disappeared. While maintaining the temperature of the reaction system below 10 ° C with ice bath, a solution of potassium tert-butoxide in tetrahydrofuran (30 ml, 1.67 mol/L, 50 mmol) was added dropwise, and the reaction mixture gradually changed from pale yellow to white turbid. Stirring was continued for 30 min. The plate was monitored for reaction until the starting material disappeared and the reaction was stopped. The reaction mixture was evaporated under reduced pressure, and water (20 ml) Chloroformamide extraction (100 mlx3), the organic phase was washed with saturated sodium chloride (100 ml×l), dried over anhydrous magnesium sulfate, and filtered. Methyl-morpholine 78b (5.52 g, yellow oil), Yield: 77.2%.

MS m/z (ESI): 144·4(Μ+1)。第二步 MS m/z (ESI): 144·4 (Μ +1). Second step

(R)-l-氨基 -3-***啉 -4-基-异丙醇 (R)-l-amino-3-morpholine-4-yl-isopropanol

冰浴下，将 (S)-4-环氧乙烷基甲基-***啉 78b(5.52 g， 38.6 mmol)缓慢滴入 395 ml氨水 (25%, 5.8 mol)中，控制温度低于 0°C，加毕，反应体系温度自然升至室温，继续搅拌 18小时。点板监测反应至原料基本消失，停止反应。反应液减压下蒸除溶剂，得到标题产物 (R)-l-氨基 -3-***啉 -4-基-异丙醇 78c(6.1 g，微黄色液体)，产率: 99%。 (S)-4-Ethoxyethylmethyl-morpholine 78b (5.52 g, 38.6 mmol) was slowly dropped into 395 ml of ammonia (25%, 5.8 mol) under ice bath to control the temperature below 0 ° C, after the addition, the temperature of the reaction system naturally rose to room temperature, and stirring was continued for 18 hours. The plate was monitored for reaction until the starting material disappeared and the reaction was stopped. The solvent was evaporated under reduced pressure to give the title compound (d)-l-amino-3-morpholine-4-yl-isopropanol 78c (6.1 g, slightly yellow liquid), yield: 99%.

MS m/z (ESI): 161.3(M+1)。第三步 MS m/z (ESI): 161.3 (M + 1). third step

(3)-5-[3-(2- 基-3-***啉 -4-基-丙氨基) -丙基 ]-3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 (3)-5-[3-(2-yl-3-morpholine-4-yl-propylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-un Butyrate 4-ethyl ester

室温下，将 5-(3-甲磺酰氧-丙基) -3-甲基 -1H-吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 lg(1.13 g, 2.9 nmioI)搅拌下溶解于 5.6 ml二氯甲烷中，加入 (R)-l-氨基 -3-***啉 -4- 基-异丙醇 78c(0.93 g， 5.8 mmol), 加毕，室温搅拌过夜，再于 45°C油浴中加热反应 14小时，点板监测反应至原料反应完全，停止反应。向反应液中加入 15 ml饱和氯化钠溶液，用二氯甲烷萃取 (20 ml X 3)，合并有机相，有机相减压下蒸除溶剂后柱层析得到标题产物 (S)-5-[3-(2-轻基 -3-***啉 -4-基-丙氨基) -丙基 ]-3-甲基 -1H- 吡咯 -2,4-二羟酸 2-叔丁酯 4-乙酯 78d(600 mg，无色油状物)，产率： 72.5 %。 5-(3-Methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester lg (1.13 g, 2.9 nmioI) Dissolve in 5.6 ml of dichloromethane with stirring, add (R)-l-amino-3-morphinolin-4-yl-isopropanol 78c (0.93 g, 5.8 mmol), add, stir at room temperature overnight, then The reaction was heated in an oil bath at 45 ° C for 14 hours, and the reaction was monitored by spotting until the reaction of the starting material was complete, and the reaction was stopped. 15 ml of a saturated sodium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane (20 ml EtOAc). [3-(2-Light-methyl-3-morpholine-4-yl-propylamino)-propyl]-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-B Ester 78d (600 mg, colorless oil), yield: 72.5 %.

(S)-5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4- 酮 (S)-5-(2-hydroxy-3-morpholine-4-yl-propyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c吖因 -4- ketone

氩气氛下，将 (S)-5-[3-(2-羟基 -3-***啉 -4-基-丙氨基) -丙基 ]-3-甲基 -1H-吡咯 (S)-5-[3-(2-Hydroxy-3-morpholine-4-yl-propylamino)-propyl]-3-methyl-1H-pyrrole under argon atmosphere

-2,4-二羟酸 2-叔丁酯 4-乙酷 78d(580 mg, 1.28 mmol)搅拌下溶解于 6 ml甲苯中，边用冰浴冷却边滴加三甲基铝的甲苯溶液 (1.9 ml, 2 mol/L, 3.84 mmol), 加毕，撤去冰浴，反应液加热回流 24小时。点板监测反应至原料反应完全，停止反应。反应液减压下蒸除溶剂，加入 20 1^盐酸(6 1^)1/¾，室温搅拌 20分钟，再于冰浴中用氢氧化钠溶液 (12 mol/L)调节 pH至 12左右，用二氯甲烷萃取 (50 ml X 2), 合并有机相，有机相减压蒸除溶剂后柱层析得到标题产物 (S)-5-(2-羟基 -3-***啉 -4-基- 丙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 78e(300 mg，白色固体)，产率： 57.6% ₀ -2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ketone 78d (580 mg, 1.28 mmol) was dissolved in 6 ml of toluene with stirring, and a solution of trimethylaluminum in toluene was added dropwise while cooling with an ice bath ( 1.9 ml, 2 mol/L, 3.84 mmol), after the addition, the ice bath was removed and the reaction was heated to reflux for 24 hours. The plate was monitored until the reaction of the starting material was complete and the reaction was stopped. The reaction solution was evaporated to dryness under reduced pressure. EtOAc (EtOAc (EtOAc) The pH was adjusted to about 12 with sodium hydroxide solution (12 mol/L), extracted with dichloromethane (50 ml X 2 ), and the organic phase was combined. -5-(2-hydroxy-3-morpholine-4-yl-propyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c] In 4-ketone 78e (300 mg, white solid), Yield: 57.6% ₀

MS m/z (ESI): 308.2(M+1)。第五步 MS m/z (ESI): 308.2 (M+1). the fifth step

(S)-5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2-甲酉签 (S)-5-(2-hydroxy-3-morpholine-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrole And [3,2-c] 吖庚因-2-甲酉

氩气氛下，将氯亚甲基二甲基氯化胺 (130 mg， 0.977 mmol)搅拌下溶解于 3 ml 二氯甲垸中，冰浴冷却至 0。C。将 (S)-5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -5,6,7,8- 四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 78e(300 mg， 0.977 mmol)搅拌下溶解于 2 ml 二氯甲烷中，缓慢滴加到上述溶液中并控制反应液温度在 0°C以下。加毕室温搅拌 20分钟，点板监测反应至原料反应完全，向反应液中加入氢氧化钠溶液 (12 mol/L) 淬灭反应。向反应液中加入 10 ml饱和氯化钠溶液，用二氯甲烷和甲醇的混合溶液 (V:V=10:1)萃取 (100 mi x 3), 合并有机目，有机相用饱和氯化钠溶液洗涤 (100 ml X I)-无水硫酸镁干燥，抽滤除去干燥剂，滤液浓缩后柱层析得到标题产物 (S)-5-(2- 羟基 -3-***啉 -4-基-丙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢-吡咯并 [3,2-c] 吖庚因 -2- 甲醛 78f(200 mg，白色固体)，产率： 61 %。 Under an argon atmosphere, chloromethylene dimethylamine chloride (130 mg, 0.977 mmol) was dissolved in 3 ml of dichloromethane, and cooled to 0 in an ice bath. C. (S)-5-(2-Hydroxy-3-morphinolin-4-yl-propyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2- c] Azepin-4-ketone 78e (300 mg, 0.977 mmol) was dissolved in 2 ml of dichloromethane with stirring, slowly added dropwise to the above solution and the temperature of the reaction solution was below 0 °C. After stirring at room temperature for 20 minutes, the reaction was monitored by spotting until the reaction of the starting material was complete, and a sodium hydroxide solution (12 mol/L) was added to the reaction solution to quench the reaction. 10 ml of a saturated sodium chloride solution was added to the reaction solution, and extracted with a mixed solution of dichloromethane and methanol (V: V = 10:1) (100 mi x 3), and the organic phase was combined, and the organic phase was saturated sodium chloride. The solution was washed (100 ml XI) - dried over anhydrous magnesium sulfate. 3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (200 mg, white Solid), Yield: 61%.

MS m/z (ESI): 336.2(M+1)。第六步 MS m/z (ESI): 336.2 (M + 1). Step 6

(S)-2-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -5,6,7,8-四氢 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 (S)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methylol)-5-(2-hydroxy-3-morphinolin-4-yl-propane Benzyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one

室温下，将 (S)-5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢- 吡咯并 [3,2-c] 吖庚因 -2-甲醛 78f(50 mg，0.149 mmol)搅拌下溶解于 261 μ ΐ乙醇中，加入 5-氟 -1,3-二氢 -吲哚 -2-酮 (20.28 mg， 0.134 mmol)和哌啶 (7.3 μ 1， 0.074 rnrnol), 加毕，于 80Ό油浴中避光搅拌 2小时。点板监测反应至原料反应完全，停止反应。撤去油浴，反应体系温度自然降至室温，反应液经抽滤并干燥得到标题产物 (S)-2-(5-氟 -2-氧代 -1,2-二氢 -Π引哚 -3-次甲基 )-5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -5,6,7,8-四氫 -1H-吡咯并 [3,2-c] 吖庚因 -4-酮 78(40 mg，黄色固体)，产率： 57%。 MS m/z (ESI)： 469.2(M+ 1 )。 (S)-5-(2-Hydroxy-3-morphinolin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8- at room temperature Hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (50 mg, 0.149 mmol) was dissolved in 261 μM ethanol with stirring, and 5-fluoro-1,3-dihydro-indole was added. Indole-2-one (20.28 mg, 0.134 mmol) and piperidine (7.3 μl, 0.074 rnrnol) were added, and the mixture was stirred in an 80-inch oil bath for 2 hours. The plate was monitored until the reaction of the starting material was complete and the reaction was stopped. The oil bath was removed, the temperature of the reaction system was naturally lowered to room temperature, and the reaction liquid was suction filtered and dried to give the title product (S)-2-(5-fluoro-2-oxo-1,2-dihydro-indole hydrazine-3 - methine)-5-(2-hydroxy-3-morphinolin-4-yl-propyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2 -c] azepin-4-one 78 (40 mg, yellow solid), yield: 57%. MS m/z (ESI): 469.2 (M + 1).

iH MRWOO MHz, DMSO-d6) δ 13.73(s, IH, 吡咯环 -NH)， 10.91 (s, IH, 吲哚 -NH)， 7.79~6.84(m, 3H, -Ai'H), 7.56(s, IH, -CH=C), 4.73(d, IH, -OH), 3.90(m, IH, -CHOH), 3.76(dd, IH,七环外接酰胺 -NCH₂), 3.58(t, 4H, 吗啉环 2 X -CH₂0), 3.42(m, 2H，七环接 -NCH₂), 3.15(dd, IH, 七环外接酰胺 -NCH₂), 2.94(t, 2H, -CH₂C=C), 2.457(s, 3H, 吡咯环 -C¾), 2.413(m, 4H, 吗啉环内 2 X -CH₂N), 2.306(m, 2H, 吗啉环外 -NCH₂), 2.08(m, 2H,七环 CH₂-C¾-C¾)。实施例 79 iH MRWOO MHz, DMSO-d6) δ 13.73(s, IH, pyrrole ring-NH), 10.91 (s, IH, 吲哚-NH), 7.79~6.84(m, 3H, -Ai'H), 7.56(s , IH, -CH=C), 4.73(d, IH, -OH), 3.90(m, IH, -CHOH), 3.76 (dd, IH, heptacyclic external amide-NCH ₂ ), 3.58(t, 4H, Morpholine ring 2 X -CH ₂ 0), 3.42 (m, 2H, heptacyclo-NCH ₂ ), 3.15 (dd, IH, heptacyclic external amide-NCH ₂ ), 2.94 (t, 2H, -CH ₂ C =C), 2.457(s, 3H, pyrrole ring-C3⁄4), 2.413 (m, 4H, morpholine ring 2 X -CH ₂ N), 2.306 (m, 2H, morpholine ring-NCH ₂ ), 2.08 (m, 2H) , seven-ring CH ₂ -C3⁄4-C3⁄4). Example 79

(S，Z)-2-((5-氯 -2-氧代吲哚 -3-亚基)甲基) -5-(2-羟基 -3-***啉丙基) -3-甲基 -5,6,7,8-四氢口比咯并 [3,2- -4(1H)-酮 (S,Z)-2-((5-Chloro-2-oxoindole-3-ylidene)methyl)-5-(2-hydroxy-3-morphinanpropyl)-3-methyl- 5,6,7,8-tetrahydro-portion and [3,2- -4(1H)-one

室温下，将 (S)-5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢- 吡咯并 [3,2-c] 吖庚因 -2-甲醛 78f (40 mg， 0.12 mmol)和 5-氯 -1,3-二氢 -吲哚 -2-酮 (20 mg, 0.12 mmol)加入到 1.5 ml乙醇中，再加入 6μ1哌啶，加毕 45Ό搅拌 16小时。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗涤 (1 mi x 2), 干燥后得到 (S,Z)-2-((5-氯 -2-氧代吲哚 -3-亚基）甲基) -5-(2-羟基 -3-***啉丙基) -3-甲基 -5,6,7,8-四氢吡咯并 [3,2-c] 吖庚因 -4(1Η)-酮 79(46 mg, 黄色固体)，产率： 79%。

(S)-5-(2-Hydroxy-3-morphinolin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8- at room temperature Hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (40 mg, 0.12 mmol) and 5-chloro-1,3-dihydro-indol-2-one (20 mg, 0.12) Methyl) was added to 1.5 ml of ethanol, 6 μl of piperidine was added, and the mixture was stirred for 45 hours. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was naturally cooled to room temperature, suction filtered under reduced pressure, and the filter cake was washed with anhydrous ethanol (1 mi x 2), and dried to give (S,Z)-2-((5-chloro-2-oxoindole- 3-ylidenemethyl)-5-(2-hydroxy-3-morphinorylpropyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c] 4-(1Η)-one 79 (46 mg, yellow solid), Yield: 79%.

MS m/z (ESI): 485.2(M+1)。 MS m/z (ESI): 485.2 (M + 1).

¹HNMR(400 MHz, DMS0-d6) δ 13.679(s， 1H,吡咯环 -NH)， 11.008 (s, 1H, 吲哚 -NH), 7.994(s, 1H, -Ai'H), 7.803(s, 1H, -CH=C), 7.159~6.869(m, 2H, -ArH), 4.727(d, 1H, -OH), 3.90(m, 1H, -CHOH), 3.76(dd, 1H,七环外接酰胺 -NCH₂), 3.58(t, 4H, 吗啉环 2 X -CH₂0), 3.418(m, 2H，七环接 -NCH₂), 3.15(m, 1H, 七环外接酰胺 -NCH₂), 2.937(t, 2H, -CH₂C=C), 2.464(s, 3H, 吡咯环 -CH₃), 2.428(m, 4H, 吗啉环内 2 X -CH₂N), 2.299(m, 2H, 吗啉环外 -NC¾), 2.076(m, 2H,七环 CH₂-CH₂-C¾)。实施例 80 ¹ H NMR (400 MHz, DMS0-d6) δ 13.679 (s, 1H, pyrrole ring-NH), 11.008 (s, 1H, 吲哚-NH), 7.994 (s, 1H, -Ai'H), 7.803 (s , 1H, -CH=C), 7.159~6.869(m, 2H, -ArH), 4.727(d, 1H, -OH), 3.90(m, 1H, -CHOH), 3.76(dd, 1H, 7-ring external amide-NCH ₂ ), 3.58 (t, 4H, morpholine ring 2 X -CH ₂ 0), 3.418 (m, 2H, heptacyclo-NCH ₂ ), 3.15 (m, 1H, heptacyclic external amide-NCH ₂ ), 2.937(t, 2H, -CH ₂ C=C), 2.464 (s, 3H, pyrrole ring-CH ₃ ), 2.428 (m, 4H, morpholine ring 2 X -CH ₂ N), 2.299 (m , 2H, morpholine ring-NC3⁄4), 2.076 (m, 2H, heptacyclic CH ₂ -CH ₂ -C3⁄4). Example 80

(S,Z)-2-((5-溴 -2-氧代吲哚 -3-亚基)甲基) -5-(2-羟基 -3-***啉丙基) -3-甲基 -5,6,7,8-四氢吡咯并 [3,2-c] 吖庚因 -4(1H)-酮 (S,Z)-2-((5-Bromo-2-oxoindole-3-ylidene)methyl)-5-(2-hydroxy-3-morphinanpropyl)-3-methyl- 5,6,7,8-tetrahydropyrrolo[3,2-c]azepine-4(1H)-one

室温下，将 (S)-5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -4-氧代 -1，4,5,6,7,8-六氢- 吡咯并 [3,2-c] 吖庚因 -2-甲醛 78f (40 mg， 0.12 mmol)和 5-溴 -1,3-二氢 -吲哚 -2-酮 (25 mg， 0.12 mmol)加入到 1.5 ml乙醇中，再加入 6μ1哌啶，加毕 45Ό搅拌 16小时。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗涤 (1 ml X 2), 干燥后得到 (S，Z)-2-((5-溴 -2-氧代吲哚 -3-亚基）甲基) -5-(2-羟基 -3-***啉丙基) -3-甲基 -5,6,7,8-四氢吡咯并 [3，2-c] 吖庚因 -4(1Η)-酮 80(51 mg, 黄色固体)，产率： 81 %。

(S)-5-(2-Hydroxy-3-morphinolin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8- at room temperature Hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (40 mg, 0.12 mmol) and 5-bromo-1,3-dihydro-indol-2-one (25 mg, 0.12) Methyl) was added to 1.5 ml of ethanol, 6 μl of piperidine was added, and the mixture was stirred for 45 hours. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was naturally cooled to room temperature, suction filtered under reduced pressure, and the filter cake was washed with anhydrous ethanol (1 ml X 2), and dried to give (S,Z)-2-((5-bromo-2-oxoindole- 3-ylidenemethyl)-5-(2-hydroxy-3-morphinorylpropyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c] 4-(1Η)-one 80 (51 mg, yellow solid), Yield: 81%.

MS m/z (ESI): 529.1(M+1)。 MS m/z (ESI): 529.1 (M+1).

¹HNMR(400 MHz, DMSO-d6) δ 13.673(s, IH,吡咯环 -NH)， 11.014 (s， IH,吲哚 -NH)， 8.120~8.115(s, IH, -ArH), 7.807(s, IH, -CH=C), 7.287-7.262(dd, IH, -ArH), 6.847〜6.826(d, IH, -ArH), 4.734~4.722(d, IH, -OH), 3.90(m, IH, -CHOH), 3.792~3.748(dd, 1H，七环外接酰胺 -NCH₂)， 3.58(t, 4H, 吗啉环 2 X -CH₂0), 3.437-3.398 (in, 2H, 七环接 -NCH₂), 3.193-3.140(m, IH, 七环外接酰胺 -NC¾), 2.936(t, 2H, -CH₂C=C), 2.465(s, 3H,吡咯环 -CH₃), 2.431~2.420(m, 4H, 吗啉环内 2 X -CH₂N), 2.315(m, 2H, 吗啉环外 -NCH₂)， 2.09(m, 2H,七环 CH₂-CH₂-CH₂)。实施例 81 ¹ H NMR (400 MHz, DMSO-d6) δ 13.673 (s, IH, pyrrole ring-NH), 11.014 (s, IH, 吲哚-NH), 8.120~8.115 (s, IH, -ArH), 7.807 (s , IH, -CH=C), 7.287-7.262(dd, IH, -ArH), 6.847~6.826(d, IH, -ArH), 4.734~4.722(d, IH, -OH), 3.90(m, IH , -CHOH), 3.792~3.748 (dd, 1H, heptacyclic external amide-NCH ₂ ), 3.58 (t, 4H, morpholine ring 2 X -CH ₂ 0), 3.437-3.398 (in, 2H, seven-ring -NCH ₂ ), 3.193-3.140 (m, IH, heptacyclic external amide-NC3⁄4), 2.936 (t, 2H, -CH ₂ C=C), 2.465 (s, 3H, pyrrole ring-CH ₃ ), 2.431~ 2.420 (m, 4H, morpholine ring 2 X -CH ₂ N), 2.315 (m, 2H, morpholine-outer-NCH ₂ ), 2.09 (m, 2H, heptacyclic CH ₂ -CH ₂ -CH ₂ ) . Example 81

(S,Z)-2-((4-溴 -2-氧代吲哚 -3-亚基)甲基) -5-(2-羟基 -3-***啉丙基) -3-甲基 -5,6,7,8-四氢吡咯并 [3,2-c] 吖庚因 -4 -酮 (S,Z)-2-((4-Bromo-2-oxoindole-3-ylidene)methyl)-5-(2-hydroxy-3-morphinanpropyl)-3-methyl- 5,6,7,8-tetrahydropyrrolo[3,2-c]azepine-4-one

室温下，将 (S)-5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -4-氧代 -1，4，5,6，7,8-六氢- 吡咯并 [3,2-c] 吖庚因 -2-甲醛 78f (40 mg，' 0.12 mmol)和 4-溴 -1,3-二氢 -吲哚 -2-酮 (25 mg, 0.12 mmol)加入到 1.5 ml乙醇中，再加入 6μ1哌啶，加毕 45°C搅拌 16小时。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗涤 (1 ml X 2) , 干燥后得到 (S,Z)-2-((4-溴 -2-氧代吲哚 -3-亚基）甲基) -5-(2-羟基 -3-***啉丙基) -3-甲基 -5,6,7,8-四氢吡咯并 [3,2-c] 吖庚因 -4(1H)-酮 81(34 mg, 黄色固体)，产率： 54%。

(S)-5-(2-Hydroxy-3-morphinolin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8- at room temperature Hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (40 mg, '0.12 mmol) and 4-bromo-1,3-dihydro-indol-2-one (25 mg, 0.12 mmol) was added to 1.5 ml of ethanol, and 6 μl of piperidine was added thereto, and the mixture was stirred at 45 ° C for 16 hours. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was naturally cooled to room temperature, suction filtered under reduced pressure, and the filter cake was washed with anhydrous ethanol (1 ml X 2 ) and dried to give (S,Z)-2-((4-bromo-2-oxoindole- 3-ylidenemethyl)-5-(2-hydroxy-3-morphinorylpropyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c] 4-(1H)-one 81 (34 mg, yellow solid), Yield: 54%.

MS m/z (ESI): 529.3(M+l)c MS m/z (ESI): 529.3 (M+l).

¹H MR(400 MHz, DMSO-d6) δ 13.647(s, IH,吡咯环 -NH)， 11.185 (s, IH, 吲哚 -NH)， 8.588(s, IH, -CH=C), 7.238-7.218(d, IH, -ArH), 7.095~7.055(t, IH, -ΑιΉ), 6.956~6.936(d, IH, -ArH), 4.739~4.726(d, IH, -OH), 3.90(m, IH, -CHOH), 3.800~3.757(dd, IH,七环外接酰胺 -NCH₂), 3.593~3.570(t, 4H, 吗啉环 2 X -CH₂0), 3.446(m, 2H, 七环接 -NCH₂), 3.192(dd, IH, 七环外接酰胺 -NCH₂), 2.956(ΐ, 2H, -CH₂C=C), 2.447~2.428(m, 4H, 吗啉环内 2 X -CH₂N), 2.411(s, 3H，吡咯环 -CH₃), 2.30 l(m, 2H, 吗啉环外 -NCH₂), 2.08(m, 2H,七环 CH₂-CH₂-CH₂)。实施例 82 ¹ H MR (400 MHz, DMSO-d6) δ 13.647 (s, IH, pyrrole ring-NH), 11.185 (s, IH, 吲哚-NH), 8.588 (s, IH, -CH=C), 7.238- 7.218(d, IH, -ArH), 7.095~7.055(t, IH, -ΑιΉ), 6.956~6.936(d, IH, -ArH), 4.739~4.726(d, IH, -OH), 3.90(m, IH, -CHOH), 3.800~3.757 (dd, IH, heptacyclic external amide-NCH ₂ ), 3.593~3.570 (t, 4H, morpholine ring 2 X -CH ₂ 0), 3.446 (m, 2H, 7 ring -NCH ₂ ), 3.192 (dd, IH, heptacyclic external amide-NCH ₂ ), 2.956 (ΐ, 2H, -CH ₂ C=C), 2.447~2.428 (m, 4H, morpholine ring 2 X - CH ₂ N), 2.411 (s, 3H, pyrrole ring-CH ₃ ), 2.30 l (m, 2H, morpholine-external-NCH ₂ ), 2.08 (m, 2H, heptacyclic CH ₂ -CH ₂ -CH ₂ ). Example 82

(S,Z)-2-((7-溴 -5-氟 -2-氧代吲哚 -3-亚基）甲基) -5-(2-羟基 -3-***啉丙基) -3_甲基 -5,6,7,8-四氢吡咯并 [³,2-c -4(1Η)-酮 (S,Z)-2-((7-bromo-5-fluoro-2-oxoindole-3-ylidene)methyl)-5-(2-hydroxy-3-morphinanylpropyl)-3 _Methyl-5,6,7,8-tetrahydropyrrolo[ ³ ,2-c -4(1Η)-one

室温下，将 (S)-5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -4-氧代 -1,4,5,6,7,8-六氢- 吡咯并 [3,2-c] 吖庚因 -2-甲醛 78f (40 mg， 0.12 mmol)和 7-溴 -5-氟 -1,3-二氢 -吲哚 -2- 酮 4b (27 mg, 0.12 mmol)加入到 1.5 ml乙醇中，再加入 6μ1哌啶，加毕 45°C搅拌 16小时。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗涤 (1 ηύ Χ 2)，干燥后得到 (S,Z)-2-((7-溴 -5-氟 -2-氧代吲哚 -3-亚基)甲基) -5-(2-羟基 -3-***啉丙基) -3-甲基 -5,6,7,8-四氢吡咯并 [3,2-c] 吖庚因 -4(1H)-酮 82(48 mg，黄色固体)，产率： 73.8 %。

(S)-5-(2-Hydroxy-3-morphinolin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8- at room temperature Hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (40 mg, 0.12 mmol) and 7-bromo-5-fluoro-1,3-dihydro-indol-2-one 4b (27 mg, 0.12 mmol) was added to 1.5 ml of ethanol, then 6 μl of piperidine was added, and the mixture was stirred at 45 ° C for 16 hours. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was naturally cooled to room temperature, suction filtered under reduced pressure, and the filter cake was washed with anhydrous ethanol (1 η ύ Χ 2), and dried to give (S,Z)-2-((7-bromo-5-fluoro-2-oxo) Deutero-3-ylidene)methyl)-5-(2-hydroxy-3-morphinorylpropyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2- c] aglycone-4(1H)-one 82 (48 mg, yellow solid), yield: 73.8 %.

MS m/z (ESI): 547.5(M+1)。 MS m/z (ESI): 547.5 (M+1).

^!ΗΝΜΚ(400 MHz, DMSO-d6) δ 13.665(s, IH,吡咯环 -NH)， 11.188 (s, IH, 吲哚 -NH)， 7.876~7.848(dd, IH, -ArH), 7.797~7.055(s₃ IH, -ArH), 7.270-7.24 l(dd, IH, -ArH), 4.74(m, IH, -OH), 3.93(m, IH, -CHOH), 3.75 (dd, IH,七环外接酰胺 -NCH₂), 3.583(t, 4H, 吗啉环 2 X -CH₂0), 3.480~3.415(m, 2H,七环接 -NCH₂), 3.15(dd, IH,七环外接酰胺 -NCH₂), 2.471 (s, 3H, 吡咯环 -CH₃), 2.430(m, 4H，吗啉环内 2 X -CH₂N), 2.310(t, 2H, 吗啉环外 -NC¾), 2.086(m, 2H,七环 CH₂-CH₂-CH₂)。实施例 83 ^{! ΗΝΜΚ (400 MHz, DMSO-} d6) δ 13.665 (s, IH, pyrrole ring -NH), 11.188 (s, IH , indole -NH), 7.876 ~ 7.848 (dd , IH, -ArH), 7.797 ~ 7.055 (s ₃ IH, -ArH), 7.270-7.24 l(dd, IH, -ArH), 4.74(m, IH, -OH), 3.93(m, IH, -CHOH), 3.75 (dd, IH, seven rings Externally amide-NCH ₂ ), 3.583 (t, 4H, morpholine ring 2 X -CH ₂ 0), 3.480~3.415 (m, 2H, heptacyclo-NCH ₂ ), 3.15 (dd, IH, heptacyclic external amide -NCH ₂ ), 2.471 (s, 3H, pyrrole ring-CH ₃ ), 2.430 (m, 4H, morpholine ring 2 X -CH ₂ N), 2.310 (t, 2H, morpholine exocyclic -NC¾), 2.086 (m, 2H , seven ring CH _{_₂} -CH ₂ -CH _2). Example 83

(S,Z)-5-(2-羟基 -3-***啉丙基) -3-甲基 -2-((4-甲基 -2-氧代吲哚 -3-亚基)甲基) -5,6,7,8- 四氢吡咯并 [3，2-c] 吖庚因 -4 -酮 (S,Z)-5-(2-hydroxy-3-morpholinepropyl)-3-methyl-2-((4-methyl-2-oxoindole-3-ylidene)methyl) -5,6,7,8-tetrahydropyrrolo[3,2-c]azepine-4-one

室温下，将 (S)-5-(2-羟基 -3-***啉 -4-基-丙基) -3-甲基 -4-氧代 -1,4,5,6,7，8-六氢- 吡咯并 [3,2-c] 吖庚因 -2-甲醛 78f (40 mg， 0.12 mmol)和 4-甲基 -1,3-二氢 -吲哚 -2-酮 (18 mg， 0.12 mmol)加入到 1.5 ml乙醇中，再加入 6μ1哌啶，加毕 45Ό搅拌 16小时。点板监测表明原料反应完全，停止反应。反应液自然冷却至室温，减压抽滤，滤饼用无水乙醇洗涤 (1 mi x 2), 干燥后得到 (S,Z)-5-(2-羟基 -3-***啉丙基) -3-甲基 -2-((4-甲基 -2-氧代吲哚 -3-亚基）甲基) -5,6，7,8-四氢吡咯并 [3,2-c] 吖庚因 -4(1H)-酮 83(35 mg, 黄色固体)，产率： 63.6%。

(S)-5-(2-Hydroxy-3-morphinolin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8- at room temperature Hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (40 mg, 0.12 mmol) and 4-methyl-1,3-dihydro-indol-2-one (18 mg, 0.12 mmol) was added to 1.5 ml of ethanol, 6 μl of piperidine was added, and the mixture was stirred for 45 hours. Spot plate monitoring indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction solution was naturally cooled to room temperature, suction filtered under reduced pressure, and the filter cake was washed with anhydrous ethanol (1 mi x 2) and dried to give (S,Z)-5-(2-hydroxy-3-morpholinepropyl) 3-methyl-2-((4-methyl-2-oxoindole-3-ylidene)methyl)-5,6,7,8-tetrahydropyrrolo[3,2-c]indole Gyne-4(1H)-one 83 (35 mg, yellow solid), Yield: 63.6%.

MS m/z (ESI): 465.2(M+1)。 MS m/z (ESI): 465.2 (M + 1).

¹HNMR(400 MHz, DMSO-d6) δ 13.715(s, 1H，吡咯环 -NH)， 10.934(s, 1H,吲哚 -NH)， 7.572(s, 1H, -CH=C), 7.057 (t， 1H， -ArH), 6.840~6.821(d, 1H, -ArH), 6.790~6.771(d, 1H, -ArH), 4.737~4.725(d, 1H, -OH), 3.92(m, 1H, -CHOH), 3.75 (dd, 1H,七环外接酰胺 -NCH₂), 3.58(t, 4H, 吗啉环 2 X -CH₂0), 3.441(m, 2H，七环接 -NCH₂), 3.15(m, 1H,七环外接酰胺 -NCH₂), 2.939(t, 2H, -CH₂CH=C), 2.594(s, 3H, 吡咯环 -CH₃)， 2.426 (m, 4H, 吗啉环内 2 X -CH₂N), 2.388(s, 3H，吡咯环 -CH₃)， 2.309~2.293(m, 2H, 吗啉环外 -NCH₂), 2.078(m， 2H,七环 C¾-CH₂-CH₂)。 ¹ H NMR (400 MHz, DMSO-d6) δ 13.715 (s, 1H, pyrrole ring-NH), 10.934 (s, 1H, 吲哚-NH), 7.572 (s, 1H, -CH=C), 7.057 (t , 1H, -ArH), 6.840~6.821(d, 1H, -ArH), 6.790~6.771(d, 1H, -ArH), 4.737~4.725(d, 1H, -OH), 3.92(m, 1H, - CHOH), 3.75 (dd, 1H, heptacyclic external amide-NCH ₂ ), 3.58 (t, 4H, morpholine ring 2 X -CH ₂ 0), 3.441 (m, 2H, heptacyclo-NCH ₂ ), 3.15 (m, 1H, heptacyclic external amide-NCH ₂ ), 2.939 (t, 2H, -CH ₂ CH=C), 2.594 (s, 3H, pyrrole ring-CH ₃ ), 2.426 (m, 4H, morpholine ring 2 X -CH ₂ N), 2.388 (s, 3H, pyrrole ring-CH ₃ ), 2.309~2.293 (m, 2H, morpholine-external-NCH ₂ ), 2.078 (m, 2H, heptacyclic C3⁄4-CH ₂ -CH ₂ ).

测试例: Test case:

生物学评价 Biological evaluation

例 1: 抑制细胞增殖测试 Example 1: Inhibition of cell proliferation test

下面的体外试验是用来测定本发明化合物对于人类肿瘤细胞 HUVEC VEGFR 高表达的细胞株抑制增殖活性。 The following in vitro assays were used to determine the inhibitory activity of the compounds of the invention against cell lines with high expression of human tumor cells HUVEC VEGFR.

下面所述的体外细胞试验可确定受试化合物的对髙表达 VEGFR的肿瘤细胞的抗血管生成活性和抑制增殖活性，其活性可用 IC_5Q值来表示。此类试验的一般方案如下：首先选择高表达 VEGFR的人类肿瘤细胞，以适宜细胞浓度下 (exp 5000 个细胞 /ml介质)接种在 96孔培养板上，然后将细胞在二氧化碳恒温箱内进行培养，当它们生长至 85 %汇合，更换培养基为加有一系列浓度递度 (一般 6到 7个浓度) 受试化合物溶液的培养基，将培养板重新放回培养箱，连续培养 72个小时。 72小时后，可用磺酰罗丹明 B(SRB)方法进行测试化合物对于抑制细胞增殖活性。 IC₅₍₎ 值可通过一系列不同浓度下，受试化合物对于细胞的抑制数值进行计算。材料和方法： The in vitro cell assay described below determines the anti-angiogenic activity and the proliferative activity of the test compound against VEGFR-expressing tumor cells, and its activity can be expressed by the IC _5Q value. The general protocol for such an experiment is as follows: first select human tumor cells with high expression of VEGFR, at the appropriate cell concentration (exp 5000 Cells/ml medium) were seeded on 96-well culture plates, and then the cells were cultured in a carbon dioxide incubator. When they grew to 85% confluence, the medium was changed to a series of concentration (generally 6 to 7 concentrations). The culture medium of the test compound solution was returned to the incubator for 72 hours. After 72 hours, the test compound was tested for its ability to inhibit cell proliferation using the sulforhodamine B (SRB) method. The IC ₅₍₎ value can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations. Materials and Method:

a. 二甲基亚砜 (Sinophma chemical reagent company, 目录 T20050806号) b. HUVEC细胞（购于 Institute of biochemistry and cell biology) a. Sodium sulfoxide (Sinophma chemical reagent company, catalogue T20050806) b. HUVEC cells (purchased from the Institute of biochemistry and cell biology)

c. Falcon 100 mm细胞培养板 (Baton Dickison Labware, Baton Dickison and company, 目录 18677号） c. Falcon 100 mm Cell Culture Plate (Baton Dickison Labware, Baton Dickison and company, Catalog No. 18677)

d. 康氏 (Corning) 96孔培养板（Coming Incorporated, 目录 3599号） d. Corning 96-well culture plate (Coming Incorporated, catalogue 3599)

e. Fisher移液管（Fisher scientific, 目录 03-692-164号） e. Fisher pipette (Fisher scientific, catalogue 03-692-164)

f. DMEM/F12细胞培养基（Gibco, 目录 12400-024号） f. DMEM/F12 cell culture medium (Gibco, catalog 12400-024)

g. 澳大利亚胎牛血清（Gibco, 目录 10099-141号） g. Australian fetal bovine serum (Gibco, catalogue 10099-141)

h. 磷酸盐缓冲盐水（Gibco, 目录 10010-072号） h. Phosphate buffered saline (Gibco, catalogue 10010-072)

i. 0.25 %胰岛素 -EDTA (Gibco, 目录 25200-056号） i. 0.25 % insulin - EDTA (Gibco, catalog 25200-056)

j. 磺酰罗丹明 B (Sigma, 目录 3520-42-1号） j. Sulfonhodamine B (Sigma, Table of Contents 3520-42-1)

k. 酉昔酸（Sinophma chemical reagent company, 目录 T20060508号) k. Sinoxma chemical reagent company, catalogue T20060508

1. 三氯醋酸（Sinophma chemical reagent company, 目录 T20060305号） 1. Trichloroacetic acid (Sinophma chemical reagent company, catalogue T20060305)

m. Ti'is碱（Amresco，目录 0826号） m. Ti'is base (Amresco, catalogue 0826)

n. II级 A/B3 型生物学安全工作橱 (Thei'moForma目录. HB0053-03号） n. Class II A/B3 Biological Safety Work Cabinet (Thei'moForma Catalogue. HB0053-03)

0. 系列 II水套式二氧化碳培养箱（ThermoForma模型： 3111) 0. Series II water jacketed carbon dioxide incubator (ThermoForma model: 3111)

p. 离心机（Fisher Scientific Marathon 8 k, 目录 0027-02号） p. Centrifuge (Fisher Scientific Marathon 8 k, Catalogue 0027-02)

q. Novastar板读取器（BMG Labtech, 目录 700-0081号） q. Novastar Board Reader (BMG Labtech, Catalog 700-0081)

r. 定轨摇床（Qilinbeier, 目录 TS-1号）方案： r. Orbital shaker (Qilinbeier, catalog TS-1)

下面的方案用来测试本发明受试化合物对于 HUVEC细胞的抑制细胞增殖 IC₅o值。 1. 将 HUVEC细胞殖于 100mm康氏培养板在生长基（以 DMEM/F12+10%胎牛血清为培养液)中进行培养 (37 V, 5 % C0₂), 直至细胞充分汇合； The following protocol was used to test the inhibitory cell proliferation IC ₅ o values of the test compounds of the present invention against HUVEC cells. 1. The HUVEC cells were cultured in a 100 mm Connaught plate and cultured in a growth medium (DMEM/F12 + 10% fetal bovine serum as a medium) (37 V, 5 % C0 ₂ ) until the cells were fully confluent;

2. 在 100 imn培养板中用胎牛血清洗涤 HUVEC细胞，以胰蛋白酶 (Tyrpsin )消化细胞后，再将细胞接种在康氏 96孔细胞培养板上，浓度为 50000孔 /ml，每个板空 6孔，作为对照孔.； 2. Wash HUVEC cells with fetal bovine serum in 100 μn plates, digest the cells with trypsin (Tyrpsin), and inoculate the cells in a Confucius 96-well cell culture plate at a concentration of 50,000 wells/ml, each plate. 6 holes empty, as a control hole.;

3. 在 37 'C，5 % C0₂条件下，将细胞在 96孔板中培养，直至达到约 85 %汇合； 4. 用 DMSO溶解受试化合物，配置 20 mM母液，后用 DMSO稀释母液，得到一系列浓度的受试化合物的溶液，即 2 mM, 1 mM, 0.2 mM, 20 μΜ, 2 μΜ, 0.2 μΜ;3. Incubate the cells in 96-well plates at 37 'C, 5 % C0 ₂ until approximately 85% confluence is reached; 4. Dissolve the test compound in DMSO, configure 20 mM stock, and dilute the stock with DMSO. Get a series of solutions of the test compound, ie 2 mM, 1 mM, 0.2 mM, 20 μΜ, 2 μΜ, 0.2 μΜ;

5. 使用细胞培养基（DMEM/F12 +10 %胎牛血清为培养液）稀释上面所配置的化合物溶液。每个 DMSO系列浓度化合物溶液稀释 20倍，每次在细胞培养基中加入 5μ1 DMSO化合物溶液和 95μ1培养液，确保 HUVEC细胞暴露在 DMSO溶液中的浓度不超过 0.5 %，用涡旋混合，； 5. Dilute the compound solution configured above using cell culture medium (DMEM/F12 +10% fetal bovine serum as the culture medium). Each DMSO series concentration compound solution was diluted 20 times, and 5 μl DMSO compound solution and 95 μl culture solution were added to the cell culture medium each time to ensure that the concentration of HUVEC cells exposed to the DMSO solution did not exceed 0.5%, and the mixture was vortexed;

6. 当 HUVEC细胞贴壁，生长达到 85%汇合后，将培养基换为加有 DMEM/F12 +10 %胎牛血清培养液的新培养基，每孔中再加入 180μ1培养液和 20 μΐ在第五步中所制备的受试化合物溶液。阴性对照细胞组，加入含有 0.5%DMSO的 20 μΐ培养液，这样 HUVEC细胞暴露在受试化合物溶液中的最终浓度为 100 μΜ, 10 μΜ, 5 μΜ, 1 μΜ, 0.1 μΜ, 0.01 μΜ, and 0.001 μΜ; 6. When the HUVEC cells are adherent and the growth reaches 85% confluence, the medium is changed to a new medium supplemented with DMEM/F12 +10% fetal bovine serum, and 180 μl of the culture medium and 20 μM are added to each well. The test compound solution prepared in the fifth step. In the negative control cell group, 20 μL of culture medium containing 0.5% DMSO was added, so that the final concentration of HUVEC cells exposed to the test compound solution was 100 μΜ, 10 μΜ, 5 μΜ, 1 μΜ, 0.1 μΜ, 0.01 μΜ, and 0.001. Μ

7. 将培养板放入恒温箱内，在 37 °C, 5 % C0₂条件下，连续培养 72小时；7. Place the culture plate in an incubator and continue to culture for 72 hours at 37 °C, 5 % C0 ₂ ;

8. 72小时后，将培养板从恒温箱中转移到无菌工作室； 8. After 72 hours, transfer the plate from the incubator to the sterile studio;

9. 将试药级纯水加入到 TCA中制备固定剂（50 %三氯醋酸 -TCA),将细胞慢慢地分层放在 50 μΐ冷 TCA溶液中； 9. Add reagent grade pure water to TCA to prepare fixative (50% trichloroacetic acid -TCA), and slowly layer the cells in 50 μL cold TCA solution;

10.在 4°C下，培养 1小时，后用水洗涤数次以除去 TCA、血清蛋白等。培养板在空气中干燥，存储待用。空白背景光学密度值的测定是在没有细胞生长的培养基中温育培养所得的数值。 10. Incubate at 4 ° C for 1 hour, and then wash several times with water to remove TCA, serum protein, and the like. The plates are dried in air and stored for later use. The blank background optical density value is determined by incubating the culture in a medium without cell growth.

11.用 10 %醋酸溶液制备 0.4 %磺酰罗丹明 B溶液，并向每孔中加入 50 μΐ磺酰罗丹明 Β溶液； 11. Prepare a 0.4% sulforhodamine B solution with 10% acetic acid solution, and add 50 μM of sulfonyl rhodamine solution to each well;

12.细胞着色 30分钟； 12. Cell staining for 30 minutes;

13.制备 10%醋酸洗涤溶液。当着色将要完毕时，弃去着色剂，用 10%的醋酸溶液快速冲洗细胞。重复上述的操作直至着色剂洗净为止，尽量减少冲洗次数以减少与蛋白结合的着色剂的去吸附。冲洗完毕后，将培养板在空气中干燥； 13. Prepare a 10% acetic acid wash solution. When the coloring is about to be completed, the coloring agent is discarded and the cells are quickly rinsed with a 10% acetic acid solution. The above operation is repeated until the coloring agent is washed, and the number of rinsing is minimized to reduce the desorption of the protein-bound coloring agent. After the rinsing is completed, the plate is dried in the air;

14.混合的着色剂溶解在一定体积的磺酰罗丹明 Β中，增溶溶液（lO mM Tris)与培养基原体积相同，将培养板在室温下放置 5分钟，用摇床缓慢搅拌加快与染料的混合； 14. The mixed colorant is dissolved in a certain volume of sulforhodamine, the solubilizing solution (10 mM Tris) is the same as the original volume of the medium, and the plate is allowed to stand at room temperature for 5 minutes, and slowly stirred with a shaker to accelerate Mixing of dyes;

15.用分光光度测量，在波长 565 nm下读取吸光度值。吸光度数值为 565 mil下吸光度减去 690 nm下 96孔板背景吸光度所得的数值； 15. Using a spectrophotometric measurement, read the absorbance at a wavelength of 565 nm. The absorbance values are the absorbance at 565 mil minus the background absorbance at 96 nm for 690 nm;

16.使用如下方法计算抑制率比值： 16. Calculate the inhibition ratio using the following method:

IR= lOOx (对照组吸光度值 -用药组吸光度值) /对照组吸光度值％. IR = lOOx (absorbance value of the control group - absorbance value of the drug group) / % absorbance value of the control group.

IC₅₀值可通过不同浓度下化合物抑制率比值计算得到。本发明化合物的活性 The IC ₅₀ value can be calculated from the ratio of compound inhibition rates at different concentrations. Activity of the compounds of the invention

本发明化合物的生化学活性通过以上的试验进行测定，测得的 IC50值见下表。

2 0.288 The biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC50 values are shown in the following table.

2 0.288

3 0.1 3 0.1

4 0.404 4 0.404

5 0.1 5 0.1

6 0.28 6 0.28

8 8

9 0.068 9 0.068

10 0.12310 0.123

11 0.20711 0.207

12 0.3 12 0.3

13 0.804 13 0.804

14 0.45714 0.457

15 1.2 15 1.2

16 0.21 16 0.21

17 0.129 17 0.129

19 0.146 例 2: VEGF- 2激酶活性测定 19 0.146 Example 2: Determination of VEGF-2 kinase activity

o o

本试验采用酶联吸附免疫测定法 (ELISA)测定重组人类 VEGF-R2蛋白体外激酶活性。材料与试剂： In this experiment, the in vitro kinase activity of recombinant human VEGF-R2 protein was determined by enzyme-linked immunosorbent assay (ELISA). Materials and reagents:

a. 洗涤缓冲液（PBS-T 缓冲液)： lx PBS (137 mM NaCK 2.7 mM KC1、 4.3 mMNa₂HP0₄、 1.4 mM KH₂P0₄, 调 pH至 7.2)禾 Π 0.05 % Tween-20 a. Wash buffer (PBS-T buffer): lx PBS (137 mM NaCK 2.7 mM KC1, 4.3 mM Na ₂ HP0 ₄ , 1.4 mM KH ₂ P0 ₄ , adjusted to pH 7.2) and 0.05% Tween-20

b. 1 %牛血清白蛋白 (BSA, Calbioc em #136593)PBS-T缓冲液 b. 1% bovine serum albumin (BSA, Calbioc em #136593) PBS-T buffer

c. 中止反应缓冲液： 50 mM EDTA , pH 8.0 c. Stop reaction buffer: 50 mM EDTA, pH 8.0

d. DELFIA®铕标记抗鼠 IgG (PerkinElmer Life Sciences #AD0124) d. DELFIA® 铕 labeled anti-mouse IgG (PerkinElmer Life Sciences #AD0124)

e. DELFIA®信号倍增液 (PerkinElmer Life Sciences #1244-105) e. DELFIA® Signal Multiplier (PerkinElmer Life Sciences #1244-105)

f. DELFIA®链酶亲和素包 96孔黄板（PerkinElmer Life Sciences #AAAND-0005) g. 重组人类 VEGF-R2激酶（50 mM Tris-HCl (pH 8.0), 100 mM NaCl, 5 mM DTT, 15 mM谷酖基胱氨酰甘氨酸和 20 %甘油(。611 signaling technology #7787) h. 10 mM ATP溶液（Cell signaling technology #9804) f. DELFIA® Streptavidin 96-well yellow plate (PerkinElmer Life Sciences #AAAND-0005) g. Recombinant human VEGF-R2 kinase (50 mM Tris-HCl (pH 8.0), 100 mM NaCl, 5 mM DTT, 15 mM glutathione glycine and 20% glycerol (.611 signaling technology #7787) h. 10 mM ATP solution (Cell signaling technology #9804)

i. 生物素 -胃泌素前体 (Biotin-Gasti'in Precursor) (Tyi'87)肽（Cell signaling technology #1310) i. Biotin-Gasti'in Precursor (Tyi'87) peptide (Cell signaling technology #1310)

j.磷-酪氨酸小鼠 mAb (P-Tyr-100) (Cell signaling technology #9411) j. Phosphorus-tyrosine mouse mAb (P-Tyr-100) (Cell signaling technology #9411)

k. HTScan™酪氨酸激酶缓冲液 (4x) k. HTScanTM Tyrosine Kinase Buffer (4x)

lx激酶缓冲液. - 60 n M HEPES 5 mM MgCl₂ Lx kinase buffer. - 60 n M HEPES 5 mM MgCl ₂

5 mM MnCl₂ 5 mM MnCl ₂

3 μΜ Να₃νθ₄ 3 μΜ Να ₃ νθ ₄

(Cell signaling technology #9805) (Cell signaling technology #9805)

1. 1.25 M DTT (1 OOOx) (Cell signaling technology) 1. 1.25 M DTT (1 OOOx) (Cell signaling technology)

方案： Program:

使用如下方案进行试验-Use the following scheme to test -

1.用 DMSO稀释受试化合物至所需最终浓度，在每个试验中加入 1 μΐ待测化合物、一个阴性对照和空白对照 (均不接受任何受试化合物)； 1. Dilute the test compound to the desired final concentration in DMSO, adding 1 μM of test compound, one negative control, and a blank control in each test (all do not accept any test compound);

2. 用 dH₂01:l稀释 6 μΜ底物蛋白 (Tyr87),并在每个测试中加入 15 μΐ; 2. Dilute 6 μΜ substrate protein (Tyr87) with dH ₂ 01:1 and add 15 μM to each test;

3. 将 VEGF-R2酶从 -80°C直接转移到冰上，酶解冻在冰上； 3. Transfer the VEGF-R2 enzyme directly from -80 ° C to ice, and thaw the enzyme on ice;

4. 取 2.2 g VEGF-R2酶到每个测试中； 4. Take 2.2 g of VEGF-R2 enzyme into each test;

5.加入 10 μΐ DTT (1.25 M)到 2.5 ml 4x HTScan™酪氨酸激酶缓冲液 (240 mM HEPES pH 7.5, 20 mM MgCI₂, 20 mM MnCI₂, 12 μΜ Na₃V0₄) 中，制得 DTT/激酶缓冲液； 5. Add 10 μΐ DTT (1.25 M) to 2.5 ml 4x HTScanTM tyrosine kinase buffer (240 mM HEPES pH 7.5, 20 mM MgCI ₂ , 20 mM MnCI ₂ , 12 μΜ Na ₃ V0 ₄ ). DTT/kinase buffer;

6. 转移 0.75 , πιΓ DTT/激酶缓冲液到每个每个测试中，制得 4x反应混合液，并在每个测试中加入 7.5 μΐ 4χ反应液；； 6. Transfer 0.75, πιΓ DTT/kinase buffer to each of the tests to prepare a 4x reaction mixture, and add 7.5 μΐ 4χ reaction solution to each test;

7.加入 2 μ1ΑΤΡ (10 ιηΜ)至 498 μ1 (1Η₂0中，并在每个测试中加入 7.5 μΐ; 7. Add 2 μl ΑΤΡ (10 ηηΜ) to 498 μ1 (1 Η ₂ 0 and add 7.5 μΐ to each test);

30 μΐ反应最终测试条件为- 60 mM HEPES pH 7.5 30 μΐ reaction final test conditions - 60 mM HEPES pH 7.5

5 mM MgCl₂ 5 mM MgCl ₂

5 mM MnCl₂ 5 mM MnCl ₂

3 μΜ α₃νθ₄ 3 μΜ α ₃ νθ ₄

1.25 mM DTT 1.25 mM DTT

10 μΜΑΤΡ 10 μΜΑΤΡ

I.5 μΜ多肽底物 I.5 μΜ polypeptide substrate

22 ng VEGF-R2激酶 22 ng VEGF-R2 kinase

8. 在 25°C下，将反应管温育 30分钟； 8. Incubate the reaction tube for 30 minutes at 25 °C;

9. 每个测试中加入 30 μΐ反应中止缓冲液 (50 mM EDTA, pH 8.0)中止反应； 10.在 96孔链酶亲和素 (streptavidin)包被培养板每孔中加入 25 μΐ反应液和 75 μΐ dH₂0，在室温下，振摇 60分钟； 9. Stop the reaction by adding 30 μM reaction stop buffer (50 mM EDTA, pH 8.0) in each test. 10. Add 25 μM reaction solution to each well of a 96-well streptavidin-coated plate. 75 μΐ dH ₂ 0, shake at room temperature for 60 minutes;

II. 每孔用 200 ^ PBS-T缓冲液洗涤 3次，在纸巾上轻拍以除去剩佘的液体； II. Wash each well 3 times with 200 ^ PBS-T buffer, tap on a paper towel to remove the remaining liquid;

12. 用 1 %牛血清白蛋白 PBS-T 缓冲液 1:1000 稀释主要抗体磷-酪氨酸 mAb (P-Tyr-100), 并在每孔中加入 100 μΐ稀释的 p-Tyr-100抗体； 12. Dilute the primary antibody phospho-tyrosine mAb (P-Tyr-100) with 1% bovine serum albumin PBS-T buffer 1:1000 and add 100 μM diluted p-Tyr-100 antibody to each well. ;

13. 室温下，振摇温育 60分钟； 13. Incubate for 60 minutes at room temperature with shaking;

14. 按第 11步所述方法进行洗涤； 14. Wash as described in step 11;

15. 用 1 %牛血清白蛋白 PBS-T缓冲液 1:500稀释铕标记的抗鼠 IgG，并在每个孔中加入 100 μΐ稀释的抗体； 15. Dilute 铕-labeled anti-mouse IgG with 1% bovine serum albumin PBS-T buffer 1:500 and in each well 100 μΐ diluted antibody was added to the solution;

16. 室温下，振摇温育 30分钟； 16. Incubate for 30 minutes at room temperature;

17.每孔用 PBS-T缓冲液 200 μΐ洗涤 5次，在纸巾上轻拍以除去剩余的液体; 17. Wash each well 5 times with PBS-T buffer 200 μM, tap on a paper towel to remove the remaining liquid;

18.每孔中加入 100 μϋΕΠΊΑ®信号倍增液； 18. Add 100 μϋΕΠΊΑ® signal multiplier to each well;

19.室温下，振摇温育 5分钟； 19. Incubate for 5 minutes at room temperature;

20.在波长 615 rnn下，用合适的时间分辨板读取器读取荧光强度。 20. At a wavelength of 615 rnn, read the fluorescence intensity with a suitable time-resolving plate reader.

计算抑制率比值： IR (%) =100- 100*(X-B)/ (N-B) Calculate the inhibition ratio: IR (%) =100- 100*(X-B)/ (N-B)

X=受试化合物吸光度 X = absorbance of test compound

N 阳性对照 N positive control

B=空白 B=blank

IC₅₀值通过受测化合物一系列浓度递度下的 IR值来计算。本发明化合物的活性 The IC ₅₀ value is calculated from the IR values at a range of concentration concentrations of the test compound. Activity of the compounds of the invention

本发明化合物的生化学活性通过以上的试验进行测定，测得的 IC_5Q值见下表。 The biochemical activity of the compound of the present invention was measured by the above test, and the measured IC _5Q value is shown in the following table.

19 0.012

20 0.072 20 0.072

21 0.16 体内药效评价 21 0.16 in vivo efficacy evaluation

评价实施例 63对人结肠癌 HT-29裸小鼠移植瘤的疗效 Evaluation Example 63 Effect of human colon cancer HT-29 nude mice xenografts

1. 摘要 Summary

评价实施例 63对人结肠癌 HT-29裸小鼠移植瘤的疗效。实施例 63连续口服均能显著抑制人结肠癌 HT-29的生长，并引起肿瘤缩小，小鼠对此化合物有较好地耐受。 Evaluation Example 63 Effect on human colon cancer HT-29 nude mouse xenografts. Example 63 Continuous oral administration significantly inhibited the growth of human colon cancer HT-29 and caused tumor shrinkage, and the mice were well tolerated by this compound.

2. 实验目的- 评价实施例 63 人结肠癌 ΗΤ-29裸小鼠移植瘤的疗效。 2. Experimental purpose - Evaluation Example 63 Human colon cancer The effect of ΗΤ-29 nude mice xenografts.

3. 受试药物： 3. Test drug:

药物名称和批号：实施例 63为黄色粉末。 Drug Name and Lot Number: Example 63 is a yellow powder.

配置方法：实施例 63用蒸馏水配成相应浓度。 Configuration Method: Example 63 was formulated to the corresponding concentration with distilled water.

4. 实验动物： 4. Experimental animals:

BALB/cA-nude裸小鼠， 6〜7周，？，购自上海斯莱克实验动物有限责任公司。合格证号： SCXK (沪) 2003〜0003。饲养环境： SPF级。 BALB/cA-nude nude mice, 6 to 7 weeks, ? , purchased from Shanghai Slack Laboratory Animals Co., Ltd. Certificate No.: SCXK (Shanghai) 2003~0003. Feeding environment: SPF level.

5. 实验步骤： 5. Experimental steps:

裸小鼠皮下接种人结肠癌 HT-29细胞，待肿瘤生长至 100〜300mm³后，将动物随即分组 (d0)。给药剂量和给药方案见表 1。每周测 2〜3此肿瘤体积，称鼠重，记录数据。肿瘤体积 (V)计算公式为： The nude mice were subcutaneously inoculated with human colon cancer HT-29 cells, and after the tumors were grown to 100 to 300 mm ³ , the animals were immediately grouped (d0). The dosage and administration schedule are shown in Table 1. The tumor volume was measured 2 to 3 per week, the rats were weighed, and the data were recorded. The tumor volume (V) is calculated as:

V= l/2 X aX b2 其中 a、 b分别表示长、宽。实施例 63对人结肠癌 HT-29裸小鼠移植瘤的疗效 V= l/2 X aX b2 where a and b represent length and width, respectively. Example 63 Efficacy of human colon cancer HT-29 nude mice xenografts

组别剂量给药动物数 TV(X±SD， mm3) RTV T/C(%) Group Dosage Administration Number of animals TV (X±SD, mm3) RTV T/C (%)

(mg/kg) dO/dn d0 dn X土 SD 对照 p.o 9/9 291 ± 66 729 ±298 2.54± 1.01 实施例 63 40 d0~12 5/5 364±46 300± 154 0.80±0.42 31.5* d0: 第一.次给药时间； dn: 第一次给药后 13天； TV: 肿瘤体积； RTV: 相对肿瘤提及； *P<0.01 vs对照 (mg/kg) dO/dn d0 dn X soil SD control po 9/9 291 ± 66 729 ± 298 2.54 ± 1.01 Example 63 40 d0~12 5/5 364±46 300± 154 0.80±0.42 31.5* d0: First administration time; dn: 13 days after the first administration; TV: tumor volume; RTV: relative tumor mentioned; *P<0.01 vs control

6. 结果： 6. Results:

实施例 63显著抑制人结肠癌 HT-29的生长，并引起肿瘤缩小；小鼠对此化合物有较好地耐受，没有明显的毒性。 Example 63 significantly inhibited the growth of human colon cancer HT-29 and caused tumor shrinkage; the mice were well tolerated by this compound and showed no significant toxicity.

Claims

权利要求书 Claim

1. 一种由通式 (I)表示的化 - 1. A chemical represented by the general formula (I) -

其中： among them:

和 R₂在各种情况分别独立地选自氢原子或烷基； And R ₂ are independently selected from a hydrogen atom or an alkyl group in each case;

R₃ 选自烷基、三氟甲基、芳基或芳烷基，其中烷基、芳基或芳烷基进一步被一个或多个卤素所取代； R _{3 is} selected from alkyl, trifluoromethyl, aryl or aralkyl, wherein alkyl, aryl or aralkyl is further substituted by one or more halogens;

¾ 选自烷基、环烷基、杂环烷基、芳基、杂芳基、 -(CHzMOCHzCH^Ru , -[CH₂CH(OH)]_rCH₂NR₉Rio或 -(CH₂)_nNR₉Ri₀，其中烷基、环垸基、杂环烷基、芳基、杂芳基、杂环芳基进一步被一个或多个选自芳基、羟基、氨基、酰胺基、氨基羰基、垸氧基、芳氧基、氨基垸基、羟基烷基、杂环垸基、羧酸、羧酸酯或 -NR₉R₁₀ 的取代基所取代； 3⁄4 selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -(CHzMOCHzCH^Ru, -[CH ₂ CH(OH)] _r CH ₂ NR ₉ Rio or -(CH ₂ ) _n NR ₉ Ri ₀ , wherein alkyl, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, heterocyclic aryl is further further selected from one or more selected from the group consisting of an aryl group, a hydroxyl group, an amino group, an amide group, an aminocarbonyl group, Substituted by a substituent of a methoxy group, an aryloxy group, an amino fluorenyl group, a hydroxyalkyl group, a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or -NR ₉ R ₁₀ ;

当 X为氮原子时， R₅不存在， R₆， R₇，分别独立地选自氢原子或卤素；当 X为碳原子时， R₅， R₆， R₇， R_s分别独立地选自氢原子、卤素、羟烷基、烷基、环烷基、杂环烷基、芳基、杂芳基、羟基、氰基、硝基、 -OR₉、 -0[CH₂CH₂0]_rRn, -NR₉R₁₍)、 -(C¾)_nC0₂R₉、 -(C¾)_nCONR₉Ri。、 -COR₉、 -NR₉COR₁₍₎、 -S0₂R₉ 或 -NHCO₂R₁₀, 其中芳基、杂芳基、环烷基、杂环垸基进一步被一个或多个选自烷基、垸氧基或卤素的取代基所取代； When X is a nitrogen atom, R ₅ is absent, and R ₆ and R ₇ are each independently selected from a hydrogen atom or a halogen; when X is a carbon atom, R ₅ , R ₆ , R ₇ and R _s are independently selected. From hydrogen atom, halogen, hydroxyalkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, cyano, nitro, -OR ₉ , -0[CH ₂ CH ₂ 0] _r Rn, -NR ₉ R ₁₍ ), -(C3⁄4) _n C0 ₂ R ₉ , -(C3⁄4) _n CONR ₉ Ri. , -COR ₉ , -NR ₉ COR ₁₍₎ , -S0 ₂ R ₉ or -NHCO ₂ R ₁₀ , wherein the aryl, heteroaryl, cycloalkyl, heterocyclic fluorenyl group is further selected from one or more selected from the group consisting of an alkane Substituted by a substituent of a methoxy group or a halogen;

R₉ 和 0 分别独立地选自氢原子、垸基、环烷基、芳基、杂环烷基或杂芳基，其中所述烷基、环垸基、芳基、杂环垸基、杂芳基进一步被一个或多个选自烷基、芳基、卤代芳基、羟基、氨基、氰基、烷氧基、芳氧基、羟垸基、杂环烷基、羧酸、羧酸酯或 -NR₉R_1Q的取代基所取代； R ₉ and 0 are each independently selected from a hydrogen atom, a fluorenyl group, a cycloalkyl group, an aryl group, a heterocycloalkyl group or a heteroaryl group, wherein the alkyl group, cyclodecyl group, aryl group, heterocyclic fluorenyl group, hetero The aryl group is further selected from one or more selected from the group consisting of alkyl, aryl, haloaryl, hydroxy, amino, cyano, alkoxy, aryloxy, hydroxydecyl, heterocycloalkyl, carboxylic acid, carboxylic acid Substituted by an ester or a substituent of -NR ₉ R _1Q ;

同时 R₉和 Rio—起形成 4〜8元杂环基，其中 5〜8元杂环内含有一个或多个 N、 0、 S杂原子，并且 4〜8元杂环上进一步被一个或多个选自烷基、卤素、芳基、杂芳基、卤代烷基、羟基、氰基、烷氧基、芳氧基、氨烷基、羟烷基、杂环烷基、羧酸、羧酸酯或 -NR₉R₁₍₎的取代基所取代； At the same time, R ₉ and Rio together form a 4 to 8 membered heterocyclic group, wherein the 5 to 8 membered heterocyclic ring contains one or more N, 0, S heteroatoms, and the 4 to 8 membered heterocyclic ring is further subjected to one or more Selected from alkyl, halogen, aryl, heteroaryl, haloalkyl, hydroxy, cyano, alkoxy, aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester Or substituted with a substituent of -NR ₉ R _{1 ()} ;

Rn选自氢原子或焼基； Rn is selected from a hydrogen atom or a fluorenyl group;

n是 2〜6； n is 2 to 6;

z是〗〜 4; z is 〗〖 4;

r是 1〜6。 r is 1 to 6.

2. 根据权利要求 1所述的吡咯并 N杂环类衍生物其药学上可接受的盐，其中 R₃ 是甲基。 The pharmaceutically acceptable salt of a pyrrolo N heterocyclic derivative according to claim 1, wherein R ₃ is a methyl group.

3. 根据权利要求 1所述的吡咯并 N杂环类衍生物其药学上可接受的盐，其中和 R₂是氢原子。 The pharmaceutically acceptable salt of a pyrrolo N heterocyclic derivative according to claim 1, wherein R ₂ is a hydrogen atom.

4. 根据权利要求 1所述的吡咯并 N杂环类衍生物其药学上可接受的盐，其中包括下述通式 (IA)表示的化合 The pharmaceutically acceptable salt of the pyrrolo N heterocyclic derivative according to claim 1, which comprises a compound represented by the following formula (IA)

其中- among them-

Ri 和 ¾在每种情况下各自独立地选自氢原子或垸基； Ri and 3⁄4 are each independently selected from a hydrogen atom or a fluorenyl group in each case;

R₃选自烷基、三氟甲基、芳基、芳烷基，其中垸基、芳基或芳烷基进一步被一个或多个卤素所取代； R _{3 is} selected from the group consisting of alkyl, trifluoromethyl, aryl, aralkyl, wherein the fluorenyl, aryl or aralkyl group is further substituted with one or more halogens;

EU选自烷基、环垸基、杂环烷基、芳基、杂芳基、 -(CH₂)_n(OCH₂CH₂ R_u、 -[Οί₂ ί(ΟΗ)]^Η₂Ν 。或

其中所述烷基、环烷基、杂环烷基、芳基、杂芳基、杂环芳基进一步被一个或多个选自芳基、羟基、氨基、酰胺基、氨基羰基、烷氧基、芳氧基、氨基烷基、羟基垸基、杂环烷基、羧酸、羧酸酯或 -NR₉R₁₀ 的取代基所取代； EU is selected from the group consisting of alkyl, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, -(CH ₂ ) _n (OCH ₂ CH ₂ R _u , -[Οί ₂ ί(ΟΗ)]^Η ₂ Ν . or

Wherein the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, heterocyclic aryl group is further selected from one or more selected from the group consisting of an aryl group, a hydroxyl group, an amino group, an amide group, an aminocarbonyl group, and an alkoxy group. Substituted with an aryloxy group, an aminoalkyl group, a hydroxyindenyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or a substituent of -NR ₉ R ₁₀ ;

当 X为氮原子时， R₅不存在， R₆， R₇， R₈分别独立地选自氢原子或卤素；当 X为碳原子时， R₅， R₆， R₇， R₈分别独立地选自氢原子、素、羟烷基、烷基、环烷基、杂环烷基、芳基、杂芳基、羟基、氰基、硝基、 -OR₉、 -0[CH₂CH₂0]_rR„、 -NR₉R₁₀、 -(CH₂)nC0₂R₉、 -(CH₂)nCONR₉R₁₀、 -COR₉、 -NR₉COR₁₀、 -S0₂R₉或 -NHCO₂R₁₀, 其中芳基、杂芳基、环烷基、杂环院基进一步被一个或多个选自垸基、烷氧基或卤素的取代基所取代； When X is a nitrogen atom, R ₅ is absent, and R ₆ , R ₇ and R ₈ are each independently selected from a hydrogen atom or a halogen; when X is a carbon atom, R ₅ , R ₆ , R ₇ and R ₈ are each independently Selected from hydrogen atom, cyano, hydroxyalkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, cyano, nitro, -OR ₉ , -0[CH ₂ CH ₂ 0] _r R„, -NR ₉ R ₁₀ , -(CH ₂ )nC0 ₂ R ₉ , -(CH ₂ )nCONR ₉ R ₁₀ , -COR ₉ , -NR ₉ COR ₁₀ , -S0 ₂ R ₉ or -NHCO ₂ R ₁₀ , wherein aryl, heteroaryl, cycloalkyl, heterocyclic is further substituted by one or more substituents selected from decyl, alkoxy or halogen;

R₉和 R_1G分别选自氢原子、烷基、环烷基、芳基、杂环垸基、杂芳基、其中所述的烷基、环烷基、芳基、杂环垸基、杂芳基进一步被一个或多个选自烷基、芳基、卤代芳基、羟基、氨基、氰基、烷氧基、芳氧基、羟垸基、杂环烷基、羧酸、羧酸酯或 -NR₉R_1Q的取代基所取代； R ₉ and R _1G are each _{independently} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heterocyclic fluorenyl group, a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the aryl group, the heterocyclic fluorenyl group, and the hetero The aryl group is further selected from one or more selected from the group consisting of alkyl, aryl, haloaryl, hydroxy, amino, cyano, alkoxy, aryloxy, hydroxydecyl, heterocycloalkyl, carboxylic acid, carboxylic acid Substituted by an ester or a substituent of -NR ₉ R _1Q ;

同时 R₉和 R₁₍₎—起形成 4〜8元杂环基，其中 5〜8元杂环内含有一个或多个 N、 0、 S杂原子，并且 4〜8元杂环上进一步被一个或多个选自垸基、卤素、芳基、杂芳基、卤代垸基、羟基、氰基、垸氧基、芳氧基、氨烷基、羟烷基、杂环烷基、羧酸、羧酸酯或 -NR₉R_1Q的取代基所取代； At the same time, R ₉ and R _{1 () together} form a 4 to 8 membered heterocyclic group, wherein the 5 to 8 membered heterocyclic ring contains one or more a N, 0, S heteroatom, and a 4 to 8 membered heterocyclic ring further further selected from one or more selected from the group consisting of a fluorenyl group, a halogen, an aryl group, a heteroaryl group, a halogenated fluorenyl group, a hydroxy group, a cyano group, a decyloxy group, Substituted with an aryloxy group, an aminoalkyl group, a hydroxyalkyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or a substituent of -NR ₉ R _1Q ;

选自氢原子或烷基； Selected from a hydrogen atom or an alkyl group;

n是 2〜6； n is 2 to 6;

r是 1〜6。 r is 1 to 6.

5. 根据权利要求 1所述的化合物或其医药上可以接受的盐,其中包括下述通式 (IB) 表示的化合物或其医药上 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises a compound represented by the following formula (IB) or a pharmaceutical thereof

其中- among them-

Ri 和 R₂在各种情况下分别独立地选自氢原子或烷基； Ri and R ₂ are each independently selected from a hydrogen atom or an alkyl group in each case;

¾ 选自烷基、三氟甲基、芳基、芳垸基，其中垸基、芳基或芳烷基进一步被一个或多个卤素所取代； 3⁄4 is selected from the group consisting of alkyl, trifluoromethyl, aryl, aryl fluorenyl, wherein the fluorenyl, aryl or aralkyl group is further substituted by one or more halogens;

¾ 选自垸基、环烷基、杂环垸基、芳基、杂芳基、

3⁄4 selected from fluorenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,

-[C¾CH(OH)]_rCH₂NR₉Rio或 -(CH₂)_nNR₉R_1Q，其中垸基、环垸基、杂环垸基、芳基、杂芳基、杂环芳基进一步被一个或多个选自芳基、羟基、氨基、酰胺基、氨基羰基、垸氧基、芳氧基、氨基垸基、羟基垸基、杂环烷基、羧酸、羧酸酯或 -NR₉R₁₀ 的取代基所取代； -[C3⁄4CH(OH)] _r CH ₂ NR ₉ Rio or -(CH ₂ ) _n NR ₉ R _1Q , wherein fluorenyl, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, heteroaryl further One or more selected from the group consisting of an aryl group, a hydroxyl group, an amino group, an amide group, an aminocarbonyl group, a decyloxy group, an aryloxy group, an amino group, a hydroxy group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or a -NR Substituted by a substituent of ₉ R ₁₀ ;

当 X为氮原子时， R₅不存在， R₆， R₇， R₈分别独立地选自氢原子或卤素；当 X 为碳原子时， R₅， R₆， R₇, R₈分别独立地选自氢原子、素、羟焼基、垸基、环垸基、杂环垸基、芳基、杂芳基、羟基、氰基、硝基、 -OR₉、 -0[CH₂CH₂0]_rR_n , -NR₉R₁₀、 -(CH₂)_nC0₂R₉、 -(CH^nCONRsRn)、 -COR₉、 -NR₉COR₁₀ -S0₂R₉ 或 -NHCO₂R₁₀, 其中芳基、杂芳基、环烷基、杂环垸基进一步被一个或多个选自垸基、垸氧基或卤素的取代基所取代； When X is a nitrogen atom, R ₅ is absent, and R ₆ , R ₇ and R ₈ are each independently selected from a hydrogen atom or a halogen; when X is a carbon atom, R ₅ , R ₆ , R ₇ and R ₈ are each independently Selected from a hydrogen atom, a hydrazine, a hydroxy fluorenyl group, a fluorenyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group, a heteroaryl group, a hydroxyl group, a cyano group, a nitro group, -OR ₉ , -0[CH ₂ CH ₂ 0] _r R _n , -NR ₉ R ₁₀ , -(CH ₂ ) _n C0 ₂ R ₉ , -(CH^nCONRsRn), -COR ₉ , -NR ₉ COR ₁₀ -S0 ₂ R ₉ or -NHCO ₂ R ₁₀ Wherein an aryl group, a heteroaryl group, a cycloalkyl group, a heterocyclic fluorenyl group is further substituted with one or more substituents selected from the group consisting of a fluorenyl group, a decyloxy group or a halogen;

R₉和 R₁₍₎分别选自氢原子、烷基、环垸基、芳基、杂环烷基、杂芳基、其中所述的垸基、环烷基、芳基、杂环垸基、杂芳基进一歩被一个或多个选自烷基、芳基、卤代芳基、羟基、氨基、氰基、烷氧基、芳氧基、羟垸基、杂环烷基、羧酸、羧酸酯或 -NR₉R_1Q的取代基所取代； R ₉ and R _{1 ()} are respectively selected from a hydrogen atom, an alkyl group, a cyclodecyl group, an aryl group, a heterocycloalkyl group, a heteroaryl group, wherein the fluorenyl group, the cycloalkyl group, the aryl group, the heterocyclic fluorenyl group And a heteroaryl group is one or more selected from the group consisting of an alkyl group, an aryl group, a halogenated aryl group, a hydroxyl group, an amino group, a cyano group, an alkoxy group, an aryloxy group, a hydroxymethyl group, a heterocycloalkyl group, a carboxylic acid. Substituting a carboxylic acid ester or a substituent of -NR ₉ R _1Q ;

同时和 0—起形成 4〜8元杂环基，其中 5〜8元杂环内含有一个到多个 N、 0、 S杂原子，并且 4〜8元杂环上进一步被一个或多个烷基、卤素、芳基、杂芳基、卤代垸基、羟基、氰基、烷氧基、芳氧基、氨垸基、羟烷基、杂环垸基、羧酸、羧酸酯或 -NR₉R_1D所取代； - ι选自氢原子或垸基； At the same time, a 4- to 8-membered heterocyclic group is formed from 0 to 0, wherein the 5 to 8 membered heterocyclic ring contains one or more a hetero atom of N, 0, S, and a 4 to 8 membered heterocyclic ring further further substituted with one or more alkyl, halogen, aryl, heteroaryl, haloalkyl, hydroxy, cyano, alkoxy, aryloxy Substituted with an amino group, an amino group, a hydroxyalkyl group, a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester or -NR ₉ R _1D ; - ι is selected from a hydrogen atom or a fluorenyl group;

n是 2〜6； n is 2 to 6;

r是卜 6。 r is Bu 6.

6. 根据权利要求 1或 2所述的吡咯并 N杂环衍生物或其药学上可接受的盐，其 The pyrrolo N heterocyclic derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof,

7. 一种药物组合物，其包括药物有效剂量的如权利要求 1〜6中任何一项所述的吡咯并 N杂环类衍生物或其药学上可接受的盐，和药学上可接受的载体。 A pharmaceutical composition comprising a pharmaceutically effective amount of the pyrrolo N heterocyclic derivative according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof Carrier.

8. 根据权利要求 1所述的吡咯并 N杂环类衍生物或其药学上可接受的盐，其中所述的药学上可接受的盐为化合物与选自以下的酸形成的盐：苹果酸、乳酸、马来酸、盐酸、甲磺酸、硫酸、磷酸、柠檬酸、酒石酸、乙酸或三氟乙酸。 The pyrrolo N heterocyclic derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is a salt of a compound with an acid selected from the group consisting of malic acid , lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid.

9. 一种如下列通式 (IC)或者 (ID)所示的化合物，其作为通式 (I)化合物合成的中间体： A compound represented by the following formula (IC) or (ID) which is an intermediate synthesized by the compound of the formula (I):

(IC) (ID) (IC) (ID)

其中： among them:

选自氢原子或烷基； Selected from a hydrogen atom or an alkyl group;

选自焼基、三氟甲基、芳基、芳烷基，其中烷基、芳基或芳烷基进一步被一个或多个卤素所取代； R4选自垸基、环烷基、杂环烷基、芳基、杂芳基、 -(CHb OCitCHyrRu, -[CHbCH OHACI^NR^o或 -(CH₂)_nNR₉R₁₀，其中烷基、环烷基、杂环烷基、芳基、杂芳基、杂环芳基进一步被一个或多个选自芳基、羟基、氨基、酰胺基、氨基羰基、烷氧基、芳氧基、氨基烷基、羟基烷基、杂环烷基、羧酸、羧酸酯或 -NR₉R₁₀ 的取代基所取代； Selected from a mercapto group, a trifluoromethyl group, an aryl group, an aralkyl group, wherein the alkyl group, the aryl group or the aralkyl group is further substituted with one or more halogens; R4 is selected from the group consisting of fluorenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -(CHb OCitCHyrRu, -[CHbCH OHACI^NR^o or -(CH ₂ ) _n NR ₉ R ₁₀ , wherein alkyl , a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocyclic aryl group further further selected from one or more selected from the group consisting of an aryl group, a hydroxyl group, an amino group, an amide group, an aminocarbonyl group, an alkoxy group, an aryloxy group, Substituted by an aminoalkyl group, a hydroxyalkyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or a substituent of -NR ₉ R ₁₀ ;

R₉和 R_1Q分别选自氢原子、烷基、环烷基、芳基、杂环烷基、杂芳基、其中所述的烷基、环烷基、芳基、杂环烷基、杂芳基进一步被一个或多个选自烷基、芳基、卤代芳基、羟基、氨基、氰基、垸氧基、芳氧基、羟烷基、杂环垸基、羧酸、酸酯或 -NR₉R_1Q的取代基所取代； R ₉ and R _1Q are each _{independently} selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heterocycloalkyl group, a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the aryl group, the heterocycloalkyl group, and the hetero The aryl group is further selected from one or more selected from the group consisting of an alkyl group, an aryl group, a halogenated aryl group, a hydroxyl group, an amino group, a cyano group, a decyloxy group, an aryloxy group, a hydroxyalkyl group, a heterocyclic fluorenyl group, a carboxylic acid, an acid ester. Or substituted with a substituent of -NR ₉ R _1Q ;

同时和 ο—起形成 4〜8元杂环基，其中 5〜8元杂环内含有一个到多个 N、 0、 S杂原子，并且 4〜8元杂环上进一步被一个或多个选自烷基、卤素、芳基、杂芳基、卤代烷基、羟基、氰基、垸氧基、芳氧基、氨烷基、羟烷基、杂环烷基、羧酸、羧酸酯或 -NR₉R_1Q的取代基所取代； At the same time, a 4- to 8-membered heterocyclic group is formed, wherein the 5- to 8-membered heterocyclic ring contains one to a plurality of N, 0, S heteroatoms, and the 4 to 8-membered heterocyclic ring is further selected by one or more From alkyl, halogen, aryl, heteroaryl, haloalkyl, hydroxy, cyano, decyloxy, aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or - Substituted by a substituent of NR ₉ R _1Q ;

Rii选自氢原子或烷基； Rii is selected from a hydrogen atom or an alkyl group;

n是 2〜6； n is 2 to 6;

z是 1〜4； z is 1~4;

r是 1〜6。 r is 1 to 6.

10.根据权利要求 9所述的中间体 (IC)的制备方法，所述方法包括： The method of preparing an intermediate (IC) according to claim 9, the method comprising:

将原料吡咯甲基羧酸二酯 IC-1在室温条件下，在四氢呋喃溶液中，在醋酸存在下与硝酸铈 Raw material pyrrole methyl carboxylic acid diester IC-1 at room temperature in tetrahydrofuran solution in the presence of acetic acid with cerium nitrate

IC-1 IC-2 化合物吡咯甲醛羧酸二酯 IC-2在无水四氢呋喃中与 (乙酯基亚甲基)三苯基正膦发生魏 IC-1 IC-2 compound pyrrole formaldehyde carboxylic acid diester IC-2 in the anhydrous tetrahydrofuran with (ethyl ester methylene) triphenylphosphorane

IC-2 IC-3 IC-2 IC-3

钯 /碳催化下，吡咯乙氧羰基乙烯基二羧酸酯 IC-3在无水乙醇中，经氢气室温还原得到吡咯乙氧羰基乙基二羧酸酯 IC-4;

Palladium/carbon catalyzed, pyrrole ethoxycarbonyl vinyl dicarboxylate IC-3 in anhydrous ethanol, hydrogen sulfide at room temperature to obtain pyrrole ethoxycarbonyl ethyl dicarboxylate IC-4;

吡咯乙氧羰基乙基二羧酸酯 IC-4在氢氧化锂水溶液水解得到吡咯羧基乙基: 羧酸酯 I

Hydrogenation of pyrrole ethoxycarbonylethyldicarboxylate IC-4 in aqueous lithium hydroxide solution to give pyrrole carboxyethyl: carboxylate I

吡咯羧基乙基二羧酸酯 IC-5在无水四氢呋喃中， -20 -5°C下，经硼烷的四氢呋喃溶液还原成得吡咯羟丙基二羧酸酯 IC-6; Pyrrole carboxyethyl dicarboxylate IC-5 in anhydrous tetrahydrofuran, reduced to pyridine hydroxypropyl dicarboxylate IC-6 in borane in tetrahydrofuran at -20 -5 ° C;

IC-5 IC-6 IC-5 IC-6

-步，吡咯羟丙基二羧酸酯 IC-6在无水二氯甲烷中， -20〜- 5°C，三乙胺存甲丙基二羧 IC-7;- Step, pyrrole hydroxypropyl dicarboxylate IC-6 in anhydrous dichloromethane, -20~- 5 ° C, triethylamine in the presence of methyl propyl dicarboxylate IC-7;

IC-6 IC-7 IC-6 IC-7

接下来，吡咯甲磺酰氧丙基二羧酸酯 IC-7与不同的胺反应得到吡咯酰胺二羧酸酯 IC-8;

Next, pyrrole mesylate oxypropyl dicarboxylate IC-7 is reacted with a different amine to obtain pyrrolamide dicarboxylate IC-8;

IC-7 IC-8 IC-7 IC-8

吡咯酰胺二羧酸酯 IC-8在无水甲苯中，与三甲基铝加热回流得到吡咯并七元 N 杂环酯 IC-9; Pyrrole amide dicarboxylate IC-8 in anhydrous toluene, and refluxed with trimethylaluminum to obtain pyrrole penta-N heterocyclic ester IC-9;

11. 根据权利要求 9所述的中间体 (ID)的制备方法，所述方法包括： 11. The method of preparing an intermediate (ID) according to claim 9, the method comprising:

氩气氛下，吡咯甲醛羧酸二酯 IC-2在室温条件下，在无水四氢呋喃中与格氏试剂溴化环丙 Pyrrole formaldehyde carboxylic acid diester IC-2 under argon atmosphere at room temperature in anhydrous tetrahydrofuran with Grignard reagent brominated cyclopropyl

吡咯环丙基羟基羧酸二酯 ID-1室温下，在甲醇溶剂中与氢溴酸反应得到溴化丁烯基吡咯 Pyrrole cyclopropyl hydroxycarboxylic acid diester ID-1 is reacted with hydrobromic acid in methanol solvent to obtain butyl bromide at room temperature.

钯 /碳催化下，溴化丁烯基吡咯二酯 ID-2在无水乙醇中，经氢气室温还原得到溴化

Palladium/carbon catalyzed bromination of butenylpyrroledicarboxylate ID-2 in anhydrous ethanol by hydrogen at room temperature to obtain bromination

溴化丁基吡咯二酯 ID-3在二氯甲垸中，加热回流与不同的胺反应得到吡咯酰 Bromobutylpyrrolediester ID-3 in dichloromethane, heated to reflux with different amines to give pyrrolidyl

12.根据权利要求 1〜6所述的吡咯并 N杂环类衍生物的制备方法，包括在三乙胺或哌啶存在下，将醛和吲哚酮反应，反应液加热 2〜12小时，其中所述醛为下列 The method for preparing a pyrrole N heterocyclic derivative according to any one of claims 1 to 6, which comprises reacting an aldehyde with an anthrone in the presence of triethylamine or piperidine, and heating the reaction solution for 2 to 12 hours. Wherein the aldehyde is the following

13.一种调节蛋白激酶催化活性的方法，其中包括将所述的蛋白激酶与权利要求 1〜6中任何一项所述的吡咯并 N杂环类衍生物或其药学上可接受的盐接触。 A method for modulating a catalytic activity of a protein kinase, which comprises contacting the protein kinase with the pyrrole N heterocyclic derivative according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof. .

14.根据权利要求 13所述的方法，其中所述蛋白激酶选自受体酪氨酸激酶、非受体酪氨酸激酶或丝氨酸-苏氨酸激酶。 14. The method of claim 13, wherein the protein kinase is selected from the group consisting of a receptor tyrosine kinase, a non-receptor tyrosine kinase, or a serine-threonine kinase.

15. —种根据权利要求 1所述的化合物在制备治疗与蛋白质激酶有关的疾病的药物中的用途。 15. A compound according to claim 1 for the preparation of a medicament for treating a protein kinase-related disease Use in the body.

16.根据权利要求 15所述的用途，其中所述与蛋白质激酶有关的疾病选自与 VEGFR-2, EGFR, HER-2, HER-3, HER-4, PDGFR, c-Kit, c-Met, FGFR或 Flt3相关的疾病。 The use according to claim 15, wherein the protein kinase-associated disease is selected from the group consisting of VEGFR-2, EGFR, HER-2, HER-3, HER-4, PDGFR, c-Kit, c-Met , FGFR or Flt3 related diseases.

17. 根据权利要求 15所述的用途，其中所述与蛋白激酶有关的疾病选自白血病，糖尿病，自免疫病，过度增生病，牛皮癣，骨关节炎，类风湿性关节炎，血管生成，心血管病，多发性成血管细胞瘤，炎症或纤维变性病。 17. The use according to claim 15, wherein the protein kinase-related disease is selected from the group consisting of leukemia, diabetes, autoimmune disease, hyperproliferative disease, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, heart Vascular disease, multiple hemangioblastoma, inflammation or fibrosis.

18.根据权利要求 15所述的用途，其中所述与蛋白激酶有关的疾病是癌症，选自鳞状细胞癌，肾细胞癌，卡波济氏肉瘤，非小细胞肺癌，小细胞肺癌，淋巴癌，甲状腺癌，乳腺癌，头颈癌，子宫癌，食道癌，黑素癌，膀胱癌，生殖泌尿癌，胃肠癌，神经胶质癌，结肠直肠癌或卵巢癌。 The use according to claim 15, wherein the protein kinase-related disease is cancer, selected from the group consisting of squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma, non-small cell lung cancer, small cell lung cancer, lymph Cancer, thyroid cancer, breast cancer, head and neck cancer, uterine cancer, esophageal cancer, melanoma, bladder cancer, genitourinary cancer, gastrointestinal cancer, glial cancer, colorectal cancer or ovarian cancer.

19.一种调节蛋白激酶催化活性的方法，其中包括将所述的蛋白激酶与权利要求 7 所述的组合物接触。 19. A method of modulating catalytic activity of a protein kinase comprising contacting said protein kinase with a composition of claim 7.