WO2007085205A1

WO2007085205A1 - Pyrrole substituted 2-indolinone derivatives, the preparation methods and medical uses thereof

Info

Publication number: WO2007085205A1
Application number: PCT/CN2007/000323
Authority: WO
Inventors: Peng Cho Tang; Pingyan Bie; Weili Liu; Shibo Yang; Lei Zhang
Original assignee: Shanghai Hengrui Pharmaceutical Co.Ltd.
Priority date: 2006-01-27
Filing date: 2007-01-29
Publication date: 2007-08-02
Also published as: CN101007801A

Abstract

The present application discloses the pyrrole substituted 2-indolinone derivatives of general formula (I), in which the substituents defined as the description, their pharmaceutically acceptable salts and the compositions thereof. The present application also discloses the preparation methods of the general formula(I), their uses for preventing and treating the protein kinase related cellular disorders, and their uses for preparing the protein kinase inhibitors.

Description

吡咯取代的 2-二氢吲哚酮衍生物、其制法与医药上的用途技术领域本发明涉及一种吡咯取代的 2-二氢哚酮衍生物，特别是 3-(3-三氟甲基 -4- 酰氨基吡咯 -2-基亚甲基) -2-二氢吲哚酮衍生物，其制备方法以及该衍生物在制备蛋白激酶抑制剂中的用途。背景技术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，涉及到特定蛋白徼酶和磷酰化酶。 TECHNICAL FIELD The present invention relates to a pyrrole-substituted 2-indanone derivative, particularly 3-(3-trifluoromethyl). Alkyl-4-acylaminopyrrol-2-ylmethylene)-2-indanone derivative, a process for its preparation and the use of the derivative in the preparation of a protein kinase inhibitor. BACKGROUND OF THE INVENTION Signaling of cells is a fundamental mechanism of action in which, during signal transduction, extracellular stimuli are transmitted to the interior of the cell, thereby regulating the progression of different cells. These signals regulate a variety of physiological responses, including cell proliferation, differentiation, apoptosis, and exercise, in the form of different types of lytic factors, including growth factors that are dominated by paracrine, autocrine, and endocrine factors. 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 peptidases 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。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) catalyze the phosphorylation of hydroxyl groups on tyrosine, serine, and threonine residues of proteins. The reverse mechanism of protein kinases and phosphorylating enzymes 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 to an activated form resulting in more A variation of human cells, it can be said that over-expressed normal tyrosine kinase 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使蛋白质上的丝氮酸、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, 19, 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剌激因子 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, 383)。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, CD 8, 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， Chk， Axl, Pim-1, Plh-1, IGF-1R, IKK, IK 1, IK 2, IKK3, INS-R, Integrin-linked kinase, Jak, JA 1, JAK2， JAK3,皿，應， Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKBl, PKB2, PKB3, PKC, PKCa， PKCb, PKCd, PKCe, PKCg, PKCl, PKCm, PKCz, PLK1, Polo-like kinase, PYK2, tiei, 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: Ce/ /o/. 1991， 1 13, 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 Strawn 等 Ccmcef 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, Rev. Immunol. 1997, 15, 371)、传染病如病毒（参见 Littler, E. Nat 'e 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。 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, 19, 5548-5557). The RTKs subfamily includes the following: (1) EGF families, such as EGF, TGFa, Neu and erbB; (2) Insulin family, including insulin receptor, insulin-like growth factor I receptor (IGF1) and insulin receptor-related Sex 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 kinase 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, 383). 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, CD 8, 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, Chk, Axl, Pim-1, Plh-1, IGF-1R, IKK, IK 1, IK 2, IKK3 , INS-R, Integrin-linked kinase, Jak, JA 1, JAK2, JAK3, dish, should, Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKBl, PKB2, PKB3, PKC, PKCa, PKCb , PKCd, PKCe, PKCg, PKCl, PKCm, PKCz, PLK1, Polo-like kinase, PYK2, tiei, 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: Ce/ /o/) 1991, 1 13, 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) Proliferative diseases such as angiogenesis (see Strawn et al. Ccmcef Res. 1996, 56, 3540; Jackson et al. J. Pharm. Exp. Ther. 1998, 284, 687), autoimmune diseases and transplant rejection (see Bolen and Brugge, Rev) Immunol. 1997, 15, 371), infectious diseases such as viruses (see Littler, E. Nat 'e 19 92, 358, 160) is closely related to the target of diseases such as fungal infection (see Lum, RT PCT Int Appl, WO 9805335 Al 980212).

PT s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 PT s signaling, specific growth factors (ligands) interact extracellularly, followed by receptor dimerization, which activates the intrinsic activity of protein kinases and phosphorylates. The binding site of the internal signaling molecule is generated to form a complex with the cytoplasmic signaling molecule, which promotes various cellular responses such as cell division (proliferation) and expression of extracellular microenvironment metabolism.

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 sr_C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 high affinity for the SH2 (synchronous to sr _C ) domain of the signaling molecule. Many intracellular substrate proteins associated with receptor tyrosine kinases have been Determined, can be divided into two categories: (1) there is a catalytic zone substrate (2) no catalytic zone substrate, but can be used as a combination, and related to some catalytically active molecules. 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, and can also be determined by downstream region signal transduction pathways activated by specific receptors. Thus, phosphorylation provides an important, regulatable step that determines the selectivity of signaling and the differentiation factor receptor that is activated by a particular 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 kinases are 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 HER1(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 (PB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 is not enzymatically active, 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 phosphatidylinosides Alcohol (-3) kinase (PB 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- Π相互作用，生成了由两种完全胞外糖基化 α 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-associated receptor (IRR). IR, IGF-1R interacts with insulin, IGF-I and IGF-Π to produce two fully extracellular glycosylated alpha 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 PDGFRa, PDGFR , 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 PDGFRa, PDGFR, 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. Broken.

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)。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。 Platelet-derived growth factor receptors such as PDGFRa and PDGFRp are also transmembrane tyrosine kinase receptors. When they are combined with a ligand, either a homodimer (PDGF-AA, PDGF-BB), or a heterodimer (PDGF-AB) is formed. Subsequent receptor dimerization, tyrosine kinase is activated, signaling downstream regions 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, prodramide, 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 Schiitte 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.₅ Cancer Res. 60， 6223-6 (2000))。 c-Kit is a member of the PDGF receptor family and 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 found 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 all have c-Kit expression (see Schiitte et aL, innovartis 3/) 2001). As we all know, .RET (rearranged during transfection). Proto-oncogene genetic mutations are tumorigenic, and patients with multiple endocrine neoplasia 2 (MEN 2) may cause pheochromocytoma, medullary thyroid carcinoma, and parathyroid adenoma and hyperplasia ( See Huang et al. ₅ 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(KDR/FLK-1， VEGFR2), Flk-1R, Flk-4和 fms样酪氨酸激酶 1 (Flt-1)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 (KDR/FLK-1, VEGFR2), Flk-1R, Flk-4 and fms-like tyrosine kinase 1 (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氯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 containing various immunoglobulin-like circular glycosylation and an intracellular domain in which the tyrosine kinase sequence is blocked by an unrelated chloro 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 and inhibits angiogenesis by inhibiting VEGFRs. It 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 malignant 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 the 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 factors (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 can induce vascular sprouting phenotype, which induces endothelial cell proliferation, protease expression and migration to promote capillary formation, thereby forming a super-osmotic, immature vascular network, which is a typical characteristic of 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 (PTK)Ill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 (PTK) type Ill 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, 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 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, patients with mutant form of receptor expression are less likely to be cured. 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 Rev, 22, 309-25; Maulik, G.等（2002b). 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 Rev, 22, 309-25; Maulik, G. et al. (2002b). 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。 00323 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。 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. 00323 Regarding 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 11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 iBoIen, 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 most, 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 the CTKs, see iBoIen, 1993, Oncogen 8: 2025-2031, which is hereby incorporated by reference in its entirety in its entirety in its entirety.

与 CTKs相类似，丝氨酸-苏氨酸激酶或 STKs，在细胞内占裾主导地位，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 predominantly intracellular, although there are only a few STK-type receptor kinases. STKs are the most prevalent cytosolic kinases, ie, they function in part of the cytoplasm, not in 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 progression 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分裂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 treat and improve super-mediated by PTKs, CTKs or STKs and angiogenesis. Proliferative physiological disorders.

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)所示的新的吡咯取代的 2-二氢吲哚酮衍生物，特别是 3-(3-三氟甲基 -4-酰氨基吡咯 -2-基亚甲基 )-2-二氢吲哚酮衍生物，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 Z构型和 E构型。

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 pyrrole-substituted 2-indanone derivative of the formula ((1), especially 3-(3) -Trifluoromethyl-4-acylaminopyrrol-2-ylmethylene)-2-indanone derivatives, and their tautomers, enantiomers, diastereomers, racemic And pharmaceutically acceptable salts, as well as metabolites and metabolic precursors or prodrugs, wherein the tautomers include the Z configuration and the E configuration.

其中- among them-

R R₂， R₃和分别选自氢原子、卤素、垸基、卤代烷基、卤代烧氧基、环垸基、烯基、炔基、芳基、杂芳基、杂环烷基、羟基、 -OR₈、 -0[CH₂CH₂0]_rR_u、 -SR₈、 -NR₈R₉、 -SOR₈、 -S0₂R₈、 -NS0₂R₈ > -S0₂NR₈R₉ -(C¾)_nCOOR₈、 -(CH₂)_nCO R₈R₉、 -C(=S)NR₈R₉、 -COR₈、 -NR8COR₉、 - HC(=0)OR₉、 -OCOOR₉、 -OCONR₈R₉ -CN或者 -N0₂, 其中芳基、杂芳基、杂环烷基官能团可以进一步被一个或多个烷基或者卤素取代； RR ₂ , R ₃ and each selected from the group consisting of a hydrogen atom, a halogen, a fluorenyl group, a halogenated alkyl group, a halogenated alkoxy group, a cyclodecyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, a heterocycloalkyl group, a hydroxyl group, _{_{-OR 8, -0 [CH 2 CH}} 2 0] r R u, -SR 8, -NR 8 R 9, -SOR 8, -S0 2 R 8, -NS0 2 R 8> -S0 2 NR 8 R 9 -(C3⁄4) _n COOR ₈ , -(CH ₂ ) _n CO R ₈ R ₉ , -C(=S)NR ₈ R ₉ , -COR ₈ , -NR8COR ₉ , - HC(=0)OR ₉ , -OCOOR ₉ or -OCONR ₈ R ₉ -CN or -N0 ₂ , wherein the aryl, heteroaryl, heterocycloalkyl functional group may be further substituted by one or more alkyl groups or halogens;

R₅和至少有一个是三氟甲基；和分别选自氢原子、烷基、芳基或三氟甲基，优选地，是三氟甲基； R ₅ and at least one is trifluoromethyl; and respectively selected from a hydrogen atom, an alkyl group, an aryl group or a trifluoromethyl group, preferably a trifluoromethyl group;

R₇选自氢原子，烷基，氨基，芳基， -N(CO)R₁₀ ¾-(CO)R₁₀, 其中芳基可以进一步被一个或多个卤素所取代； R _{7 is} selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, an aryl group, -N(CO)R ₁₀ 3⁄4-(CO)R ₁₀ , wherein the aryl group may be further substituted with one or more halogens;

和 R₉分别选自氢原亍、垸基、环焼基、芳基、杂芳基或者杂环垸基，其中烷基、环烷基、芳基、杂芳基或者杂环垸基可以进一步被一个或多个烷基、芳基、羟基、氨基、烷氨基、酰胺基、胺酰基、氰^、垸氧基、芳氧基、胺烷基、羟烷基、杂环垸基、羧酸或者羧酸酯所取代； And R ₉ are each independently selected from the group consisting of hydrogen protopium, fluorenyl, cyclodecyl, aryl, heteroaryl or heterocycloalkyl, wherein the alkyl, cycloalkyl, aryl, heteroaryl or heterocyclic fluorenyl group can be further By one or more alkyl, aryl, hydroxy, amino, alkylamino, amide, aminoacyl, cyanide, decyloxy, aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid Or substituted with a carboxylic acid ester;

同时，和 R₉可以形成一个 4〜8元杂环基；其中 5〜8元杂环内可以进一步含有一个或多个 N、 0、 S原子，并且 4〜8元杂环上可以进一步被；二个或多个垸基、芳基、杂芳基、卤代垸基、卤代烷氧基、羟基、氨基、烷氨基、酰胺基、胺酰基、氰基、垸氧基、芳氧基、胺烷基、羟垸基、杂环垸基、羧酸、羧酸酯、卤素或 -NR₈R₉所取代； Meanwhile, and R ₉ may form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring may further contain one or more N, 0, S atoms, and the 4 to 8 membered heterocyclic ring may be further; Two or more mercapto, aryl, heteroaryl, halodecyl, haloalkoxy, hydroxy, amino, alkylamino, amide, aminyl, cyano, decyloxy, aryloxy, amin Substituted with a hydroxy group, a hydroxymethyl group, a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester, a halogen or -NR ₈ R ₉ ;

R₁₍₎选自羟基、烷氧基、芳氧基、杂环垸氧基、芳烷氧基、 -0(CH₂)_mR₁₂、 -N(R_u)(CH₂)_mR₁₂、 -NRn[CH₂CH₂0]_rR_u > -NR₈R₉、 -N-Z-O-Z 或 -NR^CH^ [CH(OH)CH₂]_pZ ，其中 Z 是芳基、杂芳基、杂环烷基、 - R₈R₉、 -COOR_n或 CONR₈R₉; R _{1 () is} selected from the group consisting of hydroxyl, alkoxy, aryloxy, heterocyclomethoxy, aralkyloxy, -0(CH ₂ ) _m R ₁₂ , -N(R _u )(CH ₂ ) _m R ₁₂ -NRn[CH ₂ CH ₂ 0] _r R _u > -NR ₈ R ₉ , -NZOZ or -NR^CH^ [CH(OH)CH ₂ ] _p Z , wherein Z is aryl, heteroaryl, hetero Cycloalkyl, - R ₈ R ₉ , -COOR _n or CONR ₈ R ₉ ;

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

R₁₂选自 -NR₈R₉、羟基、芳基、杂环垸基，杂芳基、烷氧基、 -0[CH₂C¾0]_rR„、

-N(OH)R₈、 -NHC(0)R₁₃或 -C0R₁₃，其中 R₁₃是未取代的烷基、卤代烷基或者芳烷基，其中芳基、杂环烷基，杂芳基可以进一步被一个或多个羟基， -COOR_u所取代； R _{12 is} selected from the group consisting of -NR ₈ R ₉ , hydroxy, aryl, heterocycloalkyl, heteroaryl, alkoxy, -0[CH ₂ C3⁄40] _r R„,

-N(OH)R ₈ , -NHC(0)R ₁₃ or -C0R ₁₃ , wherein R ₁₃ is unsubstituted alkyl, haloalkyl or aralkyl, wherein aryl, heterocycloalkyl, heteroaryl may Further substituted by one or more hydroxyl groups, -COOR _u ;

n是 0〜4； r是 1〜 n is 0~4; r is 1~

m是 1 m is 1

p是 1〜本发明的典型化合物包括，但不限于: p is 1~ Typical compounds of the invention include, but are not limited to:

下述实施例 The following examples

结构名称 Structure name

序号 Serial number

5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3- 亚基-甲基) -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-二乙胺基-乙基) -酰胺 5-(5-fluoro-2-oxo-1,2-dihydro-inden-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3- Carboxylic acid-(2-diethylamino-ethyl)-amide

5-(5-氯 -2-氧代 -1，2-二氢 -Π引哚 -3- 亚基-甲基) -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-二乙胺基-乙基) -酰胺 5-(5-chloro-2-oxo-1,2-dihydro-indole hydrazone-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3 -carboxylic acid-(2-diethylamino-ethyl)-amide

5-(5-溴 -2-氧代 -1，2-二氢 -Π引哚 -3- 亚基-甲基) -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-二乙胺基-乙基) -酰胺 5-(5-bromo-2-oxo-1,2-dihydro-indole hydrazone-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3 -carboxylic acid-(2-diethylamino-ethyl)-amide

5-(5-甲磺酰胺 -2-氧代 -1,2-二氢- 吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -B比咯 -3-羧酸 -(2-二乙胺基-乙基) -酰胺 5-(5-methanesulfonamide-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1 hydrogen-B ratio Ole-3-carboxylic acid-(2-diethylamino-ethyl)-amide

5-(5-乙酰胺 -2-氧代 -1,2-二氢-吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-二乙胺基-乙基) -酰胺 5-(5-acetamide-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3 -carboxylic acid-(2-diethylamino-ethyl)-amide

5-(6-乙酰胺 -5-氟 -2-氧代 -1,2-二氢^ I哚 -3-亚基-甲基) -2-甲基 -4- 三氟甲基 -1氢 -吡咯 -3-羧酸 -(2- 二乙胺基-乙基) -酰胺

5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3- 亚基-甲基) 2-甲基 -4-三氟甲基 -1 氢-吡咯 -3-羧酸 -(2-***啉 -4-基- 乙基) -酰胺 5-(6-acetamide-5-fluoro-2-oxo-1,2-dihydro^I哚-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1 hydrogen -pyrrole-3-carboxylic acid-(2-diethylamino-ethyl)-amide

5-(5-fluoro-2-oxo-1,2-dihydro-indole-3-ylidene-methyl) 2-methyl-4-trifluoromethyl-1 Hydro-pyrrole-3-carboxylate Acid-(2-morpholine-4-yl-ethyl)-amide

5-(5-氯 -2-氧代 -1，2-二氢 -吲哚 -3- 亚基-甲基) -2-甲基 -4-三氟甲基 -1 氢-吡咯 -3-羧酸 -(2-***啉 -4-基- 乙基) -酰胺 5-(5-Chloro-2-oxo-1,2-dihydro-inden-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1 Hydro-pyrrole-3- Carboxylic acid-(2-morpholine-4-yl-ethyl)-amide

5-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3- 亚基-甲基) -2-甲基 -4-三氟甲基 -1 氢-吡咯 -3-羧酸 -(2-***啉 -4-基- 乙基) -酰胺 5-(5-Bromo-2-oxo-1,2-dihydro-inden-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1 Hydro-pyrrole-3- Carboxylic acid-(2-morpholine-4-yl-ethyl)-amide

5-(5-甲磺酰胺 -2-氧代 -1,2-二氢- B引哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-吗啡啉 -4-基-乙基) -酰胺 5-(5-methanesulfonamide-2-oxo-1,2-dihydro-B-indole-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole 3-carboxylic acid-(2-morphinolin-4-yl-ethyl)-amide

5-(5-乙酰胺 -2-氧代 -1,2-二氢-吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -P比咯 -3-羧酸 -(2-*** 啉 -4-基-乙基) -酰胺 5-(5-acetamide-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1hydro-P ratio 3-carboxylic acid-(2-morphinolin-4-yl-ethyl)-amide

5-(6-氨基 -5-氟 -2-氧代 -1,2-二氢- H引哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-吗啡啉 -4-基-乙基) -酰胺 5-(6-Amino-5-fluoro-2-oxo-1,2-dihydro-H-indole-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1 hydrogen -pyrrole-3-carboxylic acid-(2-morphinolin-4-yl-ethyl)-amide

5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3- 亚基-甲基) -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-哌啶 -1-基-乙基) -酰胺 5-(5-fluoro-2-oxo-1,2-dihydro-inden-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3- Carboxylic acid-(2-piperidin-1-yl-ethyl)-amide

5-(5-氯 -2-氧代 -1，2-二氢 -吲哚 -3- 亚基-甲基) -2-甲基 -4-三氟甲基 -1 氢-吡咯 -3-羧酸 -(2-哌啶 -1-基-乙基) -酰胺5-(5-Chloro-2-oxo-1,2-dihydro-inden-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1 Hydro-pyrrole-3- Carboxylic acid-(2-piperidin-1-yl-ethyl)-amide

5-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3- 亚基-甲基) -2-甲基 -4-三氟甲基 -i 氢 -吡咯 -3-羧酸 -(2-哌啶 -1-基-乙基) -酰胺

5-(5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-i-hydro-pyrrole-3- Carboxylic acid-(2-piperidin-1-yl-ethyl)-amide

5-(5-乙酰胺 -2-氧代 -1,2-二氢-吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氨-吡咯 -3-羧酸 -(2-哌啶小基-乙基) -酰胺 5-(5-acetamide-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1amino-pyrrole-3 -carboxylic acid-(2-piperidinyl-ethyl)-amide

5-(6-氨基 -5-氟 -2-氧代 -1,2-: 吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -B比咯 -3-羧酸 -(2-哌啶 -1-基-乙基) -酰胺 5-(6-Amino-5-fluoro-2-oxo-1,2-:indol-3-yl-methyl)-2-methyl-4-trifluoromethyl-1 hydrogen-B ratio R--3-carboxylic acid-(2-piperidin-1-yl-ethyl)-amide

5-氟 -3-[5-甲基 -4-(4-***啉 -4-基 ■1-羰基) -3-三氟甲基 -1H-吡咯 -2- 次甲基 ]-1 , 3-二氢吲哚 -2-酮 5-fluoro-3-[5-methyl-4-(4-morphinolin-4-yl-l-carbonyl)-3-trifluoromethyl-1H-pyrrole-2-methine-1, 3 -indoline-2-one

5-氯 -3-[5-甲基 -4-(4-***啉 -4-基 -1-羰基) -3-三氟甲基 -1H-吡咯 -2- 次甲基 ]-1， 3-二氢吲哚 -2-酮 5-Chloro-3-[5-methyl-4-(4-morphinolin-4-yl-1-carbonyl)-3-trifluoromethyl-1H-pyrrole-2-methine-1,3 -indoline-2-one

5-溴 -3-[5-甲基 -4-(4-***啉 -4-基小羰基) -3-三氟甲基 -1H-吡咯 -2- 次甲基 ]-1， 3-二氢吲哚 -2-酮 5-bromo-3-[5-methyl-4-(4-morphinolin-4-ylsuccinylcarbonyl)-3-trifluoromethyl-1H-pyrrole-2-methine]-1, 3-di Hydroquinone-2-one

N-{3-[5-甲基 -4-(4-***啉 -4-基小羰基 )-3-三氟甲基 -1H-吡咯 -2- 次甲基 ]-2-氧 -2,3-二氢 -1H-吲哚 -5-基乙酰胺 N-{3-[5-Methyl-4-(4-morphinolin-4-ylsuccinyl)-3-trifluoromethyl-1H-pyrrol-2-methyl]-2-oxo-2, 3-dihydro-1H-indol-5-ylacetamide

5-氟 -7-溴 -3-[5-甲基 -4-(4-***啉 —4-基 -1-羰基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-1， 3-二氢吲哚 -2- 酮5-fluoro-7-bromo-3-[5-methyl-4-(4-morpholine-4-yl-1-carbonyl)-3-trifluoromethyl-1H-pyrrole-2-methine] -1,3-indoline-2-one

N-{3-[5-甲基 -4-(4-***啉 -4-基小羰基) -3-三氟甲基 -1H-吡咯 -2- 次甲基 ]-2-氧 -2,3-二氢 -1H-吲哚

N-{3-[5-Methyl-4-(4-morphinolin-4-ylsuccinyl)-3-trifluoromethyl-1H-pyrrole-2- methine]-2-oxo-2, 3-dihydro-1H-indole

-5-基}-甲酰胺 -5-yl}-carboxamide

N-{5-氟 -3-[5-甲基 -4-(4-***啉 -4-基小羰基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -7-基} -甲磺酰胺 N-{5-fluoro-3-[5-methyl-4-(4-morphinolin-4-yloxycarbonyl)-3-trifluoromethyl-1H-pyrrole-2-methine]-2- Oxo-2,3-dihydro-1H-indol-7-yl}-methanesulfonamide

N-{3-[5-甲基 -4-(4-***啉 -4-基- 哌啶 -1-羰基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -5-基甲磺酰胺 N-{3-[5-Methyl-4-(4-morphinolin-4-yl-piperidin-1-carbonyl)-3-trifluoromethyl-1H-pyrrole-2-methine]-2 -oxo-2,3-dihydro-1H-indol-5-ylmethanesulfonamide

N-{5-氟 -3-[5-甲基 -4-(4-***啉 _4-哌啶 -1-载基) -3-三氟甲基 -1H- 吡咯 -2-次甲基 ]-2-氧代 -2，3-二氢 -1H-吲哚 -7-基甲酰胺 N-{5-fluoro-3-[5-methyl-4-(4-morpholine-4-piperidine-1-yl)-3-trifluoromethyl-1H-pyrrole-2-methine ]-2-oxo-2,3-dihydro-1H-indol-7-ylformamide

N-{5-氟 -3-[5-甲基 -4-(4-***啉 _4-哌啶 -1-羰基) -3-三氟甲基 -1H- 吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H-B引哚 -6-基}-甲酰胺 N-{5-fluoro-3-[5-methyl-4-(4-morpholine-4-piperidine-1-carbonyl)-3-trifluoromethyl-1H-pyrrole-2-methine] -2-oxo-2,3-dihydro-1H-B 哚-6-yl}-carboxamide

N-{5-氟 -3-[5-甲基 -4-(4-***啉 -4-哌啶小羰基) -3-三氟甲基 -1H- 吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -7-基}-乙酰胺 N-{5-fluoro-3-[5-methyl-4-(4-morpholine-4-piperidines small carbonyl)-3-trifluoromethyl-1H-pyrrole-2-methine]-2 -oxo-2,3-dihydro-1H-indol-7-yl}-acetamide

5-(5-氟 -2-氧代 -1,2-二氢 -Π引哚 -3- 次甲基 )-2-甲基 -4-三氟甲基 -1H- 吡咯 -3-羧酸（2-吡咯烷小乙基) - 酰胺5-(5-fluoro-2-oxo-1,2-dihydro-indole 哚-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidine small ethyl)-amide

5-(5-氯 -2-氧代 -1，2-二氢』31哚 -3- 次甲基 )-2-甲基 -4-三氟甲基 -1H- 吡咯 -3-羧酸（2-吡咯烷 -1-乙基) - 酰胺

5-(5-Chloro-2-oxo-1,2-dihydro]31哚-3-methine)-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ( 2-pyrrolidine-1-ethyl)-amide

5-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3- 次甲基 )-2-甲基 -4-三氟甲基 -1H- 吡咯 -3-羧酸（2-吡咯烷 -1-乙基) - 酰胺 5-(5-Bromo-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ( 2-pyrrolidine-1-ethyl)-amide

5-(5-氯 -7-溴 -2-氧代 -1，2-二氢-吲哚 -3-次甲基) -2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸（2-吡咯烷 -1-乙基) -酰胺 5-(5-chloro-7-bromo-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3 -carboxylic acid (2-pyrrolidine-1-ethyl)-amide

5-(5-氟 -6-甲酰胺基 -2-氧代 -1，2- 二氢 - 哚 -3-次甲基 )-2-甲基 -4- 三氟甲基 -1H-吡咯 -3-羧酸（2-吡咯烷 -1-乙基) -酰胺 5-(5-fluoro-6-carboxamido-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole- 3-carboxylic acid (2-pyrrolidine-1-ethyl)-amide

5-(5-氟 -7-甲酰胺基 -2-氧代 -1,2- 二氢 -吲哚 -3-次甲基) -2-甲基 -4- 三氟甲基 -1H-吡咯 -3-羧酸（2-吡咯烷 -1-乙基) -酰胺 5-(5-fluoro-7-carboxamido-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole 3-carboxylic acid (2-pyrrolidine-1-ethyl)-amide

₅_(₅_氟 _7-甲磺酰胺基 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸 (2-吡咯烷 -1-乙基) -酰胺 5-(5-甲磺酰胺基 -2-氧代 -1，2-二氢-吲哚 -3-次甲基 )-2-甲基斗三氟甲基 -1H-吡咯 -3-羧酸（2-吡咯烷 -1-乙基) -酰胺

氟 -2-氧代 -1,2- 基 )-2-甲基 -⁴- -3-羧酸（2-吡 ) -酰胺氧代 -1,2-二氢- -甲基 -4--1H-吡烷小乙基) -酰氧代 -1,2-二氢- -甲基 -4--1H-吡烷 -1-乙基) -酰胺基) -2-氧代 -次甲基 ]-2-甲 -吡咯 -3-羧酸乙基) -酰胺 ₅ _( ₅ _fluoro_7-methanesulfonamido-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H- Pyrrole-3-carboxylic acid (2-pyrrolidin-1-ethyl)-amide 5-(5-methanesulfonamido-2-oxo-1,2-dihydro-indole-3-methine) -2-methyl-trifluoromethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidine-1-ethyl)-amide

Fluoro-2-oxo-1,2-yl)-2-methyl- ⁴ -carboxylic acid (2-pyridyl)-amide oxo-1,2-dihydro-methyl-4-- 1H-pyridinium small ethyl)-acyloxy-1,2-dihydro-methyl-4--1H-pyridin-1-ethyl)-amido)-2-oxo-methine ]-2-methyl-pyrrole-3-carboxylic acid ethyl)-amide

基 -1'-羰基) -⁵- -1H-吡咯 -2-次

氢 -吲哚 -2-酮 -1'-carbonyl) - ⁵ - -1H-pyrrole-2-order

Hydrogen-indol-2-one

3-[4-([1，4']二哌啶基 -Γ-羰基) -5- 甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基] -5-氯 -1,3-二氢 -B引哚 -2-酮 3-[4-([1,4']Dipiperidinyl-fluorenyl-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2-methylidene]-5-chloro-1 , 3-dihydro-B-indol-2-one

₃_[4-([1，4']二哌啶基 -Γ-羰基) -5- 甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基] -5-溴 -1 ,3-二氢』引哚 -2-酮

³-[⁴_([l，⁴']二哌啶基 -1'-羰基) -5- 甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基] -5-氯 -7溴 -1,3-二氢 -Π引哚 -2- 酮 ₃ _[4-([1,4'] Dipiperidinyl-fluorenyl-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2-methine]-5-bromo-1 , 3-dihydro"-indol-2-one

^3- [ ⁴ _([l, ⁴ '] Dipiperidinyl-1 '-carbonyl) -5-methyl-3-trifluoromethyl-1H-pyrrole-2-methine]-5-chloro- 7Br-1,3-dihydro-indole-2-one

Ν-{3-[4-([1,4']二脈啶基 -1'-羰基) -5-基 -3-三氟甲基 -1Η-吡咯 -2- 次甲基 ]-2-氧代 -2,3-二氢 -1Η-吲哚 -5-基甲酰胺 Ν-{3-[4-([1,4'] Diazinyl-1'-carbonyl)-5-yl-3-trifluoromethyl-1Η-pyrrole-2-methine]-2- Oxo-2,3-dihydro-1Η-indole-5-ylcarboxamide

Ν-{3-[4-([1,4']二哌啶基 - -羰基) -5-基 -3-三氟甲基 -1Η-吡咯 -2- 次甲基 ]-2-氧代 -2,3-二氢 -1Η-吲哚 -5-基}-乙酰胺 Ν-{3-[4-([1,4']Dipiperidinyl-carbonyl)-5-yl-3-trifluoromethyl-1Η-pyrrole-2-methine]-2-oxo -2,3-dihydro-1Η-吲哚-5-yl}-acetamide

Ν-{3-[4-([1,4']二哌啶基 -1'-羰基) -5-甲基 -3-三氟甲基 - 1H-吡咯 -2-次甲基 ]-5-氟 -2-氧代 -2,3-二氢 -1Η-吡咯 -7-基甲酰胺 Ν-{3-[4-([1,4']Dipiperidinyl-1'-carbonyl)-5-methyl-3-trifluoromethyl- 1H-pyrrole-2-methine]-5 -fluoro-2-oxo-2,3-dihydro-1Η-pyrrole-7-ylformamide

Ν-{3-[4-([1,4']二哌啶基 -1'-羰基) -5-甲基 -3-三氟甲基 -1Η-吡咯 -2-次甲基 ]-5-氟 -2-氧代 -2，3-二氢 -1Η-吡咯 -6-基甲酰胺 Ν-{3-[4-([1,4']Dipiperidinyl-1'-carbonyl)-5-methyl-3-trifluoromethyl-1Η-pyrrole-2-methine]-5 -fluoro-2-oxo-2,3-dihydro-1Η-pyrrole-6-ylformamide

Ν-{3-[4-([1,4']二哌啶基 -1'-羰基) -5-甲基 -3-三氟甲基 -1Η-吡咯 -2-次甲基 ]-5-氟 -2-氧代 -2，3-二氢 -1Η-吡咯 -6-基}-乙酰胺 Ν-{3-[4-([1,4']Dipiperidinyl-1'-carbonyl)-5-methyl-3-trifluoromethyl-1Η-pyrrole-2-methine]-5 -fluoro-2-oxo-2,3-dihydro-1Η-pyrrole-6-yl}-acetamide

Ν-{3-[4-([1,4']二哌啶基 -Γ-羰Ν-{3-[4-([1,4'] Dipiperidinyl-fluorene-carbonyl

-甲基 -3-三氟甲基 -1Η-吡咯 2-次甲基 ]-2-氧代 -2，3-二氢 -1Η-

-methyl-3-trifluoromethyl-1Η-pyrrole 2-methine]-2-oxo-2,3-dihydro-1Η-

吡咯 -5-基} -甲磺酰胺 Ν-{3-【4-([1，4']二哌啶基羰基) -5-甲基 -3-三氟甲基 -1Η-吡咯 -2-次甲基 ]-5-氟 -2-氧代 -2，3-二氢 -1Η-吡咯 -7-基} -甲磺酰胺哌啶 -1-羧酸一 [5-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H吡咯 -3-基] -酰胺 Pyrrol-5-yl}-methanesulfonamide Ν-{3-[4-([1,4']Dipiperidinylcarbonyl)-5-methyl-3-trifluoromethyl-1Η-pyrrole-2-methine]-5-fluoro-2 -oxo-2,3-dihydro-1Η-pyrrole-7-yl}-methanesulfonamide piperidine-1-carboxylic acid-[5-(5-bromo-2-oxo-1,2-dihydrol -吲哚-3-methine)-2-methyl-4-trifluoromethyl-1Hpyrrol-3-yl]-amide

哌啶 -1-羧酸— [5-(5-氯 -2-氧代 -1 ,2-二氢』引哚 -3-次甲基) -2-甲基 -4-三氟甲基 -1H吡咯 -3-基] -酰胺哌啶 -1-羧酸一 [5-(5-甲酰胺基 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基) -2-甲基 -4-三氟甲基 -1H吡咯 Piperidine-1-carboxylic acid — [5-(5-chloro-2-oxo-1,2-dihydro]indol-3-ylmethyl)-2-methyl-4-trifluoromethyl- 1H pyrrol-3-yl]-amide piperidine-1-carboxylic acid mono[5-(5-carboxamido-2-oxo-1,2-dihydro-indole-3-methine)-2 -methyl-4-trifluoromethyl-1Hpyrrole

-3-基] -酰胺' · 哌啶 -1-羧酸— [5-(5-氟 -7-溴 -2- 氧代 -1,2-二氢 -吲哚 -3-次甲基 )_2-甲基 -4-三氟甲基 -1H吡咯 -3-yl]-amide' · piperidine-1-carboxylic acid — [5-(5-fluoro-7-bromo-2-oxo-1,2-dihydro-indole-3-methine) _2-methyl-4-trifluoromethyl-1Hpyrrole

-3-基] -酰胺哌啶 -1-羧酸一 [5-(5-氟 -6-氨基 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基) -2-甲基 -4-三氟甲基 -1H吡咯 -3-yl]-amidopiperidine-1-carboxylic acid mono[5-(5-fluoro-6-amino-2-oxo-1,2-dihydro-indol-3-methylol)-2 -methyl-4-trifluoromethyl-1Hpyrrole

-3-基] -酰胺 -3-yl]-amide

哌啶 -1-羧酸一 [5-(5-氟 -7-乙酰胺基 -2-氧代 -1,2-二氢 -Π引哚 -3-次甲基) -2-甲基 -4-三氟甲基 -1H吡咯 -3-基] -酰胺

哌啶 -1-羧酸一 [5-(5-氟 -7-甲酰胺基 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基) -2-甲基 -4-三氟甲基 -1H吡咯 Piperidine-1-carboxylic acid-[5-(5-fluoro-7-acetamido-2-oxo-1,2-dihydro-indole fluoren-3-phenylmethyl)-2-methyl- 4-trifluoromethyl-1Hpyrrol-3-yl]-amide

Piperidine-1-carboxylic acid mono[5-(5-fluoro-7-carboxamido-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4 -trifluoromethyl-1Hpyrrole

-³-基] -酰胺 - ³ -yl]-amide

哌啶 -1-羧酸一 [5-(5-氟 -7-甲磺酰胺基 -2-氧代 -1，2-二氢^ I哚 -3- 次甲基 )-2-甲基 -4-三氟甲基 -1H 吡咯 -3-基] -酰胺 Piperidine-1-carboxylic acid-[5-(5-fluoro-7-methanesulfonamido-2-oxo-1,2-dihydro^I哚-3-methine)-2-methyl- 4-trifluoromethyl-1H pyrrol-3-yl]-amide

4-({[5-(5-氟 -2-氧代 -1,2-二氢-吲哚 -3-次甲基) -2-甲基 -4-三氟甲基 -1H-吡咯 -3-羰基] -氨基甲基 -4- 羟基 -1-羧酸叔丁酯 4-({[5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole- 3-carbonyl]-aminomethyl-4-hydroxy-1-carboxylic acid tert-butyl ester

4-({[5-(5-溴 -2-氧代 -1,2-二氢-吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羰基] -氨基 } -甲基 -4- 羟基 -1-羧酸叔丁酯 4-({[5-(5-Bromo-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole- 3-carbonyl]-amino}-methyl-4-hydroxy-1-carboxylic acid tert-butyl ester

4-({[5-(5-氟 -7-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-幾基] -氨基 } - 甲基 -4-羟基 -1-羧酸叔丁酯 4-({[5-(5-fluoro-7-bromo-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl- 1H-pyrrole-3-yl]-amino}-tert-butyl methyl-4-hydroxy-1-carboxylate

5-(5-氟 -7-甲酰胺基 -2-氧代 -1,2- 二氢 -吲哚 -3-次甲基) -2-甲基 -4- 三氟甲基 -1H-吡咯 -3-羧酸- (4-羟基 -哌啶 -4-甲基) -酰胺 5-(5-fluoro-7-carboxamido-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole 3-carboxylic acid-(4-hydroxy-piperidin-4-methyl)-amide

5-(5-氟 -7-甲酰胺基 -2-氧代 -1,2- 二氢 -B引哚 -3-次甲基 )-2-甲基 -4- 三氟甲基 -1H-吡咯 -3-羧酸- (4-羟

基 -哌啶 -4-甲基) -酰胺 5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3- 次甲基 )-2-甲基 -4-三氟甲基 -1H- 吡咯 -3-羧酸- (4-轻基 -哌啶 -4-甲基:) -酰胺 5-(5-fluoro-7-carboxamido-2-oxo-1,2-dihydro-B 哚-3-methylol)-2-methyl-4-trifluoromethyl-1H- Pyrrole-3-carboxylic acid - (4-hydroxyl

Base-piperidin-4-methyl)-amide 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid- (4-light-piperidine-4-methyl:)-amide

5-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3- 次甲基 )-2-甲基 -4-三氟甲基 -1H- 吡咯 -3-羧酸- (4-羟基 -哌啶 -4-甲基) -酰胺 5-(5-Bromo-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid- (4-hydroxy-piperidin-4-methyl)-amide

5-(5-氟 -7-溴 -2-氧代 -1,2-二氢-吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸- (4-轻基 -哌啶 -4-甲基) -酰胺 5-(5-fluoro-7-bromo-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3 -carboxylic acid - (4-light-piperidin-4-methyl)-amide

₅-₍₅_氟 _₇_甲酰胺基 -2-氧代 -1 ,2- 二氢 -吲哚 -3-次甲基 )-2-甲基 -4- 三氟甲基 -1H-吡咯 -3-羧酸- (4-羟基 -哌啶 -4-甲基) -酰胺 _5- _(5- Fluoro- ₇ -formamide-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole 3-carboxylic acid-(4-hydroxy-piperidin-4-methyl)-amide

5-[5-氟 -6-(3-甲氧基 -2-氧代-丙基) -1,2-二氢 -Π引哚 -3-次甲基] -2- 甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸- (4-羟基 -哌! ¾-4-甲基) -酰胺 5-[5-fluoro-6-(3-methoxy-2-oxo-propyl)-1,2-dihydro-indole 哚-3-methine]-2-methyl-4- Trifluoromethyl-1H-pyrrole-3-carboxylic acid-(4-hydroxy-peline! 3⁄4-4-methyl)-amide

5-氟 -3-[4-(1-羟基小哌啶小甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-1,3-二氢- 哚 -2-酮 5-fluoro-3-[4-(1-hydroxypiperidines small methyl-piperidine-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2-methine] -1,3-dihydro-indol-2-one

5-氯 -3-[4-(1-轻基 -1 -哌啶小甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-1,3-：

n引哚 -2-酮 5-溴 -3-[4-(l-羟基 -1-哌啶 -1-甲基 5-chloro-3-[4-(1-lightyl-1 -piperidinylmethyl-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2-order Methyl]-1,3-:

N-indol-2-one 5-bromo-3-[4-(l-hydroxy-1-piperidin-1-methyl)

-哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基] -1，3-二氢- 吲哚 -2-酮 - piperidine-4-carbonyl) -5-methyl-3-trifluoromethyl-1H-pyrrole-2-methine]-1,3-dihydro-indol-2-one

5-氯 -7-溴 -3-[4-(1-羟基 -1-呢啶 -1- 甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-1，³- 二氢 -吲哚 -2-酮 5-Chloro-7-bromo-3-[4-(1-hydroxy-1-n-pyridin-1-methyl-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H- pyrrole-2-methylene] -1, ³ - dihydro - indol-2-one

Ν-{5-氟 -3-[4-(1-羟基 -1-呃啶 -1- 甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1Η-吡咯 -2-次甲基] -2-氧代 -2,3-二氢 -1Η-吲哚 -7-基} -乙酰胺 Ν-{5-fluoro-3-[4-(1-hydroxy-1-acridin-1-methyl-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1Η-pyrrole 2-Methyl-methyl]-2-oxo-2,3-dihydro-1Η-吲哚-7-yl}-acetamide

Ν-{5-氟 -3-[4-(1-羟基 -1-哌啶 -1- 甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1Η-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1Η-吲哚 -7-基甲酰胺 Ν-{5-Fluoro-3-[4-(1-hydroxy-1-piperidin-1-methyl-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1Η-pyrrole -2-Methyl]-2-oxo-2,3-dihydro-1Η-吲哚-7-ylformamide

Ν-{5-氟 -3-[4-(1 -羟基 -1 -哌啶 - 1 - 甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1Η-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1Η-吲哚 -6-基甲酰胺 Ν-{5-fluoro-3-[4-(1-hydroxy-1 -piperidin-1 -methyl-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1Η-pyrrole -2-Methyl]-2-oxo-2,3-dihydro-1Η-吲哚-6-ylformamide

Ν-{5-氟 -3-[4-(1-轻基小哌啶小甲基 -哌啶 -4-驟基) -5-甲基 -3-三氟甲基 -1Η-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -6-基}-2-羟基-乙酰胺 Ν-{5-fluoro-3-[4-(1-light-based small piperidine small methyl-piperidin-4-yl)-5-methyl-3-trifluoromethyl-1Η-pyrrole-2 - methine]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide

N-{5-氟 -3-[4-(1-羟基 -1-哌啶小甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2，3-二氢 -1H-吲哚 -7-基}-2-甲

氧基-乙酰胺 N-{5-氟 -3-[4-(l-羟基 -1-哌啶 -1- 甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基] -2-氧代 -2,3-二氢 -1H-吲哚 -6-基}-2-甲氧基-乙酰胺 N-{5-fluoro-3-[4-(1-hydroxy-1-piperidinylmethyl-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2 -Methyl-methyl]-2-oxo-2,3-dihydro-1H-indol-7-yl}-2-A

Oxy-acetamide N-{5-fluoro-3-[4-(l-hydroxy-1-piperidin-1-methyl-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole 2-Methyl-methyl]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxy-acetamide

N-{5-氟 -3-[4-(1-羟基 -1 -哌啶 -1- 甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1Η-η引哚 -7-基} -甲磺酰胺 N-{5-fluoro-3-[4-(1-hydroxy-1 -piperidin-1-methyl-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole -2-Methyl]-2-oxo-2,3-dihydro-1Η-η 哚-7-yl}-methanesulfonamide

1-[5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基) -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -3-(2-吡咯烷小乙基) -脲 1-[5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3- -3-(2-pyrrolidine small ethyl)-urea

1-[5-(5-氯 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -3-(2-吡咯烧 -1-乙基) -脲 1-[5-(5-Chloro-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3- -3-(2-pyrrolidino-1-ethyl)-urea

1-[5-(5-溴 -2-氧代 -1,2-二氢 - 哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -3-(2-吡咯烷小乙基) -脲 1-[5-(5-Bromo-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl -3-(2-pyrrolidine small ethyl)-urea

1-[5-(7善 5-氟 -2-氧代 -1,2-二吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -3-(2-吡咯垸 -1- 乙基) -脲 1-[5-(7 good 5-fluoro-2-oxo-1,2-diindol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3- -3-(2-pyrrole-1-ethyl)-urea

₃-(4-氨基 -5-甲基 -3-三氟甲基 - 1 H-吡咯 -2-次甲基) -5-氟- 1 ,3-二氢 -吲哚 -2-酮 _3- (4-Amino-5-methyl-3-trifluoromethyl- 1 H-pyrrole-2-methine)-5-fluoro-1,3-dihydro-indol-2-one

3-(5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 )-5-氟 -1,3-二氢 -吲哚 3-(5-methyl-3-trifluoromethyl-1H-pyrrole-2-methine)-5-fluoro-1,3-dihydro-indole

-2-酮 2-ketone

5-溴 -3-(5-甲棊 -3-三氟甲基 -1H- 吡咯 -2-次甲基，3-二氢 -吲哚

5-bromo-3-(5-formamidine-3-trifluoromethyl-1H-pyrrole-2-methine, 3-dihydro-indole

1-2-酮 1-2-ketone

5-(4-溴 -2-氧代 -1,2-二氢』引哚 -3- 次甲基 )-2-甲基 -4三氟甲基- 1H-吡咯 -3-羧酸 (二乙氨基乙基）酰胺 5-(4-bromo-2-oxo-1,2-dihydro)anthracene-3-methyl)-2-methyl-4trifluoromethyl- 1H-pyrrole-3-carboxylic acid (II Ethylaminoethyl)amide

5-[4-(2-氟苯基 )-2-氧代 -1，2-二氢 -吲哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸 (二乙氨基甲基)酰胺 5-[4-(2-Fluorophenyl)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-2-methyl-4-trifluoromethyl-1H-pyrrole 3-carboxylic acid (diethylaminomethyl) amide

5-[4-(4-氯 -2-氟苯基 )-2-氧代 -1 ,2- 二氢 -吲哚 -3-次甲基 ]-2-甲基 -4- 三氟甲基 -1H-吡咯 -3-羧酸 (二乙氨基甲基)酰胺 5-[4-(4-Chloro-2-fluorophenyl)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-2-methyl-4-trifluoromethyl -1H-pyrrole-3-carboxylic acid (diethylaminomethyl)amide

5-[4-(2,6-二氟苯基) -2-氧代 -1,2- 二氢 -吲噪 -3-次甲基 ]-2-甲基 -4- 三氟甲基 -1H-吡咯 -3-羧酸 (二乙氨基甲基)酰胺 5-[4-(2,6-difluorophenyl)-2-oxo-1,2-dihydro-noise-3-methyl>-2-methyl-4-trifluoromethyl- 1H-pyrrole-3-carboxylic acid (diethylaminomethyl)amide

-[4-(2,3-二氟苯基) -2-氧代 -1，2- 二氢 -吲哚 3-次甲基 ]-2-甲基 -4- ：氟甲基 -1H-吡咯 -3-羧酸（2-乙氨基乙基) -酰胺 -[4-(2,3-difluorophenyl)-2-oxo-1,2-dihydro-indole-3-methine]-2-methyl-4-:fluoromethyl-1H- Pyrrole-3-carboxylic acid (2-ethylaminoethyl)-amide

5-[4-(3-氯 -2-11：-苯基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸5-[4-(3-Chloro-2-11:-phenyl)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-2-methyl-4-trifluoro Methyl-1H-pyrrole-3-carboxylic acid

(二乙氨基甲基)酰胺

5-[4-(4-氟苯基 )-2-氧代- 1 ,2-二氢 - 哚 -3-次甲基] -2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸 (二乙氮基甲基)酰胺 (diethylaminomethyl)amide

5-[4-(4-Fluorophenyl)-2-oxo-1,2-dihydro-indol-3-methylol]-2-methyl-4-trifluoromethyl-1H-pyrrole- 3-carboxylic acid (diethylaminomethyl) amide

5-氟 -3-(5-甲基 -4-苯基 -3-三氟甲基 -1H-吡咯 -2-次甲基) -1，3-二氢- B引哚 -2-酮 5-fluoro-3-(5-methyl-4-phenyl-3-trifluoromethyl-1H-pyrrole-2-methine)-1,3-dihydro-B-indole-2-one

5-溴 -3-(5-甲基 -4-苯基 -3-三氟甲基 - 1H-吡咯 -2-次甲基) - 1 ,3-二氢- 吲哚 -2-酮 5-bromo-3-(5-methyl-4-phenyl-3-trifluoromethyl-1H-pyrrole-2-methine)-1,3-dihydro-indol-2-one

N-[5-氟 -3-(5-甲基 -4-苯基 -3-三氟甲基 -1H-吡咯 -2-次甲基 )-2-氧代 -2,3-二氢 -1H-吲哚 -6-基] -2-甲氧基-乙酰胺 N-[5-fluoro-3-(5-methyl-4-phenyl-3-trifluoromethyl-1H-pyrrole-2-methine)-2-oxo-2,3-dihydro- 1H-indol-6-yl]-2-methoxy-acetamide

N-[5-氟 -3-(5-甲基 -4-苯基 -3-三氟甲基 -1H-吡咯 -2-次甲基 )-2-氧代 -2，3-二氢 -1H-吲哚 -6-基] -2-羟基乙酰胺 N-[5-fluoro-3-(5-methyl-4-phenyl-3-trifluoromethyl-1H-pyrrole-2-methine)-2-oxo-2,3-dihydro- 1H-吲哚-6-yl]-2-hydroxyacetamide

5-氟 -3-[4-(4-氟苯基 )-5-甲基 -3- 三氟甲基 -1H-吡咯 -2-次甲基] -1,3-二氢 -吲噪 -2-酮 5-fluoro-3-[4-(4-fluorophenyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2-methine]-1,3-dihydro-noise- 2-ketone

5-溴 -3-[4-(4-氟苯基 )-5-甲基 -3- 三氟甲基 -1H-吡咯 -2-次甲基] -1,3-二氢』引哚 -2-酮 5-bromo-3-[4-(4-fluorophenyl)-5-methyl-3-trifluoromethyl-1H-pyrrol-2-ylmethyl]-1,3-dihydro] hydrazine- 2-ketone

N-{5-氟 -3-[4-(4-氟苯基 )-5-甲基N-{5-fluoro-3-[4-(4-fluorophenyl)-5-methyl

-3-三氟甲基 -1H-吡咯 -2-次甲基〗_2-氧代 -2,3-二氢 -1H-吲哚 -6-

基] -2-甲氧基-乙酰胺 N- {5-氟 -3-[4-(4-氟苯基 )-5-甲基 -3-trifluoromethyl-1H-pyrrol-2-methylidene-2-oxo-2,3-dihydro-1H-indole-6-

-2-methoxy-acetamide N- {5-fluoro-3-[4-(4-fluorophenyl)-5-methyl

-3-三氟甲基 -1H-吡咯 -2-次甲基 ]_2-氧代 -2,3-二氢 -1H-H引哚 -6- 基] -2-羟基-乙酰胺 -3-trifluoromethyl-1H-pyrrole-2-ylmethyl]_2-oxo-2,3-dihydro-1H-H 哚-6-yl]-2-hydroxy-acetamide

[5-(5-氟 -2-氧代 -1，2-二氢』引哚 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸 - 2-吗啉 -4-乙酯 [5-(5-Fluoro-2-oxo-1,2-dihydro) fluorene-3-methylene)-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl] -carbamic acid- 2-morpholin-4-ethyl ester

[5-(7-溴 -5-氟 -2-氧代 -1,2-二氢- 吲哚 -3-亚甲基) -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸- 2- 吗啉 -4-乙酯 [5-(7-Bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-methylene)-2-methyl-4-trifluoromethyl-1H-pyrrole- 3-yl]-carbamic acid 2- 2-morpholine-4-ethyl ester

5-{-[5-氟 -6-(2-羟基-乙酰氨基) -2-氧代 -1，2-二氢 -吲哚 -3-亚甲基] -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基氨基甲酸- 2-吗啉 -4-乙酯 5-{-[5-fluoro-6-(2-hydroxy-acetylamino)-2-oxo-1,2-dihydro-indol-3-methylene]-2-methyl-4-tri Fluoromethyl-1H-pyrrol-3-ylcarbamic acid 2- 2-morpholine-4-ethyl ester

5-{-[5-氟 -6-(2-甲氧基-乙酰氨基) -2-氧代 -1,2-二氢 -吲哚 -3-亚甲基] -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基氨基甲酸- 2-吗啉 -4-乙 5-{-[5-fluoro-6-(2-methoxy-acetylamino)-2-oxo-1,2-dihydro-indol-3-methylene]-2-methyl-4 -trifluoromethyl-1H-pyrrol-3-ylcarbamic acid- 2-morpholine-4-B

5-[4-(2，3-二氟苯基) -2-氧代 -1,2- 二氢 -B引哚 -3-亚甲基 ]-2-甲基 -4- 三氟甲基 -1H-吡咯 -3-基] -氨基甲酸 _ 2-吗啉 -4-乙酯 5-[4-(2,3-difluorophenyl)-2-oxo-1,2-dihydro-B 哚-3-methylidene]-2-methyl-4-trifluoromethyl -1H-pyrrol-3-yl]-carbamic acid _ 2-morpholin-4-ethyl ester

5-[4-(3-氟苯基 )-2-氧代 -1，2-二氢 -吲哚 -3-亚甲基 ]-2- ¾-4-三氟甲基 -1H-吡咯 -3-羧酸（2-乙氨基乙基) -酰胺 5-[4-(3-Fluorophenyl)-2-oxo-1,2-dihydro-indole-3-methylene]-2- 3⁄4-4-trifluoromethyl-1H-pyrrole- 3-carboxylic acid (2-ethylaminoethyl)-amide

5-(5-溴 -2-氧代 -1,2-二氢吡咯 [2,3-b]吡啶 -3-亚甲基 )-2-甲基 -4- 三顦甲基 -1H-吡咯 -3-羧酸（2-乙氨基乙基) -酰胺

[5-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3-亚甲基) -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯 5-(5-Bromo-2-oxo-1,2-dihydropyrrole[2,3-b]pyridine-3-methylene)-2-methyl-4-trimethyl-1H-pyrrole 3-carboxylic acid (2-ethylaminoethyl)-amide

[5-(5-Bromo-2-oxo-1,2-dihydro-indole-3-methylene)-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl] - tert-butyl carbamate

[5-(5-乙酰胺基 -2-氧代 -1，2-二氢- 吲哚 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁 [5-(5-Acetylamino-2-oxo-1,2-dihydro-indol-3-methylene)-2-methyl-4-trifluoromethyl-1H-pyrrole-3- Tert-butyl

[5-(5-甲酰胺基 -2-氧代 -1，2-二氢- 吲哚 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基 ]-氨基甲酸叔丁 [5-(5-carboxamido-2-oxo-1,2-dihydro-indol-3-methylene)-2-methyl-4-trifluoromethyl-1H-pyrrole-3- Tert-butyl carbamate

[5-(5-氟 -7-甲酰胺基 -2-氧代 -1，2- 二氢 -吲哚 -3-亚甲基 )-2-甲基 -4- 三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯 [5-(5-Fluoro-7-carboxamido-2-oxo-1,2-dihydro-indole-3-methylene)-2-methyl-4-trifluoromethyl-1H- Pyrrol-3-yl]-carbamic acid tert-butyl ester

[5-(7-乙酰胺基 -5-氟 -2-氧代 -1,2- 二氢-吲哚 -3-亚甲基) -2-甲基 -4- 三氟甲基 -1H-吡咯 -3-基] -氮基甲酸叔丁酯 [5-(7-Acetylamino-5-fluoro-2-oxo-1,2-dihydro-indole-3-methylene)-2-methyl-4-trifluoromethyl-1H- Tert-butyl pyrrol-3-yl]-carbocarboxylate

[5-(7-漠 -5-氟 -2-氧代 -1，2-二氢- 吲哚 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯 [5-(7-Di-5-fluoro-2-oxo-1,2-dihydro-indol-3-methylene)-2-methyl-4-trifluoromethyl-1H-pyrrole- 3-yl]-carbamic acid tert-butyl ester

{5-[5-氟 -6-(2-羟基 -乙酰胺基) - 2- 氧代 -1，2-二氢 -吲哚 -3-亚甲基] -2-甲基 -4-三氟甲基 -1H-吡咯 -3- 基] -氨基甲酸叔丁酯 {5-[5-Fluoro-6-(2-hydroxy-acetamido)-2-oxo-1,2-dihydro-indol-3-methylene]-2-methyl-4-tri Fluoromethyl-1H-pyrrol-3-yl]-carbamic acid tert-butyl ester

{5-[5-氟 -6-(2-甲氧基乙酰胺基) - 2-氧代 -I,²-二氢 -吲哚 -3-亚甲基] -2-甲基 -4-三氟甲基 -1H-吡咯 -3-

基] -氨基甲酸叔丁酯 [5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 {5-[5-Fluoro-6-(2-methoxyacetamido)-2-oxo-I, ² -dihydro-indole-3-methylene]-2-methyl-4- Trifluoromethyl-1H-pyrrole-3-

Tert-butyl carbamate [5-(5-fluoro-2-oxo-1,2-dihydro-indole)

-3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-yl]-氨基甲酸 -2-二乙 -3-methine)-2-methyl-4-trifluoromethyl-1H-pyrrole-3-yl]-carbamic acid-2-diethyl

[5-(7-溴 -5-氟 -2-氧代 -1，2-二氢- 吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-yl〗-氨基甲酸 -2-二乙氨基乙酯 [5-(7-Bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole- 3-yl-carbamic acid-2-diethylaminoethyl ester

{5-[4-(2,3-氟苯基 )-2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 - 1H-吡咯 -3-基} -氨基甲酸 -2-二乙氨基乙酯 {5-[4-(2,3-Fluorophenyl)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-2-methyl-4-trifluoromethyl- 1H-pyrrol-3-yl}-carbamic acid-2-diethylaminoethyl ester

{5-[5-氟 -6-(2-径基-酰胺基 )-2-氧代 -1，2-二氢 -吲哚 -3-次甲基 ]-2- 甲基 -4-三氟甲基 -1H-吡咯 -3- 基氨基甲酸 -2-二乙氨基乙酯{5-[5-Fluoro-6-(2-diabase-amido)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-2-methyl-4-tri Fluoromethyl-1H-pyrrol-3-ylcarbamic acid-2-diethylaminoethyl ester

{5-[5-氟 -6-(2-甲氧基-酰胺基) -2- 氧代 -1，2-二氢 -吲哚 -3-次甲基] -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基氨基甲酸 -2-二乙氨基乙酯 {5-[5-Fluoro-6-(2-methoxy-amido)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-2-methyl-4- Trifluoromethyl-1H-pyrrol-3-ylcarbamic acid-2-diethylaminoethyl ester

{5-[5-(2-甲'氧基-酰胺基 )-2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基氨基甲酸 -2-二乙氨基乙酯 {5-[5-(2-Methoxy-amido)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-2-methyl-4-trifluoromethyl 2-H-pyrrol-3-ylcarbamic acid-2-diethylaminoethyl ester

4-(4-{3-[5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲¾-4-三氟甲基 -1H-吡咯 -3-基] -酰脲基笨氧基) -嘧啶 -2-羧酸甲酯4-(4-{3-[5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl 3⁄4-4-trifluoromethyl- Methyl 1H-pyrrol-3-yl]-acylureido-p-oxy)pyrimidine-2-carboxylate

4-[4-(3-{5-[5-氟 -6-(2-羟基酰胺基) -²-氧代 -1,²-二氢 -吲哚 -3-次甲基] -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基} -酰脲基苯氧基) -嘧啶

-2-羧酸甲酯 [5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 4- [4- (3- {5- [5-fluoro-6- (2-hydroxy-amido) - ² - oxo-1, ² - dihydro - indol-3-methylene] -2- Methyl-4-trifluoromethyl-1H-pyrrol-3-yl}-acylureidophenoxy)-pyrimidine

Methyl 2-carboxylate [5-(5-fluoro-2-oxo-1,2-dihydro-indole)

-3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸 -2-吡咯烷小乙酯 3-Methylmethyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3-yl]-carbamic acid-2-pyrrolidine small ethyl ester

5-[4-(2,3-二氟苯基) -2-氧代 -1,2- 二氢 -吲哚 -3-次甲基] -2-甲基 -4- 三氟甲基 -1H-吡咯 -3-基氨基甲

酸 -2-吡咯烷 -1-乙酯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。 5-[4-(2,3-difluorophenyl)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-2-methyl-4-trifluoromethyl- 1H-pyrrol-3-ylcarbamate

Acid-2-pyrrolidine-1-ethyl ester In another aspect of the invention, a pharmaceutical composition comprising a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable Acceptable carrier.

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。 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.

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。 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.

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 ^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， ^风湿性关节炎，血管生成，心血管病， Von-Heppel-Lindau 氏病，炎症，纤维变性病。与蛋白质潋酶有关的疾病还可以是鳞状细胞癌，肾细胞癌， Kaposi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，结肠直肠癌和卵巢癌。优选的，所述的哺乳动物是人。 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. Related to protein kinases ^ Diseases can also be leukemia, diabetes, autoimmune diseases, hyperproliferative diseases, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, cardiovascular disease, Von-Heppel-Lindau's disease, inflammation, Fibrosis disease. The disease associated with protein chymase may also be squamous cell carcinoma, renal cell carcinoma, Kaposi sarcoma, non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid cancer, breast cancer, head and neck cancer, uterine cancer, esophageal cancer, black Cancer, bladder cancer, genitourinary cancer, gastrointestinal cancer, glial cancer, colorectal cancer and ovarian cancer. Preferably, the mammal is a human.

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， Von-Heppel-Lindau 氏病，炎症或纤维变性病；或者所述与蛋白激酶有关的疾病焉癌症，选自鳞状细胞癌，肾细胞癌， Kaposi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。 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 to a mammal in need of treatment a therapeutically effective amount of another selected from the group consisting of taxol Or carboplatin anticancer drugs. 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, bone and joint Inflammation, rheumatoid arthritis, angiogenesis, cardiovascular disease, Von-Heppel-Lindau's disease, inflammatory or fibrotic disease; or the protein kinase-related disease, cancer, selected from squamous cell carcinoma, kidney cells Cancer, Kaposi 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.

在本发明的另一个方面，是制备通式 (I)所述化合物的方法，包括以下步骤：将三氟甲基化合物 a环合生成三氟甲基化合物 c； In another aspect of the invention, there is provided a process for the preparation of a compound of the formula (I), comprising the steps of: cyclizing a trifluoromethyl compound a to form a trifluoromethyl compound c;

将所述的三氟甲基化合物 c由无机碱选择性水解成化合物 d; Selectively hydrolyzed said trifluoromethyl compound c from an inorganic base to compound d;

将三氟甲基化合物 e由 PCC氧化成化合物 f。

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 The trifluoromethyl compound e is oxidized from PCC to compound f.

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

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。 "垸基 "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、戊基登。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。烷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、低级烷氧基、芳基、芳氧基、杂芳基、杂环烷基、 -OR₈、 -NR₈R₉、 -COR₈、 -NR₈COR₉和 -S0₂N R₉。 Unless otherwise stated, the following terms used in the specification and claims have the following meanings. "Mercapto" refers to 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, pentyldenyl. 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. The alkyl group may be substituted or unsubstituted, and when substituted, preferred groups are halogen, hydroxy, lower alkoxy, aryl, aryloxy Alkyl, heteroaryl, heterocycloalkyl, -OR ₈ , -NR ₈ R ₉ , -COR ₈ , -NR ₈ COR ₉ and -S0 ₂ NR ₉ .

"环烷基"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，单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、环己烷、环己二烯、金刚垸、环庚烷、环庚三烯等。环垸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，独立地选自由低级烷基、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、低级垸基或低级烷氧基)、 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、低级垸基或低级垸氧基)、或 5或 6元杂环烷基 (具有 1 至 3个选自氮、氧和硫地杂原子，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、低级垸基或低级垸氧基)、巯基、（低级垸基)硫基、氰基、硝基、羧酸、羧酸酯、 -OR₈、 -NR₈R₉、 -COR₈、 -N ₈COR₉和 -S0₂N ₈R₉。 "Cycloalkyl" means a 3 to 8 membered all carbon monocyclic, all carbon 5/6 or 6/6 fused or polycyclic fused ring ("fused" ring system means each in the system The rings share 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, and none of the rings have a fully conjugated pi-electron system. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene and the like. The cycloalkyl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more substituents independently selected from lower alkyl, trihaloalkyl, halogen, hydroxy, lower alkoxy, aryl (optionally selected from one or more groups) a group substituted, 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, a hydroxyl group, Lower alkyl or lower alkoxy), 6-membered heteroaryl (having from 1 to 3 nitrogen atoms in the ring, the carbon in the ring is optionally substituted by one or more groups, the substituents being independently of each other halogen, a hydroxy, lower sulfhydryl or lower alkoxy), 5-membered heteroaryl (having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, the carbon and nitrogen atoms of which are optionally one or more Substituted, the substituents are, independently of each other, halogen, hydroxy, lower fluorenyl or lower decyloxy), or 5 or 6 membered heterocycloalkyl (having from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, The carbon and nitrogen atoms of the group, if any, are optionally substituted by one or more groups, substituting Is independently halogen, hydroxy, lower alkyl with or lower embankment group), a mercapto group, a (lower embankment yl) thio, cyano, nitro, carboxylic acid, carboxylic _{_{_{ester, -OR 8, -NR 8 R 9}}} , -COR ₈ , -N ₈ COR ₉ and -S0 ₂ N ₈ R ₉ .

"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垸基。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、 -OR₈、 -NR₈R₉、 -COR₈、 -NR₈COR₉和 -S0₂NR₈R₉。 "Alkenyl" means a fluorenyl 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, etc. 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 ₈ , -NR ₈ R ₉ , -COR ₈ , -NR ₈ COR ₉ and -S0 ₂ NR ₈ R ₉ .

"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垸基。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、垸基、羧酸、羧酸酯、 -OR₈、 -NR₈R₉、 -COR₈、 -NR₈COR₉ 和 -S0₂NR₈R₉。 "Alkynyl" means a fluorenyl 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, etc. The alkynyl group may be optionally substituted by one or more substituents selected from the group consisting of: halogen, trihalomethyl, hydroxy, nitro, cyano, alkane Oxyl, decyl, carboxylic acid, carboxylic acid ester, -OR ₈ , -NR ₈ R ₉ , -COR ₈ , -NR ₈ COR ₉ and -S0 ₂ NR ₈ R ₉ .

"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机任选取代：卤素、三卤甲基、羟基、硝基、氰基、烷氧基、垸基、羧酸、羧酸酯、 -OR₈、 -NR₈R₉、 -COR₈、 -NR₈COR₉和 -S0₂NR₈R₉。 "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 substitution machines selected from the group consisting of halogen, trihalomethyl, hydroxy, nitro, cyano, alkoxy, decyl, carboxylic acid, carboxylic acid ester, -OR ₈ , -NR ₈ R ₉ , -COR ₈ , -NR ₈ COR ₉ and -S0 ₂ NR ₈ R ₉ .

"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-烧基吡咯基、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、 -OR₈、 -NR₈R₉、 -COR₈、 -NR₈COR₉ 和 -S0₂ ¾R9。 "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 the heterocyclic aryl group include a furyl group, a thienyl group, a pyridyl group, a pyrrole, an N-alkyl pyrrolyl group, a pyrimidinyl group, a pyrazinyl group, an imidazolyl group and the like. Place 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 ester, -OR ₈ , -NR ₈ R ₉ , -COR ₈ , -NR ₈ COR ₉ and -S0 ₂ 3⁄4R9.

"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、哌嗪子基、吗啉基、硫代吗啉基、髙哌嗪其等、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、垸氧基、烷基、羧酸、羧酸酯、 -OR₈、 -NR₈R₉、 -COR₈、 -NR₈COR₉ 和 -S0₂N¾R9。 "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, piperazino, morpholinyl, thiomorpholinyl, piperazine, etc., heterocycloalkyl can be substituted or Unsubstituted. When substituted, the substituent is preferably one or more substituents selected from the group consisting of: halogen, trihalomethyl, hydroxy, nitro, cyano, decyloxy, alkyl, carboxylic acid, carboxylic acid Ester, -OR ₈ , -NR ₈ R ₉ , -COR ₈ , -NR ₈ COR ₉ and -S0 ₂ N3⁄4R9.

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

"烧氧基，，指 -O- (烷基)和 -O- (未取代地环垸基)。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。所述的垸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、垸氧基、垸基、羧酸、羧酸酯、 -OR₈、 -NR₈R₉、 -COR₈、 -NR₈COR₉ 和 -S0₂NR8R₉。 '. "Alkoxy, means -O-(alkyl) and -O- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, Cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc. The oximeoxy 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 ester, -OR ₈ , -NR ₈ R ₉ , -COR ₈ , -NR ₈ COR ₉ and -S0 ₂ NR8R ₉ .

"卤代烷氧基 "指 -O- (卤代垸基)。代表性实例包括但不限于三氟甲氧基、三溴甲氧基等。 . "Haloalkoxy" means -O-(halofluorenyl). 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、垸氧基、垸基、羧酸、羧酸酯、 -OR₈、 -NR₈R₉、 -COR₈、 -NR₈COR₉和 -S0₂ R₈R₉。 "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, decyloxy, decyl, carboxylic acid, carboxylic acid esters. , -OR ₈ , -NR ₈ R ₉ , -COR ₈ , -NR ₈ COR ₉ and -S0 ₂ R ₈ R ₉ .

"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 -C¾，其中 X是如上所定义的卤素。 "Trihalomethyl" means -C3⁄4, wherein X is a halogen as defined above.

"可选 "或"可选地 "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地场合。例如， "可选被垸基取代地杂环基团" 意味着烷基可以但不必存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被垸基取代的情形。 "Optional" or "optionally" 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 a fluorenyl group to a heterocyclic group" means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with a thiol 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，本发明采用如下技术方案： "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. Method for synthesizing the compound of the present invention In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:

为了制备本发明所述的化合物，主要用下述一般合成方法来完成： In order to prepare the compounds of the present invention, the following general synthetic methods are used:

将原料 a在醋酸存在下与亚硝酸钠反应得到化合物 b; 化合物 b与 3-羰基- 丁酸-叔丁酯在锌粉作用下环合得到化合物 c; 以四氢呋喃、甲醇和水做溶剂，化合物 c在氢氧化钾作用下发生酯水解得到化合物 d;化合物 d经硼烷还原得到化合物 e; 化合物 e经 PCC氧化成醛化合物 f;进一步，化合物 f在三氟乙酸的作用下脱去叔丁基后得到化合物 g; 接下来，化合物 g与不同的胺反应得到酰胺化合物 h; 最后，化合物 h与不同取代的吲哚酮缩合就制得通式 (I)所示的化合物。

The raw material a is reacted with sodium nitrite in the presence of acetic acid to obtain a compound b; the compound b and 3-carbonyl-butyric acid-tert-butyl ester are cyclized under the action of zinc powder to obtain a compound c; using tetrahydrofuran, methanol and water as a solvent, the compound c is ester-hydrolyzed by potassium hydroxide to obtain compound d; compound d is reduced by borane to obtain compound e; compound e is oxidized by PCC to aldehyde compound f; further, compound f is de-t-butyl group under the action of trifluoroacetic acid Thereafter, compound g is obtained; next, compound g is reacted with a different amine to obtain amide compound h; finally, compound h is condensed with a differently substituted anthrone to obtain a compound of the formula (I).

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 H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 H 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。 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 from the nuclear magnetic data. Usually, the chemical shift of H 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 H to shift to the lower field. This is also described in the patent WO0160814 (Su-11248).

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 The invention is further described below in conjunction with the examples, but these examples are not intended to limit the scope of the invention. Example

本发明涉及的所有衍生化合物的结构是通过核磁共振 ( MR)或质谱 (MS)来确定的。 MR位移 (δ)以百万分之一 (ppm)的单位给出。 NMR的测定是用 Bruker 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 structure of all derivative compounds involved in the present invention is determined by nuclear magnetic resonance (MR) or mass spectrometry (MS). The MR displacement (δ) is given in parts per million (ppm). NMR is determined by Bruker AVANCE-400 NMR instrument, measurement solvent was deuterated chloroform (CDC1 _3), deuterated dimethyl sulfoxide (DMSO-D _6), the internal standard tetramethylsilane (TMS), chemical shifts are ^10-6 ( Ppm) is given as a unit.

MS的测定用 FINNIGAN LCQAd (ESI)质谱仪。 The MS was measured using a FINNIGAN 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;

PCC: 吡啶三氧化铬盐酸盐制备实施例: 实施例 1 PCC: Pyridine trioxide hydrochloride Preparation Examples: Example 1

-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 -(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylate Acid

-(2-二乙胺基-乙基) -酰胺 -(2-diethylamino-ethyl)-amide

4,4,4-三氟 -2-肟基 3-羰基-丁酸乙酯

4,4,4-trifluoro-2-indolyl 3-carbonyl-butyrate

冰浴条件下，将 4,4,4-三氟 -3-羰基-丁酸乙酯 la(3.822 g， 20.75 mmol)和冰醋酸 (6 ml)加入到 100 ml的圆底烧瓶中，搅拌下逐滴滴加亚硝酸钠的水溶液 (1.43 g, 20.75 mmol溶解在 4 ml水中)，在整个过程中控制反应温度为 0〜5°C ,滴加结束后，再加水 (1 ml), 于冰水浴中反应半小时，撤去冰水浴，在室温下继续反应约 3小时，点板跟踪至原料消失，反应结束，得到标题产物 4，4,4-三氟 -2-肟基 3-羰基-丁酸乙酯 lb的溶液，直接投下一步反应。 4,4,4-trifluoro-3-carbonyl-butyrate ethyl la (3.822 g, 20.75 mmol) and glacial acetic acid (6 ml) were added to a 100 ml round bottom flask under ice-cooling, stirring An aqueous solution of sodium nitrite (1.43 g, 20.75 mmol dissolved in 4 ml of water) was added dropwise, and the reaction temperature was controlled to 0 to 5 ° C throughout the process. After the addition, water (1 ml) was added to the ice. The reaction was carried out in a water bath for half an hour, the ice water bath was removed, the reaction was continued at room temperature for about 3 hours, the spot was traced until the starting material disappeared, and the reaction was completed to obtain the title product 4,4,4-trifluoro-2-indolyl 3-carbonyl-butyl A solution of ethyl lbate is directly administered to the next reaction.

5-甲基 -3-三氟甲基 -1氢-吡咯 -2,4二羧酸 -4-叔丁酯 -2-乙酯取一个配有温度计，滴液漏斗的 loo _mi的三颈烧瓶，称取 3-羰基 -丁酸 -叔丁酯 (3.28g， 20.75mmol), 冰醋酸 (9.3 ml)于三颈瓶中，搅拌下升温至 65°C , 称量锌粉 (2.7 g， 41.5 mmol), 用滴液漏斗滴加第一步反应的反应液 lb，分多次加入锌粉，水浴控制体系温度保持在 75'C左右，反应 2小时,然后降低温度到 40〜45Ό，反应过夜。点板跟踪反应结束，在反应液中加入水 (30 ml)和乙酸乙酯 (50 ml), 搅拌 15分钟后，用乙酸乙酯 (50 mlx3)萃取反应液。合并有机相，依次用水 (50 mlx2)、饱和碳酸氢钠水溶液 (50 mlx2)、饱和氯化钠水溶液 (50 mlx2)洗涤，乙酸乙酯层用无水硫酸钠干燥，过滤，减压浓缩，残余物用甲苯-正己垸重结晶得到标题产物 5-甲基 -3-三氟甲基 -1氢 -吡咯 -2,4二羧酸 -4-叔丁酯 -2-乙酯 lc(3.66 g，白色絮状固体)，产率： 55%。 5-methyl-3-trifluoromethyl-1H - pyrrole-2,4-dicarboxylic acid 4-tert-butyl ester ethyl ester -2- taken equipped with a thermometer, a dropping funnel, a three-necked loo _m i The flask was weighed to 3-carbonyl-butyric acid-tert-butyl ester (3.28 g, 20.75 mmol), glacial acetic acid (9.3 ml) in a three-necked flask, and the mixture was heated to 65 ° C with stirring, and zinc powder (2.7 g, 41.5 mmol), the reaction solution lb of the first step reaction was added dropwise with a dropping funnel, and the zinc powder was added in multiple portions. The temperature of the water bath control system was maintained at about 75 ° C for 2 hours, and then the temperature was lowered to 40 to 45 Torr. overnight. The reaction was completed by the spotting, and water (30 ml) and ethyl acetate (50 ml) were added to the mixture, and the mixture was stirred for 15 minutes, and then the mixture was extracted with ethyl acetate (50 ml×3). The combined organic layers were washed with EtOAc EtOAc EtOAc (EtOAc m. Recrystallization from toluene-n-hexane gave the title product 5-methyl-3-trifluoromethyl-1 hydrogen-pyrrole-2,4dicarboxylic acid-4-tert-butyl ester-2-ethyl ester lc (3.66 g, White flocculent solid), Yield: 55%.

MS m/z (ESI): 320(M-l MS m/z (ESI): 320 (M-l

1H NMR ( 400 MHz, CDCl₃-d ) 9.94 (brs,lH， NH), 4.37(q, J=7.2Hz, 2H， CH2CH3), 2.45(s, 3H, CH3), 1.56(s，9H, 3 CCH3), 1.37(t, J=7.2Hz, 3H,。¾0¾)。 ' 1H NMR ( 400 MHz, CDCl ₃ -d ) 9.94 (brs, lH, NH), 4.37 (q, J = 7.2 Hz, 2H, CH2CH3), 2.45 (s, 3H, CH3), 1.56 (s, 9H, 3 CCH3), 1.37 (t, J = 7.2 Hz, 3H, .3⁄403⁄4). '

5-甲基 -3-三氟甲基 -1氢 -吡咯 -2，4二羧酸 -4-叔丁酯在 1000 ml的圆底烧瓶中分别加入 5-甲基 -3-三氟甲基 -1氢-吡咯 -2，4二羧酸 -4-叔丁酯 -2-乙酯 lc(19.0 g, 59.2 mmol)、四氢呋喃 (150 ml)、水 (60 ml)及醋酸 (2 ml), 搅拌下加入硝酸铈铵 (14.2g， 25.4 mmol), 混合物在 60°C下搅拌 3小时后反应完毕。加入 5%碳酸氢钠溶液调节 pH值至弱碱性，再用乙酸乙酯 (50 mlx3)萃取液，合并的有机相用饱和氯化钠洗漆 (50 mlx3)，无水硫酸钠干燥，过滤，减压下浓缩得到的粗品通过柱层析 (正己烷：乙酸乙酯 = 10: 1)进一步分离纯化得到 5-羟甲基 -3-三氟甲基 -1氢 -吡咯 -2，4二羧酸 -4-叔丁酯 ld(120 mg，黄色固体)，产率 56%。 5-methyl-3-trifluoromethyl-1hydro-pyrrole-2,4dicarboxylic acid-4-tert-butyl ester was added to a 1000 ml round bottom flask with 5-methyl-3-trifluoromethyl -1 hydrogen-pyrrole-2,4dicarboxylic acid-4-tert-butyl ester-2-ethyl ester lc (19.0 g, 59.2 mmol), tetrahydrofuran (150 ml), water (60 ml), and acetic acid (2 ml), Ammonium cerium nitrate (14.2 g, 25.4 mmol) was added with stirring, and the mixture was stirred at 60 ° C for 3 hours and the reaction was completed. Add 5% sodium bicarbonate solution to adjust the pH to weakly alkaline, then extract with ethyl acetate (50 ml×3). The combined organic phases are washed with saturated sodium chloride (50 ml×3), dried over anhydrous sodium sulfate, filtered The crude product obtained by concentration under reduced pressure was further purified by column chromatography (hexane: ethyl acetate = 10:1) to give 5-hydroxymethyl-3-trifluoromethyl-1 hydrogen-pyrrole-2,4 Carboxylic acid 4-tert-butyl ester ld (120 mg, yellow solid), yield 56%.

5-羟甲基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -4-叔丁酯氮气氛下，在 250 ml 圆底烧瓶中，将 5-甲基 -3-三氟甲基 -1氢 -吡咯 -2,4二羧酸 _4-叔丁酯 ld(9.8 g, 33.4 mmol)搅拌下溶解于无水四氢呋喃 (20 ml)中，向反应液中滴加硼烷的四氢呋喃溶液 (67 ml， 1 mol/L, 67 mmol), 室温搅拌 4小时。点板跟踪至原料消失，向反应液中慢慢滴加稀醋酸 (2 ml, 50% v/v)以淬灭反应，再加入乙酸乙酯 (200 ml),用饱和碳酸氢钠溶液提取反应液 (100 mlx3 合并有机相，乙酸乙酯层用无水硫酸镁干燥，过滤，滤液减压浓缩，用硅胶柱色谱法纯化所得残余物 (乙酸乙酯 /正己垸 =1 : 4)，得到标题产 5-羟甲基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -4-叔丁酯 le(5.0 g, 白色固体)，产率 55%。 5-Hydroxymethyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-4-tert-butyl ester 5-methyl in a 250 ml round bottom flask under nitrogen atmosphere -3-trifluoromethyl-1 hydrogen-pyrrole-2,4 dicarboxyl Acid 4-tert-butyl ester ld (9.8 g, 33.4 mmol) was dissolved in anhydrous tetrahydrofuran (20 ml) with stirring, and a solution of borane in tetrahydrofuran (67 ml, 1 mol/L, 67 mmol) was added dropwise to the reaction mixture. ), stirred at room temperature for 4 hours. The plate was traced until the starting material disappeared. Dilute acetic acid (2 ml, 50% v/v) was slowly added dropwise to the reaction mixture to quench the reaction. Then ethyl acetate (200 ml) was added and the mixture was extracted with saturated sodium hydrogen carbonate solution. The mixture was combined with EtOAc EtOAc (EtOAc m. 5-Hydroxymethyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid-4-tert-butyl ester le (5.0 g, white solid), yield 55%.

MS m/z (ESI): 278(M-1)。 MS m/z (ESI): 278 (M-1).

1H NMR ( 400 MHz, CDCl₃-d ) 8.05 (brs,lH, NH), 4.80(s, 2H, CH2OH), 2.47(s, 3H, CH3), 1.55 (s;9H, 3?^ )。 1H NMR (400 MHz, CDCl ₃ -d) 8.05 (brs,lH, NH), 4.80 (s, 2H, CH2OH), 2.47 (s, 3H, CH3), 1.55 (s; 9H, 3?).

5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -4-叔丁酯将吡啶三氧化铬盐酸盐 (4.3 g， 19.99 mmol),醋酸钠 (1.0 g， 12.36 mmol)及二氯甲浣 (50 ml)加至一个 250 ml 圆底烧瓶中，搅拌下缓慢滴加 5-羟甲基 -2-甲基 -4- 三氟甲基 -1氢 -吡咯 -3-羧酸 -4-叔丁酯 le的二氯甲烷混悬溶液 (5.0 g， 80 ml), 室温反应 5小时，点板跟踪原料基本消失。反应液经硅藻土过滤，减压浓缩，用硅胶柱色谱法纯化所得残余物 (乙酸乙酯 /正己烷 =1 : 8), 得到标题产物 5-甲酰基 -2- 甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -4-叔丁酯 'lf(3.51 g, '白色固体)，产率 70%。 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-4-tert-butyl ester pyridine trioxide hydrochloride (4.3 g, 19.99 mmol), sodium acetate (1.0 g, 12.36 mmol) and methylene chloride (50 ml) were added to a 250 ml round bottom flask, and 5-hydroxymethyl-2-methyl-4-trifluoromethyl-1 was slowly added dropwise with stirring. A suspension of hydrogen-pyrrole-3-carboxylic acid-4-tert-butyl ester le in dichloromethane (5.0 g, 80 ml) was reacted at room temperature for 5 hours, and the material was almost disappeared by the spotting. The reaction mixture was filtered over EtOAc EtOAcjjjjjjjj Fluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid-4-tert-butyl ester 'lf (3.51 g, 'white solid), yield 70%.

MS m/z (ESI): 276(M-l MS m/z (ESI): 276 (M-l

Ή NMR ( 400 MHz, CDCl₃-d ) 9.83 (s, 1H,CH0), 9.57 (brs,lH, NH), 2.57(s, 3H, CH3), 1.57 (s,9H, 3xCCH3 NMR NMR ( 400 MHz, CDCl ₃ -d ) 9.83 (s, 1H, CH0), 9.57 (brs, lH, NH), 2.57 (s, 3H, CH3), 1.57 (s, 9H, 3xCCH3

5-甲酰基 -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid

在 100 ml的三口瓶中，将 5-甲酰基 -2-甲基 -4-三氟甲基 -1氧-吡咯 -3-羧酸 -4- 叔丁酯 lf(3.5 g， 12.67 mmol)溶解于二氯甲烷 (35 ml)中，搅拌下加入三氟醋酸 (9.4 ml, 126.7 mmol), 室温反应 5小时，点板跟踪原^ )·基本消失，将反应液减压浓缩旋干溶剂，得到标题产物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 lg(2.95 g, 白色固体)，产率 100%。直接用于下一步反应。 Dissolve 5-formyl-2-methyl-4-trifluoromethyl-1 oxo-pyrrole-3-carboxylic acid-4-tert-butyl ester lf (3.5 g, 12.67 mmol) in a 100 ml three-necked flask Trifluoroacetic acid (9.4 ml, 126.7 mmol) was added to dichloromethane (35 ml), and the mixture was reacted at room temperature for 5 hours. The spot was traced to the original ^)·substantially disappeared, and the reaction mixture was concentrated under reduced pressure to dryness solvent. The title product 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid lg (2.95 g, white solid). Used directly in the next step.

MS m/z (ESI) ： 220(M-1)。 MS m/z (ESI): 220 (M-1).

5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-二乙胺基-乙基) -酰胺氮气氛下，在一个 250 ml的三口瓶中，将 5-甲酰基 -2-甲基 -4-三氟甲基 -1葶 -吡咯 -3-羧酸 lg(2.95 g, 12.67 mmol)溶解于 Ν'Ν- 甲基甲酰胺 (40 ml)中，搅拌十依次加入 N-乙基 -N，- (二甲氨基丙基) -碳二亚胺盐酸盐 (3.64 g， 19.00 mmol)、 1-羟基苯并*** (2.57 g， 19.00 mmol)>三乙胺 (3.2 g, 31.68 mmol)及二乙胺基乙胺 (2·20 g, 19.00 mmol), 室温搅拌 8小时，点板跟踪至原料基本消失，搅拌下向反应液中加入二氯甲烷 (200 ml), 用饱和碳酸氢钠溶液 (80 mlx3)洗涤混合液，合并水层用二氯甲烷 (80 mlxl)回萃。合并有机相，二氯甲垸层用无水硫酸钠干燥，过滤，滤液减压浓缩标题产物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 -(2-二乙胺基-乙基) -酰胺 lh(5.1 g，油状物)，直接进行下一步反应。 .■ ' 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-(2-diethylamino-ethyl)-amide under nitrogen atmosphere, in a 250 ml three-neck In a flask, 5-formyl-2-methyl-4-trifluoromethyl-1葶-pyrrole-3-carboxylic acid lg (2.95 g, 12.67 mmol) was dissolved in Ν'Ν-methylformamide (40 In ml), N-ethyl-N,-(dimethylaminopropyl)-carbodiimide hydrochloride (3.64 g, 19.00 mmol), 1-hydroxybenzotriazole (2.57 g, 19.00 mmol)>Triethylamine (3.2 g, 31.68 mmol) and diethylaminoethylamine (2·20) g, 19.00 mmol), stirred at room temperature for 8 hours, the plate was traced until the starting material disappeared, dichloromethane (200 ml) was added to the reaction mixture with stirring, and the mixture was washed with saturated sodium hydrogen carbonate solution (80 ml×3), and water was combined. The layers were extracted with dichloromethane (80 ml x 1). The organic phase was combined, the methylene chloride layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated to give the title product 5-formyl-2-methyl-4-trifluoromethyl-1 -hydro-pyrrole-3-carboxylic acid -(2-Diethylamino-ethyl)-amide lh (5.1 g, oil), directly to the next reaction. .■ '

MS m/z (ESI) ： 320(M+1)。 , ' MS m/z (ESI): 320 (M+1). , '

5-(5-氟 -2-氧代 -1，2-二氢 -吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3- Carbohydrate

-(2-二乙胺基-乙基) -酰胺 -(2-diethylamino-ethyl)-amide

将上一步产物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-二乙胺基- 乙基) -酰胺 lh(5.1 g)不经纯化直接溶解于乙醇 (10 ml)中，搅拌下加入 5-氟 -1,3-二氢 -吲哚 -2-酮 (1.53 g， 10.14 mmol)及六氢吡啶 (85 mg， 1.01 mmol), 加热回流 8 小时，点扳跟踪至原料基本消失，反应液自然冷却至室温，有黄色固体产生，过滤，固体用冷乙醇 (2 mlx2)洗涤，真空干燥，得到标题产物 5-(5-氟 -2-氧代 -1,2- 二氢』引哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-二乙胺基-乙基) - 酰胺 1(3.4 g，黄色固体)，产率 55%。 The product of the previous step, 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-(2-diethylamino-ethyl)-amide lh (5.1 g) Purified directly in ethanol (10 ml), and added 5-fluoro-1,3-dihydro-indol-2-one (1.53 g, 10.14 mmol) and hexahydropyridine (85 mg, 1.01 mmol) with stirring. The mixture was heated to reflux for 8 hours, and the mixture was traced until the starting material disappeared. The reaction mixture was allowed to cool to room temperature, and a yellow solid was obtained, which was filtered, and the solid was washed with cold ethanol (2 ml×2) and dried in vacuo to give the title product 5-(5-fluoro -2-oxo-1,2-dihydro"indol-3-anoyl-methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-(2- Diethylamino-ethyl)-amide 1 (3.4 g, yellow solid), yield 55%.

MS m/z (ESI) ： 453(M+1)。 MS m/z (ESI): 453 (M+1).

1H NM ( 400 MHz, DMSO-d6 ) 7.61(d, J = 8.4Hz,lH, ArH), 7.57 (s, 1H,CH), 7.07 (m，lH, ArH), , 6.92(m,lH, ArH), 3.28 (t, J= 6.8Hz, 2H， Ν 。Η₂ Εί₂), 2.51 (m, 6H: 2x NCHzCHi and ₂), 2.39 (s, 3H, CH3), 0.97 (t， J = 6.8Hz, 6H， 2x

实施例 2 1H NM ( 400 MHz, DMSO-d6 ) 7.61 (d, J = 8.4 Hz, lH, ArH), 7.57 (s, 1H, CH), 7.07 (m, lH, ArH), , 6.92 (m, lH, ArH ), 3.28 (t, J= 6.8Hz, 2H, Ν.Η ₂ Εί ₂ ), 2.51 (m, 6H: 2x NCHzCHi and ₂ ), 2.39 (s, 3H, CH3), 0.97 (t, J = 6.8Hz) , 6H, 2x

Example 2

5-(5-氯 -2-氧代 -1,2-二氢 -吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 5-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3- Carbohydrate

-(2-二乙胺基-乙基) -酰胺 -(2-diethylamino-ethyl)-amide

重复本发明实施例 1第一步至第七步的反应，不同的是使用上述第七步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 -(2-二乙胺基-乙基) - 酰胺 lh作原料，按照本发明实施例 1第八步所述相同方式使得该原料与 5-氯 -1，3- 二氢 -吲哚 -2-酮的反应，则得到标题产物 5-(5-氯 -2-氧代 -1,2-二氢 - 哚 -3-亚基-甲基 )_2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-二乙胺基-乙基) -酰胺 2(98 mg, 黄色固体)，产率： 35.4%。

The reaction of the first to seventh steps of Example 1 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole obtained in the above seventh step was used. 3-carboxylic acid-(2-diethylamino-ethyl)-amide lh as a starting material, the starting material and 5-chloro-1,3-dihydrogen are obtained in the same manner as described in the eighth step of Example 1 of the present invention. -Indole-2-one reaction, the title product 5-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene-- 2,2-Methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-(2-diethylamino-ethyl)-amide 2 (98 mg, yellow solid), Yield: 35.4 %.

MS m/z (ESI): 469(M+1)。 MS m/z (ESI): 469 (M + 1).

1H NMR ( 400 MHz, DMSO-d6 ) 57.83(s, IH, ArH), 7.62 (s, 1H,CH), 7.27 (d, J= 8.4Hz，lH， ArH), 6.94(d, J= 8.4Hz,lH, ArH), 3.28 (t, J= 6.8Hz, 2H, 1H NMR (400 MHz, DMSO-d6) 57.83 (s, IH, ArH), 7.62 (s, 1H, CH), 7.27 (d, J = 8.4 Hz, lH, ArH), 6.94 (d, J = 8.4 Hz ,lH, ArH), 3.28 (t, J= 6.8Hz, 2H,

NCH2CH₂NEt₂), 2.51 (m, 6H, 2XNCH2CH3 and 戮₂)， 2.39 (s， 3H， CH3), 0.97 (t_: J= 6.8Hz, 6H, 2xNCH₂CH₃) c 实施例 3 NCH2CH ₂ NEt ₂ ), 2.51 (m, 6H, 2XNCH2CH3 and 戮₂ ), 2.39 (s, 3H, CH3), 0.97 (t _: J = 6.8 Hz, 6H, 2xNCH ₂ CH ₃ ) c Example 3

5-(5-漠 -2-氧代 -1,2-二氢』引哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 5-(5-indol-2-oxo-1,2-dihydroindol-3-indolyl-methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3- Carbohydrate

-(2-二乙胺基-乙基) -酰胺 -(2-diethylamino-ethyl)-amide

重复本发明实施例 1第一步至第七步的反应，不同的是使用上述第七步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-二乙胺基-乙基) - 酰胺 lh作原料，按照本发明实施例 1第八步所述相同方式使得该原料与 5-溴 -1,3- 二氢 - |哚 -2-酮的反应，则得到标题产物 5-(5-溴 -2-氧代 -1，2-二氢 -吲哚 -3-亚基-甲基) -2-甲基 -4-三氣甲基 -1氢-吡咯 -3-羧酸 -(2-二乙胺基-乙基) -酰胺 3(124 mg，黄色固体)，产率： 38%。

The reaction of the first to seventh steps of Example 1 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole obtained in the above seventh step was used. 3-carboxylic acid-(2-diethylamino-ethyl)-amide lh as a starting material, the starting material and 5-bromo-1,3-dihydrogen are obtained in the same manner as described in the eighth step of the present invention. - the reaction of indole-2-one gives the title product 5-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl- 4-trimethylmethyl-1 hydrogen-pyrrole-3-carboxylic acid-(2-diethylamino-ethyl)-amide 3 (124 mg, yellow solid), yield: 38%.

MS m/z (ESI)： 513(M)。 MS m/z (ESI): 513 (M).

1H NMR ( 400 MHz, DMSO-d6 ) 67.94(s, 1H, ArH), 7.61 (s, 1H,CH), 7.39 (d, J= 8.4Hz， 1H， ArH), 6.89(d， J= 8.0Hz, 1H, ArH), 3.28 (t, J= 6.8Hz, 2H, 1H NMR (400 MHz, DMSO-d6) 67.94 (s, 1H, ArH), 7.61 (s, 1H, CH), 7.39 (d, J = 8.4 Hz, 1H, ArH), 6.89 (d, J = 8.0 Hz , 1H, ArH), 3.28 (t, J= 6.8Hz, 2H,

NCP^CHaNEtz), 2.51 (m, 6H, 2 NCH2CH3 and 膽2), 2.39 (s, 3H, CH3), 0.97 (t， J= 6.8Hz, 6H, 2xNCH₂CH3) o 实施例 4 NCP^CHaNEtz), 2.51 (m, 6H, 2 NCH2CH3 and biliary 2), 2.39 (s, 3H, CH3), 0.97 (t, J = 6.8 Hz, 6H, 2xNCH ₂ CH3) o Example 4

5-(5-甲磺酰胺 -2-氧代 -1，2-二氢 -H引哚 -3-亚基-甲基) -2-甲基 -4-三镢甲基 -1氢 -吡咯 5-(5-methanesulfonamide-2-oxo-1,2-dihydro-H-indol-3-yl-methyl)-2-methyl-4-trimethyl-1-hydrogen-pyrrole

-3-羧酸 -(2-二乙胺基-乙基) -酰胺

重复本发明实施例 1第一步至第七步的反应，不同的使用上述第七步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-二乙胺基-乙基) -酰胺 lh作原料，按照本发明实施例 1第八步所述相同方式使得该原料与 5-甲磺酰胺 -1,3-二氢 - .哚 -2-酮的反应，则得到标题产物 5-(5-甲磺酰胺 -2-氧代 -1,2-二氢- B引哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-二乙胺基-乙基) -酰胺 4(50 mg, 黄色固体)，产率： 15%。 3-carboxylic acid-(2-diethylamino-ethyl)-amide

The reaction of the first step to the seventh step of Example 1 of the present invention was repeated, and the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole obtained in the above seventh step was used differently. 3-carboxylic acid-(2-diethylamino-ethyl)-amide lh as a starting material, which is obtained in the same manner as described in the eighth step of Example 1 of the present invention, with 5-methanesulfonamide-1,3-di The reaction of hydrogen-.indol-2-one gives the title product 5-(5-methanesulfonamide-2-oxo-1,2-dihydro-B-indole-3-ylidene-methyl)-2 -Methyl-4-trifluoromethyl-1 Hydro-pyrrole-3-carboxylic acid-(2-diethylamino-ethyl)-amide 4 (50 mg, yellow solid). Yield: 15%.

MS ra/z (ESI): 528(M+1)。 MS ra/z (ESI): 528 (M + 1).

1H NMR ( 400 MHz, DMSO-d6 ) . 14.14(s, IH, ΝΉ), 12.23(s, 1H， NH), 9.40(s, 1H， NH), 8.03(s， IH, NH), 7.46(s， IH, ArH), 7.44(d, J = 8.4Hz, IH, ArH), 7.16(d, J = 8.4Hz, IH, ArH), 6.93(d, J = 8.0Hz, IH, ArH), 3.28 (t， J = 6.8Hz, 2H, NCifcCHsNEfe), 2.95(s， 3H， CH3S0₂)₅ 2.51 (m, 6H， 2 NCH2CH3 and CH2NEt₂), 2.40 (s, 3H, CH3), 0.97 (t, J= 6.8Hz, 6H， 2x NCH₂CH3)₀ - 实施例 5 1H NMR (400 MHz, DMSO-d6). 14.14 (s, IH, ΝΉ), 12.23 (s, 1H, NH), 9.40 (s, 1H, NH), 8.03 (s, IH, NH), 7.46 (s , IH, ArH), 7.44 (d, J = 8.4 Hz, IH, ArH), 7.16 (d, J = 8.4 Hz, IH, ArH), 6.93 (d, J = 8.0 Hz, IH, ArH), 3.28 ( t, J = 6.8Hz, 2H, NCifcCHsNEfe), 2.95(s, 3H, CH3S0 ₂ ) ₅ 2.51 (m, 6H, 2 NCH2CH3 and CH2NEt ₂ ), 2.40 (s, 3H, CH3), 0.97 (t, J= 6.8 Hz, 6H, 2x NCH ₂ CH3) ₀ - Example 5

5-(5-乙酰胺 -2-氧代 -1,2-二氢 -吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3- 羧酸 -(2-二乙胺基-乙基) -酰胺 5-(5-acetamide-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3 - Carboxylic acid-(2-diethylamino-ethyl)-amide

重复本发明实施例 1第一步至第七步的反应，不同的是使用上述第七步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-二乙胺基-乙基) - 酰胺 lh作原料，按照本发明实施例 1第八步所述相同方式使得该原料与 5-乙酰胺 -1,3-二氢 -吲哚 -2-酮的反应,则得到标题产物 5-(5-乙酰胺 -2-氧代 -1,2-二氢 -吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-二乙胺基-乙基) -酰胺 5(120 mg, 黄色固体)，产率： 38.7%。

The reaction of the first to seventh steps of Example 1 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole obtained in the above seventh step was used. 3-carboxylic acid-(2-diethylamino-ethyl)-amide lh as a starting material, the starting material is made with 5-acetamide-1,3-di in the same manner as described in the eighth step of Example 1 of the present invention. The reaction of hydrogen-indol-2-one gives the title product 5-(5-acetamide-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl Base-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-(2-diethylamino-ethyl)-amide 5 (120 mg, yellow solid), yield: 38.7%.

MS m/z (ESI) ： 492(M+1)。 MS m/z (ESI): 492 (M+1).

1H NMR ( 400 MHz, DMSO-d6 ) 57.79(s, IH, ArH), 7.44 (d, J = 8.4Hz, IH, ArH), 7.39 (s, IH, CH), 6.88(d, J = 8.0Hz, IH, ArH), 3.28 (t, J = 6量， 2H， NCH2CH₂NEt₂), 2.51 (m， 6H， 2χΝ 。Η₃ and CHaNEtz), 2.38 (s, 3H， C^), 2.04 (s, 3H, CH3CO), 0.97 (t, J= 6.8Hz, 6H， 2xNC¾CH3)° 实施例 6 1H NMR (400 MHz, DMSO-d6) 57.79 (s, IH, ArH), 7.44 (d, J = 8.4 Hz, IH, ArH), 7.39 (s, IH, CH), 6.88 (d, J = 8.0 Hz, IH, ArH), 3.28 (t, J = 6 quantities, 2H, NCH2CH ₂ NEt ₂ ), 2.51 (m, 6H, 2χΝ.Η ₃ And CHaNEtz), 2.38 (s, 3H, C^), 2.04 (s, 3H, CH3CO), 0.97 (t, J= 6.8Hz, 6H, 2xNC3⁄4CH3)° Example 6

5-(6-乙酰胺 -5-氟 -2-氧代 -1，2-二氢 -吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 -(2-二乙胺基-乙基) -酰胺 5-(6-acetamide-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1 hydrogen -pyrrole-3-carboxylic acid-(2-diethylamino-ethyl)-amide

化合物 6-乙酰胺 -5-氟 -1，3-二氢 -B引哚 -2-酮由 6-氨基 -5-氟 -1，3-二氢 -吲哚 -2-酮与等当量的乙酰氯反应制备而成。

Compound 6-acetamide-5-fluoro-1,3-dihydro-B-indol-2-one from 6-amino-5-fluoro-1,3-dihydro-indol-2-one with equivalents Prepared by acetyl chloride reaction.

重复本发明实施例 1 ^一步至第七步的反应，不同的是使用上述第七步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-二乙胺基-乙基) - 酰胺 lh作原料，按照本发明实施例 1第八步所述相同方式使得该原料与 6-乙酰胺 -5-氟 -1,3-二氢 -吲哚 -2-酮的反应,则得到标题产物 5-(6-乙酰胺 -5-氟 -2-氧代 -1,2- 二氢 -吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-二乙胺基-乙基) - 酰胺 6(84 mg，黄色固体)， . 产率： 26%。 The reaction of the first to seventh steps of the present invention was repeated, except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole obtained in the above seventh step was used. 3-carboxylic acid-(2-diethylamino-ethyl)-amide lh as a starting material, the starting material and 6-acetamide-5-fluoro-1 are obtained in the same manner as described in the eighth step of the present invention. The reaction of 3-dihydro-inden-2-one gives the title product 5-(6-acetamide-5-fluoro-2-oxo-1,2-dihydro-indole-3-ylidene)- Methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-(2-diethylamino-ethyl)-amide 6 (84 mg, yellow solid), Rate: 26%.

MS m/z (ESI) ： 510(M+1)。 MS m/z (ESI): 510 (M+1).

1H NMR ( 400 MHz, DMSO-d6 ) 7.71(s, IH, ArH), 7.68 (s, IH, ArH), 7.46 (s, 1H， CH), 3.27 (t, J = 6.8Hz， 2H, NCH₂CH₂NEt₂), 2.51 (m, 6H, 2χΝ。Η^¾ and CHzNEtz), 2.37 (s, 3H, CH3), 2.12 (s, 3H， CH3CO), 0.97 (t, J = 6.8Hz, 6H, 2x NCH₂CH3) c 实施例 7 1H NMR (400 MHz, DMSO-d6) 7.71 (s, IH, ArH), 7.68 (s, IH, ArH), 7.46 (s, 1H, CH), 3.27 (t, J = 6.8 Hz, 2H, NCH ₂ CH ₂ NEt ₂ ), 2.51 (m, 6H, 2χΝ.Η^3⁄4 and CHzNEtz), 2.37 (s, 3H, CH3), 2.12 (s, 3H, CH3CO), 0.97 (t, J = 6.8Hz, 6H, 2x NCH ₂ CH3) c Example 7

5-(5-氟 -2-氧代 -1，2-二氢 -吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3- Carbohydrate

-(2-***啉 -4-基-乙基) -酰胺 -(2-morpholine-4-yl-ethyl)-amide

5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-***啉 -4-基-乙基) -甲酰胺按照本发明实施例 1第七步所述相同方式，氮气氛下，在一个 250 ml的三口瓶中，将 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 lg (0.605 g， 2.73 mmol) 溶解于 N，N-二甲基甲酰胺 (8.5 ml)中，搅拌下依次加入 N-乙基 -N，- (二甲氨基丙基) -碳二亚胺盐酸盐 (1.047 g， 5.46 mmol), 1-羟基苯并*** (553 mg， 2.73 mmol)、三乙胺 (0.689 g， 6.83 mmol)及 N-***啉 -4-基 -乙胺 (532 mg, 4.095 mmol), 室温搅拌 8 小时，点板跟踪至原料基本消失，搅拌下向反应液中加入二氯甲院 (200 ml), 用饱和碳酸氢钠溶液 (80 mlx2)洗涤混合液，合并水层用二氯甲烷 (50 mix 1) 回萃。合并有机相，二氯甲烷层用无水硫酸钠干燥，过滤，滤液减压浓缩标题产物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢-吡咯 -3-羧酸 -(2-***啉 -4-基-乙基) -酰胺 7a(1.190 g, 油状物)，直接进行下一步反应。 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-(2-morphinolin-4-yl-ethyl)-carboxamide according to Example 1 of the present invention In the same manner as described in seven steps, in a 250 ml three-necked flask, 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid lg (0.605) g, 2.73 mmol) dissolved in N,N-dimethylformamide (8.5 ml), and then added N-ethyl-N,-(dimethylaminopropyl)-carbodiimide hydrochloride (with stirring) 1.047 g, 5.46 mmol), 1-hydroxybenzotriazole (553 mg, 2.73 mmol), triethylamine (0.689 g, 6.83 mmol) and N-morpholine-4-yl-ethylamine (532 mg, 4.095 mmol) Stirring at room temperature for 8 hours, the plate was traced until the raw material disappeared, and the solution was added to the reaction solution (200 ml), and the mixture was washed with saturated sodium bicarbonate solution (80 ml×2). Methyl chloride (50 mix 1) is extracted. The combined organic layers were dried with anhydrous sodium sulfate and filtered and evaporated (2-morpholine-4-yl-ethyl)-amide 7a (1.190 g, oil) was taken directly to the next step.

5-(5-氟 -2-氧代 -1,2-二氢 -Π引哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 5-(5-fluoro-2-oxo-1,2-dihydro-indole hydrazone-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3 -carboxylic acid

-(2-***琳 -4-基-乙基) -酰胺 -(2-morphine--4-yl-ethyl)-amide

按照本发明实施例 1第八步所述相同方式，将上一步产物 5-甲酰基 -2-甲基 -4- 三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-***啉 -4-基-乙基) -甲酰胺 7a (137 mg， 0.41 mmol) 不经纯化直接溶解于乙醇 (2 ιήΐ)中，搅拌下加入 5-氟 -1,3-二氢 -Β引哚 -2-酮 (59 mg, 0.39 mmol)及哌啶（4 mg， 0.04 mmol), 加热回流 8小时，点板跟踪至原料基本消失，反应自然冷却至室温，有黄色固体产生，过滤，固体用冷乙醇 (5 ml)洗漆，真空干燥，得到标题产物 5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-亚基-甲基) -2-甲基 -4- 三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-***啉 -4-基-乙基) -酰胺 7(84 mg, 黄色固体)，产率 44%。 ' In the same manner as described in the eighth step of Example 1 of the present invention, the product of the previous step, 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-(2-morpholine) 4--4-ethyl-ethyl)-carboxamide 7a (137 mg, 0.41 mmol) was dissolved in ethanol (2 ιήΐ) without purification, and 5-fluoro-1,3-dihydro-indole was added with stirring. 2-ketone (59 mg, 0.39 mmol) and piperidine (4 mg, 0.04 mmol), heated under reflux for 8 hours, the plate was traced until the starting material disappeared, the reaction was naturally cooled to room temperature, a yellow solid was produced, filtered, and the solid was cooled. Ethanol (5 ml) was washed and dried in vacuo to give the title product 5-(5-fluoro-2-oxo-1,2-dihydro-indole-3-ylidene-methyl)-2-methyl- 4-Trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-(2-morphinolin-4-yl-ethyl)-amide 7 (84 mg, yellow solid), yield 44%. '

MS m/z (ESI)： 467(M+1)。 MS m/z (ESI): 467 (MH).

'Η NMR ( 400 MHz, DMSO-d6 ) 7.63 (d, J= 8.4Hz, 1H， ArH), 7.58 (s, 1H， CH), 7.07(d， J = 8.0Hz, 1H, ArH), 6.93(m,lH, ArH), 3.57 (t, J = 6.8Hz, 4H, 2x NCH2CH2O), 3.35(t， J = 6.8Hz, 2H， NCHbCHaN), 2.45 (m, 6H, 2XNCH2CH2O and NCH₂CH2N), 2.34(s, 3H, )。实施例 8 'Η NMR (400 MHz, DMSO-d6) 7.63 (d, J = 8.4 Hz, 1H, ArH), 7.58 (s, 1H, CH), 7.07 (d, J = 8.0 Hz, 1H, ArH), 6.93 ( m,lH, ArH), 3.57 (t, J = 6.8 Hz, 4H, 2x NCH2CH2O), 3.35 (t, J = 6.8 Hz, 2H, NCHbCHaN), 2.45 (m, 6H, 2XNCH2CH2O and NCH ₂ CH2N), 2.34 (s, 3H, ). Example 8

5-(5-氯 -2-氧代 -1,2-二氢 -吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 -(2-***啉 -4-基-乙基) -酰胺 5-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3- carboxylic acid -(2-morpholine-4-yl-ethyl)-amide

重复本发明实施例 7第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1.氢-吡咯 -3-羧酸 -(2-,***啉 -4-基-乙基) -酰胺 7a 作原料，按照本发明实施例 Ί第二步所述相同方式使得该原料与 5-氯 -1,3-二氢- 吲哚 -2-酮的反应，则得到标题产物 5-(5-氯 -2-氧代 -1,2-二氢 -吲哚 -3-亚基-甲基) -2- 甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-***啉 -4-基-乙基) -酰胺 8(98 mg，橙黄色固体)，产率： 35.6%。

The first step reaction of Example 7 of the present invention was repeated except that the compound obtained in the above first step was used. 5-formyl-2-methyl-4-trifluoromethyl-1.hydro-pyrrole-3-carboxyl The acid-(2-, morphinolin-4-yl-ethyl)-amide 7a is used as a starting material, and the starting material is reacted with 5-chloro-1,3-dihydrogen in the same manner as described in the second step of the present invention. The reaction of indole-2-one gives the title product 5-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl-4 -Trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-(2-morphinolin-4-yl-ethyl)-amide 8 (98 mg, orange-yellow solid), Yield: 35.6%.

MS m/z (ESI): 483(M+1)。 MS m/z (ESI): 483 (M + 1).

1H NMR ( 400 MHz, DMSO-d6 ) 7.83(s, 1H， ArH), 7.62 (s， 1H， CH)₅ 7.28 (d, J = 8.0Hz, 1H, ArH), 6.95(d, J= 8.0Hz, 1H, ArH), 3.57(m， 4H, 2><NCH₂CH20), 3.38 (t, J = 6.8Hz, 2H， NCiiiCHzN), 2.45 (m， 6H, 2XNCH2CH2O and NCH2CH2N), 2.34(s, 3H, 1H NMR (400 MHz, DMSO-d6) 7.83 (s, 1H, ArH), 7.62 (s, 1H, CH) ₅ 7.28 (d, J = 8.0 Hz, 1H, ArH), 6.95 (d, J = 8.0 Hz , 1H, ArH), 3.57(m, 4H, 2><NCH ₂ CH20), 3.38 (t, J = 6.8Hz, 2H, NCiiiCHzN), 2.45 (m, 6H, 2XNCH2CH2O and NCH2CH2N), 2.34(s, 3H ,

实施例 9 Example 9

5-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 5-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3- Carbohydrate

.(2-***啉 4-基-乙基) -酰胺 (2-morpholine-4-yl-ethyl)-amide

重复本发明实施例 7第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-***啉 -4-基-乙基) -酰胺 7a 作原料，按照本发明实施例 7第二步所述相同方式使得该原料与 5-溴 -1,3-二氢- 吲哚 -2-酮的反应，则得到标题产物 5-(5-溴 -2-氧代 -1,2-二氢』引哚 -3-亚基-甲基) -2- 甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-***啉 -4-基-乙基) -酰胺 9(77 mg, 黄色固体)，产率： 37%。

The first step reaction of Example 7 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-morpholine-4-yl-ethyl)-amide 7a as a starting material, the starting material is made with 5-bromo-1,3-dihydro-indole in the same manner as described in the second step of Example 7 of the present invention. The reaction of 2-ketone gives the title product 5-(5-bromo-2-oxo-1,2-dihydro)pyridin-3-ylidene-methyl)-2-methyl-4-tri Fluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid-(2-morphinolin-4-yl-ethyl)-amide 9 (77 mg, yellow solid), yield: 37%.

1H NMR ( 400 MHz, DMSO-d6 ) 7.98(s, IH, ArH), 7.63 (s， 1H， CH), 7.40 (d, J = 8.4Hz, 1H， ArH), 6.90(d， J= 8.0Hz, 1H， ArH), 3.57(t, J= 6.8Hz, 4H, 2xNCH₂CH20), 3.34 (t, J= 6.8Hz, 2H， NCI^CHzN), 2.43 (m, 6H， 2 NCH2CH₂0 and NCHaCI^ ), 2.39(s, 3H，Cg )。实施例 10 1H NMR (400 MHz, DMSO-d6) 7.98 (s, IH, ArH), 7.63 (s, 1H, CH), 7.40 (d, J = 8.4 Hz, 1H, ArH), 6.90 (d, J = 8.0 Hz , 1H, ArH), 3.57(t, J= 6.8Hz, 4H, 2xNCH ₂ CH20), 3.34 (t, J= 6.8Hz, 2H, NCI^CHzN), 2.43 (m, 6H, 2 NCH2CH ₂ 0 and NCHaCI ^ ), 2.39(s, 3H, Cg ). Example 10

-(5-甲磺酰胺 -2-氧代 -1,2-二氢 -吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -(5-methanesulfonamide-2-oxo-1,2-dihydro-indole-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole

-3-羧酸 -(2-***啉 -4-基-乙基) -酰胺 3-carboxylic acid -(2-morpholine-4-yl-ethyl)-amide

重复本发明实施例 7第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-***啉斗基-乙基) -酰胺 7a 作原料，按照本发明实施例 7第二步所述相同方式使得该原料与 5-甲磺酰胺 -1,3- 二氢 -吲哚 -2-酮的反应，则得到标题产物 5-(5-甲磺酰胺 -2-氧代 -1，2-二氢 -吲哚 -3- 亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-***啉 -4-基-乙基) -酰胺 10(35 mg, 黄色固体)，产率： 16%。

The first step reaction of Example 7 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-morpholine phenyl-ethyl)-amide 7a as a starting material, the starting material and 5-methanesulfonamide-1,3-dihydro-indole are obtained in the same manner as described in the second step of Example 7 of the present invention. The reaction of 2-ketone gives the title product 5-(5-methanesulfonamide-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl-4 -Trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-(2-morphinolin-4-yl-ethyl)-amide 10 (35 mg, yellow solid), yield: 16%.

MS m/z (ESI): 542(M+1)。 j MS m/z (ESI): 542 (M + 1). j

1H ( 400 MHz, DMSO-d6 ) 7.46(s, IH, ArH), 7.43 (s, IH, CH), 7.15 (d， J = 8.4Hz, IH, ArH), 6.94(d, J= 8.0Hz, IH, ArH), 3.66(t, J= 6.8Hz， 4H， 2x NC¾CH20)， 3.30 (t, J = 6.8Hz, 2H, NCHzCHaN), 2.98(s, 3H, CHBSOZ), 2.43 (m, 6H, 2XNCH2CH2O and NCH2CH2N), 2.39(s, 3H, CHa)₀ 实施例 11 1H (400 MHz, DMSO-d6) 7.46 (s, IH, ArH), 7.43 (s, IH, CH), 7.15 (d, J = 8.4 Hz, IH, ArH), 6.94 (d, J = 8.0 Hz, IH, ArH), 3.66 (t, J = 6.8 Hz, 4H, 2x NC3⁄4CH20), 3.30 (t, J = 6.8 Hz, 2H, NCHzCHaN), 2.98(s, 3H, CHBSOZ), 2.43 (m, 6H, 2XNCH2CH2O And NCH2CH2N), 2.39(s, 3H, CHa) ₀ Example 11

5-(5-乙酰胺 -2-氧代 -1，2-二氢^ I哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢-吡咯 -3- 羧酸 -(2-***啉 -4-基-乙基) -酰胺 5-(5-acetamide-2-oxo-1,2-dihydro^I哚-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3 - Carboxylic acid-(2-morpholine-4-yl-ethyl)-amide

重复本发明实施例 7第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-***啉 -4-基-乙基) -酰胺 7a 作原料，按照本发明实施例 7第二步所述相同方式进行该原料与 5-乙酰胺 -1,3- 二氢 -吲哚 -2-酮的反应，则得到标题产物 5-(5-乙酰胺 -2-氧代 -1,2-二氢 -吲哚 -3-亚基-甲基) _2-甲基 -4-三氟甲基 -1 氢-吡咯 -3-羧酸 -(2-***啉 -4-基-乙基) -酰胺 11(86 mg, 黄色固体)，产率： 31.5%。

The first step reaction of Example 7 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-morpholine-4-yl-ethyl)-amide 7a as a starting material, the starting material and 5-acetamide-1,3-dihydro-indole were carried out in the same manner as described in the second step of Example 7 of the present invention. The reaction of indole-2-one gives the title product 5-(5-acetamide-2-oxo-1,2-dihydro-indol-3-ylidene-methyl) _2-methyl-4- Trifluoromethyl-1 Hydrogen-pyrrole-3-carboxylic acid-(2-morphinolin-4-yl-ethyl)-amide 11 (86 mg, yellow solid), Yield: 31.5%.

MS m/z (ESI): 506(M)。 MS m/z (ESI): 506 (M).

1H MR ( 400 MHz, DMSO-d6 ) 7.79(s, IH, ArH), 7.44 (d, J = 8.4Hz, 1H， ArH), 7.40 (s， IH, CH), 6.88(d, J= 8.0Hz, IH, ArH), 3.57(m, 4H, 2XNCH2CH2O), 3.34 (t, J = 6.4Hz， 2H, NCH2CH2N), 2.44 (m, 6H， 2xNCH2CH₂0 and Ν。Η₂ Ν)， 2.40(s, 3H， CH3), 2.04 (s, 3H, CH3CO)。实施例 12 1H MR (400 MHz, DMSO-d6) 7.79 (s, IH, ArH), 7.44 (d, J = 8.4 Hz, 1H, ArH), 7.40 (s, IH, CH), 6.88 (d, J = 8.0 Hz , IH, ArH), 3.57(m, 4H, 2XNCH2CH2O), 3.34 (t, J = 6.4Hz, 2H, NCH2CH2N), 2.44 (m, 6H, 2xNCH2CH ₂ 0 and Ν.Η ₂ Ν), 2.40(s, 3H, CH3), 2.04 (s, 3H, CH3CO). Example 12

-(6-氨基 -5-氟 -2-氧代 -1,2-二氢哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -(6-amino-5-fluoro-2-oxo-1,2-dihydroindole-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole

重复本发明实施例 7第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢-吡咯 -3-羧酸 -(2-***啉 -4-基-乙基) -酰胺 7a 作原料，按照本发明实施例 7第二步所述相同方式使得该原料与 6-氨基 -5-氟 -1,3- 二氢 -吲哚 -2-酮的反应，则得到标题产物 5-(6-氨基 -5-氟 -2-氧代 -1,2-二氢哚 -3- 亚基-甲基) -2-甲基 -4-三氟甲基 -1 氢-吡咯 -3-羧酸 -(2-***啉 -4-基-乙基) -酰胺 12(115 mg, 黄色固体)，产率： 61%。

The first step reaction of Example 7 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-morpholine-4-yl-ethyl)-amide 7a as a starting material, the starting material is 6-amino-5-fluoro-1,3-di in the same manner as described in the second step of Example 7 of the present invention. The reaction of hydrogen-indol-2-one gives the title product 5-(6-amino-5-fluoro-2-oxo-1,2-dihydroindole-3-ylidene-methyl)-2- Methyl-4-trifluoromethyl-1 Hydrogen-pyrrole-3-carboxylic acid-(2-morphinolin-4-yl-ethyl)-amide 12 (115 mg, yellow solid), yield: 61%.

MS m/z (ESI): 482(M+1)。 Ή NM ( 400 MHz, DMSO-d6 ) 7.36 (d， J = 10.8Hz, 1H， ArH), 7.16 (s_s 1H， CH), 6.37(d, J = 7.6Hz, 1H, ArH), 3.58(m, 4H, 2x NCH2CH2O), 3.32 (t， J = 6.4Hz, 2H_: NCH2CH₂ ), 2.42 (m， 6H, 2 NCH2CH₂0 and NCH₂CH₂N), 2.34(s, 3H, )。实施例 13 MS m/z (ESI): 482 (M + 1). Ή NM ( 400 MHz, DMSO-d6 ) 7.36 (d, J = 10.8 Hz, 1H, ArH), 7.16 (s _s 1H, CH), 6.37 (d, J = 7.6 Hz, 1H, ArH), 3.58 (m , 4H, 2x NCH2CH2O), 3.32 (t, J = 6.4 Hz, 2H _: NCH2CH ₂ ), 2.42 (m, 6H, 2 NCH2CH ₂ 0 and NCH ₂ CH ₂ N), 2.34 (s, 3H, ). Example 13

5-(5-氟 -2-氧代 -1,2-二氢 -1¾|哚-3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 5-(5-fluoro-2-oxo-1,2-dihydro-13⁄4|indol-3-yl-methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3 -carboxylic acid

-(2-哌啶 -1-基-乙基) -酰胺 -(2-piperidin-1-yl-ethyl)-amide

5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-哌啶小基-乙基) -酰胺按照本发明实施例 1第七步所述相同方式，氮气氛下，在一个 250 ml的三口瓶中，将 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 lg(0.605 g， 2.73 mmol) 溶解于 N'N-二甲基甲酰胺 (8 ml)中，搅拌下依次加入: N- 基 -Ν'- (二甲氮基丙基) - 碳二亚胺盐酸盐 (1.047 g， 5.46 mmol) 1-羟基苯并*** (0.553 g， 4.09 mmol), 三乙胺 (0.689 g， 6.82 mmol)及 N-哌啶 -1-基 -乙胺 (0.525 g， 4.09 mmol), 室温搅拌 8 小时，点板跟踪至原料基本消失，搅拌下向反应液中加入二氯甲烷 (200 ml), 用饱和碳酸氢钠溶液 (80 mlx2)洗涤混合液，合并水层用二氯甲烷 (50 mlxl)回萃。合并有机相，二氯甲垸层用无水硫酸钠干燥，过滤，滤液减压浓缩标题产物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-哌啶 -1-基-乙基) -酰胺 13a(U88 g, 油状物)，直接进行下一步反应。 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-(2-piperidinyl-ethyl)-amide according to the seventh step of Example 1 of the present invention In the same manner, in a 250 ml three-necked flask, 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid lg (0.605 g, 2.73) Methyl acetate was dissolved in N'N-dimethylformamide (8 ml) and added with stirring: N-yl-Ν'-(dimethylazopropyl)-carbodiimide hydrochloride (1.047 g) , 5.46 mmol) 1-Hydroxybenzotriazole (0.553 g, 4.09 mmol), triethylamine (0.689 g, 6.82 mmol) and N-piperidin-1-yl-ethylamine (0.525 g, 4.09 mmol) After stirring for 8 hours, the plate was traced until the starting material disappeared. Methylene chloride (200 ml) was added to the reaction mixture under stirring, and the mixture was washed with saturated sodium hydrogen carbonate solution (80 ml×2), and the aqueous layer was combined with dichloromethane. Mlxl) back. The organic phase was combined, the methylene chloride layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give the title product 5-formyl-2-methyl-4-trifluoromethyl-1 -hydro-pyrrole-3-carboxylic acid -(2-Piperidin-1-yl-ethyl)-amide 13a (U88 g, oil).

5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3- Carbohydrate

-(2-哌小基-乙基) -酰胺 -(2-pipeletyl-ethyl)-amide

按照本发明实施例 ί第八步所述相同方式,将上一步产物 5-甲酰基 -2-甲基 -4- 三氟甲基 -1氢-吡咯 -3-羧酸 -(2-哌啶小基-乙基) -酰胺 13a(121 mg, 0.364 mmol)不经纯化溶解于乙醇 (2 ml)中，搅拌下加入 5-氟 -1,3-二氢 - 哚 -2-酮 (52 mg, 0.346 mmol)及六氢吡啶 (3 mg, 0.036 mmol), 加热回流 8小时，点板跟踪至原料基本消失，反应自然冷却至室温，有黄色固体产生，过滤，固体用冷乙醇 (5 ml)洗涤，真空干燥，得到标题产物 5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-亚基-甲基) -2-甲基 -4- 三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-哌啶 -1-基-乙基) -酰胺 7(62 mg, 黄色固体)，产率 37%。 In the same manner as described in the eighth step of the present invention, the product of the previous step, 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-(2-piperidine) Small-ethyl)-amide 13a (121 mg, 0.364 mmol) was dissolved in ethanol (2 ml) without purification, and 5-fluoro-1,3-dihydro-indol-2-one (52 mg) was added with stirring. , 0.346 Methyl) and hexahydropyridine (3 mg, 0.036 mmol), heated under reflux for 8 hours, the spot was traced until the starting material disappeared, the reaction was allowed to cool to room temperature, and a yellow solid was obtained. The solid was washed with cold ethanol (5 ml). Drying in vacuo gave the title product 5-(5-fluoro-2-oxo-1,2-dihydro-indole-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1 Hydrogen-pyrrol-3-carboxylic acid-(2-piperidin-1-yl-ethyl)-amide 7 (62 mg, yellow solid), yield 37%.

MS m/z (ESI): 465(M+1)。 MS m/z (ESI): 465 (M+1).

1H NMR ( 400 MHz, DMSO-d6 ) 7.63(d, J= 6.8Hz, 1H, ArH )， 7.58 (s， 1H, CH), 7.06(m， 1H, ArH ), 6,93(m，lH, ArH), 3.32 (t, J= 6.4Hz， 2H， NCH2CH2N), 2.45(s, 3H CH3), 2.39 (m, 6H， 2xCH₂NCH₂CH₂ and ΝΟί₂ Ν), 1.50(m, 4H, CH2CH₂CH2), 1.38(m,2H, C¾CH2C¾)。 ^ 实施例 14 1H NMR (400 MHz, DMSO-d6) 7.63 (d, J = 6.8 Hz, 1H, ArH), 7.58 (s, 1H, CH), 7.06 (m, 1H, ArH), 6,93 (m, lH, ArH), 3.32 (t, J= 6.4Hz, 2H, NCH2CH2N), 2.45(s, 3H CH3), 2.39 (m, 6H, 2xCH ₂ NCH ₂ CH ₂ and ΝΟί ₂ Ν), 1.50(m, 4H, CH2CH ₂ CH2), 1.38 (m, 2H, C3⁄4CH2C3⁄4). ^ Example 14

5-(5-氯 -2-氧代 -1,2-二氢 -吲哚 -3-亚基-甲基) -2-甲基斗三氟甲基 -1氢 -吡咯 -3-羧酸 5-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methylidenetrifluoromethyl-1hydro-pyrrole-3-carboxylic acid

-(2-哌啶 -1-基-乙基) -酰胺 -(2-piperidin-1-yl-ethyl)-amide

重复本发明实施例 13第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-哌小基-乙基) -酰胺 13a 作原料，按照本发明实施例 7第二步所述相同方式使得该原料与 5-氯 -1,3-二氢- 吲哚 -2-酮的反应，则得到标题产物 5-(5-氯 -2-氧代 -1，2-二氢』引哚 -3-亚基-甲基) -2- 甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-哌啶 -1-基-乙基) -酰胺 14(84 mg,黄色固体)，产率： 50%。

The first step of the reaction of Example 13 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-Pheptidyl-ethyl)-amide 13a as a starting material, the starting material is made with 5-chloro-1,3-dihydro-indole-2- in the same manner as described in the second step of Example 7 of the present invention. The reaction of the ketone gives the title product 5-(5-chloro-2-oxo-1,2-dihydro)pyridin-3-ylidene-methyl)-2-methyl-4-trifluoromethyl -1 Hydro-pyrrole-3-carboxylic acid-(2-piperidin-1-yl-ethyl)-amide 14 (84 mg, yellow solid), yield: 50%.

MS m/z (ESI): 481(M+l) o ' MS m/z (ESI): 481 (M+l) o '

1H NMR ( 400 MHz, DMSO-d6 ) 7.83(s, 1H, ArH ), 7.62 (s， 1H, CH), 7.27(d, J= 8.4Hz, 1H, ArH ), 6.95(d,J = 8.4Hz, 1H, ArH), 3.32 (t, J = 6.4Hz, 2H, NCHz^N), 2.41 (s, 3H， CH3), 2.38(m, 6H, 2xCH₂NCH₂CH₂ and ΝΟ¾ Ν), 1.50(m, 4H， CH2CH₂CiJ2)，1.38(m,2H， CH₂CH₂CH₂) o 实施例 15 1H NMR (400 MHz, DMSO-d6) 7.83 (s, 1H, ArH), 7.62 (s, 1H, CH), 7.27 (d, J = 8.4 Hz, 1H, ArH ), 6.95 (d, J = 8.4 Hz , 1H, ArH), 3.32 (t, J = 6.4Hz, 2H, NCHz^N), 2.41 (s, 3H, CH3), 2.38 (m, 6H, 2xCH ₂ NCH ₂ CH ₂ and ΝΟ3⁄4 Ν), 1.50 ( m, 4H, CH2CH ₂ CiJ2), 1.38 (m, 2H, CH ₂ CH ₂ CH ₂ ) o Example 15

-(2-哌晚小基-乙基) -酰胺 -(2-piperylsyl-ethyl)-amide

重复本发明实施例 13第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-哌啶 -1-基-乙基) -酰胺 13a 作原料，按照本发明实施例 7第二步所述相同方式使得该原料与 5-溴 -1,3-二氢- 吲哚 -2-酮的反应，则得到标题产物 5-(5-溴 -2-氧代 -1,2-二氢 - 哚 -3-亚基-甲基) -2- 甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-哌啶小基-乙基) -酰胺 15(110 mg, 黄色固体)，产率： 21 %。

The first step of the reaction of Example 13 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-piperidin-1-yl-ethyl)-amide 13a as a starting material, the starting material is made with 5-bromo-1,3-dihydro-indole in the same manner as described in the second step of Example 7 of the present invention. The reaction of 2-ketone gives the title product 5-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidene-methyl)-2-methyl-4-trifluoro Methyl-1 Hydrogen-pyrrole-3-carboxylic acid-(2-piperidinyl-ethyl)-amide 15 (110 mg, yellow solid), Yield: 21%.

MS m/z (ESI): 525(M)。 MS m/z (ESI): 525 (M).

1H NM ( 400 MHz, DMSO-d6 ) 7.96(s，lH， ArH )， 7.62 (s， 1H,CH), 7.40(d, J= 8·4Ηζ,1Η， ArH ), 6.90(d，J= 8.4Hz, 1H, ArH), 3.32 (t, J= 6.4Hz, 2H, NCH2C¾N)₅ 2.41 (s, 3H，CH3)， 2.37 (m， 6H， 2xCH₂NCH2CH₂ and NCH₂CH2N), 1.50(m， 4H, CH2CH₂CH2),1.38(m, 2H, 实施例 16 1H NM ( 400 MHz, DMSO-d6 ) 7.96 (s, lH, ArH ), 7.62 (s, 1H, CH), 7.40 (d, J = 8·4 Ηζ, 1 Η, ArH ), 6.90 (d, J = 8.4) Hz, 1H, ArH), 3.32 (t, J= 6.4Hz, 2H, NCH2C3⁄4N) ₅ 2.41 (s, 3H, CH3), 2.37 (m, 6H, 2xCH ₂ NCH2CH ₂ and NCH ₂ CH2N), 1.50 (m, 4H, CH2CH ₂ CH2), 1.38 (m, 2H, Example 16

5-(5-乙酰胺 -2-氧代 -1,2-二氢 -II引哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3- 羧酸 -(2-哌啶 -1-基-乙基) -酰胺 5-(5-acetamide-2-oxo-1,2-dihydro-II fluorene-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole- 3-carboxylic acid-(2-piperidin-1-yl-ethyl)-amide

重复本发明实施例 13第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-哌啶小基-乙基) -酰胺 13a 作原料，按照本发明实施例 7第二步所述相同方式使得该原料与 5-乙酰胺 -1,3- 二氢 -吲哚 -2-酮的反应，则得到标题产物 5-(5-乙酰胺 -2-氧代 -1,2-二氢 -B引哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-哌啶小基-乙基) -酰胺 16(76 mg，黄色固体)，产率： 44%。

The first step of the reaction of Example 13 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-piperidinyl-ethyl)-amide 13a as a starting material, the starting material is reacted with 5-acetamide-1,3-dihydro-indole in the same manner as described in the second step of Example 7 of the present invention. 2-keto reaction gives the title product 5-(5-acetamide-2-oxo-1,2-dihydro-B-indol-3-yl-methyl)-2-methyl-4- Trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-(2-piperidinyl-ethyl)-amide 16 (76 mg, yellow solid), yield: 44%.

Ή NMR ( 400 MHz, DMSO-d6 ) 7.79(s, 1H, ArH ), 7.44(d, J = 8.4Hz, 1H， ArH ): 7.39 (s, 1H， CH), 6.88(d₅ J = 8.4Hz,lH, ArH), 3.30 (t， J = 6.4Hz, 2H, NCH2CH₂N)_: 2.4 l(s, 3H, CH3), 2.38 (m, 6H， 2 CH₂NCH2CH₂ and NCH₂CH2N), 2.03(s, 3H: CH3CO), 1.50(m, 4H, CifcCH₂CH2),1.38(m, 2H， CH₂CH2CH₂)。实施例 17

NMR NMR (400 MHz, DMSO-d6) 7.79 (s, 1H, ArH), 7.44 (d, J = 8.4 Hz, 1H, ArH): 7.39 (s, 1H, CH), 6.88 (d ₅ J = 8.4 Hz , lH, ArH), 3.30 (t, J = 6.4Hz, 2H, NCH2CH ₂ N) _: 2.4 l(s, 3H, CH3), 2.38 (m, 6H, 2 CH ₂ NCH2CH ₂ and NCH ₂ CH2N), 2.03 (s, 3H: CH3CO), 1.50 (m, 4H, CifcCH ₂ CH2), 1.38 (m, 2H, CH ₂ CH ₂ CH ₂ ). Example 17

5-(6-氨基 -5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 5-(6-Amino-5-fluoro-2-oxo-1,2-dihydro-inden-3-ylidene-methyl)-2-methyl-4-trifluoromethyl-1 hydrogen- Pyrrole

-3-羧酸 -(2-哌啶 -1-基-乙基) -酰胺 3-carboxylic acid -(2-piperidin-1-yl-ethyl)-amide

重复本发明实施例 13第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-呢啶 -1-基-乙基) -酰胺 13a 作原料，按照本发明实施例 7第二步所述相同方式使得该原料与 6-氨基 -5-氟 -1，3- 二氢 -吲哚 -2-酮的反应，贝 lj得到标题产物 5-(6-氨基 -5-氟 -2-氧代 -1,2-二氢 -吲哚 -3- 亚基-甲基) -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-哌啶小基-乙基) -酰胺 17(130 mg), 产率： 78%。

The first step of the reaction of Example 13 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-oxaridin-1-yl-ethyl)-amide 13a as a starting material, in the same manner as described in the second step of Example 7 of the present invention, the starting material is 6-amino-5-fluoro-1,3- Reaction of hydrogen-indol-2-one, the title product 5-(6-amino-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidene-methyl) was obtained from the title compound. 2-Methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-(2-piperidinyl-ethyl)-amide 17 (130 mg), Yield: 78%.

MS m/z (ESI): 480(M+1)。 MS m/z (ESI): 480 (M + 1).

Ή NMR ( 400 MHz, DMSO-d6 ) 7.35(d, J= 7.6Hz, 1H, ArH ), 7.16 (s, 1H, CH), 6.37(d, J = 7.6Hz， 1H, ArH), 3.32 (t, J = 6.4Hz， 2H, NCHzCHzN), 2.39(m, 6H, 2x CH₂NCffcCH₂ and NCHzCHaN), 2.30(s, 3H, CH3), 1.49(m, 4H, CH₂CH₂CH₂), 1.37(m, 2H, 实施例 18 NMR NMR (400 MHz, DMSO-d6) 7.35 (d, J = 7.6 Hz, 1H, ArH), 7.16 (s, 1H, CH), 6.37 (d, J = 7.6 Hz, 1H, ArH), 3.32 (t , J = 6.4Hz, 2H, NCHzCHzN), 2.39(m, 6H, 2x CH ₂ NCffcCH ₂ and NCHzCHaN), 2.30(s, 3H, CH3), 1.49(m, 4H, CH ₂ CH ₂ CH ₂ ), 1.37 (m, 2H, Example 18

-氟 -3-[5-甲基 -4-(4-***啉 -4-基 -1-羰基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-1, 3-二氢吲哚 -2-酮 -fluoro-3-[5-methyl-4-(4-morphinolin-4-yl-1-carbonyl)-3-trifluoromethyl-1H-pyrrole-2-methine]-1, 3- Dihydroindol-2-one

按照本发明实施例 1第七步所述相同方式，氮气氛下，在一个 250 ml的三口瓶中，将 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -P比咯 -3-羧酸 l_g (1.0 g, 4.52 mmol)溶解于 N，N-二甲基甲酰胺 (10 ml)中，搅拌下依次加入 N-乙基 -N，- (二甲氨基丙基) - 碳二亚胺盐酸盐 (1.047 g, 5.46 mmol)、 1-羟基苯并*** (0.92 g， 6.78 mmol)、三乙胺 (0.689 g, 6.82 nunol)及 4-哌啶基 -4-***啉 (1.15 g， 6.78 ramol), 室温搅拌 8 小时，点板跟踪至原料基本消失，搅拌下向反应液中加入二氯甲烷 (200 ml), 用饱和碳酸氢钠溶液 (80 mlx2)洗漆混合液，合并水层用二氯甲烷 (50 mM)回萃。合并有机相，二氯甲垸层用无水硫酸钠千燥，过滤，滤液减压浓缩标题产物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 -[2-(4-***啉 -4-哌啶 -1-基)乙基]酰胺 18a (1.91 g, 油状物)，直接进行下一步反应。 In the same manner as described in the seventh step of Example 1 of the present invention, a 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-P ratio was obtained in a 250 ml three-necked flask under a nitrogen atmosphere. 1-3-carboxylic acid l _g (1.0 g, 4.52 mmol) N-ethyl-N,-(dimethylaminopropyl)-carbodiimide hydrochloride (1.047 g, 5.46 mmol) was added to N,N-dimethylformamide (10 ml). , 1-hydroxybenzotriazole (0.92 g, 6.78 mmol), triethylamine (0.689 g, 6.82 nunol) and 4-piperidinyl-4-morpholine (1.15 g, 6.78 ramol), stirred at room temperature for 8 hours The plate was traced until the starting material disappeared. Dichloromethane (200 ml) was added to the reaction mixture with stirring, and the mixture was washed with saturated sodium hydrogen carbonate solution (80 ml×2), and the aqueous layer was combined with dichloromethane (50 mM). Back to top. The organic phase was combined, the methylene chloride layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated to give the title product 5-formyl-2-methyl-4-trifluoromethyl-1 -hydro-pyrrole-3-carboxyl Acid-[2-(4-morpholine-4-piperidin-1-yl)ethyl]amide 18a (1.91 g, oil) was taken directly to the next step.

按照本发明实施例 1第八步所述相同方式，将上一步产物 5-甲酰基 -2-甲基 -4- 三氟甲基 -1 氢-吡咯 -3-羧酸 -[2-(4-***啉 -4-哌啶 -1-基)乙基] 18a (200 mg， 0.536 mmd)不经纯化溶解于乙醇 (3 ml)中，搅拌下加入 5-氟 -1,3-二氢 -吲哚 -2-酮 (81 mg, 0.536 mmol)及六氢吡啶 (5 mg, 0.036 mmol), 加热回流 8小时，点板跟踪至原料基本消失，反应自然冷却至室温，有黄色固体产生，过滤，固体用冷乙醇 (5 ml) 洗涤，真空干燥，得到标题产物 5-氟 -3-[5-甲基 -4-(4-***啉斗基 -1-羰基 )-3-三氟甲基 -1H-吡咯 -2-次甲基 ]-1， 3-二氢吲哚 -2-酮 18 (97 mg, 黄色固体)，产率 35.7 %。 In the same manner as described in the eighth step of Example 1 of the present invention, the product of the previous step, 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-[2-(4) - morpholine-4-piperidin-1-yl)ethyl] 18a (200 mg, 0.536 mmd) was dissolved in ethanol (3 ml) without purification, and 5-fluoro-1,3-dihydro- Indole-2-one (81 mg, 0.536 mmol) and hexahydropyridine (5 mg, 0.036 mmol), heated under reflux for 8 hours, the spot was traced until the starting material disappeared, the reaction was naturally cooled to room temperature, and a yellow solid was produced. The solid was washed with EtOAc (EtOAc) (EtOAc) -1H-pyrrole-2-methine]-1,3-dihydroindol-2-one 18 (97 mg, yellow solid), mp.

MS m/z (ESI)： 507.3 (M+l) MS m/z (ESI): 507.3 (M+l)

lH NMR ( 400 MHz, DMSO-d ) 57.66(dxd, 1H, ArH ), 7.55 (s, 1H, CH), 7.05(dxd, 1H, ArH ), 6.91(dxd,lH, ArH), 4.46 (s，lH， C瞬， 4.32(t, 4H, J=5.2Hz), 3.53(m， 4H, 2xCH20CH2), 2.40(m, 4H, 2xCH2NCH2), 2.09(s, 3H, CH3), 1.87(m， 2H,CH2CH), 1.30(m, 2H,CH2CH) 实施例 19 lH NMR (400 MHz, DMSO-d) 57.66 (dxd, 1H, ArH), 7.55 (s, 1H, CH), 7.05 (dxd, 1H, ArH), 6.91 (dxd, lH, ArH), 4.46 (s, lH, C instantaneous, 4.32(t, 4H, J=5.2Hz), 3.53(m, 4H, 2xCH20CH2), 2.40(m, 4H, 2xCH2NCH2), 2.09(s, 3H, CH3), 1.87(m, 2H, CH2CH), 1.30 (m, 2H, CH2CH) Example 19

-氯 -3-[5-甲基斗 (4-***啉 -4-基小裁基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-1， 3-二氢吲哚 -2-酮 -Chloro-3-[5-methylidene (4-morpholine-4-yl), -3-trifluoromethyl-1H-pyrrole-2-methine]-1, 3-dihydroindole Indole-2-one

重复本发明实施例 18第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-哌啶小基-乙基) -酰胺 18a作原料，按照本发明实施例 7第二步所述相同方式使得该原料与 5-氯 -1 ,3-二氢-吲哚 -2-酮的反应，则得到标题产物 5-氯 -3-[5-甲基 -4-(4-***啉 -4-基小羰基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-1， 3-二氢吲哚 -2-酮 19 (158 mg，黄色固体)，产率： 56.4

The first step of the reaction of Example 18 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-piperidinyl-ethyl)-amide 18a as a starting material, the starting material is made with 5-chloro-1,3-dihydro-indole-2 in the same manner as described in the second step of Example 7 of the present invention. - ketone reaction, the title product 5-chloro-3-[5-methyl-4-(4-morphinolin-4-yl carbonyl)-3-trifluoro Methyl-1H-pyrrole-2-methine]-1,3-dihydroindol-2-one 19 (158 mg, yellow solid), Yield: 56.4

%。 . %. .

MS m/z (ESI): 523.4(M+1) MS m/z (ESI): 523.4 (M+1)

1H MR ( 400 MHz, DMSO-d6 ) S7.67(s， 1H, ArH ), 7.55 (s， 1H， CH), 7.04(dxd， 1H， ArH ), 6.91(d,lH, J=8.4Hz ArH), 4.46 (s,lH, CHN), 4.32(m, 4H), 3.53(m, 4H, 2xCH20CH2), 2.95 (m， 4H， 2xCH2NCH2), 2.40(m， 4H， 2xCH2NCH2), 2.09(s, 3H, CH3), 1.87(m₅ 2H,CH2CH), 1.30(m, 2H,CH2CH). 实施例 20 1H MR (400 MHz, DMSO-d6) S7.67 (s, 1H, ArH), 7.55 (s, 1H, CH), 7.04 (dxd, 1H, ArH), 6.91 (d, lH, J = 8.4 Hz ArH ), 4.46 (s,lH, CHN), 4.32(m, 4H), 3.53(m, 4H, 2xCH20CH2), 2.95 (m, 4H, 2xCH2NCH2), 2.40(m, 4H, 2xCH2NCH2), 2.09(s, 3H , CH3), 1.87 (m ₅ 2H, CH 2 CH), 1.30 (m, 2H, CH 2 CH). Example 20

-溴 -3-[5-甲基 -4-(4-***啉 -4-基小羰基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-l , 3-：氢吲哚 -2-酮 -Bromo-3-[5-methyl-4-(4-morphinolin-4-ylsuccinylcarbonyl)-3-trifluoromethyl-1H-pyrrole-2-methine]-l, 3-: hydrogen Indole-2-one

重复本发明实施例 13第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -[2-(4-***啉 -4-哌啶 -1-基)乙基] -酰胺 18a作原料，按照本发明实施例 7第二步所述相同方式使得该原料与 5- 溴 -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 5-溴 -3-[5-甲基 -4-(4-***啉 -4-基小羰基 )-3-三氟甲基 -1H-吡咯 -2-次甲基 ]-1 , 3-二氢吲哚 -2-酮 20 (120 mg，黄色固体)，产率： 43.9%

The first step of the reaction of Example 13 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -[2-(4-morpholine-4-piperidin-1-yl)ethyl]-amide 18a as a starting material, which is obtained in the same manner as described in the second step of Example 7 of the present invention. , 3-dihydro-indol-2-one reaction, the title product 5-bromo-3-[5-methyl-4-(4-morphinolin-4-ylsuccinyl)-3-trifluoro Methyl-1H-pyrrole-2-methine]-1 , 3-indan-2-one 20 (120 mg, yellow solid), Yield: 43.9%

MS m/z (ESI): 567.5 MS m/z (ESI): 567.5

1H NMR ( 400 MHz, DMSO-d6 ) 58.00(s, 1H, ArH), 7.60 (s, 1H, CH), 7.39(d, 1H， J=8.4Hz, ArH ), 6.88(d,lH, J=8.4Hz, ArH), 4.46 (s，lH， CHN), 3.53(m, 4H, 2xCH20CH2), 2.96(m, 4H， 2xCH2NCH2), 2.40(m, 4H, 2xCH2NCH2), 2.09(s, 3H, CH3), 1.87(m， 2H,CH2CH), 1.30(m, 2H,CH2CH). 实施例 21 1H NMR (400 MHz, DMSO-d6) 58.00 (s, 1H, ArH), 7.60 (s, 1H, CH), 7.39 (d, 1H, J = 8.4 Hz, ArH ), 6.88 (d, lH, J = 8.4 Hz, ArH), 4.46 (s, lH, CHN), 3.53 (m, 4H, 2xCH20CH2), 2.96 (m, 4H, 2xCH2NCH2), 2.40 (m, 4H, 2xCH2NCH2), 2.09 (s, 3H, CH3) , 1.87 (m, 2H, CH2CH), 1.30 (m, 2H, CH2CH). Example 21

N-{3-[5-甲基 -4-(4-***啉 -4-基 -1-羰基) -3-三氟甲基 -1H-吡咯 -2-次甲基] -2-氧 -2,3- 二氢 -1H-吲哚 -5-基}-乙酰胺

重复本发明实施例 18第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -[2-(4-***啉 -4-哌啶小基)乙基] -酰胺 18a作原料，按照本发明实施例 18第二步所述相同方式使得该原料与 5-乙酰基「1,3-二氢 -Π引哚 -2-酮的反应，则得到标题产物 N-{3-[5-甲基 -4-(4-***啉 -4-基小羰基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧 -2,3-二氢 -1H-吲哚 -5-基乙酰胺 21 (27 mg, 黄色固体)，产率： 13 %。 N-{3-[5-Methyl-4-(4-morphinolin-4-yl-1-carbonyl)-3-trifluoromethyl-1H-pyrrol-2-ylmethyl]-2-oxo- 2,3-Dihydro-1H-indol-5-yl}-acetamide

The first step of the reaction of Example 18 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -[2-(4-morpholine-4-piperidinyl)ethyl]-amide 18a as a starting material, which is made in the same manner as described in the second step of Example 18 of the present invention, and the 5-acetyl group "1, 3-Dihydro-indole fluoren-2-one reaction, the title product N-{3-[5-methyl-4-(4-morphinolin-4-yl carbonyl)-3-trifluoromethyl Base-1H-pyrrole-2-methine]-2-oxo-2,3-dihydro-1H-indol-5-ylacetamide 21 (27 mg, yellow solid), yield: 13%.

MS m/z (ESI): 546.3(M+1) MS m/z (ESI): 546.3 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 67.78 (s, 1H， CH), 7.46 (s, 1H， ArH), 7.33(d, 1H, J=8.4Hz, ArH ), 6.87(m,lH， J=8.4Hz,ArH), 4.46 (s，lH, CHN), 3.53(ra, 4H, 2xCH20CH2), 2.96(m, 4H, 2xCH2NCH2), 2.40(m, 4H， 2xCH2NCH2), 2.09(s, 3H, CHj), 2.00(s， 3H， CH3)1.87(m, 2H,CH2CH), 1.30(m, 2H,CH2CH) 实施例 22 1H NMR (400 MHz, DMSO-d6) 67.78 (s, 1H, CH), 7.46 (s, 1H, ArH), 7.33 (d, 1H, J = 8.4 Hz, ArH ), 6.87 (m, lH, J = 8.4 Hz, ArH), 4.46 (s, lH, CHN), 3.53 (ra, 4H, 2xCH20CH2), 2.96 (m, 4H, 2xCH2NCH2), 2.40 (m, 4H, 2xCH2NCH2), 2.09 (s, 3H, CHj) , 2.00(s, 3H, CH3) 1.87 (m, 2H, CH2CH), 1.30 (m, 2H, CH2CH) Example 22

5-氟 -7-溴 -3-[5-甲基 -4-(4-***啉 -4-基 -1-幾基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-1， 5-fluoro-7-bromo-3-[5-methyl-4-(4-morphinolin-4-yl-1-yl)-3-trifluoromethyl-1H-pyrrole-2-methine ]-1,

3-二氢吲哚 -2-酮 3-dihydroindole-2-one

重复本发明实施例 18第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -[2-(4-***啉 -4-哌啶 -1-基)乙基] -酰胺 18a作原料，按照本发明实施例 18第二步所述相同方式使得该原料与 5-氟 -7-溴 -1,3-二氢引哚 -2-酮的反应，则得到标题产物 N-{3-[5-甲基 -4-(4-***啉 -4-基 -1-羰基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧 -2,3-二氢 -1H-吲哚 -5-基} -乙酰胺 22(118mg，黄色固体)，产率： 67%。

The first step of the reaction of Example 18 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -[2-(4-morpholine-4-piperidin-1-yl)ethyl]-amide 18a as a starting material, which is obtained in the same manner as described in the second step of Example 18 of the present invention. -Bromo-1,3-dihydroindol-2-one reaction, the title product N-{3-[5-methyl-4-(4-morphinolin-4-yl-1-carbonyl)- 3-trifluoromethyl-1H-pyrrole-2-methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-acetamide 22 (118 mg, yellow solid) Rate: 67%.

MS m/z (ESI): 585.5(M+1) MS m/z (ESI): 585.5 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 57.77 (d, 1H， J=8.4Hz, ArH), 7.59 (s, 1H, CH), 7.39(d, 1H， J=8.4Hz, ArH ), 4.49 (s,lH, CHN), 3.53(m, 4H, 2xCH20CH2), 2.96(m: 4H, 2xCH2NCH2), 2.40(m, 4H， 2xCH2NCH2) 2.09(s, 3H， CHa), 1.87(m_: 2H,CH2CH), 1.30(m, 2H,CH2CH) 实施例 23 1H NMR (400 MHz, DMSO-d6) 57.77 (d, 1H, J = 8.4 Hz, ArH), 7.59 (s, 1H, CH), 7.39(d, 1H, J=8.4Hz, ArH ), 4.49 (s,lH, CHN), 3.53(m, 4H, 2xCH20CH2), 2.96(m: 4H, 2xCH2NCH2), 2.40(m, 4H, 2xCH2NCH2) 2.09 (s, 3H, CHa), 1.87 (m _: 2H, CH2CH), 1.30 (m, 2H, CH2CH) Example 23

N-{3-[5-甲基 -4-(4-***啉 -4-基小羰基) -3-三氟甲基 -IH-吡咯 -2-次甲基 ]-2-氧 -2,3- 二氢 -1Η-Π引哚 -5-基甲酰胺 N-{3-[5-Methyl-4-(4-morphinolin-4-ylsuccinyl)-3-trifluoromethyl-IH-pyrrol-2-ylmethyl]-2-oxo-2, 3-Dihydro-1Η-Π 哚-5-ylformamide

重复本发明实施例 18第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢-吡咯 -3-羧酸 -[2-(4-***啉 -4-哌啶 -1-基)乙基] -酰胺 18a作原料，按照本发明实施例 18第二步所述相同方式使得该原料与 5-甲酰基 -1，3-二氢 -吲哚 -2-酮的反应，则得到标题产物 N-{3-[5-甲基 -4-(4-***啉 -4-基 -1-羰基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧 -2,3-二氢 -1H-吲哚 -5-基} -甲酰胺 23(110 mg，黄色固体)，产率： 22.7%。

The first step of the reaction of Example 18 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -[2-(4-morpholine-4-piperidin-1-yl)ethyl]-amide 18a as a starting material, the starting material and 5-formyl group are obtained in the same manner as described in the second step of Example 18 of the present invention. The reaction of 1,3-dihydro-indol-2-one gives the title product N-{3-[5-methyl-4-(4-morphinolin-4-yl-1-carbonyl)-3- Trifluoromethyl-1H-pyrrole-2-methylidene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-carboxamide 23 (110 mg, yellow solid), yield : 22.7%.

MS m/z (ESI): 532.3(M+1) MS m/z (ESI): 532.3 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 510.11(s,lH, HCON), 8.25(s, 1H， CH )， 7.84 (s， 1 ArH), 7.45 (d, IH, J=8.4Hz, ArH ), 6.89(d,lH, J=8.4Hz, ArH), 4.47 (s，lH， CHN), 3.53(m, 4H, 2xCH20CH2), 2.96(m, 4H， 2xCH2NCH2), 2.40(m， 4H, 2xCH2NCH2), 2.09(s， 3H, CH3), 1.87(m, 2H,CH2CH), 1.30(m, 2H,CH2CH) 实施例 24 1H NMR (400 MHz, DMSO-d6) 510.11 (s, lH, HCON), 8.25 (s, 1H, CH), 7.84 (s, 1 ArH), 7.45 (d, IH, J = 8.4 Hz, ArH ), 6.89 (d, lH, J = 8.4 Hz, ArH), 4.47 (s, lH, CHN), 3.53 (m, 4H, 2xCH20CH2), 2.96 (m, 4H, 2xCH2NCH2), 2.40 (m, 4H, 2xCH2NCH2), 2.09 (s, 3H, CH3), 1.87 (m, 2H, CH2CH), 1.30 (m, 2H, CH2CH) Example 24

_N_{5_氟 _3-[5-甲基 -4-(4-***啉 -4-基 -1-羰基) -3-三氟甲基 -IH-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 ,-lH-吲哚 -7-基} -甲磺酰胺 _N _{5_fluoro_3-[5-methyl-4-(4-morphinolin-4-yl-1-carbonyl)-3-trifluoromethyl-IH-pyrrole-2-methine]- 2-oxo-2,3-dihydro, -lH-indol-7-yl}-methanesulfonamide

重复本发明实施例 18第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟.甲基 -1 氢 -吡咯 -3-羧酸 -[2-(4-***啉 -4-哌啶小基)乙基] -酰胺 18a作原料，按照本发明实施例 18第二步所述相同方式使得该原料与 5-氟 -7-甲磺酰胺基 -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 N-{5-氟 -3-[5-甲基 _4-(4-***啉 -4-基小羰基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H- 吲哚 -7-基} -甲磺酰胺 24 (110mg, 黄色固体)，产率： 59.6%。

The first step of the reaction of Example 18 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1-hydrogen-pyrrole-3-carboxylate obtained in the above first step was used. The acid-[2-(4-morpholine-4-piperidinyl)ethyl]-amide 18a is used as a starting material, and the starting material is reacted with 5-fluoro-7- in the same manner as described in the second step of Example 18 of the present invention. The reaction of methanesulfonamido-1,3-dihydro-inden-2-one gives the title product N-{5-fluoro-3-[5-methyl- 4-(4-morpholine-4- Small carbonyl)-3-trifluoromethyl-1H-pyrrole-2-methino]-2-oxo-2,3-dihydro-1H-indol-7-yl}-methanesulfonamide 24 ( 110 mg, yellow solid), Yield: 59.6%.

MS m/z (ESI): 600.2(M+1) MS m/z (ESI): 600.2 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) S7.59(m,lH， ArH)), 7.58(s, 1H, CH ), 7.05 (m, 1H, ArH), 4.47 (s,lH, CHN), 3.53(m, 4H， 2xCH20CH2), 3.07(s,3H,CH3), 2.96(m, 4H, 2XCH2NCH2), 2.4O(m,4H, 2xCH2NCH2), 2.09(s, 3H, CH3), 1.87(m， 2H,CH2CH), 1.30(m, 2H,CH2CH) 实施例 25 1H NMR (400 MHz, DMSO-d6) S7.59 (m,lH, ar), 7.58 (s, 1H, CH), 7.05 (m, 1H, arH), 4.47 (s,lH, CHN), 3.53 (m, 4H, 2xCH20CH2), 3.07(s,3H,CH3), 2.96(m, 4H, 2XCH2NCH2), 2.4O(m,4H, 2xCH2NCH2), 2.09(s, 3H, CH3), 1.87(m, 2H , CH2CH), 1.30 (m, 2H, CH2CH) Example 25

N-{3-[5-甲基 -4-(4-***啉 -4-基-哌啶小羰基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -5-基甲磺酰胺 N-{3-[5-Methyl-4-(4-morphinolin-4-yl-piperidine carbonyl)-3-trifluoromethyl-1H-pyrrole-2-methine]-2-oxo 2,3-dihydro-1H-indole-5-ylmethanesulfonamide

重复本发明实施例 18第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -[2-(4-***啉 -4-哌啶 -1-基)乙基] -酰胺 18a作原料，按照本发明实施例 18第二步所述相同方式使得该原料与 5-甲磺酰胺基 -1，3-二氢 - 哚 -2-餉的反应，则得到标题产物 N-{3-[5-甲基 -4-(4-吗啡啉斗基-哌啶小羰基) _3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -5-基甲磺酰胺 25(84 mg, 黄色固体)，产率： 45 %。

The first step of the reaction of Example 18 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -[2-(4-morpholine-4-piperidin-1-yl)ethyl]-amide 18a as a starting material, the starting material and 5-methanesulfonamide are obtained in the same manner as described in the second step of Example 18 of the present invention. The reaction of benzyl-1,3-dihydro-indole-2-indole gives the title product N-{3-[5-methyl-4-(4-morphinolinyl-piperidine carbonyl) _3-three Fluoromethyl-1H-pyrrole-2-methino]-2-oxo-2,3-dihydro-1H-indol-5-ylmethanesulfonamide 25 (84 mg, yellow solid), yield: 45 %.

MS m/z (ESI): 582.2(M+1) MS m/z (ESI): 582.2 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 57.78 (s, 1H， CH), 7.46 (m， 1H， ArH), 7.33(d, 1H， J=8.4Hz, ArH ), 6.87(d,lH, J=8.4Hz,ArH), 4.46 (s,lH， CHN), 3.53(m, 4H， 2xCH20CH2), 3.07(s,3H,CH3), 2.96(m， 4H, 2xCH2NCH2), 2.40(m, 4H, 2xCH2NCH2), 2.09(s, 3H, CH3), 2.00(s, 3H, CH3)1.87(m, 2H,CH2CH), 1.30(m, 2H,CH2CH). 实施例 26 1H NMR (400 MHz, DMSO-d6) 57.78 (s, 1H, CH), 7.46 (m, 1H, ArH), 7.33 (d, 1H, J = 8.4 Hz, ArH ), 6.87 (d, lH, J = 8.4 Hz, ArH), 4.46 (s, lH, CHN), 3.53 (m, 4H, 2xCH20CH2), 3.07 (s, 3H, CH3), 2.96 (m, 4H, 2xCH2NCH2), 2.40 (m, 4H, 2xCH2NCH2) , 2.09(s, 3H, CH3), 2.00(s, 3H, CH3) 1.87(m, 2H, CH2CH), 1.30(m, 2H, CH2CH). Example 26

N-{5-氟 -3-[5-甲基 -4-(4-***啉 -4-哌啶 -1-羰基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2- 氧代 -2,3-二氢 -1H-吲哚 -7-基}-甲酰胺 N-{5-fluoro-3-[5-methyl-4-(4-morpholine-4-piperidin-1-carbonyl)-3-trifluoromethyl-1H-pyrrole-2-methine] -2- Oxo-2,3-dihydro-1H-indol-7-yl}-carboxamide

重复本发明实施例 18第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲 '-4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -[2-(4-***啉 -4-哌啶 -1-基)乙基] -酰胺 18a作原料，按照本发明实施例 18第二步所述相同方式使得该原料与 5-氟 -7-甲酰胺基 -1,3-二氢 -H引哚 -2-酮的反应，则得到标题产物 N-{5-氟 -3-[5-甲基 _4-(4-***啉 -4-哌啶 -1-羰基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H- 吲哚 -7-基甲酰胺 26 (162 mg, 黄色固体)，产率： 61.4%。

The first step reaction of Example 18 of the present invention was repeated except that the compound 5-formyl-2-methyl'-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -[2-(4-morpholine-4-piperidin-1-yl)ethyl]-amide 18a as a starting material, which is obtained in the same manner as described in the second step of Example 18 of the present invention. -formamide-1,3-dihydro-H-indol-2-one reaction to give the title product N-{5-fluoro-3-[5-methyl- 4-(4-morpholine-4 -piperidin-1-carbonyl)-3-trifluoromethyl-1H-pyrrol-2-ylmethyl]-2-oxo-2,3-dihydro-1H-indol-7-ylcarboxamide 26 (162 mg, yellow solid), Yield: 61.4%.

MS m/z (ESI): 550.3(M+1) MS m/z (ESI): 550.3 (M+1)

1H MR ( 400 MHz, DMSO-d6 ) 59.85(s,lH, HCONH), 8.34(s, 1H, CH ),7.53(m,2H, ArH)), 4.46 (s,lH, CHN), 3.53(m, 4H, 2><CH20CH2), 2.92(m,4H, 2xCH2NCH2), 2.40(m,4H, 2xCH2NCH2), 2.09(s， 3H, CH3), 1.87(m, 2H,CH2CH), 1.30(m, 1H MR (400 MHz, DMSO-d6) 59.85 (s, lH, HCONH), 8.34 (s, 1H, CH), 7.53 (m, 2H, ArH)), 4.46 (s, lH, CHN), 3.53 (m) , 4H, 2><CH20CH2), 2.92 (m, 4H, 2xCH2NCH2), 2.40 (m, 4H, 2xCH2NCH2), 2.09 (s, 3H, CH3), 1.87 (m, 2H, CH2CH), 1.30 (m,

2H,CH2CH) 实施例 27 2H, CH2CH) Example 27

N-{5-氟 -3-[5-甲基 -4-(4-***啉 -4-哌啶 -1-羰基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2- 氧代 -2,3-二氢 -1H-H引哚 -6-基}-甲酰胺 N-{5-fluoro-3-[5-methyl-4-(4-morpholine-4-piperidin-1-carbonyl)-3-trifluoromethyl-1H-pyrrole-2-methine] -2-oxo-2,3-dihydro-1H-H 哚-6-yl}-carboxamide

重复本发明实施例 18第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 -[2-(4-***啉 -4-呢啶小基)乙基] -酰胺 18a作原料，按照本发明实施例 18第二步所述相同方式使得该原料与 5- 氟 -7-甲酰胺基 -1，3-二氢 -吲哚 -2-酮的反应，则得到标题产物 N-{5-氟 -3-[5-甲基 -4-(4-***啉 -4-哌啶 -1-羰基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H- B引哚 -7-基}-甲酰胺 27(150 mg，黄色固体)，产率： 56.9%。

The first step of the reaction of Example 18 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -[2-(4-morpholine-4-oxaridinyl)ethyl]-amide 18a as a starting material, the starting material and 5-fluoro-7-A are obtained in the same manner as described in the second step of Example 18 of the present invention. The reaction of the amido-1,3-dihydro-inden-2-one gives the title product N-{5-fluoro-3-[5-methyl-4-(4-morphinolin-4-piperidine) -1-carbonyl)-3-trifluoromethyl-1H-pyrrole-2-methine]-2-oxo-2,3-dihydro-1H- B 哚-7-yl}-carboxamide 27 (150 mg, yellow solid), yield: 56.9%.

MS m/z (ESI): 550.3(M+1) MS m/z (ESI): 550.3 (M+1)

1H MR ( 400 MHz, DMSO-d6 ) S9,85(s,lH, HCONH), 8.33(s, 1H, CH ),7.57(d,lH: J=6.4, ArH)), 7.52 (m， 1H， J=6.8， ArH), 4.46 (s,lH, CHN), 3.53(m, 4H, 1H MR (400 MHz, DMSO-d6) S9, 85 (s, lH, HCONH), 8.33 (s, 1H, CH), 7.57 (d, lH: J = 6.4, ArH)), 7.52 (m, 1H, J=6.8, ArH), 4.46 (s,lH, CHN), 3.53(m, 4H,

2xCH20CH2), 2.92(m，4H， 2xCH2NCH2), 2.40(m,4H, 2xCH2NCH2), 2.09(s, 3H, CH3), 1.87(m， 2H,CH2CH), 1.30(m, 2H,CH2CH) 实施例 28 2xCH20CH2), 2.92 (m, 4H, 2xCH2NCH2), 2.40 (m, 4H, 2xCH2NCH2), 2.09 (s, 3H, CH3), 1.87 (m, 2H, CH2CH), 1.30 (m, 2H, CH2CH) Example 28

N-{5-氟 -3-[5-甲基 -4-(4-***啉 -4-哌啶小羰基) -3-三氟甲基 -1H-吡咯 -2-次甲 N-{5-fluoro-3-[5-methyl-4-(4-morphinphyrin-4-piperidines small carbonyl)-3-trifluoromethyl-1H-pyrrole-2-second

'基] -'2-氧代 -2,3-二氢 -1Η-Π引哚 -7-基}-乙酰胺 'Base' -'2-oxo-2,3-dihydro -1Η-Π 哚-7-yl}-acetamide

重复本发明实施例 18第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -[2-(4-羟基哌啶 -4-基)乙基] - 酰胺 18a作原料，按照本发明实施例 18第二步所述相同方式使得该原料与 5-氟 -7-乙酰胺基 -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 N-{5-氟 -3-[5-甲基 -4-(4- ***啉 -4-哌啶小羰基) -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -7-基甲酰胺 26 (173 mg，黄色固体)，产率： 67.5%。

The first step of the reaction of Example 18 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -[2-(4-Hydroxypiperidin-4-yl)ethyl]-amide 18a as a starting material, the starting material and 5-fluoro-7-acetamido group are obtained in the same manner as described in the second step of Example 18 of the present invention. -1,3-Dihydro-indol-2-one reaction, the title product N-{5-fluoro-3-[5-methyl-4-(4-morphinolin-4-piperidine carbonyl) -3-trifluoromethyl-1H-pyrrole-2-methino]-2-oxo-2,3-dihydro-1H-indol-7-ylcarboxamide 26 (173 mg, yellow solid) , Yield: 67.5%.

MS m/z (ESI): 564.4(M+1) MS m/z (ESI): 564.4 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 57.55(s,lH, ArH)), 7.48(s, 1H， CH )，7.45(m, 1H, J=3.6Hz, ArH), 4.46 (s，lH, CHN), 3.53(m, 4H, 2xCH20CH2), 2.96(m,4H, 1H NMR (400 MHz, DMSO-d6) 57.55 (s, lH, ArH)), 7.48 (s, 1H, CH), 7.45 (m, 1H, J = 3.6 Hz, ArH), 4.46 (s, lH, CHN ), 3.53 (m, 4H, 2xCH20CH2), 2.96 (m, 4H,

2xCH2NCH2), 2.40(m,4H, 2xCH2NCH2), 2.26(s, 3H, CHs), 2.09(s， 3H, Q^), 1.87(m, 2H,CH2CH), 1.30(m, 2H,CH2CH) 实施例 29 2xCH2NCH2), 2.40 (m, 4H, 2xCH2NCH2), 2.26 (s, 3H, CHs), 2.09 (s, 3H, Q^), 1.87 (m, 2H, CH2CH), 1.30 (m, 2H, CH2CH) 29

5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸（2- 吡咯垸 -1-乙基) -酰胺

按照本发明实施例 1第七步所述相同方式，氮气氛下，在一个 250 ml的三口瓶中，将 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -B比咯 -3-羧酸 lg (1.0 g， 4.52 mmol) 溶解于 N，N-二甲基甲酰 (10 ml)中，搅拌下依次加入 N-乙基 -N，- (二甲氨基丙基) - 碳二亚胺盐酸盐 (1.047 g， 5.46 mmol), 1-羟基苯并*** (0.92 g， 6.78 mmol) 三乙胺 (0.689 g, 6.82 mmol)及 2- (吡咯烷 -1-基)乙胺 (0.774g， 6.78 mmol), 室温搅拌 8小时，点板跟踪至原料基本消失，搅拌下向反应液中加入二氯甲烷 (200 ml), 用饱和碳酸氢钠溶液 (80 m½)洗涤混合液，合并水层用二氯甲垸 (50 mlxl)回萃。合并有机相，二氯甲垸层用无水硫酸钠干燥，过滤，滤液减压浓缩标题产物 5- 甲酰基 -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 -(2-吡咯烷 -1-基-乙基）酰胺 29a (1.7 g, 油状物)，直接进行下一步反应。 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid ( 2-pyrrole-1-ethyl)-amide

5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-B ratio in a 250 ml three-necked flask in the same manner as described in the seventh step of Example 1 of the present invention. L--3-carboxylic acid lg (1.0 g, 4.52 mmol) was dissolved in N,N-dimethylformyl (10 ml), and N-ethyl-N,-(dimethylaminopropyl) was added sequentially with stirring. - carbodiimide hydrochloride (1.047 g, 5.46 mmol), 1-hydroxybenzotriazole (0.92 g, 6.78 mmol) triethylamine (0.689 g, 6.82 mmol) and 2-(pyrrolidin-1-yl) Ethylamine (0.774 g, 6.78 mmol), stirred at room temperature for 8 hours, the plate was traced until the starting material disappeared, and dichloromethane (200 ml) was added to the reaction mixture with stirring, and washed with saturated sodium hydrogen carbonate solution (80 m1⁄2) The mixture was combined and the aqueous layer was combined with dichloromethane (50 ml×l). The organic phase was combined, and the methylene chloride layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to give the title product 5--formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid -(2-Pyrrolidin-1-yl-ethyl)amide 29a (1.7 g, oil).

按照本发明实施例 1第八步所述相同方式，将上一歩产物 5-甲酰基 -2-甲基 -4- 三氟甲基 -1氢-吡咯 -3-羧酸 -(2-吡咯烷小基-乙基）酰胺 29a (150 mg, 0.473 mmol) 不经纯化溶解于乙醇 (3 ml)中，搅拌下加入 5-氟 -1,3-二氢 -吲哚 -2-酮 (72 m_g， 0.473 mmol)及六氢吡啶 (4 mg， 0.05 mmol), 加热回流 8小时，点板跟踪至原料基本消失，反应自然冷却至室温，有黄色固体产生，过滤，固体用冷乙醇 (5 ml)洗涤，真空干燥，得到标题产物 5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸（2-吡咯烧 -1-乙基) -酰胺 29 (110 mg，黄色固体)，产率 73.7 %。 In the same manner as described in the eighth step of Example 1 of the present invention, the above product, 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-(2-pyrrolidine) Small base-ethyl)amide 29a (150 mg, 0.473 mmol) was dissolved in ethanol (3 ml) without purification, and 5-fluoro-1,3-dihydro-indol-2-one (72 m) was added with stirring. _g , 0.473 mmol) and hexahydropyridine (4 mg, 0.05 mmol), heated under reflux for 8 hours, the plate was traced until the starting material disappeared, the reaction was naturally cooled to room temperature, and a yellow solid was produced, filtered, and solid ethanol (5 ml) Washing and drying in vacuo gave the title product 5-(5-fluoro-2-oxo-1,2-dihydro-indole-3-methylmethyl)-2-methyl-4-trifluoromethyl- 1H-Pyrrol-3-carboxylic acid (2-pyrrole-1-ethyl)-amide 29 (110 mg, yellow solid), yield 7.37.

MS m/z (ESI) : 451.2 (M+1) MS m/z (ESI): 451.2 (M+1)

1H MR ( 400 MHz, DMSO-d6 ) 57.64(dxd,lH, ArH)), S7.59(s, 1H, CH ), 7.06(dxd, 1H, ArH), 6.91(dxd, 1H， ArH), 3.33 (m,4H, 2xNCH2CH2N), 2.54(m, 4H, 2xCH2NCH2), 2.32(s, 3H, CHs), 1.68(s, 4H, 2xCH2CH2) 实施例 30 1H MR (400 MHz, DMSO-d6) 57.64 (dxd, lH, ArH)), S7.59 (s, 1H, CH), 7.06 (dxd, 1H, ArH), 6.91 (dxd, 1H, ArH), 3.33 (m, 4H, 2xNCH2CH2N), 2.54 (m, 4H, 2xCH2NCH2), 2.32 (s, 3H, CHs), 1.68 (s, 4H, 2xCH2CH2) Example 30

-(5-氯 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸（2- 吡咯烷小乙基) -酰胺

重复本发明实施例 29第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢-吡咯 -3-羧酸 -(2-吡咯烷 -1-基-乙基）酰胺 29a作原料，按照本发明实施例 29第二步所述相同方式使得该原料与 5-氯 -7-甲酰胺基 -1,3-二氢 -吲哚 -2-酮的应,则得到标题产物 5-(5-氯 -2-氧代 -1,2-二氢 -II引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸（2-吡咯烷 -1-乙基) -酰胺 30 (lOOmg, 黄色固体)，产率： 45.3%。 -(5-chloro-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid (2 - pyrrolidine small ethyl)-amide

The first step of the reaction of Example 29 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-Pyrrolidin-1-yl-ethyl)amide 29a as a starting material, which is obtained in the same manner as described in the second step of Example 29 of the present invention, and 5-chloro-7-carboxamido-1,3- For the dihydro-indol-2-one, the title product 5-(5-chloro-2-oxo-1,2-dihydro-II fluoren-3-ylmethyl)-2-methyl 4-Trifluoromethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ethyl)-amide 30 (100 mg, yellow solid), Yield: 45.3%.

MS m/z (ESI): 467.1(M+1) MS m/z (ESI): 467.1 (M+1)

1H MR ( 400 MHz, D SO-d6 ) S7.84(m，lH， ArH)), 57.62(s, IH, CH )， 7.26(m, IH, ArH), 6.92(m, IH, ArH)， 3.33 (m，4H, 2xNCH2CH2N), 2.54(m, 4H, 2xCH2NCH2), 2.32(s, 3H, CH3), 1.66(S, 4H, 2XCH2CH2) 实施例 '31 、 1H MR ( 400 MHz, D SO-d6 ) S7.84 (m, lH, ArH)), 57.62 (s, IH, CH ), 7.26 (m, IH, ArH), 6.92 (m, IH, ArH), 3.33 (m, 4H, 2xNCH2CH2N), 2.54 (m, 4H, 2xCH2NCH2), 2.32 (s, 3H, CH3), 1.66 (S, 4H, 2XCH2CH2) Example '31

5-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -IH-吡咯 -3-羧酸（2- 吡咯垸小乙基) -酰胺 '³ 5-(5-Bromo-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-IH-pyrrole-3-carboxylic acid ( 2-pyrroleium small ethyl)-amide ' ³

重复本发明实施例 29第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-吡咯烷 -1-基-乙基）酰胺 29a作原料，按照本发明实施例 29第二步所述相同方式使得该原料与 5-溴 -7-甲酰胺基 -1，3-二氢 - 哚 -2-酮的反应，则得到标题产物 5-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸（2-吡咯烷 -1-乙基) -酰胺 31 (127mg, 黄色固体)，产率： 52.5%。 The first step of the reaction of Example 29 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-Pyrrolidin-1-yl-ethyl)amide 29a as a starting material, which is obtained in the same manner as described in the second step of Example 29 of the present invention, and 5-bromo-7-carboxamido-1,3- The reaction of dihydro-indol-2-one gives the title product 5-(5-bromo-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4 -Trifluoromethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidine-1-ethyl)-amide 31 (127 mg, yellow solid), yield: 52.5%.

MS m/z (ESI): 511.6(M+1) MS m/z (ESI): 511.6 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 57.97(s,lH, ArH)), 7.63(s, IH, CH ), 7.39(d, 1H， J=8.4Hz, ArH), 6.99(d, IH, J=8.4Hz, ArH), 3.42 (m，4H， 2xNCH2CH2N), 2.54(m， 4H 2xCH2NCH2), 2.32(s, 3H, CH₃), L66(s, 4H, 2xCH2CH2) 实施例 32 1H NMR (400 MHz, DMSO-d6) 57.97 (s,lH, ArH)), 7.63 (s, IH, CH), 7.39 (d, 1H, J = 8.4 Hz, ArH), 6.99 (d, IH, J = 8.4 Hz, ArH), 3.42 (m, 4H, 2xNCH2CH2N), 2.54 (m, 4H 2xCH2NCH2), 2.32 (s, 3H, CH ₃ ), L66 (s, 4H, 2xCH2CH2) Example 32

5-(5-氯 -7-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸 5-(5-chloro-7-bromo-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3 -carboxylic acid

(2-吡咯烷 -1-乙基) -酰胺 (2-pyrrolidine-1-ethyl)-amide

重复本发明实施例 29第一歩反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-吡咯烷小基-乙基）酰胺 29a作原料，按照本发明实施例 29第二步所述相同方式使得该原料与 5-氟 -7-溴 -1,3-二氢:吲哚 -2-酮的反应，则得到标题产物 5-(5-氯 -7-溴 -2-氧代 -1，2-二氢 -n引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸（2-吡咯烷 -1-乙基) -酰胺 32(86mg, 黄色固体)，产率： 43 %。

The first hydrazine reaction of Example 29 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-Pyrrolidinyl-ethyl)amide 29a as a starting material, the starting material is made with 5-fluoro-7-bromo-1,3-dihydro: oxime in the same manner as described in the second step of Example 29 of the present invention. The reaction of indole-2-one gives the title product 5-(5-chloro-7-bromo-2-oxo-1,2-dihydro-n-indol-3-methyl)-2-methyl -4-Trifluoromethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidine-1-ethyl)-amide 32 (86 mg, yellow solid), yield: 43%.

MS m/z (ESI): 529.5(M+1) MS m/z (ESI): 529.5 (M+1)

1HNMR ( 400 Hz, DMSO-d6 ) δ 7.74(m,lH, ArH)), S7.62(s, 1H,'CH)， 7.26(m， 1H: ArH), 7.38(m, 1H， ArH) 3.45 (m,4H, 2xNCH2CH2N), 3.45(2.58, 4H, 2xCH2NCH2), 2.23(s, 3H， CHs), 2.55 (s, 4H, 2xCH2CH2) 实施例 33 1HNMR (400 Hz, DMSO-d6) δ 7.74 (m, lH, ArH)), S7.62 (s, 1H, 'CH), 7.26 (m, 1H: ArH), 7.38 (m, 1H, ArH) 3.45 (m, 4H, 2xNCH2CH2N), 3.45 (2.58, 4H, 2xCH2NCH2), 2.23 (s, 3H, CHs), 2.55 (s, 4H, 2xCH2CH2) Example 33

:-(5-氟 -6-甲酰胺基 -2-氧代 -1，2-二氢 -H引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 :-(5-Fluoro-6-carboxamido-2-oxo-1,2-dihydro-H 哚-3-methylol)-2-methyl-4-trifluoromethyl-1H- Pyrrole

-3-羧酸（2-P比咯烷小乙基) -酰胺 3-carboxylic acid (2-Ppyrrolidine small ethyl)-amide

重复本发明实施例 29第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-吡咯烷小基-乙基）酰胺 29a作原料，按照本发明实施例 29第二步所述相同方式使得该原料与 5-氟 -7-甲酰胺基 -1,3-二氢哚 -2-酮的反应，则得到标题产物 5-(5-氟 -6-甲酰胺基 -2-氧代 -1,2-二氢引哚 -3-次甲基) -2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸（2-吡咯垸小乙基) -酰胺 33 (20mg，黄色固体)，产率： 10%。

The first step of the reaction of Example 29 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-Pyrrolidinyl-ethyl)amide 29a as a starting material, the starting material is reacted with 5-fluoro-7-carboxamido-1,3-dihydrogen in the same manner as described in the second step of Example 29 of the present invention. The reaction of indole-2-one gives the title product 5-(5-fluoro-6-carboxamido-2-oxo) -1,2-dihydroindol-3-ylmethyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid (2-pyrroleium small ethyl)-amide 33 ( 20 mg, yellow solid), Yield: 10%.

MS mix (ESI): 494.3(M+1) MS mix (ESI): 494.3 (M+1)

1H MR ( 400 MHz, DMSO-d6 ) S10.23(s，lH, HCONH), 7.88 (d,lH, J=4.8Hz, ArH)), 7.74(m, IH, ArH), 57.48(s, IH, CH )， 3.33 (t,4H, J=4.8Hz, 2xNCH2CH2N), 2.56 (m, 4H, 2xCH2NCH2)_s 1.98 (s， 3H， CHs), 1.70 (s, 4H, 2xCH2CH2) 实施例 34 1H MR (400 MHz, DMSO-d6) S10.23(s,lH, HCONH), 7.88 (d,lH, J=4.8Hz, ArH)), 7.74(m, IH, ArH), 57.48(s, IH , CH), 3.33 (t, 4H, J = 4.8 Hz, 2xNCH2CH2N), 2.56 (m, 4H, 2xCH2NCH2) _s 1.98 (s, 3H, CHs), 1.70 (s, 4H, 2xCH2CH2) Example 34

:-(5-氟 -7-甲酰胺基 -2-氧代 -1,2-二氢』引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -IH-吡咯 :-(5-Fluoro-7-carboxamido-2-oxo-1,2-dihydro) 哚-3-methyl)-2-methyl-4-trifluoromethyl-IH-pyrrole

-3-羧酸（2-吡咯烷 -1-乙基) -酰胺 3-carboxylic acid (2-pyrrolidine-1-ethyl)-amide

重复本发明实施例 29第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -B比咯 -3-羧酸 -(2-吡咯烷 -1-基-乙基）酰胺 29a作原料，按照本发明实施例 29第二步所述相同方式使得该原料与 5-氟 -7-甲酰胺基 -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 5-(5-氟 -7-甲酰胺基 -2-氧代 -1,2-二氢-吲哚 -3-次甲基) -2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸（2-吡咯烷小乙基) -酰胺 34 (107mg，黄色固体)，产率： 50%。

The first step of the reaction of Example 29 of the present invention was repeated, except that the compound obtained in the above first step was used. 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-B ratio -3- The carboxylic acid-(2-pyrrolidin-1-yl-ethyl)amide 29a is used as a starting material to give the starting material to 5-fluoro-7-carboxamido-1 in the same manner as described in the second step of Example 29 of the present invention. The reaction of 3-dihydro-indol-2-one gives the title product 5-(5-fluoro-7-carboxamido-2-oxo-1,2-dihydro-indole-3-indole A 2-Methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidine small ethyl)-amide 34 (107 mg, yellow solid), yield: 50%.

S m/z (ESI): 494.3(M+1) S m/z (ESI): 494.3 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 510.23(s,lH, HCONH), 7.53(m,2H), 7.48(s, IH, CH )， 3.33 (t,4H, J=4.8Hz, 2xNCH2CH2N), 2.56 (m, 4H, 2xCH2NCH2), 1.98 (s， 3H, CH3), 1.70 (s， 4H, 2xCH2CH2) 实施例 35 1H NMR (400 MHz, DMSO-d6) 510.23 (s, lH, HCONH), 7.53 (m, 2H), 7.48 (s, IH, CH), 3.33 (t, 4H, J = 4.8 Hz, 2xNCH2CH2N), 2.56 (m, 4H, 2xCH2NCH2), 1.98 (s, 3H, CH3), 1.70 (s, 4H, 2xCH2CH2) Example 35

5-(5-氣 -7-甲磺酰胺基 -2-氧代 -1，2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -IH-吡咯 -3-羧酸（2-吡咯垸 -1-乙基) -酰胺

5-(5-Gas-7-methanesulfonamido-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-IH- Pyrrole-3-carboxylic acid (2-pyrrole-1-ethyl)-amide

重复本发明实施例 29第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 -(2-吡咯烷小基-乙基）酰胺 29a 作原料，按照本发明实施例 29第二步所述相同方式使得该原料与 5-氟 -7-甲磺酰胺基 -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 5-(5-氟 -7-甲磺酰胺基 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸（2-吡咯烷 -1-乙基) -酰胺 35 (86mg, 黄色固体)，产率： 53.5 %。 The first step of the reaction of Example 29 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-pyrrolidinyl-ethyl)amide 29a as a starting material, the starting material is made in the same manner as described in the second step of Example 29 of the present invention, and 5-fluoro-7-methanesulfonylamino-1,3-di The reaction of hydrogen-indol-2-one gives the title product 5-(5-fluoro-7-methanesulfonamido-2-oxo-1,2-dihydro-indole-3-methine) 2-Methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidine-1-ethyl)-amide 35 (86 mg, yellow solid), yield: 53.5 %.

MS m/z (ESI): 544.2(M+1) MS m/z (ESI): 544.2 (M+1)

1H NM ( 400 MHz, DMSO-d6 ) 57.59(m,lH, ArH)), 7.58(s, 1H, CH ), 7.05 (m, 1H, ArH), 3.33 (t,4H， J=4.8Hz, 2xNCH2CH2N), 3.07(s,3H,CH3), 2.56 (m, 4H, 2xCH2NCH2), 1.98 (s, 3H, CH3), 1.70 (s， 4H, 2xCH2CH2) 实施例 36 1H NM ( 400 MHz, DMSO-d6 ) 57.59 (m, lH, ArH)), 7.58 (s, 1H, CH ), 7.05 (m, 1H, ArH), 3.33 (t, 4H, J = 4.8 Hz, 2xNCH2CH2N ), 3.07 (s, 3H, CH3), 2.56 (m, 4H, 2xCH2NCH2), 1.98 (s, 3H, CH3), 1.70 (s, 4H, 2xCH2CH2) Example 36

-甲磺酰胺基 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3- 羧酸（2-吡咯烷 -1-乙基) -酰胺 -Methanesulfonamido-2-oxo-1,2-dihydro-indol-3-ylmethyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid (2 -pyrrolidine-1-ethyl)-amide

重复本发施例 29第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢-吡咯 -3-羧酸 -(2-吡咯烷小基-乙基）酰胺 29a作原料，按照本发明实施例 29第二步所述相同方式使得该原料与 5-甲磺酰胺基 -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 5-(5-甲磺酰胺基 -2-氧代 -1，2-二氢引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸（2-吡咯烷小乙基) -酰胺 36 (65mg, 黄色固体)，产率： 30.1 %。

The first step of the reaction of Example 29 was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-Pyrrolidinyl-ethyl)amide 29a as a starting material, the starting material and 5-methanesulfonamido-1,3-dihydro-oxime were obtained in the same manner as described in the second step of Example 29 of the present invention. The reaction of 2-ketone gives the title product 5-(5-methanesulfonamido-2-oxo-1,2-dihydroindole-3-methyl)-2-methyl-4-tri Fluoromethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidine small ethyl)-amide 36 (65 mg, yellow solid), yield: 30.1%.

MS m/z (ESI): 526.2(M+1) MS m/z (ESI): 526.2 (M+1)

Ή NMR ( 400 MHz, DMSO-d6 ) 57.78 (s, 1H, CH), 7.46 (m, 1H， ArH), 7.33(d, 1H， J=8.4Hz, ArH ), 6.87(d,lH, J=8.4Hz,ArH), 3.34 (t,4H, J=4.8Hz, 2xNCH2CH2N), 3.07(s,3H,CH3),2.56 (m, 4H, 2xCH2NCH2), 1.98 (s, 3H， CHa), 1.70 (s， 4H: 2xCH2CH2) 实施例 37 NMR NMR (400 MHz, DMSO-d6) 57.78 (s, 1H, CH), 7.46 (m, 1H, ArH), 7.33 (d, 1H, J = 8.4 Hz, ArH ), 6.87 (d, lH, J = 8.4 Hz, ArH), 3.34 (t, 4H, J = 4.8 Hz, 2xNCH2CH2N), 3.07 (s, 3H, CH3), 2.56 (m, 4H, 2xCH2NCH2), 1.98 (s, 3H, CHa), 1.70 (s, 4H: 2xCH2CH2) Example 37

5-(7-乙酰胺基 -5-氟 -2-氧代 -1,2-二氢 - |哚-3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 5-(7-Acetylamino-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylmethyl)-2-methyl-4-trifluoromethyl-1H-pyrrole

-3-羧酸（2-吡咯垸 -1-乙基) -酰胺 3-carboxylic acid (2-pyrrole-1-ethyl)-amide

重复本发明实施例 29第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢-吡咯 -3-羧酸 -(2-吡咯烷 -1-基-乙基）酰胺 " 29a作原料，按照本发明实施例 29第二步所述相同方式使得该原料与 5-氟 -7-甲酰胺基 -1,3-二氢 -Π引哚 -2-酮的反应，则得到标题产物 5-(5-氟 -7-乙酰胺基 -2-氧代 -1，2-二氢 -吲噪 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸.（2-吡咯烷 -1-乙基) -酰胺 37 (107mg，黄色固体)，产率： 51.4%。 ^

The first step of the reaction of Example 29 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-Pyrrolidin-1-yl-ethyl)amide "29a" as a starting material, which is obtained in the same manner as described in the second step of Example 29 of the present invention, and 5-fluoro-7-carboxamido-1,3 -Dihydro-indole-indol-2-one reaction, the title product 5-(5-fluoro-7-acetamido-2-oxo-1,2-dihydro-indole-3--3- 2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid. (2-pyrrolidin-1-ethyl)-amide 37 (107 mg, yellow solid), yield: 51.4% ^

MS m/z (ESI): 508.2(M+1) MS m/z (ESI): 508.2 (M+1)

1H NMR ( 400 MHz, DMSO-d₆ ) S7.55(s,lH, ArH)), 7.48(s, 1H, CH ),7.45(m, 1H, J=3.6Hz， ArH), 3.34 (t,4H, J=4.8Hz, 2xNCH2CH2N), 2.56 (m, 4H, 2xCH2NCH2), 2.09(s, 3H, CH3),1.98 (s, 3H, CH3), 1.70 (s, 4H, 2> CH2CH2) 实施例 38 1H NMR (400 MHz, DMSO- d 6) S7.55 (s, lH, ArH)), 7.48 (s, 1H, CH), 7.45 (m, 1H, J = 3.6Hz, ArH), 3.34 (t, 4H, J=4.8 Hz, 2xNCH2CH2N), 2.56 (m, 4H, 2xCH2NCH2), 2.09 (s, 3H, CH3), 1.98 (s, 3H, CH3), 1.70 (s, 4H, 2>CH2CH2) Example 38

:-(5-乙酰胺基 -2-氧代 -1，2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4--1H-吡咯 -3-羧酸（2-吡咯烷 -1-乙基) -酰胺 :-(5-Acetylamino-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4--1H-pyrrole-3-carboxylic acid (2- Pyrrolidine-1-ethyl)-amide

重复本发明实施例 29第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-吡咯烷 -1-基-乙基）酰胺 29a作原料，按照本发明实施例 29第二步所述相同方式使得该原料与 5-乙酰胺基 -1,3-二氢 -Π引哚 -2-酮的反应，则得到标题产物 5-(5-乙酰胺基 -2-氧代 -1,2-二氢- 吲哚 -3-次甲基 )-2-甲基 -4--1H-吡咯 -3-羧酸（2-吡咯烷 -1-乙基) -酰胺 38 (90mg，暗红色固体)，产率： 44.8 %。

The first step of the reaction of Example 29 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-pyrrolidin-1-yl-ethyl)amide Using 29a as a starting material, the starting material is reacted with 5-acetamido-1,3-dihydro-indole-2-one in the same manner as described in the second step of Example 29 of the present invention to give the title product 5- (5-Acetylamino-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4--1H-pyrrole-3-carboxylic acid (2-pyrrolidine) 1-Ethyl)-amide 38 (90 mg, dark red solid), Yield: 44.8 %.

MS m/z (ESI): 490.9(M+1) - MS m/z (ESI): 490.9 (M+1) -

IH NMR ( 400 MHz, DMSO-d6 ) 57.78 (s, IH, CH), 7.46. (s, 1H， ArH), 7.33(d, IH,IH NMR (400 MHz, DMSO-d6) 57.78 (s, IH, CH), 7.46. (s, 1H, ArH), 7.33 (d, IH,

J=8.4Hz, ArH ), 6.87(m,lH, J=8.4Hz,ArH), 3.34 (t,4H, J=4.8Hz, 2xNCH2CH2N),J = 8.4 Hz, ArH ), 6.87 (m, lH, J = 8.4 Hz, ArH), 3.34 (t, 4H, J = 4.8 Hz, 2xNCH2CH2N),

2.56 (m, 4H， 2xCH2NCH2), 2.09(s, 3H, CH3),1.98 (s， 3H, CH3), 1.70 (s, 4H,2.56 (m, 4H, 2xCH2NCH2), 2.09(s, 3H, CH3), 1.98 (s, 3H, CH3), 1.70 (s, 4H,

2xCH2CH2) 实施例 39 2xCH2CH2) Example 39

5-(5-甲酰胺基 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4--1H-吡咯 -3-羧酸（2-吡咯烷 -1-乙基) -酰胺 5-(5-carboxamido-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4--1H-pyrrole-3-carboxylic acid (2- Pyrrolidine-1-ethyl)-amide

重复本发明实施例 29第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢-吡咯 -3-羧酸 -(2-吡咯垸小基-乙基）酰胺 29a作原料，按照本发明实施例 29第二步所述相同方式使得该原料与 5-甲酰胺基 -1,3-二氢^哚 -2-酮的反应，则得到标题产物 5-(5-甲酰胺基 -2-氧代 -1,2-二氢- 吲哚 -3-次甲基 )-2-甲基 -4--1H-吡咯 -3-羧酸（2-吡咯烷 -1-乙基) -酰胺 39 (18m_g，黄色固体)，产率： 35%。

The first step of the reaction of Example 29 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-pyrrolidinyl-ethyl)amide 29a as a starting material, which is obtained in the same manner as described in the second step of Example 29 of the present invention, and 5-formamido-1,3-dihydro-hydrazine-2 - Ketone reaction, the title product 5-(5-carboxamido-2-oxo-1,2-dihydro-indol-3-methylmethyl)-2-methyl-4--1H- pyrrole-3-carboxylic acid (2-pyrrolidin-1-ethyl) - amide 39 (18m _g, yellow solid), yield: 35%.

MS m/z (ESI): 476.5(M+1) MS m/z (ESI): 476.5 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 510.11(s,lH, HCON), 8.25(s, IH, CH ), 7.84 (s, 1H_: ArH), 7.45 (d, 1H， J=8.4Hz, ArH ), 6.89(d,lH, J=8.4Hz, ArH), 3.34 (t,4H， J=4.8Hz, 2xNCH2CH2N), 2.56 (m, 4H， 2xCH2NCH2), 1.98 (s, 3H, CH3), 1.70 (s, 4H， 2xCH2CH2) 实施例 40 1H NMR (400 MHz, DMSO-d6) 510.11 (s, lH, HCON), 8.25 (s, IH, CH), 7.84 (s, 1H _: ArH), 7.45 (d, 1H, J = 8.4 Hz, ArH ) , 6.89 (d, lH, J = 8.4 Hz, ArH), 3.34 (t, 4H, J = 4.8 Hz, 2xNCH2CH2N), 2.56 (m, 4H, 2xCH2NCH2), 1.98 (s, 3H, CH3), 1.70 (s , 4H, 2xCH2CH2) Example 40

5-〖6-(2-羟基 -乙酰胺基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H- 吡咯 -3-羧酸（2-吡咯烷 -1-乙基) -酰胺

重复本发明实施例 29第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-吡咯烷小基-乙基）酰胺 29a 作原料，按照本发明实施例 29第二步所述相同方式使得该原料与 2-羟基 -N-(2-氧 -2， 3-二氢 -1H-B引哚 -6-基) -乙酰胺的反应，则得到标题产物 5-[6-(2-羟基- 乙酰胺基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸 (2-吡咯垸 -1-乙基) -酰胺 40 (180m_g, 黄色固体)，产率： 27.3%。 5-[6-(2-Hydroxy-acetamido)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-2-methyl-4-trifluoromethyl-1H - Pyrrole-3-carboxylic acid (2-pyrrolidine-1-ethyl)-amide

The first step of the reaction of Example 29 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-Pyrrolidinyl-ethyl)amide 29a as a starting material, in the same manner as described in the second step of Example 29 of the present invention, the starting material is 2-hydroxy-N-(2-oxo-2, 3-di The reaction of hydrogen-1H-B-indol-6-yl)-acetamide gives the title product 5-[6-(2-hydroxy-acetamido)-2-oxo-1,2-dihydro-indole Indole-3-methylmethyl]-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid (2-pyrrole-1-ethyl)-amide 40 (180 m _g , yellow solid) , Yield: 27.3%.

MS m/z (ESI): 522.3(M-1) MS m/z (ESI): 522.3 (M-1)

1H NMR ( 400 MHz, DMSO-d6 ) 57.81 (d,lH,J=4.8Hz,ArH)), 7.76(m， 1H, 1H NMR (400 MHz, DMSO-d6) 57.81 (d, lH, J = 4.8 Hz, ArH)), 7.76 (m, 1H,

J=4.8Hz,ArH), 57.48(s, 1H, CH ), 4.05(d, 2H, J=4.2Hz, CH20H), 3.33 (m,2H, NCH2CH2N), 2.54(m,2H, NCH2CH2N), 2.48 (m， 4H, 2xCH2NCH2), 2.37 (s， 3H, CH3), 1.68 (s， 4H, 2xCH2CH2) 实施例 41 J = 4.8 Hz, ArH), 57.48 (s, 1H, CH), 4.05 (d, 2H, J = 4.2 Hz, CH20H), 3.33 (m, 2H, NCH2CH2N), 2.54 (m, 2H, NCH2CH2N), 2.48 (m, 4H, 2xCH2NCH2), 2.37 (s, 3H, CH3), 1.68 (s, 4H, 2xCH2CH2) Example 41

3-[4-([1,4']二哌啶基 -1'-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-5-氟 -1,3-二氢 -吲哚 -2-酮 3-[4-([1,4']Dipiperidinyl-1'-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2-methine]-5-fluoro- 1,3-dihydro-indol-2-one

按照本发明实施例 1第七步所述相同方式，氮气氛下，在一个 250 ml的三口瓶中，将 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 l_g (2.16 g， 9.77 mmol) 溶解于 N，N-二甲基甲酰胺 (20 ml)中，搅拌下依次加入 N-乙基 -N，- (二甲氨基丙基) - 碳二亚胺盐酸盐 (2.809 g， 14.65 mmol)、 1-羟基苯并*** (1.980 g， 14.65 mmol), 三乙胺 (0.689 g, 6.82 mmol)及 [1,4，]-二哌啶 (2.466g， 6.78 mmol)DMF溶液 (50 ml), 室温搅拌 8小时，点板跟踪至原料基本消失，搅拌下向反应液中加入乙酸乙酯 (400 ml),用饱和碳酸氢钠溶液 (150 mlx3)洗涤混合液，合并水层用乙酸乙酯 (150 ml><3) 回萃。合并有机相，乙酸乙酯层用无水硫酸钠干燥，过滤，滤液减压浓缩标题产物 4-([1，4']二哌啶基 -Γ-羰基) -5-甲基 -3-三氟甲基 -IH-吡咯 -2-甲醛 41a (3.32 g, 固体)，直接进行下一步反应。 - 按照本发明实施例 1第八步所述相同方式，将上一步产物 5-甲酰基 -2-甲基 -4- 三氟甲基 -1 氢 -吡咯 -3-羧酸 -[2-(4-***啉 -4-哌啶小基)乙基] 41a (1.26 g, 3.392 mmol)不经纯化溶解于乙醇 (30 ml)中，搅拌下加入 5-氟 -1,3-二氢 -吲哚 -2-酮 (459mg, 3.040 mmol)及哌啶 (33mg， 0.034 mmol), 加热回流 8小时，点板跟踪至原料基本消失，反应液自然冷却后在减压下蒸馏，得到的残留物用柱层析纯化 (二氯甲垸：甲醇：三乙胺 =60: 1 : 0.3),得到标题产物 3-[4-([1,4']二哌啶基 -1'-羰基) -5- 甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-5-氟 -1,3-二氢 -吲哚 -2-酮 41 (1.4 g，黄色固体)，产率 81.9%。

In the same manner as described in the seventh step of Example 1 of the present invention, 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole was introduced in a 250 ml three-necked flask under a nitrogen atmosphere. 1-carboxylic acid 1 _g (2.16 g, 9.77 mmol) was dissolved in N,N-dimethylformamide (20 ml), and N-ethyl-N,-(dimethylaminopropyl)- Carbodiimide hydrochloride (2.809 g, 14.65 mmol), 1-hydroxybenzotriazole (1.980 g, 14.65 mmol), triethylamine (0.689 g, 6.82 mmol) and [1,4,]-dipiper The pyridine (2.466 g, 6.78 mmol) in DMF (50 ml) was stirred at room temperature for 8 hrs, and the material was applied to the residue, and ethyl acetate (400 ml) was added to the reaction mixture with stirring. The mixture was washed with 150 ml x 3) and the combined aqueous layers were extracted with ethyl acetate (150 ml << The combined organic layers were dried over anhydrous sodium sulfate and filtered and evaporated. 4-([1,4']Dipiperidinyl-fluorenyl-carbonyl)-5-methyl-3-trifluoromethyl-IH-pyrrole-2-carbaldehyde 41a (3.32 g, solid), directly One step reaction. - In the same manner as described in the eighth step of Example 1 of the present invention, the product of the previous step is 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-[2-( 4-morpholine-4-piperidinyl)ethyl] 41a (1.26 g, 3.392 mmol) was dissolved in ethanol (30 ml) without purification, and 5-fluoro-1,3-dihydro-oxime was added with stirring. Indole-2-one (459 mg, 3.040 mmol) and piperidine (33 mg, 0.034 mmol), heated under reflux for 8 hours, the plate was traced until the starting material disappeared, the reaction solution was naturally cooled, and then distilled under reduced pressure. Purification by column chromatography (dichloromethane:methanol: triethylamine = 60:1: 0.3) gave the title product 3-[4-([1,4']dipiperidinyl-1'-carbonyl) -5 - methyl-3-trifluoromethyl-1H-pyrrole-2-methine]-5-fluoro-1,3-dihydro-indol-2-one 41 (1.4 g, yellow solid), yield 81.9%.

MS m/z (ESI) :505.7(M+1) MS m/z (ESI): 505.7 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 57.64 (m,lH, ArH)), 57.54 (s, IH, CH ), 7.05(m, IH, ArH), 6.9 l(m, 1H， ArH), 4.52 (d, IH, J=12Hz, CHN), 3.52 (m,2H， CH2NCH2), 2.74 (m， 2H, CH2NCH2), 2.49 (m, 4H， 2xCH2NCH2), 2.33 (s, 3H, CH3), 1.78 (m, 4H， 2xCH2CHCH2), 1.36(m, 4H, 2xCH2CH2CH2), 1.24(m, 2H, CH2CH2CH2). 实施例 42 1H NMR (400 MHz, DMSO-d6) 57.64 (m,lH, ArH)), 57.54 (s, IH, CH), 7.05 (m, IH, ArH), 6.9 l (m, 1H, ArH), 4.52 ( d, IH, J=12Hz, CHN), 3.52 (m, 2H, CH2NCH2), 2.74 (m, 2H, CH2NCH2), 2.49 (m, 4H, 2xCH2NCH2), 2.33 (s, 3H, CH3), 1.78 (m , 4H, 2xCH2CHCH2), 1.36 (m, 4H, 2xCH2CH2CH2), 1.24 (m, 2H, CH2CH2CH2). Example 42

3-[4-([1,4']二哌啶基 -1'-羰基) -5-甲基 -3-三氟甲基 -IH-吡咯 -2-次甲基 ]-5-氯 -1,3-二氢 -n引哚 -2-酮 3-[4-([1,4']Dipiperidinyl-1'-carbonyl)-5-methyl-3-trifluoromethyl-IH-pyrrole-2-methine]-5-chloro- 1,3-dihydro-n-indol-2-one

重复本发明实施例 41第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-P比咯院小基-乙基）酰胺 41a作原料，按照本发明实施例 41第二步所述相同方式使得该原料与 5-氯 -1，3- 二氢 -吲哚 -2-酮的反应，则得到标题产物 3-[4-([1,4']二哌啶基 -Γ-羰基) -5-甲基 -3- 三氟甲基 -1H-吡咯 -2-次甲基 ]-5-氯 -1,3-二氢 -H引哚 -2-酮 42 (130mg，黄色固体)，产率： 61.8%。 The first step of the reaction of Example 41 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-P than sylvestreyl-ethyl)amide 41a as a starting material, in the same manner as described in the second step of Example 41 of the present invention, the starting material and 5-chloro-1,3-dihydro-indole- 2-keto reaction gives the title product 3-[4-([1,4']dipiperidinyl-indole-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2- Hypomethyl]-5-chloro-1,3-dihydro-H-indol-2-one 42 (130 mg, yellow solid), yield: 61.8%.

MS m/z (ESI): 521.4(M+1) MS m/z (ESI): 521.4 (M+1)

1H MR ( 400 MHz, DMSO-d6 ) 57.85 (s,lH, ArH), 7.59 (s, 1H， CH ), 7.26 (dxd, IH, ArH), 6.93 (d, IH, J=8.4Hz, ArH), 4.52 (d， IH, J=12Hz, CHN), 3.52 (m, 2H, CH2NCH2), 2.98 (m， 2H， CH2NCH2), 2.50 (m, 4H, 2xCH2NCH2), 2.31 (s, 3H, CH3), 1-75 (m， 4H， 2xCH2CHCH2), 1.64 (m, 4H, 2xCH2CH2CH2), 1.24(m, 2H, CH2CH2CH2). 实施例 43 1H MR (400 MHz, DMSO-d6) 57.85 (s,lH, ArH), 7.59 (s, 1H, CH), 7.26 (dxd, IH, ArH), 6.93 (d, IH, J=8.4Hz, ArH) , 4.52 (d, IH, J=12Hz, CHN), 3.52 (m, 2H, CH2NCH2), 2.98 (m, 2H, CH2NCH2), 2.50 (m, 4H, 2xCH2NCH2), 2.31 (s, 3H, CH3), 1-75 (m, 4H, 2xCH2CHCH2), 1.64 (m, 4H, 2xCH2CH2CH2), 1.24 (m, 2H, CH2CH2CH2). Example 43

3-[4-([1，4']二哌啶基 -Γ-羰基) -5-甲基 -3-三氟甲基 -IH-吡咯 -2-次甲基 ]-5-溴 -1,3-二氢 -吲哚 -2-酮 3-[4-([1,4']Dipiperidinyl-fluorenyl-carbonyl)-5-methyl-3-trifluoromethyl-IH-pyrrole-2-methylidene]-5-bromo-1 , 3-dihydro-indol-2-one

重复本发明实施例 41第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-吡咯烷 -1-基-乙基）酰胺 41a作原料，按照本发明实施例 41第二步所述相同方式使得该原料与 5-溴 -1，3- 二氣 -吲哚 -2-酮的反应，则得到标题产物 3-[4-([1,4']二哌啶基 -1'-羰基) -5-甲基 -3- 三氟甲基 -1H-吡咯 -2-次甲基 ]-5-溴 -1,3-二氢 -吲哚 -2-酮 43 (129mg，黄色固体)，产率： 42.3 %。

The first step of the reaction of Example 41 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-Pyrrolidin-1-yl-ethyl)amide 41a as a starting material, which is obtained in the same manner as described in the second step of Example 41 of the present invention, and 5-bromo-1,3-diox-indole- 2-keto reaction gives the title product 3-[4-([1,4']dipiperidinyl-1'-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2 -Methyl-methyl]-5-bromo-1,3-dihydro-indol-2-one 43 (129 mg, yellow solid), Yield: 42.3 %.

MS m/z (ESI): 565.6(M+1) MS m/z (ESI): 565.6 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 67.98 (d，lH, J=1.2Hz,ArH))₅ 7.59 (d, IH, J=1.6Hz CH )， 7.39 (dxd, IH, ArH), 6.88 (d, IH, J=8Hz ArH), 4.52 (d, 1H， J=12Hz, CHN), 3.52 (m, 2H, CH2NCH2), 2.98 (m, 2H, CH2NCH2), 2.50 (m， 4H， 2><CH2NCH2), 2.31 (s, 3H, CH3), 1.75 (m, 4H, 2xCH2CHCH2), 1.64 (m, 2H, CH2CH2CH2), 1.24(m_: 2H， CH2CH2CH2). 实施例 44 1H NMR (400 MHz, DMSO- d6) 67.98 (d, lH, J = 1.2Hz, ArH)) 5 7.59 (d, IH, J = 1.6Hz CH), 7.39 (dxd, IH, ArH), 6.88 (d , IH, J=8Hz ArH), 4.52 (d, 1H, J=12Hz, CHN), 3.52 (m, 2H, CH2NCH2), 2.98 (m, 2H, CH2NCH2), 2.50 (m, 4H, 2><CH2NCH2 ), 2.31 (s, 3H, CH3), 1.75 (m, 4H, 2xCH2CHCH2), 1.64 (m, 2H, CH2CH2CH2), 1.24 (m _: 2H, CH2CH2CH2). Example 44

3-[4-([1,4']二哌啶基 -1'-羰基) -5-甲基 -3-三氟甲基 -IH-吡咯 -2-次甲基 ]-5-氯 -7溴 ' -1,3-二氢』引哚 -2-酮 3-[4-([1,4']Dipiperidinyl-1'-carbonyl)-5-methyl-3-trifluoromethyl-IH-pyrrole-2-methine]-5-chloro- 7 bromo '-1,3-dihydroindol-2-one

重复本发明实施例 41第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-吡咯烷小基-乙基）酰胺 41a作原料，按照本发明实施例 41第二步所述相同方式使得该原料与 5-氟 -7-溴 1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 3-[4-([1,4']二哌啶基 -1'-羰基) -5-甲基 -3-三氟甲基 -lH-吡咯 -2-次甲基 ]-5 -氯 -7溴 -1,3-二氢 -吲哚 -2-酮 44 (125mg,黄色固体)，产率： 66.3 %。

The first step of the reaction of Example 41 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-Pyrrolidinyl-ethyl)amide 41a as a starting material, the starting material is made with 5-fluoro-7-bromo1,3-dihydro-oxime in the same manner as described in the second step of Example 41 of the present invention. The reaction of 2-ketone gives the title product 3-[4-([1,4']dipiperidinyl-1'-carbonyl)-5-methyl -3-trifluoromethyl-lH-pyrrole-2-methine]-5-chloro-7bromo-1,3-dihydro-indol-2-one 44 (125 mg, yellow solid), yield: 66.3 %.

MS m/z (ESI): 583.5(M+1) MS m/z (ESI): 583.5 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 57.76 (ΙΪΙ,ΙΗ,ΑΓΗ)), 7.58 (d, 1H, J=2.4Hz, CH ), 7.39 (m, 1H, ArH), 4.52 (d， 1H， J=12Hz, CHN), 3.52 (m， 2H, CH2NCH2), 2.98 (m, 2H, CH2NCH2), 2.50 (m, 4H, 2xCH2NCH2), 2.31 (s, 3H, CH3), 1.75 (m, 4H， 2XCH2CHCH2), 1.64 (m, 2H, CH2CH2CH2), 1.24(m, 2H, CH2CH2CH2). 实施例 45 1H NMR (400 MHz, DMSO-d6) 57.76 (ΙΪΙ,ΙΗ,ΑΓΗ)), 7.58 (d, 1H, J=2.4Hz, CH ), 7.39 (m, 1H, ArH), 4.52 (d, 1H, J =12Hz, CHN), 3.52 (m, 2H, CH2NCH2), 2.98 (m, 2H, CH2NCH2), 2.50 (m, 4H, 2xCH2NCH2), 2.31 (s, 3H, CH3), 1.75 (m, 4H, 2XCH2CHCH2) , 1.64 (m, 2H, CH2CH2CH2), 1.24 (m, 2H, CH2CH2CH2). Example 45

Ν-{3-[4-([1,4']二哌啶基 -Γ-羰基) -5-基 -3-三氟甲基 -lH-吡咯 -2-次甲基 ]-2-氧代 -2，3- 二氢 -1H-吲哚 -5-基}-甲酰胺 Ν-{3-[4-([1,4']Dipiperidinyl-fluorenyl-carbonyl)-5-yl-3-trifluoromethyl-lH-pyrrole-2-methine]-2-oxo 2,3-dihydro-1H-indol-5-yl}-carboxamide

重复本发明实施例 41第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-吡咯烷 -1-基-乙基)酰胺 41a作原料，按照本发明实施例 41第二步所述相同方式使得该原料与 5-甲酰胺基 -1，3-二氢 -B引噪 -2-酮的反应，则得到标题产物 Ν-{3-[4-([1，4']二哌啶基 -Γ-羰基) -5-基 -3-三氟甲基 -1Η-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1Η-吲哚 -5-基甲酰胺 46(140mg, 红色固体)，产率： 61.4%。

The first step of the reaction of Example 41 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-Pyrrolidin-1-yl-ethyl)amide 41a as a starting material, the starting material and 5-formamido-1,3-dihydro-B are obtained in the same manner as described in the second step of Example 41 of the present invention. The reaction of the ketone-2-ketone gives the title product Ν-{3-[4-([1,4']dipiperidinyl-indole-carbonyl)-5-yl-3-trifluoromethyl-1Η - Pyrrole-2-methenyl-2-oxo-2,3-dihydro-1 fluorene-5-ylcarboxamide 46 (140 mg, red solid), Yield: 61.4%.

MS m/z (ESI): 530.6(M+1) MS m/z (ESI): 530.6 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) S10.10(s, HCONH),8.72 (m,lH,ArH), 8.25 (m， 1H, ArH), 67.60 (s， 1H， CH ), 6.88 (m， 1H， ArH), 4.52 (d, lH,J=12Hz, CHN), 3.52 (m， 2H_: CH2NCH2), 2.98 (m, 2H, CH2NCH2), 2.50 (m， 4H， 2xCH2NCH2), 2.31 (s, 3H, CH3), 1.75 (m, 4H, 2xCH2CHCH2), 1.64 (m, 2H， CH2CH2CH2), 1.24(m, 2H, CH2CH2CH2). 实施例 46 1H NMR (400 MHz, DMSO-d6) S10.10 (s, HCONH), 8.72 (m, 1H, ArH), 8.25 (m, 1H, ArH), 67.60 (s, 1H, CH), 6.88 (m, 1H, ArH), 4.52 (d, lH, J=12Hz, CHN), 3.52 (m, 2H _: CH2NCH2), 2.98 (m, 2H, CH2NCH2), 2.50 (m, 4H, 2xCH2NCH2), 2.31 (s, 3H , CH3), 1.75 (m, 4H, 2xCH2CHCH2), 1.64 (m, 2H, CH2CH2CH2), 1.24 (m, 2H, CH2CH2CH2). Example 46

Ν-{3-[4-([1，4']二哌啶基 -1'-羰基) -5-基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3- 二氢 -1H-吲哚 -5-基}-乙酰胺

Ν-{3-[4-([1,4']Dipiperidinyl-1'-carbonyl)-5-yl-3-trifluoromethyl-1H-pyrrole-2-methine]-2- Oxo-2,3-dihydro-1H-indol-5-yl}-acetamide

重复本发明实施例 41第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-P比咯浣 -1-基-乙基）酰胺 41a作原料，按照本发明实施例 41第二步所述相同方式使得该原料与 5-乙酰胺基 -1，3-二氢 -吲哚 -2-酮的反应，则得到标题产物 Ν-{3-[4-([1,4']二哌啶基 -1'-羰基) -5-基 -3-三氟甲基 -1Η-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1Η-吲哚 -5-基}-乙酰胺 46(99mg，红色固体)，产率： 39.8%。： . The first step of the reaction of Example 41 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-P-pyridin-1-yl-ethyl)amide 41a as a starting material, the starting material and 5-acetamido-1,3-dihydrogen are obtained in the same manner as described in the second step of Example 41 of the present invention. -Indole-2-one reaction, the title product Ν-{3-[[1,4']dipiperidinyl-1'-carbonyl)-5-yl-3-trifluoromethyl -1Η-pyrrole-2-methine]-2-oxo-2,3-dihydro-1Η-indol-5-yl}-acetamide 46 (99 mg, red solid), yield: 39.8%. : .

MS m/z (ESI): 544.6(M+1) MS m/z (ESI): 544.6 (M+1)

Ή NMR ( 400 MHz, DMSO-d6 ) 57.78(s, IH, CH ), 7.46(m,lH,ArH)), 7.33 (d, IH, J=4.4Hz, ArH),， 6.87 (d， IH, J=8.4Hz, AiH), 4.52 (d, IH, J=12Hz, CHN), 3.51 (m, 2H, CH2NCH2), 2.98 (m， 2H, CH2NCH2), 2.50 (m, 4H, 2xCH2NCH2), 2.31 (s， 3H， CHb), 1.99(s, 3H, CH3), 1.75 (m, 2H, CH2CHCH2), 1.64 (m， 4H， 2xCH2CH2CH2), 1.24(m, 2H, CH2CH2CH2). 实施例 47 NMR NMR (400 MHz, DMSO-d6) 57.78 (s, IH, CH), 7.46 (m, lH, ArH)), 7.33 (d, IH, J = 4.4 Hz, ArH),, 6.87 (d, IH, J=8.4Hz, AiH), 4.52 (d, IH, J=12Hz, CHN), 3.51 (m, 2H, CH2NCH2), 2.98 (m, 2H, CH2NCH2), 2.50 (m, 4H, 2xCH2NCH2), 2.31 ( s, 3H, CHb), 1.99(s, 3H, CH3), 1.75 (m, 2H, CH2CHCH2), 1.64 (m, 4H, 2xCH2CH2CH2), 1.24 (m, 2H, CH2CH2CH2). Example 47

Ν-{3-[4-([1，4']二哌啶基 -Γ-羰基) -5-甲基 -3-三氟甲基 -IH-吡咯 -2-次甲基 ]-5-氟 -2- 氧代 -2,3-二氢 -IH-吡咯 -7-基甲酰胺 Ν-{3-[4-([1,4']Dipiperidinyl-fluorenyl-carbonyl)-5-methyl-3-trifluoromethyl-IH-pyrrole-2-methine]-5- Fluor-2-oxo-2,3-dihydro-IH-pyrrol-7-ylformamide

重复本发明实施例 41第一步反应，不同的是使用上述第： ^步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-吡咯烷 -1-基-乙基）酰胺 41a 作原料，按照本发明实施例 41第二步所述相同方式使得该原料与 5-氟 -7-甲酰胺基 -1,3-二氢 -H引哚 -2-酮的反应，则得到标题产物 Ν-{3-[4-([1,4']二哌啶基 -1'-羰基) -5-甲基 -3-三氟甲基 -1Η-吡咯 -2-次甲基 ]-5-氟 -2-氧代 -2,3-二氢 -1Η-吡咯 -7-基} - 甲酰胺 47 (211mg，黄色固体)，产率： 71.5%。 The first step of the reaction of Example 41 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylate obtained in the above step: The acid-(2-pyrrolidin-1-yl-ethyl)amide 41a is used as a starting material, and the starting material is reacted with 5-fluoro-7-carboxamido-1,3 in the same manner as described in the second step of Example 41 of the present invention. -Dihydro-H-indol-2-one reaction to give the title product Ν-{3-[4-([1,4']dipiperidinyl-1'-carbonyl)-5-methyl-3 -trifluoromethyl-1Η-pyrrole-2-methine]-5-fluoro-2-oxo-2,3-dihydro-1Η-pyrrole-7-yl}-carboxamide 47 (211 mg, yellow solid ), Yield: 71.5%.

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

1H NMR ( 400 MHz, DMSO-d6 ) 59.89 (s,lH, HCO H), 8.35 (s, 1H， CH )， 7.51(m,2H,ArH), 4.52 (m, 1H， CHN), 3.49 (m， 2H， CH2NCH2), 2.94 (m, 2H， W 1H NMR (400 MHz, DMSO-d6) 59.89 (s,lH, HCO H), 8.35 (s, 1H, CH), 7.51 (m,2H,ArH), 4.52 (m, 1H, CHN), 3.49 (m , 2H, CH2NCH2), 2.94 (m, 2H, W

CH2NCH2), 2.50 (m, 4H, 2xCH2NCH2), 2.28 (s， 3H， CH3), 1.75 (m, 4H: 2xCH2CHCH2), 1.64 (m, 4H， 2xCH2CH2CH2), 1.24(m， 2H, CH2CH2CH2). 实施例 48 CH2NCH2), 2.50 (m, 4H, 2xCH2NCH2), 2.28 (s, 3H, CH3), 1.75 (m, 4H: 2xCH2CHCH2), 1.64 (m, 4H, 2xCH2CH2CH2), 1.24 (m, 2H, CH2CH2CH2). 48

Ν-{3-[4-([1，4']二哌啶基 -1'-羰基) -5-甲基 -3-三氟甲基 -IH-吡咯 -2-次甲基 ]-5-氟 -2- 氧代 -2,3-二氢 -1H-吡咯 -6-基}-甲酰胺 . Ν-{3-[4-([1,4']Dipiperidinyl-1'-carbonyl)-5-methyl-3-trifluoromethyl-IH-pyrrole-2-methine]-5 -Fluoro-2-oxo-2,3-dihydro-1H-pyrrole-6-yl}-carboxamide.

重复本发明实施例 41第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-吡咯烷 -1 -基-乙基）酰胺 41a作原料，按照本发明实施例 41第二步所述相同方式使得该原料与 5-氟 -6-甲酰胺基 -1，3-二氢 -吲哚 -2-酮的反应，则得到标题产物 Ν-{3-[4-([1,4']二哌啶基 -Γ- 羰基) -5-甲基 -3-三氟甲基 -1Η-吡咯 -2-次甲基 ]-5-氟 -2-氧代 -2,3-二氢 -1Η-吡咯 -6- 基}-甲酰胺 48 (217mg，黄色固体)，产率： 73.5 %。 The first step of the reaction of Example 41 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-Pyrrolidin-1-yl-ethyl)amide 41a as a starting material, which is obtained in the same manner as described in the second step of Example 41 of the present invention, and 5-fluoro-6-carboxamido-1,3- The reaction of dihydro-indol-2-one gives the title product Ν-{3-[4-([1,4']dipiperidinyl-fluorenyl-carbonyl)-5-methyl-3-trifluoro Methyl-1Η-pyrrole-2-methine]-5-fluoro-2-oxo-2,3-dihydro-1Η-pyrrole-6-yl}-carboxamide 48 (217 mg, yellow solid) Rate: 73.5 %.

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

Ή NMR ( 400 MHz, DMSO-d6 ) S10.23(s，lH, HCONH), 7.88(d,2H,J=6.4Hz, ArH), 7.76 (d，2H，J=6.4Hz， ArH), 7.44 (s, IH, CH ), 4.52 (d, IH, J=11.2Hz CHN), 3.48 (m, 2H, CH2NCH2), 2.94 (m， 2H, CH2NCH2), 2.50 (m, 4H, 2xCH2NCH2), 2.28 (s, 3H， CH3), 1.75 (m， 4H， 2xCH2CHCH2), 1.64 (m, 2H, CH2CH2CH2), 1.24(m, 2H, CH2CH2CH2). 实施例 49 NMR NMR (400 MHz, DMSO-d6) S10.23 (s, lH, HCONH), 7.88 (d, 2H, J = 6.4 Hz, ArH), 7.76 (d, 2H, J = 6.4 Hz, ArH), 7.44 (s, IH, CH), 4.52 (d, IH, J=11.2Hz CHN), 3.48 (m, 2H, CH2NCH2), 2.94 (m, 2H, CH2NCH2), 2.50 (m, 4H, 2xCH2NCH2), 2.28 ( s, 3H, CH3), 1.75 (m, 4H, 2xCH2CHCH2), 1.64 (m, 2H, CH2CH2CH2), 1.24 (m, 2H, CH2CH2CH2). Example 49

Ν-{3-[4-([1,4']二哌啶基 -Γ-羰基) -5-甲基 -3-三氟甲基 -IH-吡咯 -2-次甲基 ]-5-氟 -2- 氧代 -2,3-二氢 -1H-吡咯 -6-基乙酰胺 Ν-{3-[4-([1,4']Dipiperidinyl-fluorenyl-carbonyl)-5-methyl-3-trifluoromethyl-IH-pyrrole-2-methine]-5- Fluoro-2-oxo-2,3-dihydro-1H-pyrrole-6-ylacetamide

重复本发明实施例 41第一步反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢-吡咯 -3-羧酸 -(2-B比咯烷 -1-基-乙基）酰胺 41a作原料，按照本发明实施例 41第二步所述相同方式使得该原料与 5-甲磺酰胺基 -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 Ν-{3-[4-([1，4']二哌啶基 -1'-羰基) -5-甲基 -3-三氟甲基 -IH-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -IH-吡咯 -5-基} -甲磺酰胺 50 (172mg，黄色固体)，产率： 56.8%。 The first step of the reaction of Example 41 of the present invention was repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid obtained in the above first step was used. -(2-B-pyrrolidin-1-yl-ethyl)amide 41a as a starting material, which is obtained in the same manner as described in the second step of Example 41 of the present invention, and 5-methanesulfonamide-1,3-di The reaction of hydrogen-indol-2-one gives the title product Ν-{3-[4-([1,4']dipiperidinyl-1'-carbonyl -5-methyl-3-trifluoromethyl-IH-pyrrole-2-methine]-2-oxo-2,3-dihydro-IH-pyrrol-5-yl}-methanesulfonamide 50 (172 mg, yellow solid), Yield: 56.8%.

MS m/z (ESI): 562.6(M+1) MS m/z (ESI): 562.6 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 57.54 (d,lH,J=2Hz, ArH)), 7.47 (d, IH, J=3.2Hz ArH), 7.45 (s, IH, CH ), 4.52 (d， IH, J=12Hz ,CHN), 3.48 (m, 2H, CH2NCH2), 2.94 (m, 2H， CH2NCH2), 2.50 (m, 4H， 2xCH2NCH2), 2.28 (s， 3H, )， 2.09 (s, 3H, CH3), 1.75 (m, 4H, 2xCH2CHCH2), 1.64 (m, 2H, CH2CH2CH2), 1.24(m, 2H, CH2CH2CH2). 实施例 50 1H NMR (400 MHz, DMSO-d6) 57.54 (d,lH,J=2Hz, ArH)), 7.47 (d, IH, J=3.2Hz ArH), 7.45 (s, IH, CH ), 4.52 (d, IH, J=12Hz, CHN), 3.48 (m, 2H, CH2NCH2), 2.94 (m, 2H, CH2NCH2), 2.50 (m, 4H, 2xCH2NCH2), 2.28 (s, 3H, ), 2.09 (s, 3H, CH3), 1.75 (m, 4H, 2xCH2CHCH2), 1.64 (m, 2H, CH2CH2CH2), 1.24 (m, 2H, CH2CH2CH2). Example 50

Ν-{3-[4-([1,4']二哌啶基 -1'-羰基) -5-甲基 -3-三氟甲基 -IH-吡咯 -2-次甲基 ]-2-氧代 Ν-{3-[4-([1,4']Dipiperidinyl-1'-carbonyl)-5-methyl-3-trifluoromethyl-IH-pyrrole-2-methine]-2 -oxo

-2,3-二氢 -1H-吡咯 -5-基甲磺酰胺 -2,3-dihydro-1H-pyrrole-5-yl methanesulfonamide

重复本发明实施例 41第一步反应，不同的是使用上述第一步中所得到的化合物.5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢-吡咯 -3-羧酸 -(2-吡咯烷小基-乙基）酰胺 41a作原料，按照本发明实施例 41第二步所述相同方式使得该原料与 5-甲磺酰胺基 -1，3-二氢引哚 -2-酮的反应，则得到标题产物 Ν-{3-[4-([1,4']二哌啶基 -Γ-羰基) -5-甲基 -3-三氟甲基 -1Η-吡咯 -2-次甲基 ]-2-氧代 -2，3-二氢 -1Η-吡咯 -5-基甲磺酰胺 50 (140mg, 红色固体)，产率： 64.5%。 The first step of the reaction of Example 41 of the present invention was repeated, except that the compound obtained in the above first step was used. 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylate The acid-(2-pyrrolidinyl-ethyl)amide 41a is used as a starting material to make the starting material and 5-methanesulfonylamino-1,3-dihydroanthracene in the same manner as described in the second step of Example 41 of the present invention. The reaction of 2-ketone gives the title product Ν-{3-[4-([1,4']dipiperidinyl-indole-carbonyl)-5-methyl-3-trifluoromethyl-1 - Pyrrole-2-methino]-2-oxo-2,3-dihydro-1 fluorene-5-ylmethanesulfonamide 50 (140 mg, red solid), yield: 64.5%.

MS m/z (ESI): 580.8(M+1) MS m/z (ESI): 580.8 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 57.44 (s, IH, CH ), 7.40 (s, IH, ArH), 7.15 (d,lH,J=8Hz， ArH)), 6.92 (m, IH, J=8.4Hz, ArH), 4.52 (m, 1H， J=12.4Hz CHN), 3.50 (m, 2H, CH2NCH2), 2.90 (m， 2H, CH2NCH2), 2.50 (m, 4H, 2xCH2NCH2), 2.31 (s, 3H， CH3), 2.26 (s, 3H， CHs), 1.75 (m， 4H, 2xCH2CHCH2), 1.64 (m， 2H, CH2CH2CH2), 1.24(m, 2H, CH2CH2CH2). 实施例 51 1H NMR (400 MHz, DMSO-d6) 57.44 (s, IH, CH), 7.40 (s, IH, ArH), 7.15 (d,lH,J=8Hz, ArH)), 6.92 (m, IH, J= 8.4 Hz, ArH), 4.52 (m, 1H, J = 12.4 Hz CHN), 3.50 (m, 2H, CH2NCH2), 2.90 (m, 2H, CH2NCH2), 2.50 (m, 4H, 2xCH2NCH2), 2.31 (s, 3H, CH3), 2.26 (s, 3H, CHs), 1.75 (m, 4H, 2xCH2CHCH2), 1.64 (m, 2H, CH2CH2CH2), 1.24 (m, 2H, CH2CH2CH2). Example 51

Ν-{3-[4-([1,4']二哌啶基 -1'-羰基) -5-甲基 -3-三氟甲基 -IH-吡咯 -2-次甲基 ]-5-氟 -2- 氧代 -2,3-二氢 -1H-吡咯 -7-基甲磺酰胺 Ν-{3-[4-([1,4']Dipiperidinyl-1'-carbonyl)-5-methyl-3-trifluoromethyl-IH-pyrrole-2-methine]-5 -fluoro-2-oxo-2,3-dihydro-1H-pyrrol-7-ylmethanesulfonamide

重复本发明实施例 41第一步反应，不同的是使用上述第一步中所得到的化合物 .5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 -(2-吡咯浣小基-乙基）酰胺 41_¾作原料，按照本发明实施例 41第二步所述相同方式使得该原料与 5-氟 -7-甲磺酰胺基 -1,3-二氢 - |哚 -2-酮的反应，则得到标题产物 Ν-{3-[4-([1,4']二哌啶基 -Γ- 羰基) -5-甲基 -3-三氟甲基 -1Η-吡咯 -2-次甲基 ]-5-氟 -2-氧代 -2,3-二氢 -1Η-吡咯 -7- 基} -甲磺酰胺 51 (140m_g，红色固体)，产率： 64.5%。

The first step of the reaction of Example 41 of the present invention was repeated, except that the compound obtained in the above first step was used. 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylate The acid-(2-pyrrolidinyl-ethyl)amide 41 _{3⁄4 is} used as a starting material to make the starting material and 5-fluoro-7-methanesulfonamido-1,3 in the same manner as described in the second step of Example 41 of the present invention. -Dihydro- |indol-2-one reaction, the title product Ν-{3-[4-([1,4']dipiperidinyl-fluorenyl-carbonyl)-5-methyl-3-tri Fluoromethyl-1Η-pyrrole-2-methine]-5-fluoro-2-oxo-2,3-dihydro-1Η-pyrrole-7-yl}-methanesulfonamide 51 (140m _g , red solid ), Yield: 64.5%.

MS m/z (ESI): 598.6(M+1) MS m/z (ESI): 598.6 (M+1)

Ή NMR ( 400 MHz, DMSO-d6 ) 57.59(m,lH, ArH))₅ 7.58(s, 1H, CH ), 7.05 (m, 1H, ArH),4.52 (m， 1H， J=12.4Hz CHN), 3.50 (m, 2H， CH2NCH2), 2.90 (m, 2H, CH2NCH2), 2.50 (m, 4H, 2xCH2NCH2), 2.31 (s, 3H, CHa), 2.26 (s, 3H, CH3), 1.75 (m, 4H, 2xCH2CHCH2), 1.64 (m, 2H, CH2CH2CH2), 1.24(m, 2H， CH2CH2CH2). 实施例 52 Ή NMR (400 MHz, DMSO- d6) 57.59 (m, lH, ArH)) 5 7.58 (s, 1H, CH), 7.05 (m, 1H, ArH), 4.52 (m, 1H, J = 12.4Hz CHN) , 3.50 (m, 2H, CH2NCH2), 2.90 (m, 2H, CH2NCH2), 2.50 (m, 4H, 2xCH2NCH2), 2.31 (s, 3H, CHa), 2.26 (s, 3H, CH3), 1.75 (m, 4H, 2xCH2CHCH2), 1.64 (m, 2H, CH2CH2CH2), 1.24 (m, 2H, CH2CH2CH2). Example 52

哌啶 -1-羧酸— [5-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H 吡咯 -3-基] -酰胺 Piperidine-1-carboxylic acid — [5-(5-bromo-2-oxo-1,2-dihydro-indol-3-methylmethyl)-2-methyl-4-trifluoromethyl- 1H pyrrol-3-yl]-amide

将 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 1.106 g (2.16 g， 5.002 mmol) 溶解于甲苯 (50 ml)中，搅拌下依次加入叠氮磷酸二苯酯（U54g， 15.502 mmol), 三乙胺 (O.808g， 8mmol)，加热回流 2小时后，冷却至反应液温度为 50Ό，加入哌啶（0.639g，7.503mmol)，继续搅拌，点板跟踪至原料基本消失， 17h反应完毕。搅拌下向反应液中加入乙酸乙酯 (400 ml),用饱和碳酸氢钠溶液 (150 tnl 3)洗涤混合液，合并水层用乙酸乙酯 (150 mlx3) 回萃。合并有机相，乙酸乙酯层用无水硫酸钠干燥，过滤，滤液减压浓缩，柱层析纯化 (乙酸乙酯：环己垸：甲醇 =24: 24： 1)，得到产物哌啶小羧酸 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基)酰胺 52a (1.165 g, 黄色固体)，产率 76.8%。 1.106 g (2.16 g, 5.002 mmol) of 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid was dissolved in toluene (50 ml), and the mixture was sequentially added with stirring. Diphenyl diphenyl phosphate (U54g, 15.502 mmol), triethylamine (O. 808 g, 8 mmol), heated under reflux for 2 hours, cooled to 50 ° C, and then added to piperidine (0.639 g, 7.503 mmol). , the point plate is tracked until the raw material disappears, and the reaction is completed in 17 hours. Ethyl acetate (400 ml) was added to the mixture, and the mixture was washed with saturated aqueous sodium hydrogen carbonate (150 tnl 3), and the aqueous layer was combined with ethyl acetate (150 ml×3). The organic phase was combined, and the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness, and purified by column chromatography (ethyl acetate: hexane: hexane = 24: 24:1) Acid (5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl)amide 52a (1.165 g, yellow solid), yield 76.8%.

MS m/z (ESI) :302.7(M-l) MS m/z (ESI): 302.7 (M-l)

1H NMR ( 400 MHz, DMSO-d6 ) 59.75 (s, 1H, NHCO), 9.57 (s， 1H, HCO), 5.74 (m，lH,ArH), 3.37 (d， 4H,J=5.2Hz, 2xNCH2CH2), 2.15 (s, 3H， CH3), 1.46(m, 6H, 2xNCH2 CH2 and CH2CH2CH2). 1H NMR (400 MHz, DMSO-d6) 59.75 (s, 1H, NHCO), 9.57 (s, 1H, HCO), 5.74 (m,lH,ArH), 3.37 (d, 4H,J=5.2Hz, 2xNCH2CH2) , 2.15 (s, 3H, CH3), 1.46(m, 6H, 2xNCH2 CH2 and CH2CH2CH2).

将上一步产物哌啶小羧酸 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基)酰胺 52a (90mg, 0.297 mmol)溶解于乙醇 (2.5 ml)中，搅拌下加入 5-溴 -1,3-二氢 -吲哚 -2- 酮 (63mg， 0.297 mmol)及哌啶 (3 mg, 0.03 mmol), 加热回流 3小时，点板跟踪至原料基本消失，反应液自然冷却后,有黄色固体析出，用乙醇洗涤得到标题产物哌啶 -1-羧酸— [5-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基) -2-甲基 -4-三氟甲基 -1H 吡咯 -3-基] -酰胺 52 (85 mg，黄色固体)，产率 57.4%。 The previous product, piperidine carboxylic acid (5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl)amide 52a (90 mg, 0.297 mmol) was dissolved in ethanol (2.5 ml) Add 5-bromo-1,3-dihydro-indole-2- with stirring The ketone (63 mg, 0.297 mmol) and piperidine (3 mg, 0.03 mmol) were heated under reflux for 3 hours, and the material was applied to the disappearance of the material. After the reaction mixture was allowed to cool, a yellow solid was precipitated and washed with ethanol to give the title product. 1-carboxylic acid — [5-(5-bromo-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H pyrrole -3-yl]-amide 52 (85 mg, yellow solid), yield 57.4%.

MS m/z (ESI) :497(M+1) -. MS m/z (ESI): 497 (M+1) -.

1H NMR ( 400 MHz, DMSO-d6 ) 57.90 (d, 1H， J=12Hz, ArH), 7.56 (s, 1H, CH ), 7.36 (ra,lH,ArH)), 6.88 (m, 1H, ArH), 3.38 (m, 4H, 2xCH2NCH2), 2.20 (s, 3H, CH3), 1.58 (m, 2H, CH2CH2CH2), 1.46(t, 4H, CH2CH2CH2) 实施例 53 1H NMR (400 MHz, DMSO-d6) 57.90 (d, 1H, J=12Hz, ArH), 7.56 (s, 1H, CH), 7.36 (ra,lH,ArH)), 6.88 (m, 1H, ArH) , 3.38 (m, 4H, 2xCH2NCH2), 2.20 (s, 3H, CH3), 1.58 (m, 2H, CH2CH2CH2), 1.46 (t, 4H, CH2CH2CH2) Example 53

哌啶 -1-羧酸一 [5-(5-氯 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H 吡咯 -3-基] -酰胺 Piperidine-1-carboxylic acid mono[5-(5-chloro-2-oxo-1,2-dihydro-indol-3-methylmethyl)-2-methyl-4-trifluoromethyl- 1H pyrrol-3-yl]-amide

, 重复本发明实施例 52第一步反应，不同的是使用上述第一步中所得到的化合物哌啶小羧酸 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基)酰胺 52a作原料,按照本发明实施例 52第二步所述相同方式使得该原料与 5-溴 -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物哌啶 -1-羧酸 -[5-(5-氯 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2- 甲基 -4-三氟甲基 -1H吡咯 -3-基] -酰胺 53 (131 mg, 黄色固体)，产率： 87.9%。 The first step reaction of Example 52 of the present invention was repeated except that the compound piperidine small carboxylic acid (5-formyl-2-methyl-4-trifluoromethyl-1H-) obtained in the above first step was used. Pyrrol-3-yl)amide 52a is used as a starting material, and the reaction of the starting material with 5-bromo-1,3-dihydro-indol-2-one is carried out in the same manner as described in the second step of Example 52 of the present invention. The title product piperidine-1-carboxylic acid-[5-(5-chloro-2-oxo-1,2-dihydro-indol-3-methylmethyl)-2-methyl-4-trifluoromethyl Base-1H pyrrol-3-yl]-amide 53 (131 mg, yellow solid), Yield: 87.9%.

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

1H NMR ( 400 MHz, DMSO-d6 ) 57.76 (s, 1H, ArH), 7.55(s, 1H, CH ),7.22 (m,lH,ArH)), 6.92 (dxd, 1H， ArH), 3.38 (t， 4H，J=5,2Hz, 2xCH2NCH2), 2.23 (s, 3H, CH3), 1.58 (m, 2H, CH2CH2CH2), 1.46(t, 4H， 2xCH2CH2CH2) 实施例 54 1H NMR (400 MHz, DMSO-d6) 57.76 (s, 1H, ArH), 7.55 (s, 1H, CH), 7.22 (m,lH,ArH)), 6.92 (dxd, 1H, ArH), 3.38 (t , 4H, J=5, 2 Hz, 2xCH2NCH2), 2.23 (s, 3H, CH3), 1.58 (m, 2H, CH2CH2CH2), 1.46 (t, 4H, 2xCH2CH2CH2) Example 54

哌啶 -1-羧酸- [5-(5-甲酰胺基 -2-氧代 -1,2-二氢 -H引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H吡咯 -3-基] -酰胺

Piperidine-1-carboxylic acid-[5-(5-carboxamido-2-oxo-1,2-dihydro-H-indol-3-ylmethyl)-2-methyl-4-trifluoro Methyl-1H pyrrol-3-yl]-amide

重复本发明实施例 52第一步反应，不同的是使用上述第一步中所得到的化合物哌啶 -1-羧酸 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基)酰胺 52a作原料，按照本发明实施例 52第二步所述相同方式使得该原料与 5-甲酰胺基 -1,3-二氢 -H引哚 -2-酮的反应，则得到标题产物哌啶 -1-羧酸 -[5-(5-甲酰胺基 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H吡咯 -3-基] -酰胺 54 (100 mg，黄色固体)，产率： 73.0%。 The first step reaction of Example 52 of the present invention was repeated except that the compound piperidine-1-carboxylic acid (5-formyl-2-methyl-4-trifluoromethyl-1H) obtained in the above first step was used. -pyrrol-3-yl)amide 52a as a starting material, which is obtained in the same manner as described in the second step of Example 52 of the present invention, and 5-formamido-1,3-dihydro-H-indol-2-one Reaction, the title product piperidine-1-carboxylic acid-[5-(5-carboxamido-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl 4-Trifluoromethyl-1H-pyrrol-3-yl]-amide 54 (100 mg, yellow solid), yield: 73.0%.

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

1H NMR ( 400 MHz, DMSO-d6 ) 510.09(s, HCONH),8.71 (m,lH,ArH), 8.25 (m, IH, ArH), 57.59, (s, IH, CH ), 6.89 (m, IH, ArH), 3.38 (t, 4H,J=5.2Hz, 2xCH2NCH2), 2.23 (s, 3H, CH3), 1.58 (m， 2H, CH2CH2CH2), 1.46(t, 4H， 2xCH2CH2CH2) 实細 55 1H NMR (400 MHz, DMSO-d6) 510.09 (s, HCONH), 8.71 (m,lH,ArH), 8.25 (m, IH, ArH), 57.59, (s, IH, CH ), 6.89 (m, IH , ArH), 3.38 (t, 4H, J=5.2Hz, 2xCH2NCH2), 2.23 (s, 3H, CH3), 1.58 (m, 2H, CH2CH2CH2), 1.46(t, 4H, 2xCH2CH2CH2)

哌啶 -1-羧酸一 [5-(5-氟 -7-溴 -2-氧代 -1;2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 Piperidine-1-carboxylic acid-[5-(5-fluoro-7-bromo-2-oxo-1; 2-dihydro-indol-3-methyl)-2-methyl-4-tri Fluoromethyl

-IH P比咯 -3-基] -酰胺 -IH P-pyrrol-3-yl]-amide

重复本发明实施例 52第一步反应，不同的是使用上述第一步中所得到的化合物哌啶 -1-羧酸 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基)酰胺 52a作原料，按照本发明实施例 52第二步所述相同方式使得该原料与 5-氟 -7-溴 -1,3-二氣 -H引哚 -2-酮的反应，则得到标题产物哌啶 -1-羧酸 -[5-(5-氟 -7-溴 -2-氧代 -1,2-二氢 -吲哚 -3- 次甲基 )-2-甲基 -4-三氟甲基 -1H吡咯 -3-基] -酰胺 55 (120 mg，黄色固体)，产率： 78.4%。 The first step reaction of Example 52 of the present invention was repeated except that the compound piperidine-1-carboxylic acid (5-formyl-2-methyl-4-trifluoromethyl-1H) obtained in the above first step was used. - pyrrol-3-yl)amide 52a as a starting material, the starting material is reacted with 5-fluoro-7-bromo-1,3-dioxane-H in the same manner as described in the second step of Example 52 of the present invention. The reaction of the ketone gives the title product piperidine-1-carboxylic acid-[5-(5-fluoro-7-bromo-2-oxo-1,2-dihydro-indole-3-methine)- 2-Methyl-4-trifluoromethyl-1Hpyrrol-3-yl]-amide 55 (120 mg, yellow solid), Yield: 78.4%.

MS m/z (ESI): 516.0(M+1) MS m/z (ESI): 516.0 (M+1)

IH NMR ( 400 MHz, DMSO-d6 ) 67.67 (s， 1H， ArH), 7.55(s， IH, CH ),7.34 (m₅lH₅ArH))₅ 3.38 (t, 4H, J=4.8Hz,2xCH2NCH2), 2.20 (s, 3H， CH3), 1.58 (m, 2H， CH2CH2CH2), 1.45 (t， 4H, 2xCH2CH2CH2) , 实施例 56 _; IH NMR (400 MHz, DMSO-d6) 67.67 (s, 1H, ArH), 7.55 (s, IH, CH), 7.34 (m ₅ lH ₅ ArH)) ₅ 3.38 (t, 4H, J = 4.8 Hz, 2xCH2NCH2 ), 2.20 (s, 3H, CH3), 1.58 (m, 2H, CH2CH2CH2), 1.45 (t, 4H, 2xCH2CH2CH2) , Example 56 _;

哌啶 -1-羧酸一 [5-(5-氟 -6-氨基 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H吡咯 -3-基] -酰胺 Piperidine-1-carboxylic acid mono[5-(5-fluoro-6-amino-2-oxo-1,2-dihydro-indol-3-methylmethyl)-2-methyl-4-tri Fluoromethyl-1Hpyrrol-3-yl]-amide

重复本发明实施例 52第一步反应，不同的是使用上述第一步中所得到的化合物哌啶 -1-羧酸 (5-甲酰基 -2-甲基 -4-三氟甲基 -1Η-吡咯 -3-基)酰胺 52a作原料，按照本发明实施例 52第二步所述相同方式使得该原料与 5-溴 -6-氨基 -1,3-二氢-吲哚 -2-酮的反应，则得到标题产物哌啶 -1-羧酸 -[5-(5-氟 -6-氨基 -2-氧代 -1,2-二氢 -11引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H吡咯 -3-基] -酰胺 56 (50 mg, 黄色固体)，产率： 33.6% c The first step of the reaction of Example 52 of the present invention was repeated except that the compound piperidine-1-carboxylic acid (5-formyl-2-methyl-4-trifluoromethyl-1?) obtained in the above first step was used. -pyrrol-3-yl)amide 52a as a starting material, the starting material is reacted with 5-bromo-6-amino-1,3-dihydro-indol-2-one in the same manner as described in the second step of Example 52 of the present invention. Reaction, the title product piperidine-1-carboxylic acid-[5-(5-fluoro-6-amino-2-oxo-1,2-dihydro-11-indol-3-methyl)- 2-methyl-4-trifluoromethyl-1Hpyrrol-3-yl]-amide 56 (50 mg, yellow solid), Yield: 33.6% c

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

1H NMR ( 400 MHz, DMSO-d6 ) 67.30 (d, 1H, ArH), 7.11 (s, 1H, CH ),6.36 (m,lH,ArH)), 3.37 (t, 4H, J=5.2Hz, 2xCH2N;CH2), 2.15 (s, 3H, CH3), 1.58 (m, 2H, CH2CH2CH2), 1.45 (t, 4H, 2xCH2CH2CH2) 实施例 57 1H NMR (400 MHz, DMSO-d6) 67.30 (d, 1H, ArH), 7.11 (s, 1H, CH), 6.36 (m,lH,ArH)), 3.37 (t, 4H, J=5.2Hz, 2xCH2N ;CH2), 2.15 (s, 3H, CH3), 1.58 (m, 2H, CH2CH2CH2), 1.45 (t, 4H, 2xCH2CH2CH2) Example 57

哌啶小羧酸 -[5-(5-氟 -7-乙酰胺基 -2-氧代 -1，2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H吡咯 -3-基] -酰胺 Piperidine small carboxylic acid-[5-(5-fluoro-7-acetamido-2-oxo-1,2-dihydro-indol-3-methylmethyl)-2-methyl-4-tri Fluoromethyl-1Hpyrrol-3-yl]-amide

重复本发明实施例 52第一步反应，不同的是使用上述第一步中所得到的化合物哌啶 -1-羧酸 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基)酰胺 52a作原料，按照本发明实施例 52第二步所述相同方式使得该原料与 5-溴 -7-乙酰胺基 -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物哌啶 -1-羧酸 -[5-(5-氟 -7-乙酰胺基 -2-氧代 -1，2- 二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H吡咯 -3-基] -酰胺 57 (lOOmg, 黄色固体)，产率： 68.0%。 The first step reaction of Example 52 of the present invention was repeated except that the compound piperidine-1-carboxylic acid (5-formyl-2-methyl-4-trifluoromethyl-1H) obtained in the above first step was used. -pyrrol-3-yl)amide 52a as a starting material, the starting material is reacted with 5-bromo-7-acetamido-1,3-dihydro-indole-2 in the same manner as described in the second step of Example 52 of the present invention. -ketone reaction, the title product piperidine-1-carboxylic acid-[5-(5-fluoro-7-acetamido-2-oxo-1,2-dihydro-indole-3-indolyl) Benzyl-2-methyl-4-trifluoromethyl-1Hpyrrol-3-yl]-amide 57 (100 mg, yellow solid) (body), Yield: 68.0%.

MS m/z (ESI): 494.0 (M+l) MS m/z (ESI): 494.0 (M+l)

1H NMR ( 400 MHz, DMSO-d6 ) 87.5 l(s, 1H, CH), 7.45 (q, 1H, ArH ),736 (m, 1H， ArH )， 3.38 (t, 4H,J=5.2Hz, 2><CH2NCH2), 2.21 (s, 3H, CH3), 2.09 (s, 3H, CH3), 1.24 (m, 2H, CH2CH2CH2), 1.05 (t, 4H, 2xCH2CH2CH2) 实施例 58 1H NMR (400 MHz, DMSO-d6) 87.5 l (s, 1H, CH), 7.45 (q, 1H, ArH), 736 (m, 1H, ArH), 3.38 (t, 4H, J = 5.2 Hz, 2 ><CH2NCH2), 2.21 (s, 3H, CH3), 2.09 (s, 3H, CH3), 1.24 (m, 2H, CH2CH2CH2), 1.05 (t, 4H, 2xCH2CH2CH2) Example 58

哌啶 -1-羧酸— [5-(5-氟 -7-甲酰胺基 -2-氧代 -1,2-二氢』引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H吡咯 -3-基] -酰胺 Piperidine-1-carboxylic acid — [5-(5-fluoro-7-carboxamido-2-oxo-1,2-dihydro]indol-3-ylmethyl)-2-methyl-4 -trifluoromethyl-1Hpyrrol-3-yl]-amide

重复本发明实施例 52第一步反应，不同的是使用上述第一步中所得到的化合物哌啶 -1-羧酸 (5-甲酰基 -²_甲基 -⁴-三氟甲碁 -1H-吡咯 -³-基)酰胺 a作原料，按照本发明实施例 52第二步所述相同方式使得该原料与 5-溴 -7-乙酰胺基 -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物哌啶 -1-羧酸 -[5-(5-氟 -7-乙酰胺基 -2-氧代 -1,2- 二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H吡咯 -3-基] -酰胺 58 (110mg，黄色固体)，产率： 77.5%。 The first step reaction of Example 52 of the present invention was repeated except that the compound piperidine-1-carboxylic acid obtained in the above first step (5-formyl- ² -methyl- ⁴ -tetrafluoromethylhydrazine-1H) was used. - pyrrole- ³ -yl)amide a as a starting material, the starting material and 5-bromo-7-acetamido-1,3-dihydro-indole-2 are obtained in the same manner as described in the second step of Example 52 of the present invention. -ketone reaction, the title product piperidine-1-carboxylic acid-[5-(5-fluoro-7-acetamido-2-oxo-1,2-dihydro-indole-3-indolyl) Benzyl-2-methyl-4-trifluoromethyl-1Hpyrrol-3-yl]-amide 58 (110 mg, yellow solid), yield: 77.5%.

MS m/z (ESI): 480.2 (M+l) MS m/z (ESI): 480.2 (M+l)

'Η NMR ( 400 MHz, DMSO-d6 ) 68.35 (s, 1H, CH ), 7.51(m,2H,ArH)₅ 3.38 (t, 4H,J=5.2Hz, 2xCH2NCH2), 2.21 (s, 3H, CH3), 2.09 (s, 3H, CH3), 1.24 (m, 2H, CH2CH2CH2), 1.05 (t, 4H, 2xCH2CH2CH2). 实施例 59 'Η NMR ( 400 MHz, DMSO-d6 ) 68.35 (s, 1H, CH ), 7.51 (m, 2H, ArH) ₅ 3.38 (t, 4H, J = 5.2 Hz, 2xCH2NCH2), 2.21 (s, 3H, CH3 ), 2.09 (s, 3H, CH3), 1.24 (m, 2H, CH2CH2CH2), 1.05 (t, 4H, 2xCH2CH2CH2). Example 59

哌啶 -1-羧酸一 [5-(5-氟 -7-甲磺酰胺基 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4- 三氟甲基 -1H吡咯 -3-基] -酰胺 Piperidine-1-carboxylic acid-[5-(5-fluoro-7-methanesulfonamido-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl- 4-trifluoromethyl-1Hpyrrol-3-yl]-amide

重复本发明实施例 52第一步反应，不同的是使用上述第一步中所得到的化合物哌啶 -1-羧酸 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基)酰胺 52a作原料，按照本发明实施例 52第二步所述相同方式使得该原料与 5-溴 -7-甲磺酰胺基 -1，3-二氢 -吲哚 -2-酮的反应，则得到标题产物哌啶 -1-羧酸 -[5-(5-氟 -7-甲磺酰胺基 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H吡咯 -3-基] -酰胺 59 (llOmg, 黄色固体)，产率： 78.6%。 The first step reaction of Example 52 of the present invention was repeated except that the compound piperidine-1-carboxylic acid (5-formyl-2-methyl-4-trifluoromethyl-1H) obtained in the above first step was used. -pyrrol-3-yl)amide 52a as a starting material, the starting material is reacted with 5-bromo-7-methanesulfonamido-1,3-dihydro-indole in the same manner as described in the second step of Example 52 of the present invention. 2-keto reaction, the title product piperidine-1-carboxylic acid-[5-(5-fluoro-7-methanesulfonamido-2-oxo-1,2-dihydro-indole-3- Hypomethyl)-2-methyl-4-trifluoromethyl-1Hpyrrol-3-yl]-amide 59 (110 mg, yellow solid), Yield: 78.6%.

MS m/z (ESI): 530.2 (M+l) MS m/z (ESI): 530.2 (M+l)

Ή NMR ( 400 MHz, DMSO-d6 ) 57.55 (s, 1H， CH ), 7.51 (m，lH, ArH), 7.12 (m 1H， ArH),6.91(m,lH, ArH), 3.38 (t, 4H, J=5.2Hz, 2xCH2NCH2), 2.93 (s, 3H， CH3), 2.20 (s, 3H, CH3), 1.58 (m, 2H, CH2CH2CH2), 1.46 (t， 4H, 2 <CH2CH2CH2) 实施例 60 NMR NMR (400 MHz, DMSO-d6) 57.55 (s, 1H, CH), 7.51 (m,lH, ArH), 7.12 (m 1H, ArH), 6.91 (m, lH, ArH), 3.38 (t, 4H , J = 5.2 Hz, 2xCH2NCH2), 2.93 (s, 3H, CH3), 2.20 (s, 3H, CH3), 1.58 (m, 2H, CH2CH2CH2), 1.46 (t, 4H, 2 <CH2CH2CH2) Example 60

4-({[5-(5-氟 -2-氧代 -1,2-二氢 -n引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羰基] -氨基 } -甲基 -4-轻基 -1-羧酸叔丁酉 ί 4-({[5-(5-fluoro-2-oxo-1,2-dihydro-n-indolyl-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole -3-carbonyl]-amino}-methyl-4-carbyl-1-carboxylic acid tert-butyl 酉

按照本发明实施例 1第七步所述相同方式，氮气氛下，在一个 250 ml的三口瓶中，将 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 l_g (221 mg, 1 mmol)溶解于 N，N-二甲基甲酰胺 (2 ml)中，搅拌下依次加入 N-乙基 -Ν'- (二甲氨基丙基) - 碳二亚胺盐酸盐 (286 mg, 1.5mmol)、 1-羟基苯并*** (345 mg， 1.5 mmol)、三乙胺 (0.34ml， 2.5 mmol)及 4-氨甲基 -4-羟基 -哌啶 -1-羧酸叔丁酯（345 mg, 1.5 mmol)DMF溶液(50 _ml)，室温搅拌 8小时，点板跟踪至原料基本消失，搅拌下向反应液中加入乙酸乙酯 (100 ml), 用饱和碳酸氢钠溶液 (50 mlx3)洗涤混合液，合并水层用乙酸乙酯 (50 mlx3) 回萃。合并有机相，乙酸乙酯层用无水硫酸钠干燥，过滤，滤液减压浓缩标题产 5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸（4-羟基 -呢啶 _₄_甲基) -酰胺 60a (3.32 g，黄色固体)，直接进行下一步反应。 In the same manner as described in the seventh step of Example 1 of the present invention, 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole was introduced in a 250 ml three-necked flask under a nitrogen atmosphere. 3-carboxylic acid l _g (221 mg, 1 mmol) was dissolved in N,N-dimethylformamide (2 ml), and N-ethyl-Ν'-(dimethylaminopropyl)- Carbodiimide hydrochloride (286 mg, 1.5 mmol), 1-hydroxybenzotriazole (345 mg, 1.5 mmol), triethylamine (0.34 ml, 2.5 mmol) and 4-aminomethyl-4-hydroxyl - piperidine-1-carboxylate (345 mg, 1.5 mmol) DMF solution (50 _m l), stirred at room temperature for 8 hours tracked until the starting material disappeared, ethyl acetate was added under stirring to the reaction mixture ( The mixture was washed with a saturated aqueous solution of sodium bicarbonate (50 ml.sup.3). The combined organic layers were dried with anhydrous sodium sulfate and filtered and evaporated. -hydroxyl Base - hexyl _ ₄ _ methyl) - amide 60a (3.32 g, yellow solid), directly to the next reaction.

按照本发明实施例 1第八步所述相同方式，将上一步产物 5-甲酰基 -2-甲基 -4- 三氟甲基 -1H-吡咯 -3-羧酸（4-羟基 -哌啶 -4-甲基) -酰胺 60a (433 mg)不经纯化溶解于乙醇 (3 ml)中，搅拌下加入 5-氟 -1,3-二氢 -H引哚 -2-酮 (120 mg, 0.78 mmol)及哌啶 (3mg, 0.034 mmol), 加热回流 3小时，点板跟踪至原料基本消失，反应液自然冷却后在减压下蒸馏除去乙醇，有固体析出，得到 4-({[5-(5-氟 -2-氧代 -1,2-二氢- 吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羰基] -氨基 } -甲基 -4-羟基 -1-羧酸叔丁酯 60(140 mg，黄色固体)，产率 31.1 %。 In the same manner as described in the eighth step of Example 1 of the present invention, the product of the previous step, 5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid (4-hydroxy-piperidine). -4-methyl)-amide 60a (433 mg) was dissolved in ethanol (3 ml) without purification, and 5-fluoro-1,3-dihydro-H-indol-2-one (120 mg, 0.78 mmol) and piperidine (3 mg, 0.034 mmol), heated under reflux for 3 hours, the plate was traced until the starting material disappeared, the reaction solution was naturally cooled, and the ethanol was distilled off under reduced pressure, and a solid precipitated to give 4-({[5 -(5-fluoro-2-oxo-1,2-dihydro-indol-3-methylmethyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carbonyl]-amino }-Methyl-4-hydroxy-1-carboxylic acid tert-butyl ester 60 (140 mg, yellow solid), yield 31%.

MS m/z (ESI)： 567(M+1) MS m/z (ESI): 567 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 57.65 (m, 1H), 7.59 (s,lH)， 7.06 (m 1H)， 1H NMR (400 MHz, DMSO-d6) 57.65 (m, 1H), 7.59 (s,lH), 7.06 (m 1H),

6.90(m，lH), 4.57 (s, 1H)， 3.66 (d, 2H), 3.44 (m， 2H), 3.06 (t， 2H， J=2.4Hz), 2.38(s, 3H), 1.39(s, 9H). 实施例 61 6.90(m,lH), 4.57 (s, 1H), 3.66 (d, 2H), 3.44 (m, 2H), 3.06 (t, 2H, J=2.4Hz), 2.38(s, 3H), 1.39(s , 9H). Example 61

4-({[5-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羰基] -氨基 } -甲基 -4-羟基 -1-羧酸叔丁酯 4-({[5-(5-Bromo-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole- 3-carbonyl]-amino}-methyl-4-hydroxy-1-carboxylic acid tert-butyl ester

重复本发明实施例 60第一步反应，不同的是使用上述第一步中所得到的化合物哌啶 -1-羧酸 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基)酰胺 60a作原料，按照本发明实施例 60第二步使得该原料与 5-溴 -1，3-二氢引哚 -2-酮的反应，得到标题产物 4-({[5-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羰基] -氨基 } -甲基 -4-羟基小羧酸叔丁酯 61(209 mg，黄色固体)，产率： 42.7%。 The first step reaction of Example 60 of the present invention was repeated except that the compound piperidine-1-carboxylic acid (5-formyl-2-methyl-4-trifluoromethyl-1H) obtained in the above first step was used. - pyrrol-3-yl)amide 60a as a starting material, the reaction of the starting material with 5-bromo-1,3-dihydropyridin-2-one according to the second step of Example 60 of the present invention affords the title product 4-( {[5-(5-Bromo-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carbonyl ]-Amino}-methyl-4-hydroxysuccinic acid tert-butyl ester 61 (209 mg, yellow solid), yield: 42.7%.

MS m/z (ESI)： 627(M+1) MS m/z (ESI): 627 (M+1)

Ή NMR (400 MHz, DMSO-d6 ) 57.98 (d, 1H, J=1.6Hz), 7.63 (s,lH)， 7.38 (m 1H, J=2Hz), 6.88(d,lH， J=8Hz), 4.58 (s, 1H), 3.44 (m, 2H), 3.42 (m， 2H)， 3.06 (m, 4H)， 2.37(s, 3H),1.37(s,9H) 实施例 62 NMR NMR (400 MHz, DMSO-d6) 57.98 (d, 1H, J = 1.6 Hz), 7.63 (s, lH), 7.38 (m 1H, J = 2 Hz), 6.88 (d, lH, J = 8 Hz), 4.58 (s, 1H), 3.44 (m, 2H), 3.42 (m, 2H), 3.06 (m, 4H), 2.37 (s, 3H), 1.37 (s, 9H) Example 62

4_({[5-(5-氟 -7-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3- 羰基] -氨基 } -甲基 -4-羟基 -1-羧酸叔丁酯

4_({[5-(5-fluoro-7-bromo-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H -pyrrole-3-carbonyl]-amino}-methyl-4-hydroxy-1-carboxylic acid tert-butyl ester

重复本发明实施例 60第一步反应，不同的是使用上述第一步中所得到的化合物哌啶 -1-羧酸 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基)酰胺 60a作原料，按照本发明实施例 60第二步使得该原料与 5-氟 -7-溴 -1,3-二氢 -H引哚 -2-酮的反应，得到 4-({[5-(5-氟 -7-溴 -2:氧 ^-1,2-二氢 -吲哚 -3-次甲基 )-2-甲基斗三氟甲基 -1H-吡咯 -3-羰基] -氨基 } -甲基 -4-羟基 -1-羧酸叔丁酯 62(209 mg，黄色固体)，产率： 68.6%。 The first step reaction of Example 60 of the present invention was repeated except that the compound piperidine-1-carboxylic acid (5-formyl-2-methyl-4-trifluoromethyl-1H) obtained in the above first step was used. -pyrrol-3-yl)amide 60a as a starting material, in accordance with the second step of Example 60 of the present invention, the reaction of the starting material with 5-fluoro-7-bromo-1,3-dihydro-H-indol-2-one, 4-({[5-(5-fluoro-7-bromo-2:oxy^-1,2-dihydro-indol-3-methyl)-2-methyl-trifluoromethyl-1H -Pyrrol-3-carbonyl]-amino}-methyl-4-hydroxy-1-carboxylic acid tert-butyl ester 62 (209 mg, yellow solid), yield: 68.6%.

MS m/z (ESI): 645.4(M+1) MS m/z (ESI): 645.4 (M+1)

'HNMR ( 400 MHz, DMSO-d6 ) 57.74 (m, 1H)， 7.61 (s,lH), 7.38 (m IH), 4.91 (s, IH), 3.67 (m, 2H), 3.64 (m, 2H), 3.23 (m, 2H), 2.06(m,2H),2.38(s,3H),1.43(s,9H). 实施例 63 'HNMR (400 MHz, DMSO-d6) 57.74 (m, 1H), 7.61 (s,lH), 7.38 (m IH), 4.91 (s, IH), 3.67 (m, 2H), 3.64 (m, 2H) , 3.23 (m, 2H), 2.06 (m, 2H), 2.38 (s, 3H), 1.43 (s, 9H). Example 63

:-(5-氟 -7-甲酰胺基 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -IH-吡咯 :-(5-Fluoro-7-carboxamido-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-IH-pyrrole

-3-羧酸 - (4-羟基 -哌啶 -4-甲基) -酰胺 '- 3-carboxylic acid - (4-hydroxy-piperidin-4-methyl)-amide '-

重复本发明实施例 60第一步反应，不同的是使用上述第一步中所得到的化合物哌啶小羧酸 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基)酰胺 60a作原料，按照本发明实施例 60第二步使得该原料与 5-氟 -7-甲酰胺基 -1，3-二氢 -B引哚 -2-酮的反应，得到 4-({[5-(5-氟 -7-甲酰胺基 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羰基] -氨基甲基 -4-羟基 -1-羧酸叔丁酯 63 (30 mg, 黄色固体)，产率： 68.6%。 The first step reaction of Example 60 of the present invention was repeated except that the compound obtained from the above first step, piperidine carboxylic acid (5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole) was used. -3-yl)amide 60a as a starting material, in accordance with the second step of Example 60 of the present invention, the reaction of the starting material with 5-fluoro-7-carboxamido-1,3-dihydro-B-indol-2-one, 4-({[5-(5-Fluoro-7-carboxamido-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluorol) Methyl-1H-pyrrole-3-carbonyl]-aminomethyl-4-hydroxy-1-carboxylic acid tert-butyl ester 63 (30 mg, yellow solid), yield: 68.6%.

MS m/z (ESI): 610.0 (M+l) MS m/z (ESI): 610.0 (M+l)

'HNMR ( 400 MHz, DMSO-d6 ) 57.87 (d， IH, J=6Hz), 7.73 (m,lH), 7.47 (s IH), 3.65 (m, 4H)， 3.22 (m， 4H), 2.06(m，2H),2.36(s，3H),1.43(s,9H). 实施例 64 'HNMR (400 MHz, DMSO-d6) 57.87 (d, IH, J=6Hz), 7.73 (m,lH), 7.47 (s IH), 3.65 (m, 4H), 3.22 (m, 4H), 2.06 ( m, 2H), 2.36 (s, 3H), 1.43 (s, 9H). Example 64

₅_₍₅_氟 -₇_甲酰胺基 _₂_氧代 -1,2-二氢』引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -IH-吡咯 -3-羧酸- (4-羟基 -哌啶 -4-甲基) -酰胺 ₅ _ ₍₅ _Fluoro- ₇ -carboxamido- ₂ oxo-1,2-dihydro) 哚-3-methyl)-2-methyl-4-trifluoromethyl-IH-pyrrole 3-carboxylic acid-(4-hydroxy-piperidin-4-methyl)-amide

重复本发明实施例 60第一步反应，不同的是使用上述第一步中所得到的化合物呃啶 -1-羧酸 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基)酰胺 60a作原料，按照本发明实施例 60第二步使得该原料与 N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6- 基) -2-甲氧基-乙酰胺的反应，得到 4-[({5-[5-氟 -6-(3-甲氧基 -2-氧代-丙基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H」吡咯 -3-羰基 }-氨基) -甲基 ]-4-羟基 -哌啶 -1-羧酸叔丁酯 64(66 mg,黄色固体)，产率： 45.5%。 The first step of the reaction of Example 60 of the present invention was repeated except that the compound acridine-1-carboxylic acid (5-formyl-2-methyl-4-trifluoromethyl-1H) obtained in the above first step was used. -pyrrol-3-yl)amide 60a as a starting material, in accordance with the second step of Example 60 of the present invention, the starting material is N-(5-fluoro-2-oxo-2,3-dihydro-1H-indole-6 -Based on the reaction of 2-methoxy-acetamide to give 4-[({5-[5-fluoro-6-(3-methoxy-2-oxo-propyl)-2-oxo) -1,2-dihydro-indol-3-ylmethyl]-2-methyl-4-trifluoromethyl-1H"pyrrole-3-carbonyl}-amino)-methyl]-4-hydroxy- Piperidine-1-carboxylic acid tert-butyl ester 64 (66 mg, yellow solid), yield: 45.5%.

MS m/z (ESI): 654.3 (M+l) MS m/z (ESI): 654.3 (M+l)

1HNMR ( 400 MHz, DMSO-d6 ) 67.73 (d， 1H, J=9.8Hz), 7.64 (d,lH, J=6.4Hz), 7.48(s 1H), 4.06(s,2H),3.65 (m, 2H), 3.39(s,3H)， 3.22 (m， 2H), 3.06(m,2H), 1HNMR (400 MHz, DMSO-d6) 67.73 (d, 1H, J = 9.8 Hz), 7.64 (d, lH, J = 6.4 Hz), 7.48 (s 1H), 4.06 (s, 2H), 3.65 (m, 2H), 3.39(s,3H), 3.22 (m, 2H), 3.06(m,2H),

2.34 (s,3H), 1.47(m,2H), 1.38(s,9H). 实施例 . 65 2.34 (s, 3H), 1.47 (m, 2H), 1.38 (s, 9H). Examples . 65

5-(5-氟 -2-氧代 -1，2-二氢』引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 1H-吡咯 -3-羧酸 - (4- 羟基 -哌淀 -4-甲基) -酰胺 5-(5-fluoro-2-oxo-1,2-dihydro)-indolyl-3-methyl)-2-methyl-4-trifluoromethyl 1H-pyrrole-3-carboxylic acid- ( 4-hydroxy-pipera-4-methyl)-amide

将实施例 60所得的化合物 4-({[5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2- 甲基 -4-三氟甲基 -1H-吡咯 -3-羰基] -氣基甲基 -4-羟基小羧酸叔丁酯 60 (57 mg, O.lmmol)溶于二氯甲垸中，滴加三氟乙酸 (0.5 ml)室温搅拌 2小时，反应完毕。减压下蒸干溶剂，残留物用二氯甲烷萃取 (50mlx3)，有机相用饱和碳酸氢钠洗涤，无水硫酸钠干燥，减压下浓缩得到的固体用无水乙醇洗涤，得到标题产物 5-(5- 氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸- (4-羟基- 哌啶 -4-甲基) -酰胺 65 (30mg，黄色固体)，产率 64.4%。 The compound obtained in Example 60 4-({[5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoro) Methyl-1H-pyrrole-3-carbonyl]-ylmethyl-4-hydroxycarboxylic acid tert-butyl ester 60 (57 mg, 0.1 mmol) was dissolved in dichloromethane, trifluoroacetic acid (0.5) The mixture was stirred at room temperature for 2 hours, and the reaction was completed. The solvent was evaporated, evaporated, evaporated, evaporated, evaporated. Washing with absolute ethanol gave the title product 5-(5-fluoro-2-oxo-1,2-dihydro-indole-3-methylmethyl)-2-methyl-4-trifluoromethyl- 1H-Pyrrol-3-carboxylic acid-(4-hydroxy-piperidin-4-methyl)-amide 65 (30 mg, yellow solid), yield: 64.4%.

MS m/z (ESI) : 467(M+l) MS m/z (ESI): 467 (M+l)

1H NMR (400 MHz, DMSO-d6 ) 87.65 (m, 1H)， 7.60 (s,lH)， 7.07 (m lH),6.91(m,lH), 4.90 (s， lH), 3.25 (d, 2H), 3.16 (m, 2H)， 3.06 (m， 2H), 2.42(s， 3H),1.73(t,2H, 1H NMR (400 MHz, DMSO-d6) 87.65 (m, 1H), 7.60 (s, lH), 7.07 (m lH), 6.91 (m, lH), 4.90 (s, lH), 3.25 (d, 2H) , 3.16 (m, 2H), 3.06 (m, 2H), 2.42 (s, 3H), 1.73 (t, 2H,

J=3.6Hz) 实施例 66 J=3.6Hz) Example 66

5-(5-溴 -2-氧代 -1,2-二氢引噪 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸 - (4- 羟基 -呢啶 -4-甲基) -酰胺 5-(5-Bromo-2-oxo-1,2-dihydro-noisy-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid- ( 4-hydroxy-n-pyridin-4-methyl)-amide

按照本发明实施例 65所述方式，实施例 .61所得的化合物 4-({[5-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羰基] -氨基 } -甲基 -4-羟基 -1-羧酸叔丁酯 61脱去哌啶环上的保护基叔丁氧基羰基，则得到标题产物 5-(5- 溴 -2-氧代 -1，2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸- (4-经基- 哌啶 -4-甲基) -酰胺 66 (30mg, 黄色固体)，产率： 37.9%。 4-({[5-(5-Bromo-2-oxo-1,2-dihydro-indole-3-methine))). 2-methyl-4-trifluoromethyl-1H-pyrrole-3-carbonyl]-amino}-methyl-4-hydroxy-1-carboxylic acid tert-butyl ester 61 deprotected from the protective group on the piperidine ring Butoxycarbonyl, the title product 5-(5-bromo-2-oxo-1,2-dihydro-indol-3-methylmethyl)-2-methyl-4-trifluoromethyl- 1H-Pyrrol-3-carboxylic acid-(4-carbyl-piperidin-4-methyl)-amide 66 (30 mg, yellow solid), yield: 37.9%.

MS m/z (ESI): 527.7(M+1) MS m/z (ESI): 527.7 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 57.98 (d， 1H, J=1.6Hz), 7.64 (s,lH), 7.38 (m 1H,)， 6.89(d,lH, J=4.4Hz), 4.91 (s, 1H), 3.16 (m， 2H), 3.06 (m, 4H), 3.06 (m, 4H), 2.42(s, 3H),L66(m,4H). 实施例 67 1H NMR (400 MHz, DMSO-d6) 57.98 (d, 1H, J = 1.6 Hz), 7.64 (s, lH), 7.38 (m 1H,), 6.89 (d, lH, J = 4.4 Hz), 4.91 ( s, 1H), 3.16 (m, 2H), 3.06 (m, 4H), 3.06 (m, 4H), 2.42 (s, 3H), L66 (m, 4H). Example 67

-(5-氟 -7-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4- ：氟甲基 -1H-吡咯 -3-羧酸 -(5-fluoro-7-bromo-2-oxo-1,2-dihydro-indol-3-methylmethyl)-2-methyl-4-:fluoromethyl-1H-pyrrole-3- Carbohydrate

- (4-轻基 -哌^ 4-甲基) -酰胺 - (4-light base-piperidin-4-methyl)-amide

按照本发明实施例 65所述的方式，实施例 62所得的化合物 4-({[5-(5-氟 -7- 溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羰基] -氨基甲基 -4-羟基 -1-羧酸叔丁酯 62脱去哌啶环上的保护基叔丁氧基羰基，则得到标题产物 5-(5-氟 -7-溴 -2-氧代 -1 ,2-二氢-吲哚 -3-次甲基) -2-甲基 -4-三氟甲基 -1H-吡咯 -3- 羧酸 - (4-羟基 -哌啶 -4-甲基) -酰胺 67 (14mg，黄色固体)，产率： 56%。 The compound obtained in Example 62 was obtained in the manner described in Example 65 of the present invention, 4-({[5-(5-fluoro-7-bromo-2-oxo-1,2-dihydro-indole-3-) Protection of benzylidene)-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carbonyl]-aminomethyl-4-hydroxy-1-carboxylic acid tert-butyl ester 62 on a piperidine ring The tert-butoxycarbonyl group gives the title product 5-(5-fluoro-7-bromo-2-oxo-1,2-dihydro-indol-3-methylmethyl)-2-methyl-4 -Trifluoromethyl-1H-pyrrole-3-carboxylic acid-(4-hydroxy-piperidin-4-methyl)-amide 67 (14 mg, yellow solid), yield: 56%.

S m/z (ESI): 480.2 (M+1) S m/z (ESI): 480.2 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 57.73 (m, 1H)， 7.62 (s,lH), 7.40 (q, lH_;J=2Hz), 3.30 (d， 2H，J=6Hz), 3.17 (m, 2H), 3.06 (m， 2H)， 2.42(s, 3H),1.66(m，4H). 实施例 68 1H NMR (400 MHz, DMSO-d6) 57.73 (m, 1H), 7.62 (s,lH), 7.40 (q, lH _; J=2Hz), 3.30 (d, 2H, J=6Hz), 3.17 (m, 2H), 3.06 (m, 2H), 2.42 (s, 3H), 1.66 (m, 4H). Example 68

₅_₍₅_氟 _₇_甲酰胺基 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 ₅ _ ₍₅ _Fluoro- ₇ -formamide-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole

-3-羧酸- (⁴-羟基 -哌! ¾_⁴-甲基) -酰胺 3-carboxylic acid - ⁽⁴ - hydroxy -! Piperidin ¾_ ⁴ - methyl) - amide

按照本发明实施例 65所述的方式，实施例 63所得的化合物 5-(5-氟 -7-甲酰胺基 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸- (4-羟基- 哌啶 -4-甲基) -酰胺 63 脱去哌啶环上的保护基叔丁氧基羰基，则得到标题产物 5-(5-氟 -7-甲酰胺基 -2-氧代 -1,2-二氢 - 哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸 - (4-羟基 -哌啶 -4-甲基) -酰胺 68 (19mg, 黄色固体)，产率： 42.7%。 5-(5-fluoro-7-carboxamido-2-oxo-1,2-dihydro-indol-3-methylmethyl) compound obtained in Example 63 in the manner described in Example 65 -2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid-(4-hydroxy-piperidin-4-methyl)-amide 63 deprotected tert-butyl group on the piperidine ring The oxycarbonyl group gives the title product 5-(5-fluoro-7-carboxamido-2-oxo-1,2-dihydro-indol-3-methylmethyl)-2-methyl-4-tri Fluoromethyl-1H-pyrrole-3-carboxylic acid-(4-hydroxy-piperidin-4-methyl)-amide 68 (19 mg, yellow solid), yield: 42.7%.

1H NMR ( 400 MHz, DMSO-d6 ) 5757.87 (d, 1H， J=6Hz)， 7.73 (m,lH), 7.47 (s 1H)， 3.30 (d， 2H,J=6Hz), 3.17 (m， 2H), 3.06 (m, 2H), 2.4 l(s, 3H),1.65(m,4H). 实施例 69 1H NMR (400 MHz, DMSO-d6) 5757.87 (d, 1H, J=6Hz), 7.73 (m,lH), 7.47 (s 1H), 3.30 (d, 2H, J=6Hz), 3.17 (m, 2H ), 3.06 (m, 2H), 2.4 l (s, 3H), 1.65 (m, 4H). Example 69

:-[5-氟 -6-(3-甲氧基 -2-氧代-丙基) -1,2-二氢』引哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 :-[5-Fluoro-6-(3-methoxy-2-oxo-propyl)-1,2-dihydro"indol-3-ylmethyl]-2-methyl-4-tri Fluoromethyl

-1H-吡咯 -3-羧酸 - (4-羟基 -哌啶 -4-甲基) -酰胺 -1H-pyrrole-3-carboxylic acid - (4-hydroxy-piperidin-4-methyl)-amide

按照本发明实施例 65所述的方式，实施例 64所得的化合物 5-(5-氟 -7-甲酰胺基 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸- (4-羟基- 哌啶 -4-甲基) -酰胺 64 脱去哌啶环上的保护基叔丁氧基羰基，则得到标题产物 5-[5-氟 -6-(3-甲氧基 -2-氧代-丙基) -1,2-二氢-吲哚 -3-次甲基] -2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸- (4-羟基 -哌啶 -4-甲基) -酰胺 69 (21mg, 黄色固体)，产率： 42.7 %。 5-(5-fluoro-7-carboxamido-2-oxo-1,2-dihydro-indol-3-methylmethyl) compound obtained in Example 64 in the manner described in Example 65 -2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid-(4-hydroxy-piperidin-4-methyl)-amide 64 deprotected tert-butyl group on the piperidine ring The oxycarbonyl group gives the title product 5-[5-fluoro-6-(3-methoxy-2-oxo-propyl)-1,2-dihydro-indol-3-methylol]- 2-Methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid-(4-hydroxy-piperidin-4-methyl)-amide 69 (21 mg, yellow solid).

MS m/z (ESI): 554.7(M+1) MS m/z (ESI): 554.7 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 57.73 (d, 1H， J=9.8Hz), 7,63 (d，lH, J=6.8Hz), 7.5 l(s 1H), 4.06(s,2H), 3.39(s,3H), 3.29 (d, 2H,J=2Hz), 3.16(m,2H), 3.05 (m, 2H), 3.00(m,2H),2.40 (s,3H),1.67(m,4H). 实施例 70 1H NMR (400 MHz, DMSO-d6) 57.73 (d, 1H, J = 9.8 Hz), 7, 63 (d, lH, J = 6.8 Hz), 7.5 l (s 1H), 4.06 (s, 2H), 3.39(s,3H), 3.29 (d, 2H, J=2Hz), 3.16(m,2H), 3.05 (m, 2H), 3.00 (m, 2H), 2.40 (s, 3H), 1.67 (m, 4H). Example 70

5-氟 -3-[4-(l-羟基 -1 -哌啶小甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基] 二氢 -吲哚 -2-酮 5-fluoro-3-[4-(l-hydroxy-1 -piperidinylmethyl-piperidine-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2-indole Dihydro-indol-2-one

按照本发明实施例 1第七步所述相同方式，氮气氛下，在一个 250 ml的三口瓶中，将 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 lg (1.5 g， 6.787 mmol) 溶解于 N'N-二甲基甲酰胺 (20 ml)中，搅拌下依次加入 N-乙基 -N，- (二甲氨基丙基) - 碳二亚胺盐酸盐 (1.951 g， 10.18 mmol)、 1-羟基苯并*** (1.375 g， 10.18 mmol), 三乙胺 (3.128 g, 33.94 mmol)及 1-哌啶 -1-甲基哌啶 -1-醇三氟醋酸盐（3.179 g， 10.18 mmol)DMF溶液 (50 ml)，室温搅拌 8小时，点板跟踪至原料基本消失，搅拌下向反应液中加入乙酸乙酯 (300 ml)，用饱和碳酸氢钠溶液 (100 mlx3)洗涤混合液，合并水层用乙酸乙酯 (150 mlx3) 回萃。合并有机相，乙酸.乙酯层用无水硫酸钠干燥，过滤，滤液减压浓縮标题产物 4-(1-羟基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 70a (3.32 g，固体)，直接进行下一步反应。 In the same manner as described in the seventh step of Example 1 of the present invention, 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole was introduced in a 250 ml three-necked flask under a nitrogen atmosphere. 3-carboxylic acid lg (1.5 g, 6.787 mmol) was dissolved in N'N-dimethylformamide (20 ml), and N-ethyl-N,-(dimethylaminopropyl)-carbon was added sequentially with stirring. Diimine hydrochloride (1.951 g, 10.18 mmol), 1-hydroxybenzotriazole (1.375 g, 10.18 mmol), triethylamine (3.128 g, 33.94 mmol) and 1-piperidine-1-methylper Pyridin-1-ol trifluoroacetate (3.179 g, 10.18 mmol) in DMF (50 ml), stirring at room temperature for 8 hours, the plate was traced until the starting material disappeared, and ethyl acetate (300 ml) was added to the reaction mixture with stirring. The mixture was washed with a saturated aqueous solution of sodium bicarbonate (100 ml.times. The combined organic phases were dried with EtOAc EtOAc. Base-1H-pyrrole-2-carbaldehyde 70a (3.32 g, solid) was taken directly to the next reaction.

MS m/z (ESI) :339.3M⁺-1] MS m/z (ESI): 339.3M ⁺ -1]

按照本发明实施例 1第八步所述相同方式，将上一步产物 4-(1-羟基 -哌啶 -4- 羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 70a (50 mg, 0.125 mmol)不经纯化溶解于乙醇 (1 ml)中，搅拌下加入 5-氟 -1，3-二氢 -吲哚 -2-酮 (25 mg， 0.17 mmol)及哌啶 (1 mg, 0.013 mmol), 加热回流 8小时，点板跟踪至原料基本消失，反应液自然冷却后在减压下蒸馏，得到的残留物用柱层析纯化 (二氯甲烷：甲醇：三乙胺 = 60： 1： 0.3)，得到标题产物 5-氟 -3-[4-(1-轻基 -1-哌啶 -1-甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-1,3-二氢引哚 -2-酮 70(40 mg，黄色体)，产率 30%。 In the same manner as described in the eighth step of Example 1 of the present invention, the product of the previous step was 4-(1-hydroxy-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2. - Formaldehyde 70a (50 mg, 0.125 mmol) was dissolved in ethanol (1 ml) without purification, and 5-fluoro-1,3-dihydro-indol-2-one (25 mg, 0.17 mmol) was added with stirring. Piperidine (1 mg, 0.013 mmol), heated under reflux for 8 hours, the plate was traced until the starting material disappeared, the reaction mixture was allowed to cool and then distilled under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol: Triethylamine = 60: 1: 0.3), the title product 5-fluoro-3-[4-(1-lightyl-1-piperidin-1-methyl-piperidin-4-carbonyl)-5-A Base-3-trifluoromethyl-1H-pyrrole-2-methine]-1,3-dihydroindol-2-one 70 (40 mg, yellow body), yield 30%.

MS m/z (ESI)： 535.5 (M+l) MS m/z (ESI): 535.5 (M+l)

Ή NMR ( 400 MHz, DMSO-d6 ) S7.66(m, 1H), 7.55 (s, 1H), 7.06(m, 1H), 6.9 l(m, 1H), 3.28(t, 2H)， 3.12(m, 1H), 2.43(d, 4H, J=4.4Hz), 2.30(s, 2H), 2.27(s, 2H), 2.19(d, 1H， J=12Hz), 1.53(m, 8H)， 1.40(m, 2H). 实施例 71 NMR NMR ( 400 MHz, DMSO-d6 ) S7.66 (m, 1H), 7.55 (s, 1H), 7.06 (m, 1H), 6.9 l (m, 1H), 3.28 (t, 2H), 3.12 ( m, 1H), 2.43 (d, 4H, J=4.4Hz), 2.30(s, 2H), 2.27(s, 2H), 2.19(d, 1H, J=12Hz), 1.53(m, 8H), 1.40 (m, 2H). Example 71

₅-氯 _₃_[4-(l-经基小哌啶 -1-甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-次' 甲基] -1,3-二氢 -d引哚 -2-酮 ₅ -Chloro_ ₃ _[4-(l-pyridylpiperidine-1-methyl-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2-order ' Methyl]-1,3-dihydro-d-indol-2-one

按照本发明实施例 70所述的方式，实施例 70所得的化合物 4-(1-羟基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 70a，按照本发明实施例 70第二步所述相同方式使得该原料与 5-氯 -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 5- 氯 -3-[4-(1-羟基 -1-哌啶 -1-甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基] -1,3-二氢』引哚 -2-酮 71 (59 mg，黄色固体)，产率： 85.6 %。 4-(1-hydroxy-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2- obtained in Example 70 in the manner described in Example 70 Formaldehyde 70a, the starting material was reacted with 5-chloro-1,3-dihydro-indol-2-one in the same manner as described in the second step of Example 70 of the present invention to give the title product 5-chloro-3- [4-(1-Hydroxy-1-piperidin-1-methyl-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2-methine]-1 , 3-dihydro"pyridin-2-one 71 (59 mg, yellow solid), Yield: 85.6 %.

MS m/z (ESI) : 551.4(M+l) MS m/z (ESI): 551.4 (M+l)

1H NMR ( 400 MHz, DMSO-d6 ) S7.82(m, 1H), 7.56(s, 1H), 7.25(dd, 1H, J=2Hz, J=8.4Hz), 6.93(d,lH, J=8.4Hz), 3.24(s, 2H), 3.11 (m, 1H), 2.42(m, 4H)， 2.29(s, 2H), 2.17(s, 3H)，1.45(m, 8H)， 1.20(m, 2H). 实施例 72 1H NMR (400 MHz, DMSO-d6) S7.82 (m, 1H), 7.56 (s, 1H), 7.25 (dd, 1H, J = 2 Hz, J = 8.4 Hz), 6.93 (d, lH, J = 8.4Hz), 3.24(s, 2H), 3.11 (m, 1H), 2.42(m, 4H), 2.29(s, 2H), 2.17(s, 3H), 1.45(m, 8H), 1.20(m, 2H). Example 72

：-溴 _3-[4-(l-羟基小哌啶小甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -IH-吡咯 -2-次甲基] -1,3-二氢 -H引哚 -2-酮 :-Bromo-3-(4-(l-hydroxysmperidine small methyl-piperidine-4-carbonyl)-5-methyl-3-trifluoromethyl-IH-pyrrole-2-methine] -1,3-dihydro-H-indol-2-one

按照本发明实施例 70所述的方式，实施例 70所得的化合物 4-(1-羟基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 70a, 按照本发明实施例 70第二步所述相同方式使得该原料与 5-溴 -1 ,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 5-溴 -3-[4-(1-羟基 -1-哌啶 -1-甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基] -1,3-二氢 -吲哚 -2-酮 72 (50mg，黄色固体)，产率： 67.6%。 4-(1-hydroxy-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2- obtained in Example 70 in the manner described in Example 70 Formaldehyde 70a, the starting material was reacted with 5-bromo-1,3-dihydro-inden-2-one in the same manner as described in the second step of Example 70 of the present invention to give the title product 5-bromo-3- [4-(1-Hydroxy-1-piperidin-1-methyl-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2-methine]-1 , 3-dihydro-indol-2-one 72 (50 mg, yellow solid), Yield: 67.6%.

MS m/z (ESI)： 595.5(M+1) MS m/z (ESI): 595.5 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 57.72(dd, IH, J=2Hz, J=8.8Hz), 7.55(s, IH), 7.36(dd, IH, J=2Hz, J=8.8Hz), 3.24(m, 2H), 3.10(m, IH), 2.43(s, 4H), 2.28(s, 2H), 2.2 l(s, 2H)，2.17(s， 3H), 1.49(m, 8H), 1.33(m, 2H). 实施例 73 1H NMR (400 MHz, DMSO-d6) 57.72 (dd, IH, J = 2 Hz, J = 8.8 Hz), 7.55 (s, IH), 7.36 (dd, IH, J = 2 Hz, J = 8.8 Hz), 3.24 (m, 2H), 3.10(m, IH), 2.43(s, 4H), 2.28(s, 2H), 2.2 l(s, 2H), 2.17(s, 3H), 1.49(m, 8H), 1.33 (m, 2H). Example 73

-氯 -7-溴 -3-[4-(l-羟基 -1 -哌啶 -1-甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -m-吡咯 -Chloro-7-bromo-3-[4-(l-hydroxy-1 -piperidin-1-methyl-piperidine-4-carbonyl)-5-methyl-3-trifluoromethyl-m-pyrrole

-2-次甲基 ]-1，3-二氢 -吲哚 -2-酮 -2-methine]-1,3-dihydro-indol-2-one

按照本发明实施例 70所述的方式，实施例 70所得的化合物 4-(1 -羟基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 70a, 按照本发明实施例 70第二步所述相同方式使得该原料与 5-氟 -7-溴 -1,3-二氢^ I噪 -2-酮的反应，则得到标题产物 5- 氟 -7-溴 -3-[4-(1-羟基 -1-哌啶小甲基 -呢啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2- 次甲基 ]-1,3-二氢 -吲哚 -2-酮 73 (61 mg，黄色固体)，产率： 99.5 %。

4-(1-hydroxy-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2- obtained in Example 70 in the manner described in Example 70 Formaldehyde 70a, the starting material is reacted with 5-fluoro-7-bromo-1,3-dihydroindol-2-one in the same manner as described in the second step of Example 70 of the present invention to give the title product 5- Fluorine-7-bromo-3-[4-(1-hydroxy-1-piperidinesmethylene-octyl-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2- Hypomethyl]-1,3-dihydro-indol-2-one 73 (61 mg, yellow solid), Yield: 99.5 %.

MS m/z (ESI)： 613.4(M+1) MS m/z (ESI): 613.4 (M+1)

Ή NMR ( 400 MHz, DMSO-d6 ) 57.72(dd, 1H, J=2Hz, J=8.8Hz), 7.55(s, 1H), 7.36(dd, 1H, J=2Hz, J=8.8Hz), 3.24(m, 2H), 3.11(m, 1H)， 2.43(s, 4H ), 2.3 l(s, 2H), 2.28 (s， 2H),2.18(d, 3H， J=14Hz), 1.49(m， 8H), 1.34(m, 2H). 实施例 74 NMR NMR (400 MHz, DMSO-d6) 57.72 (dd, 1H, J = 2 Hz, J = 8.8 Hz), 7.55 (s, 1H), 7.36 (dd, 1H, J = 2 Hz, J = 8.8 Hz), 3.24 (m, 2H), 3.11(m, 1H), 2.43(s, 4H), 2.3 l(s, 2H), 2.28 (s, 2H), 2.18(d, 3H, J=14Hz), 1.49(m, 8H), 1.34(m, 2H). Example 74

N-{5-氟 -3-[4-(l-经基 -1-哌啶小甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2- 次甲基乙酰胺 N-{5-fluoro-3-[4-(l-carbamic-1-piperidinemethyl-piperidine-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole- 2-methyl acetamide

按照本发明实施例 70所述的方式，实施例 70所得的化合物 4-(1-羟基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 70a，按照本发明实施例 70第二步所述相同方式使得该原料与 N-(5-氟 -2-氧代 -2,3-二氢 -1H- 哚 -7-基) -乙酰胺的反应，则得到标题产物 N-{5-氟 -3-[4-(1-羟基小哌啶 -1-甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -7-基乙酰胺 74 (55 mg, 黄色固体)，产率： 74.4%。 MS m/z (ESI)： 592.3(M+1)

4-(1-hydroxy-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2- obtained in Example 70 in the manner described in Example 70 Formaldehyde 70a, the starting material is N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-acetamide in the same manner as described in the second step of Example 70 of the present invention. Reaction, the title product N-{5-fluoro-3-[4-(1-hydroxypiperidine-1-methyl-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl Base-1H-pyrrole-2-methylidene]-2-oxo-2,3-dihydro-1H-indol-7-ylacetamide 74 (55 mg, yellow solid), yield: 74.4%. MS m/z (ESI): 592.3 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) 57.50(s, lH),7,46〜739(m， 2H), 3.25(m, 2H), 3.11(m, 1H), 2.42(s, 4H ), 2.30(s, 2H)， 2.27 (s, 2H), 2.17(s, 3H), 2.08(s， 3H), 1.48(m_: 8H)， 1.3 l(m, 2H). 实施例 75 1H NMR (400 MHz, DMSO-d6) 57.50 (s, lH), 7, 46~739 (m, 2H), 3.25 (m, 2H), 3.11 (m, 1H), 2.42 (s, 4H), 2.30 (s, 2H), 2.27 (s, 2H), 2.17 (s, 3H), 2.08 (s, 3H), 1.48 (m _: 8H), 1.3 l (m, 2H). Example 75

N-{5-氟 -3-[4-(l-羟基小哌啶小甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2- 次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -7-基甲酰胺 N-{5-fluoro-3-[4-(l-hydroxysuccinyl small methyl-piperidine-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2- Methyl]-2-oxo-2,3-dihydro-1H-indol-7-ylcarboxamide

按照本发明实施例 70所述的方式，实施例 70所得的化合物 4-(1-羟基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 70a, 按照本发明实施例 70第二步所述相同方式使得该原料与 N-(5-氟 2-氧代 -2,3-二氢 -1H-吲哚 -7-基) -甲酰胺的反应，则得到标题产物 N-{5-氟 -3-[4-(1-羟基 -1-哌啶 -1-甲基 -哌啶 -4-羰基) -5-甲基 -3- 三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -7-基}-甲酰胺 75 (58 mg, 黄色固体)，产率： 80.3%。

4-(1-hydroxy-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2- obtained in Example 70 in the manner described in Example 70 Formaldehyde 70a, the starting material is N-(5-fluoro2-oxo-2,3-dihydro-1H-indol-7-yl)-carboxamide in the same manner as described in the second step of Example 70 of the present invention. The reaction gave the title product N-{5-fluoro-3-[4-(1-hydroxy-1-piperidin-1-methyl-piperidin-4-carbonyl)-5-methyl-3- Fluoromethyl-1H-pyrrole-2-methino]-2-oxo-2,3-dihydro-1H-indol-7-yl}-carboxamide 75 (58 mg, yellow solid), yield : 80.3%.

MS m/z (ESI)： 578.4(M+1) MS m/z (ESI): 578.4 (M+1)

Ή NMR ( 400 MHz, DMSO-d6 ) 57.5 l(s, lH),7.50〜7.43(m, 2H), 3.29(m, 2H), 3.10(m, 1H)， 2.43(d， 4H, J=3.6Hz ), 2.30(s, 2H), 2.26 (s， 2H), 2.09(s, 3H), 1.49(m, 8H), 1.31(m, 2H). 实施例 76 NMR NMR (400 MHz, DMSO-d6) 57.5 l (s, lH), 7.50 to 7.43 (m, 2H), 3.29 (m, 2H), 3.10 (m, 1H), 2.43 (d, 4H, J = 3.6 Hz ), 2.30(s, 2H), 2.26 (s, 2H), 2.09(s, 3H), 1.49(m, 8H), 1.31(m, 2H). Example 76

N-{5-氟 -3-[4:(1-羟基 -1-哌啶小甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -IH-吡咯 -2- 次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -6-基}-甲酰胺 N-{5-fluoro-3-[4:(1-hydroxy-1-piperidinylmethyl-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-IH-pyrrole-2 - methine]-2-oxo-2,3-dihydro-1H-indol-6-yl}-carboxamide

按照本发明实施例 70所述的方式，实施例 70所得的化合物 4-(1-羟基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 70a, 按照本发明实施例 70第二步所述相同方式使得该原料与 N-(5-氟 2-氧代 -2,3-二氢 -1H-吲哚 -6-基) -甲酰胺的反应，则得到标题产物 N-{5-氟 -3-[4-(1-轻基 -1-哌啶 -1-甲基 -哌啶 -4-羰基) -5-甲基 -3- 三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -6-基甲酰胺 76 (58 mg, 黄色固体)，产率： 80.3%。

The compound obtained in Example 70 was 4-(1-hydroxy-piperidine) obtained in the manner described in Example 70 of the present invention. 4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2-carbaldehyde 70a, the starting material is N-(5-fluoro) in the same manner as described in the second step of Example 70 of the present invention. The reaction of 2-oxo-2,3-dihydro-1H-indol-6-yl)-carboxamide gives the title product N-{5-fluoro-3-[4-(1-). -piperidin-1-methyl-piperidine-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2-methine]-2-oxo-2,3-di Hydrogen-1H-indol-6-ylcarboxamide 76 (58 mg, yellow solid), yield: 80.3%.

MS m/z (ESI)： 578.5(M+1) MS m/z (ESI): 578.5 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) S7.88(d， 1H, J=6.8Hz), 7.76(m, 1H ),7.47(s, 1H), 3.28(m, 4H), 3.12(m, 1H), 2.44(d, 4H, J=4Hz ), 2.30(s， 2H), 2.26 (s, 3H)， 2.19(s， 2H), 1.38(m, 8H), 1.29(m, 2H). 实施例 77 1H NMR (400 MHz, DMSO-d6) S7.88 (d, 1H, J = 6.8 Hz), 7.76 (m, 1H), 7.47 (s, 1H), 3.28 (m, 4H), 3.12 (m, 1H) ), 2.44 (d, 4H, J=4Hz), 2.30(s, 2H), 2.26 (s, 3H), 2.19(s, 2H), 1.38(m, 8H), 1.29(m, 2H). 77

N-{5-氟 -3-[4-(l-羟基 -1-哌啶 -1-甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2- 次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -6-基}-2-羟基-乙酰胺 N-{5-fluoro-3-[4-(l-hydroxy-1-piperidin-1-methyl-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole -2-Methylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide

按照本发明实施例 70所述的方式，实施例 70所得的化合物 4-(1-轻基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 70a，按照本发明实施例 70第二步所述相同方式使得该原料与 N-(5-氟 -2-氧代 -2，3-二氢 -1H-吲哚 -6-基) -2-轻基 -乙酰胺的反应，则得到标题产物 N-{5-氟 -3-[4-(1-轻基 -1-哌啶 -1-甲基 -哌啶 -4-羰基) -5- 甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -6-基 2-羟基-乙酰胺 77(58 mg，黄色固体)，产率： 76.3%。

4-(1-Lightyl-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2 obtained in Example 70 in the manner described in Example 70 of the present invention. - Formaldehyde 70a, the starting material is made with N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl) in the same manner as described in the second step of Example 70 of the present invention. The reaction of 2-light-acetamide gives the title product N-{5-fluoro-3-[4-(1-light-l-l-piperidine-1-methyl-piperidine-4-carbonyl)- 5-methyl-3-trifluoromethyl-1H-pyrrole-2-methino]-2-oxo-2,3-dihydro-1H-indol-6-yl 2-hydroxy-acetamide 77 (58 mg, yellow solid), Yield: 76.3%.

MS m/z (ESI) : 608.5(M+l) MS m/z (ESI): 608.5 (M+l)

1H NMR ( 400 MHz, DMSO-d6 ) 57.82(d, 1H, J=3.6Hz ),7.80(s， 1H), 7.47(d₅ 1H), 4.06(d, 2H, J=5.6Hz ), 3.53(m, 4H), 2.82(m, 1H )， 2.45(s, 4H), 2.30 (s, 3H)， 2.17(m, 2H)， 1.38(m, 8H), 1.14(m, 2H). 实施例 78 1H NMR (400 MHz, DMSO-d6) 57.82 (d, 1H, J = 3.6 Hz), 7.80 (s, 1H), 7.47 (d ₅ 1H), 4.06 (d, 2H, J = 5.6 Hz), 3.53 ( m, 4H), 2.82 (m, 1H), 2.45 (s, 4H), 2.30 (s, 3H), 2.17 (m, 2H), 1.38 (m, 8H), 1.14 (m, 2H).

N-{5-氟 -3-[4-(l-轻基 -1 -哌啶小甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2- 次甲基 ]-2-氧代 -2，3-二氢 -1H-B引哚 -7-基}-2-甲氧基-乙酰胺 N-{5-fluoro-3-[4-(l-lightyl-1 -piperidinylmethyl-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole- 2-Methyl]-2-oxo-2,3-dihydro-1H-B 哚-7-yl}-2-methoxy-acetamide

按照本发明实施例 70所述的方式，实施例 70所得的化合物 4-(1-羟基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 70a，按照本发明实施例 70第二步所述相同方式使得该原料与 N-(5-氟 -2-氧代 -2，3-二氢 -1H-吲哚 -7-基) -2-甲氧基-乙酰胺的反应，则得到标题产物 N-{5-氟 -3-[4-(1-羟基 -1-哌啶 -1-甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -7-基}-2-甲氧基-乙酰胺 78 (40 mg，黄色固体)，产率： 51.5%

4-(1-hydroxy-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2- obtained in Example 70 in the manner described in Example 70 Formaldehyde 70a, the starting material is N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-2 in the same manner as described in the second step of Example 70 of the present invention. -Methoxy-acetamide reaction, the title product N-{5-fluoro-3-[4-(1-hydroxy-1-piperidin-1-methyl-piperidine-4-carbonyl)-5 -methyl-3-trifluoromethyl-1H-pyrrole-2-methino]-2-oxo-2,3-dihydro-1H-indol-7-yl}-2-methoxy- Acetamide 78 (40 mg, yellow solid), Yield: 51.5%

MS m/z (ESI)： 622.7(M+1) MS m/z (ESI): 622.7 (M+1)

Ή MR ( 400 MHz, DMSO-d6 ) 67.5 l(s, lH),7.45(d, 1H, J=7.6Hz), 7.32(d， 1H, J=11.2Hz), 3.25(m, 2H), 3.09(m, 1H), 2.42(s, 4H )， 2.28(m, 2H), 2.20 (s, 2H), 2.17(s, 3H), 1.38(m， 8H), 1.14(m, 2H). 实施例 79 Ή MR (400 MHz, DMSO-d6) 67.5 l(s, lH), 7.45 (d, 1H, J = 7.6 Hz), 7.32 (d, 1H, J = 11.2 Hz), 3.25 (m, 2H), 3.09 (m, 1H), 2.42 (s, 4H), 2.28 (m, 2H), 2.20 (s, 2H), 2.17 (s, 3H), 1.38 (m, 8H), 1.14 (m, 2H). 79

N-{5-氟 -3-[4-(l-轻基小哌啶小甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2- 次甲基 ]-2-氧代 -2,3-二氢 -1Η-Π引哚 -6-基}-2-甲氧基-乙酰胺 N-{5-fluoro-3-[4-(l-light-based small piperidine small methyl-piperidine-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2- Hypomethyl]-2-oxo-2,3-dihydro-1Η-Π 哚-6-yl}-2-methoxy-acetamide

按照本发明实施例 70所述的方式，实施例 70所得的化合物 4-(1-羟基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 70a，按照本发明实施例 70第二步所述相同方式使得该原料与 N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基) -2-甲氧基-乙酰胺的反应，则得到标题产物 N-{5-氟 -3-[4-(1-羟基 -1-哌啶 -1-甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -6-基}-2-羟基-乙酰胺 79(59 mg，黄色固体), 产率： 76%

4-(1-hydroxy-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2- obtained in Example 70 in the manner described in Example 70 Formaldehyde 70a, the starting material is N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2 in the same manner as described in the second step of Example 70 of the present invention. -Methoxy-acetamide reaction, the title product N-{5-fluoro-3-[4-(1-hydroxy-1-piperidin-1-methyl-piperidine-4-carbonyl)-5 -methyl-3-trifluoromethyl-1H-pyrrole-2-methine]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-acetamide 79 (59 mg, yellow solid), Yield: 76%

MS m/z (ESI)： 622.5(Μ+1) MS m/z (ESI): 622.5 (Μ +1)

1H NMR ( 400 MHz, DMSO-d6 ) S7.78(m lH)，7.66(d, 1H, J=6.4Hz), 7.47(s, 1H), 4.08 (s, 2H), 3:40(s, 3H), 3.12(m, 4H ), 2.44(s, 4H), 2.28 (d， 3H, J=14Hz ), 2.19(d, 2H, =12Hz), 1.38(m, 8H), 1.14(m, 2H). 实施例 80 1H NMR (400 MHz, DMSO-d6) S7.78 (m lH), 7.66 (d, 1H, J = 6.4 Hz), 7.47 (s, 1H), 4.08 (s, 2H), 3:40 (s, 3H), 3.12(m, 4H), 2.44(s, 4H), 2.28 (d, 3H, J=14Hz), 2.19(d, 2H, =12 Hz), 1.38 (m, 8H), 1.14 (m, 2H). Example 80

N-{5-氟 -3-[4-(l-羟基 -1 -哌啶小甲基 -哌啶 -4-羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2- 次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -7-基} -甲磺酰胺 N-{5-fluoro-3-[4-(l-hydroxy-1 -piperidinylmethyl-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2 - methine]-2-oxo-2,3-dihydro-1H-indol-7-yl}-methanesulfonamide

按照本发明实施例 70所述的方式，实施例 70所得的化合物 4-(1-羟基 -哌啶 -4- 羰基) -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 70a，按照本发明实施例 70第二步所述相同方式使得该原料与 N-(5-氟 -2-氧代 -2，3-二氢 -1H-吲哚 -7-基) -甲磺酰胺的反应，则得到标题产物 N-{5-氟 -3-[4-(1-羟基 -1-哌啶 -1-甲基 -哌啶 -4-羰基) -5-甲基 -3- 三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -7-基} -甲磺酰胺 80(68mg，黄色固体)，产率： 86.6%。

4-(1-hydroxy-piperidin-4-carbonyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2- obtained in Example 70 in the manner described in Example 70 Formaldehyde 70a, the starting material is N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-A in the same manner as described in the second step of Example 70 of the present invention. The reaction of the sulfonamide gives the title product N-{5-fluoro-3-[4-(1-hydroxy-1-piperidin-1-methyl-piperidin-4-carbonyl)-5-methyl-3 - trifluoromethyl-1H-pyrrole-2-methylidene]-2-oxo-2,3-dihydro-1H-indol-7-yl}-methanesulfonamide 80 (68 mg, yellow solid) Yield: 86.6%.

MS m/z (ESI)： 628.3(M+1) MS m/z (ESI): 628.3 (M+1)

Ή NMR ( 400 MHz, DMSO-d6 ) 67.5 l(s, lH),7.45(d, 1H, J=7.6Hz), 7.32(d, 1H， J=11.2Hz), 3.25(m, 2H), 3.09(m, 1H), 2.42(s, 4H ), 2.28(m, 2H), 2.20 (s， 2H)， 2.17(s, 3H)， 1.38(m, 8H), 1.14(m, 2H). 实施例 81 NMR NMR (400 MHz, DMSO-d6) 67.5 l (s, lH), 7.45 (d, 1H, J = 7.6 Hz), 7.32 (d, 1H, J = 11.2 Hz), 3.25 (m, 2H), 3.09 (m, 1H), 2.42 (s, 4H), 2.28 (m, 2H), 2.20 (s, 2H), 2.17 (s, 3H), 1.38 (m, 8H), 1.14 (m, 2H). 81

l-[5-(5-氟 -2-氧代 -1，2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3- 基] -3-(2-吡咯垸 -1-乙基) -脲 1-[5-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3- -3-(2-pyrrole-1-ethyl)-urea

将 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 lg (663.3 mg, 3 mmol)的丙酮 (5ml)溶液在冰盐浴条件下，加入三乙胺 (336.3 mg, 3.33mmol)和氯乙酸乙酯 (361.3 mg, 3.33 mmol)的丙酮溶液 (2ml)。反应液搅拌 30分钟后加入叠氮化钠 (390 mg, 6 mmol)水溶液 (40 ml)。继续搅拌 30分钟后，原料点消失。用 40ml水猝灭反应。反应液用甲苯萃取 (20mlx3)，合并的有机相用饱和的氯化钠水溶液洗涤 (20mlx2),无水硫酸钠干燥，浓缩，得到甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3- 羰基叠氮 81a (360mg，黄色固体)，产率 48.8%。

A solution of 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid lg (663.3 mg, 3 mmol) in acetone (5 ml) was added in ice ice bath. Ethylamine (336.3 mg, 3.33 mmol) and ethyl chloroacetate (361.3 mg, 3.33 mmol) in EtOAc (2 mL). After the reaction mixture was stirred for 30 minutes, a sodium azide (390 mg, 6 mmol) aqueous solution (40 ml) was added. After stirring for 30 minutes, the starting point disappeared. Quench with 40ml water Reaction. The reaction mixture was extracted with EtOAc (EtOAc (EtOAc) (EtOAcjjjjjjjj Pyrrole-3-carbonyl azide 81a (360 mg, yellow solid), yield 48.8%.

MS m/z (ESI) :245.6(M-1) MS m/z (ESI): 245.6 (M-1)

将上述得到的化合物 81a溶于 10ml甲苯中，加热回流 1小时，自然冷却至室温。减压下蒸镏得到褐色固体，加入 10ml无水四氢呋喃，冰浴条件下缓慢加入 2-吡咯垸基 -1-乙胺， 10分钟后反应完全，加入 20ml水猝灭反应。反应液中加入乙酸乙酯萃取 (15mlx4),合并的有机相用饱和氯化钠水溶液洗漆，无水硫酸钠干燥，减压下浓缩得到褐色固体,柱层析进一步分离，得到 1-(5-甲酰基 -2-甲基 -4- 三氟甲基 -1H-吡咯 -3-基) -3-(2-吡咯烷小基-乙基) -脲 81b(230 mg, 淡黄色固体)，产率 82.4%。 The compound 81a obtained above was dissolved in 10 ml of toluene, heated under reflux for 1 hour, and then cooled to room temperature. Evaporation under reduced pressure gave a brown solid. <EMI ID=9.1>>> The reaction mixture was extracted with ethyl acetate (15 ml×4), and the combined organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated. -formyl-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl)-3-(2-pyrrolidinyl-ethyl)-urea 81b (230 mg, pale yellow solid) The yield was 82.4%.

MS m/z (ESI) :333.4(M+1) MS m/z (ESI): 333.4 (M+1)

按照本发明实施例 1第八步所述相同方式，将上一步产物 1-(5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -3-(2-吡咯垸 -1-基-乙基) -脲 81b (50 mg, 0.15 mmol) 不经纯化溶解于乙醇 (3.5 ml)中，搅拌下加入 5-氟 -1，3-二氢 -Π引哚 -2-酮 (18 mg, 0.12 mmol)及哌啶 (33mg， 0.034 mmol), 加热回流 3小时后冷却，析出晶体，用甲醇和乙醇洗漆，得到标题产物 1-[5-(5-氟 -2-氧代 -1,2-二氢 -B引哚 -3-次甲基 )-2-甲基 -4- 三氟甲基 -1H-吡咯 -3-基] -3-(2-吡咯烷小乙基) -脲 81 (30 mg,黄色固体)，产率 53.6 %。 ' In the same manner as described in the eighth step of Example 1 of the present invention, the product of the previous step, 1-(5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl)-3-( 2-pyrrole-1-yl-ethyl)-urea 81b (50 mg, 0.15 mmol) was dissolved in ethanol (3.5 ml) without purification, and 5-fluoro-1,3-dihydro-indole was added with stirring. Indole-2-one (18 mg, 0.12 mmol) and piperidine (33 mg, 0.034 mmol) were heated under reflux for 3 hours, then cooled, crystals were crystallised, washed with methanol and ethanol to give the title product 1-[5-(5- Fluoro-2-oxo-1,2-dihydro-B 哚-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl]-3-(2 - pyrrolidine small ethyl)-urea 81 (30 mg, yellow solid), yield 53.6%. '

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

1H NMR ( 400 MHz, DMSO-d6 ) 67.59 (m,lH), 7.54(s,lH), 7.03(m, 1H), 6.89(m, 1H)， 3.47(s, 2H), 3.17(d,2H, J=5.2Hz), 2.2(m,4H), 2.20 (s，3H)， 170(s， 4H). 实施例 82 1H NMR (400 MHz, DMSO-d6) 67.59 (m, lH), 7.54 (s, lH), 7.03 (m, 1H), 6.89 (m, 1H), 3.47 (s, 2H), 3.17 (d, 2H) , J = 5.2 Hz), 2.2 (m, 4H), 2.20 (s, 3H), 170 (s, 4H). Example 82

l-[5-(5-氯 -2-氧代 -1,2-二氢』引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3- 基] -3-(2-吡咯烷 -1-乙基) -脲 1-[5-(5-Chloro-2-oxo-1,2-dihydro)-indolyl-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3- -3-(2-pyrrolidin-1-ethyl)-urea

重复本发明实施例 81第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 1-(5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -3-(2-吡咯烷 -1- 基-乙基) -脲 81b作原料，按照本发明实施例 1第八步所述相同方式使得该原料与 5-氯 -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 1-[5-(5-氯 -2-氧代 -1，2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -IH-吡咯 -3-基] -3-(2-吡咯垸 -1-乙基) -脲 82 (25 mg, 黄色固体)，产率： 25.1 %。

The first and second reaction reactions of Example 81 of the present invention were repeated except that the compound 1-(5-formyl-2-methyl-4-trifluoromethyl-1H) obtained in the above first step was used. -pyrrol-3-yl)-3-(2-pyrrolidin-1-yl-ethyl)-urea 81b as a starting material, the starting material and 5-chloro- in the same manner as described in the eighth step of Example 1 of the present invention The reaction of 1,3-dihydro-indol-2-one gives the title product 1-[5-(5-chloro-2-oxo-1,2-dihydro-indole) 3-Methylmethyl)-2-methyl-4-trifluoromethyl-IH-pyrrol-3-yl]-3-(2-pyrrole-1-ethyl)-urea 82 (25 mg, yellow Solid), Yield: 25.1%.

MS m/z (ESI): 482.3 (M+1) MS m/z (ESI): 482.3 (M+1)

IH MR ( 400 MHz, DMSO-d6 ) 57.88(s,lH), 7.55(s，lH)， 7.59(d, IH, J=7.2Hz), 7.15(d, IH, J=7.2Hz), 6.90(q,lH), 3.47(s, 2H)， 3.15(t,2H, J=6Hz)， 2.47(m,4H), 2.20 (s,3H), 1.68(s, 4H). 实施例 83 IH MR (400 MHz, DMSO-d6) 57.88 (s, lH), 7.55 (s, lH), 7.59 (d, IH, J = 7.2 Hz), 7.15 (d, IH, J = 7.2 Hz), 6.90 ( q, lH), 3.47(s, 2H), 3.15(t, 2H, J=6Hz), 2.47(m, 4H), 2.20 (s, 3H), 1.68(s, 4H). Example 83

l-[5-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -IH-吡咯 -3- 基] -3-(2-吡咯垸 -1-乙基) -脲 . 1-[5-(5-Bromo-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-IH-pyrrole-3- Base] -3-(2-pyrrole-1-ethyl)-urea.

重复本发明实施例 81第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 1-(5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -3-(2-吡咯烷小基-乙基) -脲 81b作原料，按照本发明实施例 1第八步所述相同方式使得该原料与 5-溴 -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 1-[5-(5-溴 -2-氧代 -1,2-二复 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -3-(2-吡咯垸 -1-乙基) -脲 83 (75 mg, 黄色固体)，产率： 92.6%。

The first and second reaction reactions of Example 81 of the present invention were repeated except that the compound 1-(5-formyl-2-methyl-4-trifluoromethyl-1H) obtained in the above first step was used. -pyrrol-3-yl)-3-(2-pyrrolidinyl-ethyl)-urea 81b as a starting material, which is made in the same manner as described in the eighth step of Example 1 of the present invention, with 5-bromo-1, The reaction of 3-dihydro-indol-2-one gives the title product 1-[5-(5-bromo-2-oxo-1,2-di-indole-3-methyl)- 2-Methyl-4-trifluoromethyl-1H-pyrrol-3-yl]-3-(2-pyrrole-1-ethyl)-urea 83 (75 mg, yellow solid), Yield: 92.6% .

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

IH NMR ( 400 MHz, DMSO-d6 ) 57.89(s,lH), 7.55(s,lH)， 7.60(d, 1H， J=7.2Hz), 7.15(d, IH, J=7.2Hz), 6.90(q,lH), 3.47(s, 2H), 3.15(t,2H, J=6Hz), 2.47(m,4H), 2.20 (s,3H), 1.68(s, 4H). 实施例 84 IH NMR (400 MHz, DMSO-d6) 57.89 (s, lH), 7.55 (s, lH), 7.60 (d, 1H, J = 7.2 Hz), 7.15 (d, IH, J = 7.2 Hz), 6.90 ( q, lH), 3.47(s, 2H), 3.15(t, 2H, J=6Hz), 2.47(m, 4H), 2.20 (s, 3H), 1.68(s, 4H). Example 84

l_[5-(7-漠 -5-氟 -2-氧代 -1,2-二氢引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -IH-吡咯 -3- 基] -3-(2-吡咯垸 -1-乙基) -脲 L_[5-(7-Moly-5-fluoro-2-oxo-1,2-dihydroindole-3-methyl)-2-methyl-4-trifluoromethyl-IH-pyrrole- 3-yl]-3-(2-pyrrole-1-ethyl)-urea

重复本发明实施例 81第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 1-(5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -3-(2-吡咯烷 -1- 基-乙基) -脲 81b作原料，按照本发明实施例 1第八步所述相同方式使得该原料与 5-氟 -7-溴 -1,3-二氢 -B引哚 -2-爾的反应，则得到标题产物 1-[5-(5-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -3-(2-吡咯烷 -1-乙基) -脲 84 (55 mg, 黄色固体)，产率： 84.6%。

The first and second reaction reactions of Example 81 of the present invention were repeated except that the compound 1-(5-formyl-2-methyl-4-trifluoromethyl-1H) obtained in the above first step was used. -pyrrol-3-yl)-3-(2-pyrrolidin-1-yl-ethyl)-urea 81b as a starting material, the starting material and 5-fluoro- in the same manner as described in the eighth step of Example 1 of the present invention The reaction of 7-bromo-1,3-dihydro-B 哚-2-r gives the title product 1-[5-(5-bromo-2-oxo-1,2-dihydro-indole- 3-Methyl)-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl]-3-(2-pyrrolidin-1-yl)-urea 84 (55 mg, yellow solid ), Yield: 84.6%.

MS m/z (ESI): 544.4(M+1) MS m/z (ESI): 544.4 (M+1)

1H NMR ( 400 MHz, DMSO-d6 ) S7.65(q,lH), 7.55(s,lH), 7.35(d, 1H), 7.15(d, 1H, J=7.2Hz), 3.46(s, 2H), 3.16(m,2H), 2.47(m,4H), 2.22 (s,3H), 1.71(s， 4H). 实施例 85 1H NMR (400 MHz, DMSO-d6) S7.65 (q, lH), 7.55 (s, lH), 7.35 (d, 1H), 7.15 (d, 1H, J = 7.2 Hz), 3.46 (s, 2H) ), 3.16 (m, 2H), 2.47 (m, 4H), 2.22 (s, 3H), 1.71 (s, 4H). Example 85

3-(4-氨基 -5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 )-5-氟 -1,3-二氢 -吲哚 -2-酮 3-(4-Amino-5-methyl-3-trifluoromethyl-1H-pyrrole-2-methine)-5-fluoro-1,3-dihydro-indol-2-one

将本发明中实施例 1 中的化合物 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3- 基) -氨基甲酸叔丁酯 If (110 mg, 0.376 mmol)溶解于乙醇 (3 ml)中，搅拌下加入 5-氟 -1,3-二氢 -吲哚 -2-酮 (63mg， 0.297 mmol)及哌啶 (3 mg， 0.037 mmol), 加热回流 3 小时，点板跟踪至原料基本消失，反应液自然冷却后，有黄色固体析出，用乙醇洗涤得到产物 [5-(5-氟 -2-氧代 -1,2-二氢』引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯 85a (118 mg, 黄色固体)，产率 73.7%。

The compound of Example 1 (5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl)-carbamic acid tert-butyl ester If (110 mg, 0.376 mmol) Dissolved in ethanol (3 ml), and added 5-fluoro-1,3-dihydro-indol-2-one (63 mg, 0.297 mmol) and piperidine (3 mg, 0.037 mmol) with stirring, and refluxed for 3 hours. The point plate is traced until the raw material disappears substantially. After the reaction solution is naturally cooled, a yellow solid precipitates and is washed with ethanol to obtain a product [5-(5-fluoro-2-oxo-1,2-dihydro) 哚-3- Tert-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl]-carbamic acid tert-butyl ester 85a (118 mg, yellow solid), yield 73.7%.

MS m/z (ESI) :497(M-1) MS m/z (ESI): 497 (M-1)

1H NMR ( 400 MHz, DMSO-d6 ) 57.59 (d, ΙΗ,ΑΓΗ), 7.52 (s， 1H, CH ), 7.05 (m,lH,ArH)), 6.91 (m, 1H, ArH), 3.31 (m, 9H, 3 CCH3), 2.21 (m, 3H, CH3) 1H NMR (400 MHz, DMSO-d6) 57.59 (d, ΙΗ, ΑΓΗ), 7.52 (s, 1H, CH), 7.05 (m,lH,ArH)), 6.91 (m, 1H, ArH), 3.31 (m , 9H, 3 CCH3), 2.21 (m, 3H, CH3)

将上述步骤得到的化合物 [5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4- 三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯 85a(50mg, 0.117 mmol)溶解于二氯甲烷 (2.5 ml)中，缓慢加入三氟醋酸 (2.5 ml)，室温下搅拌 2小时后，反应完毕。在反应溶液中加入少量的氢氧化钾溶液，和乙酸乙酯萃取 (50mlx3).，合并有机相用饱和的氯化钠溶液洗涤，干燥 (无水硫酸镁)，减压浓缩得到标题产物 3-(4-氨基 -5- 甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 )-5-氟 -1，3-二氢 -吲哚 -2-酮 85(56 mg, 黄色固体)，产率 45.6%。 . The compound obtained in the above step [5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H- The pyrrol-3-yl]-carbamic acid tert-butyl ester 85a (50 mg, 0.117 mmol) was dissolved in dichloromethane (2.5 ml), trifluoroacetic acid (2.5 ml) was slowly added, and the mixture was stirred at room temperature for 2 hr. A small amount of potassium hydroxide solution was added to the reaction solution, and ethyl acetate (50 ml×3) was evaporated. (4-Amino-5-methyl-3-trifluoromethyl-1H-pyrrole-2-methine)-5-fluoro-1,3-dihydro-indol-2-one 85 (56 mg, Yellow solid), yield 45.6%. .

MS m/z (ESI) :326.4(M+1) - 实施例 86 MS m/z (ESI): 326.4 (M+1) - Example 86

3-(5-甲基 -3-三氟甲基 -1H-吡咯 -2-¾甲基) -5-氟 -1,3-二氢 -吲哚 -2-酮 3-(5-methyl-3-trifluoromethyl-1H-pyrrole-2-3⁄4 methyl)-5-fluoro-1,3-dihydro-indol-2-one

将亚铬酸铜 (copper chromite)(0.3g)溶解于喹啉 (5 ml)中，得到的混合物置于 200~210°C油浴中加热，当反应不再产生气体时，加入本发明实施例 1第七歩得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 lg (406 mg, 1.837 mmol), 搅拌 30分钟后反应停止，冷却。将反应液倒入冰水 (20 ml)中，缓慢加入 5 ml浓盐酸，所得到的混合物用乙酸乙酯萃取 (100mlx3)。合并有机相，用饱和的氯化钠溶液洗涤，干燥 (无水硫酸镁)，浓缩，得到的粗品通过柱层析 (环己垸：乙酸乙酯 =8: 1)纯化得到化合物 5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 86a(68 mg, 白色固体)，产率 28.3%。

Copper chromite (0.3 g) was dissolved in quinoline (5 ml), and the resulting mixture was heated in an oil bath at 200-210 ° C. When the reaction no longer produced gas, the present invention was added. The compound obtained in the seventh step of Example 1 was 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid lg (406 mg, 1.837 mmol). After stirring for 30 minutes, the reaction was stopped. cool down. The reaction mixture was poured into ice water (20 ml), and 5 ml of concentrated hydrochloric acid was added slowly, and the obtained mixture was extracted with ethyl acetate (100 ml x 3). The organic phase was combined, washed with a saturated sodium chloride solution, dried (MgSO4jjjjjjjjjjjjj 3-Trifluoromethyl-1H-pyrrole-2-carbaldehyde 86a (68 mg, white solid), yield 28.3%.

MS m/z (ESI)： 176.5(M-1) MS m/z (ESI): 176.5 (M-1)

1H NMR ( 400 MHz, DMSO-d6 ) 59.59(s, 1H), 6.23(d， 2H， J=2.4 Hz), 2.32(s, 3H). 将上述步骤所得到的化合物 86a和 5-氟 -1， 3-二氢 -3-酮溶解于 5ml无水乙醇中，加入 1滴哌啶，加热回流 2小时后冷却，析出晶体。过滤，洗涤 (无水乙醇 3x5ml),得到标题化合物 3-(5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 )-5-氟 -1,3-二氢 -吲哚 -2-酮 86(68mg，黄色固体)，产率 42%。 1H NMR (400 MHz, DMSO-d6) 59.59 (s, 1H), 6.23 (d, 2H, J = 2.4 Hz), 2.32 (s, 3H). Compound 86a and 5-fluoro-1 obtained in the above procedure 3-Dihydro-3-one was dissolved in 5 ml of absolute ethanol, and 1 drop of piperidine was added thereto, and the mixture was heated under reflux for 2 hours, and then cooled to precipitate crystals. Filtration and washing (3x5 ml of dry ethanol) afforded the title compound 3-(5-methyl-3-trifluoromethyl-1H-pyrrol-2-methylmethyl)-5-fluoro-1,3-dihydro- Indole-2-one 86 (68 mg, yellow solid), yield 42%.

MS m/z (ESI) : 309.6(M-l) MS m/z (ESI): 309.6 (M-l)

1H NMR ( 400 MHz, DMSO-d6 ) 57.62(q,lH)，7.51(s,lH), 7.02(t, lH),6.88(q, 1H, J=4Hz),6.51(s, 1H), 2.38(s, 3H). 实施例 87 1H NMR (400 MHz, DMSO-d6) 57.62 (q, lH), 7.51 (s, lH), 7.02 (t, lH), 6.88 (q, 1H, J = 4 Hz), 6.51 (s, 1H), 2.38 (s, 3H). Example 87

：-溴 -3-(5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 )-1,3-二氢 -吲哚 1-2-酮 :-Bromo-3-(5-methyl-3-trifluoromethyl-1H-pyrrole-2-methine)-1,3-dihydro-indole 1-2-one

重复本发明实施例 86第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 6-氧代 -1,6-二氢 -吡啶 -2-甲醛 86a作原料，与 5-溴 -1,3-二氢 -B引哚 -2-酮的反应，则得到标题产物 5-溴 -3-(5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 )-1,3- 二氢 -吲哚 1-2-酮 87(65 mg，黄色固体)，产率： 44.4%。

The first step and the second step of the reaction of Example 86 of the present invention are repeated, except that the compound 6-oxo-1,6-dihydro-pyridine-2-carbaldehyde 86a obtained in the above first step is used as a raw material. Reaction with 5-bromo-1,3-dihydro-B fluoren-2-one gives the title product 5-bromo-3-(5-methyl-3-trifluoromethyl-1H-pyrrole-2 -Methyl-methyl)-1,3-dihydro-indole1-2-one 87 (65 mg, yellow solid), Yield: 44.4%.

MS m/z (ESI): 371.3 (M+l) MS m/z (ESI): 371.3 (M+l)

1H MR ( 400 MHz, DMSO-d6 ) 57.96(s,lH),7.57(s,lH), 7.02(m, lH),6.87(d, 1H， J=8Hz),6.52(s, 1H), 2.39(s, 3H). 实施例 88 1H MR (400 MHz, DMSO-d6) 57.96 (s, lH), 7.57 (s, lH), 7.02 (m, lH), 6.87 (d, 1H, J = 8 Hz), 6.52 (s, 1H), 2.39 (s, 3H). Example 88

5-(4-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4三氟甲基 -1H-吡咯 -3-羧酸 (二乙氨基乙基)酰胺 5-(4-bromo-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4trifluoromethyl-1H-pyrrole-3-carboxylic acid (II Ethylaminoethyl)amide

按照本发明实施例 1第七步所述相同方式，氮气氛下，在一个 250 ml的三口瓶中，将 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 lg (880 mg， 4.0 mmol) 溶解于 N，N-二甲基甲酰胺 (4 ml)中，搅拌下依次加入 N-乙基 -N，- (二甲氨基丙基) - 碳二亚胺盐酸盐 (1.15 g, 6.0 mmol)、 1-羟基苯并*** (810 mg, 6.0 mmol)、三乙胺 (1.01 g, 10 mmol)及 N,N-二乙基乙二胺(697 mg， 6.0 mmol), 室温搅拌过夜，点板跟踪至原料基本消失，搅拌下向反应液中加入乙酸乙酯 (200 ml), 用饱和碳酸氢钠溶液 (70 mlx3)洗涤混合液，合并水层用乙酸乙酯 (50 mlxl)回萃。合并有机相，乙酸乙酯用无水硫酸钠干燥，过滤，滤液减压浓缩标题产物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 -(2-乙氨基乙基）酰胺 88a (1.3 g, 油状物)，直接进行下一步反应。

In the same manner as described in the seventh step of Example 1 of the present invention, 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole was introduced in a 250 ml three-necked flask under a nitrogen atmosphere. 3-carboxylic acid lg (880 mg, 4.0 mmol) dissolved in N,N-dimethylformamide (4 ml) with N-ethyl-N,-(dimethylaminopropyl)-carbon Diimine hydrochloride (1.15 g, 6.0 mmol), 1-hydroxybenzotriazole (810 mg, 6.0 mmol), triethylamine (1.01 g, 10 mmol) and N,N-diethylethylenediamine (697 mg, 6.0 mmol), stirring at room temperature overnight, the plate was traced until the starting material disappeared, ethyl acetate (200 ml) was added to the reaction mixture, and the mixture was washed with saturated sodium hydrogen carbonate solution (70 ml×3) and combined. The aqueous layer was extracted with ethyl acetate (50 mL×l). The combined organic layers were dried with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 2-Ethylaminoethyl)amide 88a (1.3 g, oil) was taken directly to the next step.

MS: 418.6(M+1) MS: 418.6 (M+1)

按照本发明实施例 1第八步所述相同方式，将上一步产物 5-甲酰基 -2-甲基 -4- 三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-乙氨基乙基）酰胺 88a (200 mg，）不经纯化溶解于乙醇 (l ml)中，搅拌下加入 4-溴 -1,3-二氢』引哚 -2-酮（46 mg， 0.21 mmol)及六氢吡啶 (2 mg， 0.028 mmol), 加热回流 2小时，点板跟踪至原料基本消失，反应自然冷却至室温，有黄色固体产生，过滤，固体用冷乙醇 (5 ml)洗涤，真空干燥，得到标题产物 5-(4-溴 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4三氟甲基 -1H-吡咯 -3-羧酸 (二乙氨基乙基)酰胺 88 (60 mg，黄色固体)，产率 23%。 MS: 514.8(M+1) 实施例 89 In the same manner as described in the eighth step of Example 1 of the present invention, the product of the previous step is 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole-3-carboxylic acid-(2-ethylamino). Ethyl)amide 88a (200 mg, ) was dissolved in ethanol (1 ml) without purification, and 4-bromo-1,3-dihydroindol-2-one (46 mg, 0.21 mmol) was added with stirring. Hexahydropyridine (2 mg, 0.028 mmol), heated to reflux for 2 h, the pad was traced until the starting material disappeared, the reaction was allowed to cool to room temperature, and a yellow solid was formed. The solid was washed with cold ethanol (5 ml) and dried in vacuo. The title product 5-(4-bromo-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4trifluoromethyl-1H-pyrrole-3-carboxy Acid (diethylaminoethyl)amide 88 (60 mg, yellow solid), yield 23%. MS: 514.8 (M+1) Example 89

-[4-(2-氟苯基 )-2-氧代 -1,2-二氢 -B引哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3- 羧酸 (二乙氨基甲基)酰胺 -[4-(2-Fluorophenyl)-2-oxo-1,2-dihydro-B 哚-3-methylol]-2-methyl-4-trifluoromethyl-1H-pyrrole -3-carboxylic acid (diethylaminomethyl) amide

重复本发明实施例 88第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-乙氨基乙基) 酰胺 88a作原料，与 4-(2-氟苯基 )-1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 5-[4-(2-氟苯基 )-2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3- 羧酸 (二乙氨基甲基)酰胺 89 (45 mg，黄色固体)，产率： 30.4%。

The first and second reaction reactions of Example 88 of the present invention were repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole obtained in the above first step was used. 3-carboxylic acid-(2-ethylaminoethyl)amide 88a as a starting material, which is reacted with 4-(2-fluorophenyl)-1,3-dihydro-inden-2-one to give the title product 5-[4-(2-Fluorophenyl)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-2-methyl-4-trifluoromethyl-1H-pyrrole -3-carboxylic acid (diethylaminomethyl)amide 89 (45 mg, yellow solid), yield: 30.4%.

MS m/z (ESI): 529 .6(M+1) 实施例 90 MS m/z (ESI): 529.6 (M+1) Example 90

5-[4-(4-氯 -2-氟苯基 )-2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸 (二乙氨基甲基)酰胺 5-[4-(4-Chloro-2-fluorophenyl)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-2-methyl-4-trifluoromethyl -1H-pyrrole-3-carboxylic acid (diethylaminomethyl)amide

重复本发明实施例 88第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢-吡咯 -3-羧酸 -(2-乙氨基乙基) 酰胺 88a作原料，与 4-(4-氯 -2-氟苯基 )-1，3-二氢 - 哚 -2-酮的反应，则得到标题产物 5-[4-(4-氯 -2-氟苯基 )-2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸 (二乙氨基甲基)酰胺 90(30 mg，黄色固体)，产率： 17%。

The first and second reaction reactions of Example 88 of the present invention were repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole obtained in the above first step was used. 3-carboxylic acid-(2-ethylaminoethyl)amide 88a as a starting material, and 4-(4-chloro-2-fluorophenyl)-1,3-dihydro-indol-2-one, The title product 5-[4-(4-chloro-2-fluorophenyl)-2-oxo-1,2-dihydro-indol-3-methyl]-2-methyl-4-tri Fluoromethyl-1H-pyrrole-3-carboxylic acid (diethylaminomethyl)amide 90 (30 mg, yellow solid), yield: 17%.

MS m/z (ESI): 563.5(M+1) 5-[4-(2,6-二氟苯基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1Η-吡咯MS m/z (ESI): 563.5 (M+1) 5-[4-(2,6-Difluorophenyl)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-2-methyl-4-trifluoromethyl- 1Η-pyrrole

-3-羧酸 (二乙氨基甲基)酰胺 3-carboxylic acid (diethylaminomethyl) amide

重复本发明实施例 88第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基- 1氢-吡咯 -3-羧酸 -(2-乙氨基乙基) 酰胺 88a作原料，与 4-(2,6-二氟苯基) -1,3-二氢 -H引哚 -2-酮的反应，则得到标题产物 5-[4-(2,6-二氟苯基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸 (二乙氨基甲基)酰胺 91(40 mg，黄色固体)，产率： 23%

The first and second reaction reactions of Example 88 of the present invention were repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1hydro-pyrrole obtained in the above first step was used. 3-carboxylic acid-(2-ethylaminoethyl)amide 88a as a starting material, reacting with 4-(2,6-difluorophenyl)-1,3-dihydro-H-indol-2-one, The title product 5-[4-(2,6-difluorophenyl)-2-oxo-1,2-dihydro-indol-3-methyl]-2-methyl-4-tri Fluoromethyl-1H-pyrrole-3-carboxylic acid (diethylaminomethyl)amide 91 (40 mg, yellow solid), Yield: 23%

MS m/z (ESI): 547.3(M+1) 实施例 92 MS m/z (ESI): 547.3 (M + 1).

;-[4-(2,3-二氟苯基) -2-氧代 -1，2-二氢』引哚 3-次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 ;-[4-(2,3-difluorophenyl)-2-oxo-1,2-dihydro"anthracene 3-methylidene]-2-methyl-4-trifluoromethyl-1H -pyrrole

-3-羧酸（2-乙氨基乙基) -酰胺 3-carboxylic acid (2-ethylaminoethyl)-amide

重复本发明实施例 88第一步和第二步反应反应，不同的是使用上述第一歩中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-乙氨基乙基) 酰胺 88a作原料，与 4-(2,6-二氟苯基) -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 5-[4-(2，3-二氟苯基) -2-氧代 -1,2-二氢 -H引哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸 (二乙氨基甲基)酰胺 92 (45 mg, 黄色固体)，产率： 26.3%。

The first step and the second step of the reaction of Example 88 of the present invention are repeated, except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole obtained in the above first hydrazine is used. 3-carboxylic acid-(2-ethylaminoethyl)amide 88a as a starting material, and reaction with 4-(2,6-difluorophenyl)-1,3-dihydro-inden-2-one, The title product 5-[4-(2,3-difluorophenyl)-2-oxo-1,2-dihydro-H-indol-3-ylmethyl]-2-methyl-4-tri Fluoromethyl-1H-pyrrole-3-carboxylic acid (diethylaminomethyl)amide 92 (45 mg, yellow solid), yield: 26.3%.

MS m/z (ESI): 547.3 (M+1) -[4-(3-氯 -2-氟-苯基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1Η-吡咯 -3-羧酸 (二乙氨基甲基)酰胺 MS m/z (ESI): 547.3 (M+1) -[4-(3-chloro-2-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-2-methyl-4-trifluoromethyl -1Η-pyrrole-3-carboxylic acid (diethylaminomethyl)amide

重复本发明实施例 88第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基斗三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-乙氨基乙基) 酰胺 88a作原料，与 4-(3-氯 -2-氟-苯基) -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 5-[4-(3-氯 -2-氟-苯基) -2-氧代二氢哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸 (二乙氨基甲基)酰胺 93 (55 mg，黄色固体)，产率： 31.2%。 MS m/z (ESI): 563.4 (M+l) 实施例 94

The first step and the second step of the reaction of Example 88 of the present invention were repeated except that the compound 5-formyl-2-methyl-trifluoromethyl-1-hydro-pyrrole-3 obtained in the above first step was used. -carboxylic acid-(2-ethylaminoethyl)amide 88a as a starting material, and 4-(3-chloro-2-fluoro-phenyl)-1,3-dihydro-indol-2-one, The title product 5-[4-(3-chloro-2-fluoro-phenyl)-2-oxindolin-3-methyl]-2-methyl-4-trifluoromethyl-1H- Pyrrole-3-carboxylic acid (diethylaminomethyl)amide 93 (55 mg, yellow solid), Yield: 31.2%. MS m/z (ESI): 563.4 (M+l) EXAMPLE 94

:-[4-(4-氟苯基 )-2-氧代 -1,2-二氢 -H引哚 -3-次甲基 ] -2-甲基 -4-三氟甲基 -1H-吡咯 -3- 羧酸 (二乙氨基甲基)酰胺 :-[4-(4-Fluorophenyl)-2-oxo-1,2-dihydro-H 哚-3-methylidene]-2-methyl-4-trifluoromethyl-1H- Pyrrole-3-carboxylic acid (diethylaminomethyl)amide

重复本发明实施例 88第一步和第二歩反应反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 -(2-乙氨基乙基) 酰胺 88a作原料，与 4-(4-氟苯基 )-1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 5-[4-(4-氟苯基 )-2-氧代 -1，2-二氢 -吲哚 -3-次甲基] -2-甲基 -4-三氟甲基 -1H-吡咯 -3- 羧酸 (二乙氨基甲基)酰胺 94 (50 mg，黄色固体)，产率： 30%。

The first step and the second oxime reaction of Example 88 of the present invention were repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole obtained in the above first step was used. 3-carboxylic acid-(2-ethylaminoethyl)amide 88a as a starting material, and the reaction with 4-(4-fluorophenyl)-1,3-dihydro-inden-2-one gives the title product 5-[4-(4-Fluorophenyl)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-2-methyl-4-trifluoromethyl-1H-pyrrole -3-carboxylic acid (diethylaminomethyl)amide 94 (50 mg, yellow solid), yield: 30%.

MS m/z (ESI): 529.4(M+1) 实施例 95 MS m/z (ESI): 529.4 (M+1) EXAMPLE 95

5-氟 -3-(5-甲基 -4-苯基 -3-三氟甲基 -1H-吡咯 -2-次甲基 )-1,3-二氢 -吲哚 -2-酮

将实施例 1中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸 lg (221 mg, 1 mmol)的碳酸氢钠溶液 (0.67 g, 8 mmol)加入到碘 /碘化钾溶液中，得到的混合溶液加热到 90Ό，回流 1小时。冷却至室温有固体析出，过滤，用冷乙醇洗涤数次得到化合 4-碘 -5-甲基 -3-三氟甲基 -1Η-吡咯 -2-甲醛 95a (249 mg, 粉红色固体），产率 82.1%。 5-fluoro-3-(5-methyl-4-phenyl-3-trifluoromethyl-1H-pyrrol-2-ylmethyl)-1,3-dihydro-indol-2-one

The compound obtained in Example 1 5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid lg (221 mg, 1 mmol) in sodium hydrogen carbonate solution (0.67 g) , 8 mmol) was added to the iodine/potassium iodide solution, and the resulting mixed solution was heated to 90 Torr and refluxed for 1 hour. After cooling to room temperature, a solid precipitated, which was filtered and washed with cold ethanol several times to give 4-iodo-5-methyl-3-trifluoromethyl-1?-pyrrole-2-carbaldehyde 95a (249 mg, pink solid). The yield was 82.1%.

MS m/z (ESI): 253.0(M-1) 将上述步骤所得到的化合物 4-碘 -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 95a (221 mg, 0.729 mmol), 苯硼酸 (98 mg, 0.809 mmol), 四三苯基膦钯 (28 mg, 0.025mmol), 碳酸钠 (216 mg, 1.57 mmol)加入到 Ν,Ν—二甲基甲酰胺 (1.6 ml)与水 (0.8 ml)的混合液中，在氮气气氛下加热反应液到 110°C，反应过夜。冷却反应液，加入乙酸乙酯 100ml萃取，合并有机相，浓 ^，-得到的残留物进一步通过柱层析 (乙酸乙酯： ΪΕ己烷 = 1 : 6)分离纯化得到化令^ 4-苯基 -5:甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 95b (88 mg，白色固体)，产率 47.8%。 MS m/z (ESI): 253.0 (M-1). Methyl)boronic acid (98 mg, 0.809 mmol), tetrakistriphenylphosphine palladium (28 mg, 0.025 mmol), sodium carbonate (216 mg, 1.57 mmol) added to hydrazine, hydrazine-dimethylformamide (1.6 ml) In a mixture with water (0.8 ml), the reaction solution was heated to 110 ° C under a nitrogen atmosphere and allowed to react overnight. The reaction mixture was cooled, extracted with ethyl acetate (100 ml), and the organic phase was combined, and the residue obtained was purified by column chromatography (ethyl acetate: hexane = 1:1) Base-5: methyl-3-trifluoromethyl-1H-pyrrole-2-carbaldehyde 95b (88 mg, white solid), yield 47.8%.

MS m/z (ESI): 253.0(M+1) MS m/z (ESI): 253.0 (M+1)

' 将上述步骤所得到的化合物 4-苯基 -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 5b(37 mg, 0.146 mmol)和 5-氟 -1 , 3-二氢 -3-酮 (18 mg， 0.12 mmol)溶解于 2ml 无水乙醇中，加入 1滴哌啶，加热回流 2小时后冷却，析出晶体。过滤，洗涤 (无水乙醇 3x5ml)，得到标题化合物 5-氟 -3-(5-甲基 -4-苯基 -3-三氟甲基 -1H-吡咯 -2- 次甲基 )-1,3-二氢 -吲哚 -2-酮 95(26mg,橙色固体)，产率 56.5%。 'The compound obtained in the above step 4-phenyl-5-methyl-3-trifluoromethyl-1H-pyrrole-2-carbaldehyde 5b (37 mg, 0.146 mmol) and 5-fluoro-1, 3-di Hydrogen-3-ketone (18 mg, 0.12 mmol) was dissolved in 2 ml of absolute ethanol, and 1 drop of piperidine was added thereto, and the mixture was heated under reflux for 2 hours, and then cooled to precipitate crystals. Filtration and washing (3x5 ml of dry ethanol) afforded the title compound 5-fluoro-3-(5-methyl-4-phenyl-3-trifluoromethyl-1H-pyrrole-2-methylmethyl)-1. 3-Dihydro-indol-2-one 95 (26 mg, orange solid), yield 56.5%.

MS m/z (ESI): 386.3(M+1) MS m/z (ESI): 386.3 (M+1)

实施例 96 Example 96

5-溴 -3-(5-甲基 -4-苯基 -3-三氟甲基 -1H-吡咯' -2-次甲基) - 1 ,3-二氢 -吲哚 -2-酮 5-bromo-3-(5-methyl-4-phenyl-3-trifluoromethyl-1H-pyrrole '-2-methine)-1,3-dihydro-indol-2-one

重复本发明实施例 95第一步、第二步和第三步的反应，不同的是使用上述第二步中所得到的化合物 4-苯基 -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 95b作原料，与 5-溴 -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 5-溴 -3-(5-甲基 -4-苯基 -3- 三氟甲基 -1H-吡咯 -2-次甲基 )-1,3-二氢 -吲哚 -2-酮 96 (27 mg，黄色固体)，产率： 51.9%。

Repeat the reaction of the first step, the second step and the third step of the embodiment 95 of the present invention, except that the above is used. The compound obtained in the second step, 4-phenyl-5-methyl-3-trifluoromethyl-1H-pyrrole-2-carbaldehyde 95b, is used as a starting material, and 5-bromo-1,3-dihydro-indole The reaction of 2-ketone gives the title product 5-bromo-3-(5-methyl-4-phenyl-3-trifluoromethyl-1H-pyrrol-2-methyl)-1,3- Dihydro-indol-2-one 96 (27 mg, yellow solid), Yield: 51.9%.

MS m/z (ESI): 447.2(M+1) MS m/z (ESI): 447.2 (M+1)

1H MR (400 MHz, DMSO-d6) 67.93 (d,lH, J=7.2Hz)， 7,54 (s,lH), 7.43(m, 1H), 7.39〜7.20(m, 5H), 6.88(m, 1H), 2.25 (s，3H). 实施例 97 1H MR (400 MHz, DMSO-d6) 67.93 (d, lH, J = 7.2 Hz), 7, 54 (s, lH), 7.43 (m, 1H), 7.39~7.20 (m, 5H), 6.88 (m) , 1H), 2.25 (s, 3H). Example 97

重复本发明实施例 95第一步、第二步和第三步的反应，不同的是使用上述第二步中所得到的化合物 4-苯基 -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛' 95b作原料，与 N-(5-氟 -2-氧代 -2，3-二氢 -1H-吲哚 -6-基) -2-甲氧基-乙酰胺的反应，则得到标题产物 N-[5-氟 -3-(5-甲基 -4-苯基 -3-三氟甲基 -1H-吡咯 -2-次甲基 )-2-氧代 -2,3-二氢 -1H-吲哚 -6-基] -2-甲氧基-乙酰胺 97 (57 mg，黄色固体)，产率： 70.4%。

The reaction of the first step, the second step and the third step of Example 95 of the present invention was repeated except that the compound 4-phenyl-5-methyl-3-trifluoromethyl group obtained in the above second step was used. 1H-pyrrole-2-carbaldehyde '95b as a starting material, with N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide The reaction gave the title product N-[5-fluoro-3-(5-methyl-4-phenyl-3-trifluoromethyl-1H-pyrrole-2- methine)-2-oxo- 2,3-Dihydro-1H-indol-6-yl]-2-methoxy-acetamide 97 (57 mg, yellow solid), yield: 70.4%.

MS m/z (ESI)i 474.2 (M+l) MS m/z (ESI) i 474.2 (M+l)

1H NMR (400 MHz, DMSO-d6) 57.74 (m，lH), 7.67 (m,lH), 7.54(s, 1H)， 7.46〜 7.30(m, 5H)， 7.3 l(d, 1H)， 4.08(s, 2H),.3.40(s, 3H)， 2.25 (s,3H). 实施例 98 1H NMR (400 MHz, DMSO-d6) 57.74 (m,lH), 7.67 (m,lH), 7.54 (s, 1H), 7.46~ 7.30 (m, 5H), 7.3 l(d, 1H), 4.08 ( s, 2H), 3.40 (s, 3H), 2.25 (s, 3H). Example 98

N-[5-氟 -3-(5-甲基 -4-苯基 -3-三氟甲基 -1H-吡咯 -2-次甲基) -2-氧代 -2,3-二氢 -1H-吲哚 -6-基] -2-羟基乙酰胺 N-[5-fluoro-3-(5-methyl-4-phenyl-3-trifluoromethyl-1H-pyrrole-2-methine)-2-oxo-2,3-dihydro- 1H-吲哚-6-yl]-2-hydroxyacetamide

重复本发明实施例 95第一步、第二步和第三步的反应，不同的是使用上述第二步中所得到的化合物 4-苯基 -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲酸 95b作原料，与 N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基) -2-轻基-乙酰胺的反应，则得到标题产物 N-[5-氟 -3-(5-甲基 -4-苯基 -3-三氟甲基 -1H-吡咯 -2-次甲基 )-2-氧代 -2,3-二氢 -1H-吲哚 -6-基] -2-轻基-乙酰胺 98 (48mg，黄色固体)，产率： 60%。

Repeat the reaction of the first step, the second step and the third step of the embodiment 95 of the present invention, except that the above is used. The compound obtained in the second step, 4-phenyl-5-methyl-3-trifluoromethyl-1H-pyrrole-2-carboxylic acid 95b, is used as a starting material, and N-(5-fluoro-2-oxo-2 , 3-dihydro-1H-indol-6-yl)-2-carbyl-acetamide, the title product N-[5-fluoro-3-(5-methyl-4-phenyl- 3-Trifluoromethyl-1H-pyrrole-2-methino)-2-oxo-2,3-dihydro-1H-indol-6-yl]-2-carbyl-acetamide 98 (48 mg , yellow solid), Yield: 60%.

MS m/z (ESI): 459.7(M+1) MS m/z (ESI): 459.7 (M+1)

1H NM (400 MHz, DMSO-d6) 57.81 (m，lH), 7.56(s， 1H), 7.73 (m,lH), 7.46〜 7.29(m, 5H), 4.06 (m, 2H), 2.24 (s,3H). 实施例 99 1H NM (400 MHz, DMSO-d6) 57.81 (m, lH), 7.56 (s, 1H), 7.73 (m, lH), 7.46~ 7.29 (m, 5H), 4.06 (m, 2H), 2.24 (s , 3H). Example 99

5-氟 -3-[4-(4-氟苯基 )-5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-1,3-二氢 -U引哚 -2-酮 5-fluoro-3-[4-(4-fluorophenyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2-methine]-1,3-dihydro-U 哚2-ketone

按照实施例 95第一步所述的方式得到化合物 4-碘 -5-甲基 -3-三氟甲基 -1H- 吡咯 -2-甲醛 95a(289 mg， 0.953 mmol), 对氟苯硼酸 (148 mg， 1.05 mmol), 四三苯基膦钯 (36 mg, 0.032mmol), 碳酸钠 (282 mg, 2.04 mmol)加入到 Ν,Ν—二甲基甲酰胺 (1.6 ml)与水 (0.8 ml)的混合液中，在氮气气氛下加热反应液到 110°C，反应过夜。冷却反应液，加入乙酸乙酯 (10 m 3)萃取，合并有机相，浓缩，得到的残留物进一步通过柱层析 (乙酸乙酯：石油醚 = 1 : 7)分离纯化得到化合物 4-对氟苯基 -5-甲基 -3-三氟甲基吡咯 -2-甲醛 99a (107 mg, 白色固体)，产率 41.5%。 MS m/z (ESI): 270.7(M-1)

The compound 4-iodo-5-methyl-3-trifluoromethyl-1H-pyrrole-2-carbaldehyde 95a (289 mg, 0.953 mmol) was obtained as described in the first step of Example 95, p-fluorobenzeneboronic acid ( 148 mg, 1.05 mmol), tetrakistriphenylphosphine palladium (36 mg, 0.032 mmol), sodium carbonate (282 mg, 2.04 mmol) added to hydrazine, hydrazine-dimethylformamide (1.6 ml) and water (0.8 ml) In the mixture, the reaction solution was heated to 110 ° C under a nitrogen atmosphere, and allowed to react overnight. The reaction mixture was cooled, extracted with ethyl acetate (10 m3), EtOAc (EtOAc m. Phenyl-5-methyl-3-trifluoromethylpyrrole-2-carbaldehyde 99a (107 mg, white solid), yield 41.5%. MS m/z (ESI): 270.7 (M-1)

将上述步骤所得到的化合物 4-对氟苯基 -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 99a(36 mg, 0.133 mmol)和 5-氟 -1， 3-二氢吲哚 -2-酮 (18 mg, 0.12 mmol)溶解于 3ml无水乙醇中，加入 1滴哌啶，加热回流 2小时后冷却，析出晶体。过滤，洗涤 (无水乙醇 3x5ml)，得到标题化合物 5-氟 -3-[4-(4-氟苯基 )-5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-1,3-二氢 - 哚 -2-酮 99(25mg,黄色固体)，产率 51.5 %。 MS m/z (ESI): 403.3 (M-1) The compound obtained in the above step was 4-p-fluorophenyl-5-methyl-3-trifluoromethyl-1H-pyrrole-2-carbaldehyde 99a (36 mg, 0.133 mmol) and 5-fluoro-1, 3- Dihydroindol-2-one (18 mg, 0.12 mmol) was dissolved in 3 ml of absolute ethanol, and 1 drop of piperidine was added thereto, and the mixture was heated under reflux for 2 hours, and then cooled to precipitate crystals. Filtration and washing (3x5 ml of dry ethanol) afforded the title compound 5-fluoro-3-[4-(4-fluorophenyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2- Alkyl-1,3-dihydro-indol-2-one 99 (25 mg, yellow solid), yield 51. MS m/z (ESI): 403.3 (M-1)

1H NMR (400 MHz, DMSO-d6) 57.64 (d，lH, J=3.6Hz), 7.60 (d,lH, J=3.2Hz)， 7.36(s, 1H)， 7.39〜7.03(m, 4H)， 6.92(m， 1H)， 2.20 (s,3H). 实施例 100 1H NMR (400 MHz, DMSO-d6) 57.64 (d, lH, J = 3.6 Hz), 7.60 (d, lH, J = 3.2 Hz), 7.36 (s, 1H), 7.39 to 7.03 (m, 4H), 6.92 (m, 1H), 2.20 (s, 3H). Example 100

：-溴 -3-[4-(4-氟苯基 )-5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-1,3-二氢 -U引哚 -2-酮

重复本发明实施例 99第一步、第二步的反应，不同的是使用上述第一步中所得到的化合物 4-对氟苯基 -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 99a作原料，与 5- 氟 -1， 3-二氢』引哚 -2-酮的反应，则得到标题产物 5-漠 -3-[4-(4-氟苯基 )-5-甲基 -3- 三氟甲基 -1H-吡咯 -2-次曱基 ]-1,3-二氢 -吲哚 -2-酮 _;100 (36mg，红色固体)，产率： 72%。 :-Bromo-3-[4-(4-fluorophenyl)-5-methyl-3-trifluoromethyl-1H-pyrrole-2-methine]-1,3-dihydro-U 哚2-ketone

The reaction of the first step and the second step of Example 99 of the present invention was repeated except that the compound obtained in the above first step, 4-p-fluorophenyl-5-methyl-3-trifluoromethyl-1H-, was used. Pyrrole-2-carbaldehyde 99a is used as a starting material to react with 5-fluoro-1,3-dihydroindol-2-one to give the title product 5--[3-(4-fluorophenyl). -5-methyl-3-trifluoromethyl-1H-pyrrole-2-indolyl]-1,3-dihydro-indol-2-one _; 100 (36 mg, red solid), Yield: 72 %.

MS m/z (ESI): 465.3(M+1) MS m/z (ESI): 465.3 (M+1)

1H MR (400 MHz, DMSO-d6) 57.90 (d,lH, J=8Hz)， 7.63 (m,lH)， 7.39~7.27(m， 4H), 6.89(m, 1H)， 2.20 (s，3H). 实施例 101 1H MR (400 MHz, DMSO-d6) 57.90 (d,lH, J=8Hz), 7.63 (m,lH), 7.39~7.27(m, 4H), 6.89(m, 1H), 2.20 (s,3H) Example 101

N-{5-氟 -3-[4-(4-氟苯基 )-5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 N-{5-fluoro-3-[4-(4-fluorophenyl)-5-methyl-3-trifluoromethyl-1H-pyrrol-2-ylmethyl]-2-oxo-2, 3-dihydrogen

-1H-吲哚 -6-基] -2-甲氧基-乙酰胺 -1H-吲哚-6-yl]-2-methoxy-acetamide

重复本发明实施例 99第一步、第二步的反应，不同的是使用上述第一歩中所得到的化合物 4-对氟苯基 -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 99a作原料，与 N-(5-氟氧代 -2,3-二氢 -1H-吲哚 -6-基) -2-甲氧基-乙酰胺的反应，则得到标题产物 N-{5-氟 -3-[4-(4-氟苯基 )-5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2,3-二氢 -1H-吲哚 -6-基] -2-甲氧基-乙酰胺 101 (17 mg, 红色固体)，产率： 50%。 The reaction of the first step and the second step of Example 99 of the present invention was repeated, except that the compound obtained in the above first hydrazine was used. 4-p-fluorophenyl-5-methyl-3-trifluoromethyl-1H- The reaction of pyrrole-2-carbaldehyde 99a with N-(5-fluorooxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide gives the title Product N-{5-Fluoro-3-[4-(4-fluorophenyl)-5-methyl-3-trifluoromethyl-1H-pyrrol-2-ylmethyl]-2-oxo-2 , 3-dihydro-1H-indol-6-yl]-2-methoxy-acetamide 101 (17 mg, red solid), yield: 50%.

MS m/z (ESI): 491.0(M+1) MS m/z (ESI): 491.0 (M+1)

1H NMR (400 MHz, DMSO-d6) 57.69 (m,lH)， 7.65 (m，lH)， 7.54(s, 1H), 7.35〜 1H NMR (400 MHz, DMSO-d6) 57.69 (m,lH), 7.65 (m,lH), 7.54 (s, 1H), 7.35~

7.24(m, 4H)， 4.07(s, 2H), 3.40(s, 3H), 2.22 (s,3H). 实施例 102 7.24 (m, 4H), 4.07 (s, 2H), 3.40 (s, 3H), 2.22 (s, 3H). Example 102

N— {5-氟 -3-[4-(4-氟苯基 )-5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-²_氧代 -2,3-二氢 N- {5- fluoro-3- [4- (4-fluorophenyl) -5-methyl-3-trifluoromethyl -1H- pyrrole-2-methylene] - ^2-oxo-_, 3-dihydrogen

-1H-吲哚 -6-基] -2-羟基-乙酰胺

-1H-吲哚-6-yl]-2-hydroxy-acetamide

重复本发明实施例 99第一步、第二步的反应，不同的是使用上述第一步中所得到的化合物 4-对氟苯基 -5-甲基 -3-三氟甲基 -1H-吡咯 -2-甲醛 99a作原料，与 N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基) -2-羟基-乙酰胺的反应，则得到标题产物 N-{5-氟 -3-[4-(4-氟苯基 )-5-甲基 -3-三氟甲基 -1H-吡咯 -2-次甲基 ]-2-氧代 -2，3-二氢 -1H-吲哚 -6-基] -2-羟基-乙酰胺 10² (1'8 mg，红色固体)，产率： 51.4%。 The reaction of the first step and the second step of Example 99 of the present invention was repeated, except that the compound obtained in the above first step, 4-p-fluorophenyl-5-methyl-3-trifluoromethyl-1H-, was used. Pyrrole-2-carbaldehyde 99a is used as a raw material to react with N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide. The title product N-{5-fluoro-3-[4-(4-fluorophenyl)-5-methyl-3-trifluoromethyl-1H-pyrrol-2-ylmethyl]-2-oxo- 2,3-Dihydro-1H-indol-6-yl]-2-hydroxy-acetamide 10 ² (1'8 mg, red solid), Yield: 51.4%.

MS m/z (ESI): 476.2 (M-l) MS m/z (ESI): 476.2 (M-l)

1H MR (400 MHz, DMSO-d6) 57.77 (s,lH), 7.64 (m,lH), 7.47(s， 1H)， 7.27〜 7,16(m, 4H), 3.96(s, 2H), 2.14(s,3H). 实施例 103 1H MR (400 MHz, DMSO-d6) 57.77 (s,lH), 7.64 (m,lH), 7.47(s, 1H), 7.27~ 7,16(m, 4H), 3.96(s, 2H), 2.14 (s, 3H). Example 103

[5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸 - 2-吗啉 -4-乙酯 [5-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-methylene)-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl] -carbamic acid- 2-morpholin-4-ethyl ester

氮气氛下，在干燥的 50ml单口瓶中加入原料 5-甲酰基 -2-甲基 -4-三氟甲基 -1 氢 -吡咯 -3-羧酸 lg, 甲苯 (20 ml)，搅拌下加入三乙胺 (242 mg, 2.4 mmol), 叠氮磷酸二苯酯 (495 mg, 1.8 mmol), 2-吗啉 -4-乙醇（590 mg， 4.5 mmol)加热至 100°C，持续 5小时，后冷却至室温，反应过夜，反应完毕。在反应液中加入乙酸乙酯 (200 ml), 有机层用饱和氯化钠溶液洗涤 (50mlx2)，分出的有机层用无水硫酸钠干燥，抽滤，浓缩，得到的残留物通过柱层析 (乙酸乙酯：正己垸 = 10_: 1)进一步提纯得到化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸 _2-吗啉 -4-乙酯 103a (190 mg，黄色固体)，产率 36.2% Add the raw material 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid lg, toluene (20 ml) in a dry 50 ml single-mouth flask under nitrogen atmosphere, and add with stirring. Triethylamine (242 mg, 2.4 mmol), diphenyl azide (495 mg, 1.8 mmol), 2-morpholin-4-ethanol (590 mg, 4.5 mmol) heated to 100 ° C for 5 h. After cooling to room temperature, the reaction was completed overnight and the reaction was completed. Ethyl acetate (200 ml) was added to the reaction mixture, and the organic layer was washed with saturated aqueous sodium chloride (50 ml??), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. Further purification (ethyl acetate: n-hexane = 10 _: 1) gave the compound 5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl)-carbamic acid _2-morpholine -4-ethyl ester 103a (190 mg, yellow solid), yield 36.2%

MS m/z (ESI): 350.9(M+1) MS m/z (ESI): 350.9 (M+1)

将上述步骤得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸 -2-吗啉 -4-乙酯 103a (40 mg, 0.105 mmol), 5-氟 -1，3-二氢』引哚 -2-酮 (14 mg, 0.0948 mmol)溶于 3.5ml无水乙醇中， 100Ό , 微波下反应 10 分钟。将反应体系在冰浴下静置，析出晶体，过滤，冷乙醇洗涤晶体数次得到标题化合物 [5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸- 2- 吗啉 -4-乙酯 103(28 mg，黄色固体)，产率 62.2%。 The compound obtained in the above step is 5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl)-carbamic acid-2-morpholin-4-ethyl ester 103a (40 mg, 0.105 Methyl) 5-fluoro-1,3-dihydroindol-2-one (14 mg, 0.0948 mmol) was dissolved in 3.5 ml of absolute ethanol, 100 Torr, and reacted for 10 min under microwave. The reaction system was allowed to stand in an ice bath, crystals were precipitated, filtered, and the crystals were washed with cold ethanol several times to obtain the title compound [5-(5-fluoro-2-oxo-1,2-dihydro-indole-3- Methyl)-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl]-carbamic acid- 2- Morpholine-4-ethyl ester 103 (28 mg, yellow solid), yield 62.2%.

MS m/z (ESI): 483.5(M+1) MS m/z (ESI): 483.5 (M+1)

1H NMR (400 MHz, DMSO-i/d) δ 7.59(d, 2H, J=8.4Hz), 7.5 l(s, 1H), 7.05(m， 1H)_; 6.91(m, 1H), 4.17(t, 2H), 3.58(m, 4H), 2.58(m, 2H), 2.33(m, 4H)， 2.22(s, 3H). 实施例 104 1H NMR (400 MHz, DMSO-i/d) δ 7.59 (d, 2H, J = 8.4 Hz), 7.5 l (s, 1H), 7.05 (m, 1H) _; 6.91 (m, 1H), 4.17 (t , 2H), 3.58 (m, 4H), 2.58 (m, 2H), 2.33 (m, 4H), 2.22 (s, 3H). Example 104

[5-(7-溴 -5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] - 氨基甲酸 - 2-吗啉 -4-乙酯 [5-(7-Bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-methylene)-2-methyl-4-trifluoromethyl-1H-pyrrole- 3-yl]-carbamic acid 2-morpholine-4-ethyl ester

重复本发明实施例 103第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸 -2-吗啉 -4-乙酯 103a 作原料，与 5-氟 -7-溴 -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 [5-(7-溴 -5-氟 -2-氧代 -1，2-二氢 -吲哚 -3-亚甲基 )-2-甲基 _:4-三氟甲基 -1H-吡咯 -3-基] - 氨基甲酸 - 2-吗啉 -4-乙酯 104 (45 mg，黄色固体)，产率： 84.9%。 The first and second reaction reactions of Example 103 of the present invention were repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole obtained in the above first step was used. 3-amino)-carbamic acid-2-morpholin-4-ethyl ester 103a as a starting material, and reacting with 5-fluoro-7-bromo-1,3-dihydro-inden-2-one to give the title product [5-(7-Bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-methylene)-2-methyl _: 4-trifluoromethyl-1H-pyrrole- 3-yl]-carbamic acid 2-morpholine-4-ethyl ester 104 (45 mg, yellow solid), Yield: 84.9%.

MS m7z (ESI): 561.5(M+1) MS m7z (ESI): 561.5 (M+1)

1H NMR (400 MHz, DMSO-i/d) δ 7.55(s, 1H), 7.37(d, 1H, J=2.4Hz), 7.35(d, 1H, J=2Hz), 4.17(s, 2H), 3.58(m, 4H), 2.56(m， 2H), 2.43(m, 4H), 2.21(s, 3H). 实施铜 105 1H NMR (400 MHz, DMSO-i/d) δ 7.55 (s, 1H), 7.37 (d, 1H, J = 2.4 Hz), 7.35 (d, 1H, J = 2 Hz), 4.17 (s, 2H), 3.58(m, 4H), 2.56(m, 2H), 2.43(m, 4H), 2.21(s, 3H). Implementation of copper 105

:-{-[5-氟 -6-(2-羟基 -乙酰氨基) -2-氧代 -1,2-二氢 -吲哚 -3-亚甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基} -氨基甲酸 - 2-吗啉 -4-乙酯 :-{-[5-Fluoro-6-(2-hydroxy-acetylamino)-2-oxo-1,2-dihydro-indol-3-methylene]-2-methyl-4-tri Fluoromethyl-1H-pyrrol-3-yl}-carbamic acid 2-morpholine-4-ethyl ester

重复本发明实施例 103第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸 -2-吗啉 -4-乙酯 103a作原料，与 N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基) -2-氰基乙酰氨的反应，则得到标题产物 5-{-[5-氟 -6-(2-羟基 -乙酰氨基) -2-氧代 -1,2-二氢 -H引哚 -3-亚甲基] -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基} -氨基甲酸- 2-吗啉 -4-乙酯 105 (45 mg,黄色固体)，产率： 84.9%。 The first and second reaction reactions of Example 103 of the present invention were repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole obtained in the above first step was used. 3-yl)-carbamic acid-2-morpholin-4-ethyl ester 103a as starting material, and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl) The reaction of 2-cyanoacetylamine gives the title product 5-{-[5-fluoro-6-(2-hydroxy-acetylamino)-2-oxo-1,2-dihydro-H-indole- 3-methylene]-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl}-carbamic acid- 2-morpholin-4-ethyl ester 105 (45 mg, yellow Color solid), Yield: 84.9%.

MS m/z (ESI): 556.8 (M+l) MS m/z (ESI): 556.8 (M+l)

1H NMR (400 MHz, OMSO-d6) δ 7.78(d, IH, J=2.4Hz), 7.72(d, IH, J=9.8Hz), 7.43 (s_: IH), 4.05(t, 2H), 3.58(m, 4H), 2.56(m, 2H), 2.43(m, 4H), 2.2 l(s, 3H). 实施例 106 1H NMR (400 MHz, OMSO-d6) δ 7.78 (d, IH, J = 2.4 Hz), 7.72 (d, IH, J = 9.8 Hz), 7.43 (s _: IH), 4.05 (t, 2H), 3.58 (m, 4H), 2.56 (m, 2H), 2.43 (m, 4H), 2.2 l (s, 3H). Example 106

-{-[5-氟 -6-(2-甲氧基 -乙酰氨基) -2-氧代 -1,2-二氢 -吲哚 -3-亚甲基 ]-2-甲基 -4- 甲基 -1H-吡咯 -3-基氨基甲酸 - 2-吗啉 -4-乙酯 -{-[5-fluoro-6-(2-methoxy-acetylamino)-2-oxo-1,2-dihydro-indol-3-methylene]-2-methyl-4- Methyl-1H-pyrrol-3-ylcarbamic acid 2- 2-morpholine-4-ethyl ester

重复本发明实施例 103第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸 -2-吗啉 -4-乙酯 103a作原料，与 N-(5-氟 -2-氧代 -2,3-二氢 -1H-B引哚 -6-基) -2-氰基乙酰胺的反应，则得到标题产物 5-{-[5-氟 -6-(2-羟基 -乙酰氨基) -2-氧代 -1,2-二氢 -吲哚 -3-亚甲基] -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基氨基甲酸- 2-吗啉 -4-乙酯 106 (45 mg,黄色固体)，产率： 84.9%。 The first and second reaction reactions of Example 103 of the present invention were repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole obtained in the above first step was used. 3-yl)-carbamic acid-2-morpholin-4-ethyl ester 103a as starting material, and N-(5-fluoro-2-oxo-2,3-dihydro-1H-B 哚-6-yl group The reaction of 2-cyanoacetamide gives the title product 5-{-[5-fluoro-6-(2-hydroxy-acetylamino)-2-oxo-1,2-dihydro-indole- 3-methylene]-2-methyl-4-trifluoromethyl-1H-pyrrol-3-ylcarbamic acid- 2-morpholin-4-ethyl ester 106 (45 mg, yellow solid), yield: 84.9%.

MS m/z (ESI): 570.5 (M+l) MS m/z (ESI): 570.5 (M+l)

Ή NMR (400 MHz, OMSO-d6) δ 7.71 (d, 1H， J=9.8Hz)， 7.65(d, 1H， J=6.4Hz), 7.44(s_: IH), 4.16(t, 2H), 3.58(m, 4H), 2.56(m, 2H), 2.43(m, 4H), 2.2(s, 3H). 实施例 107 NMR NMR (400 MHz, OMSO-d6) δ 7.71 (d, 1H, J = 9.8 Hz), 7.65 (d, 1H, J = 6.4 Hz), 7.44 (s _: IH), 4.16 (t, 2H), 3.58 (m, 4H), 2.56 (m, 2H), 2.43 (m, 4H), 2.2 (s, 3H). Example 107

5-[4-(2,3-二氟苯基) -2-氧代 -1,2-二氢 -吲哚 -3-亚甲基 ]-2-甲基 -4-三氟甲基 -IH-吡咯 5-[4-(2,3-Difluorophenyl)-2-oxo-1,2-dihydro-indole-3-methylene]-2-methyl-4-trifluoromethyl- IH-pyrrole

-3-基] -氨基甲酸- 2-吗啉 -4-乙酯 -3-yl]-carbamic acid- 2-morpholine-4-ethyl ester

重复本发明实施例 103第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸 -2-吗啉 -4-乙酯 103a作原料，与 4-(2,3-二氟苯基) -1，3-二氢吲哚 -2-酮的反应，则得到标题产物 5-[4-(2,3-二氟苯基) -2-氧代 -1,2-二氢 -吲哚 -3-亚甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸 - 2-吗啉 -4-乙酯 107 (30 mg，黄色固体)，产率： 34.1 %。 MS m/z (ESI): 577.3(M+1) 实施例 108 The first and second reaction reactions of Example 103 of the present invention were repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole obtained in the above first step was used. 3-yl)-carbamic acid-2-morpholin-4-ethyl ester 103a as a starting material, reacting with 4-(2,3-difluorophenyl)-1,3-dihydroindol-2-one, The title product 5-[4-(2,3-difluorophenyl)-2-oxo-1,2-dihydro-indole-3-methylene]-2-methyl-4-tri Fluoromethyl-1H-pyrrol-3-yl]-carbamic acid 2- 2-morpholin-4-ethyl ester 107 (30 mg, yellow solid), yield: 34.1%. MS m/z (ESI): 577.3 (M + 1).

5-[4-(3-氟苯基 )-2-氧代 -1,2-二氢 -B引哚 -3-亚甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3- 羧酸（2-乙氨基乙基) -酰胺 5-[4-(3-Fluorophenyl)-2-oxo-1,2-dihydro-B 哚-3-methylene]-2-methyl-4-trifluoromethyl-1H- Pyrrole-3-carboxylic acid (2-ethylaminoethyl)-amide

重复本发明实施例 88第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸（4-羟基 -哌啶 -4- 甲基) -酰胺 88a作原料，与 4-(3-氟苯基 )-1,3-二氢吲哚 -2-酮的反应，则得到标题产物 5-[4-(4-氟苯基 )-2-氧代 -1,2-二氢 -吲哚 -3-亚甲基 ]-2-甲基 -4-三氟甲基 -m-吡咯 -3-羧酸（2-二乙胺基乙基) -酰胺 108( 75 mg，黄色固体)，产率： 56.8%。 The first and second reaction reactions of Example 88 of the present invention were repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole obtained in the above first step was used. 3-carboxylic acid (4-hydroxy-piperidin-4-methyl)-amide 88a as a starting material, and reaction with 4-(3-fluorophenyl)-1,3-dihydroindol-2-one, The title product 5-[4-(4-fluorophenyl)-2-oxo-1,2-dihydro-indole-3-methylene]-2-methyl-4-trifluoromethyl- M-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide 108 (75 mg, yellow solid), yield: 56.8%.

MS m/z (ESI): 529.4(M+1) 实施例 109 MS m/z (ESI): 529.4 (M+1) EXAMPLE 109

-(5-溴 -2-氧代 -1，2-二氢吡咯 [2,3-b]吡啶 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -(5-bromo-2-oxo-1,2-dihydropyrrole [2,3-b]pyridine-3-methylene)-2-methyl-4-trifluoromethyl-1H-pyrrole

重复本发明实施例 88第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸（4-羟基 -哌啶 -4- 甲基) -酰胺 88a作原料，与 4-溴 -1,3-二氢吡咯 [2,3-b]吡啶 -2-酮的反应，则得到标题产物 5-(5-溴 -2-氧代 -1,2-二氢吡咯 [2,3-b]吡啶 -3-亚甲基 )-2-甲¾-4-三氟甲基 -1H-吡咯 -3-羧酸（2-乙氮基乙基) -酰胺 109( 75 mg，黄色固体)，产率： 56.8%。 The first and second reaction reactions of Example 88 of the present invention were repeated except that the compound 5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole obtained in the above first step was used. 3-carboxylic acid (4-hydroxy-piperidin-4-methyl)-amide 88a as a starting material, reacting with 4-bromo-1,3-dihydropyrrole[2,3-b]pyridin-2-one, The title product 5-(5-bromo-2-oxo-1,2-dihydropyrrole[2,3-b]pyridine-3-methylene)-2-methyl 3⁄4-4-trifluoromethyl -1H-pyrrole-3-carboxylic acid (2-ethylidylethyl)-amide 109 (75 mg, yellow solid), yield: 56.8%.

MS m/z (ESI): 514.8(M+1) 实施例 110 MS m/z (ESI): 514.8 (M+1) EXAMPLE 110

[5-(5-溴 -2-氧代 -1，2-二氢 -吲哚 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯

[5-(5-Bromo-2-oxo-1,2-dihydro-indol-3-methylene)-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl] - tert-butyl carbamate

将实施例 1 中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸 18 (1.105 _§, 5

₀11)中，搅拌下依次加入叠氮磷酸二苯酯（1.651 g， 6.0 mmol)、三乙胺 (0.808g, 8mmol)，叔丁醇 (18.525 g, 0.25 mol)加热回流过夜，浓缩反应液，得到的残留物通过柱层析 (乙酸乙酯：正己烷 =3 : 20)进一步分离提纯，得到产物 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸叔丁酯 110 a (700 mg，黄色固体)，产率 47.9%。 The compound obtained in Example 1 5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid 18 (1.105 _§ , 5

₀ 11), diphenyl azide (1.651 g, 6.0 mmol), triethylamine (0.808 g, 8 mmol), tert-butanol (18.525 g, 0.25 mol) were added to the mixture under reflux with stirring, and the reaction mixture was concentrated. The residue obtained was further separated and purified by column chromatography (ethyl acetate:hexanes: 3: 20) to give the product (5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole-3) -Base)-tert-butyl carbamate 110 a (700 mg, yellow solid), yield 47.9%.

MS m/z (ESI): 293.3(M+1) MS m/z (ESI): 293.3 (M+1)

将上述步骤得到的化合物 110a (50 mg， 0.171 mmol) 溶于 3 ml无水乙醇中，加入 4-溴 -1,3-二氢 -Π引哚 -2-酮（34 mg， 0.162 mmol)和 2滴哌啶，加热回流 5小时后反应完毕。将体系在低温下结晶，过滤，用冰乙醇洗涤数次得到标题产物 [5-(5- 溴 -2-氧代 -1,2-二氢 -Π引哚 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯 110(40 mg, 桔黄色固体)，产率 51.3 %。 The compound 110a (50 mg, 0.171 mmol) obtained in the above step was dissolved in 3 ml of absolute ethanol, and 4-bromo-1,3-dihydro-indole-2-one (34 mg, 0.162 mmol) was added. Two drops of piperidine were heated and refluxed for 5 hours and the reaction was completed. The system was crystallized at low temperature, filtered, and washed several times with iced ethanol to give the title product [5-(5-bromo-2-oxo-1,2-dihydro-indole-3-indolyl)-2 -Methyl-4-trifluoromethyl-1H-pyrrol-3-yl]-carbamic acid tert-butyl ester 110 (40 mg, orange solid), yield 51.

MS m/z (ESI): 286.3(M+1) MS m/z (ESI): 286.3 (M+1)

¹HNMR(400MHz, DMSO-^δ 7.92(s,lH), 7.56(s,lH), 7.37(dd,lH, J=6.4Hz)， 6.87(d,lH, J=6.4Hz), 2.2 l(s, 3H), 1.44(s,9H). 实施例 111 ¹ H NMR (400 MHz, DMSO-^ δ 7.92 (s, lH), 7.56 (s, lH), 7.37 (dd, lH, J = 6.4 Hz), 6.87 (d, lH, J = 6.4 Hz), 2.2 l ( s, 3H), 1.44(s, 9H). Example 111

[5-(5-乙酰胺基 -2-氧代 -1,2-二氢 -吲哚 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3- 基] -氨基甲酸叔丁酯' [5-(5-Acetylamino-2-oxo-1,2-dihydro-indole-3-methylene)-2-methyl-4-trifluoromethyl-1H-pyrrole-3- Base]-tert-butyl carbamate

重复本发明实施例 110第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸叔丁酯 110a作原料，与 5-乙酰胺基 -1,3-二氢吲哚 -2-酮的反应，则得到标题产物 [5-(5- 乙酰胺基 -2-氧代 -1,2-二氢 -H引哚 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯 111 ( 90 mg，黄色固体)，产率： 62.9%。 The first and second reaction reactions of Example 110 of the present invention were repeated except that the compound obtained in the above first step (5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole) was used. -3-yl)-tert-butyl carbamate 110a as a starting material, and the reaction with 5-acetamido-1,3-dihydroindol-2-one gives the title product [5-(5-acetamido) -2-oxo-1,2-dihydro-H-indole-3-methylene)-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl]-carbamic acid tert-butyl ester 111 (90 mg, yellow solid), Yield: 62.9%.

MS m/z (ESI): 463.1(M-1) MS m/z (ESI): 463.1 (M-1)

1H NMR (400 MHz, OMSO-d6) δ 7.77(s,lH), 7.43(d,lH, J=8Hz)， 7.34(s,lH，)， 7 000323 1H NMR (400 MHz, OMSO-d6) δ 7.77 (s, lH), 7.43 (d, lH, J = 8 Hz), 7.34 (s, lH,), 7 000323

6.87(d,lH， J=8Hz)， 2.21 (s, 3H), 2.08(s, 3H), 1.44(s,9H). 实施例 112 6.87 (d, lH, J = 8 Hz), 2.21 (s, 3H), 2.08 (s, 3H), 1.44 (s, 9H). Example 112

[5-(5-甲酰胺基 -2-氧代 -1,2-二氢』引哚 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3- 基] -氨基甲酸叔丁酯 [5-(5-carboxamido-2-oxo-1,2-dihydro) fluorene-3-methylene)-2-methyl-4-trifluoromethyl-1H-pyrrole-3- Tert-butyl carbamate

重复本发明实施例 110第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸叔丁酯 110a 作原料，与 5-甲酰胺基 -1,3-二氢吲哚 -2-酮的反应，则得到标题产物 [5-(5- 甲酰胺基 -2-氧代 -1,2-二氢 -B引哚 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯 112( 97 mg，黄色固体)，产率： 63.8%。 The first and second reaction reactions of Example 110 of the present invention were repeated except that the compound obtained in the above first step (5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole was used. -3-yl)-tert-butyl carbamate 110a is used as a starting material to react with 5-carboxamido-1,3-dihydroindol-2-one to give the title product [5-(5-carboxamido). -2-oxo-1,2-dihydro-B fluorene-3-methylene)-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl]-carbamic acid tert-butyl ester 112 (97 mg, yellow solid), Yield: 63.8%.

MS m/z (ESI): 449.2(M-1) MS m/z (ESI): 449.2 (M-1)

Ή NMR (400 MHz, OMSO-d6 ) δ 7.82(s,lH), 7.42(dd,lH, J=8.4Hz), 7.02(d,lH, J=8Hz), 6.89(d,lH, J=8Hz), 2.30(s, 3H), 1.44(s,9H). 实施例 113 NMR NMR (400 MHz, OMSO-d6) δ 7.82 (s, lH), 7.42 (dd, lH, J = 8.4 Hz), 7.02 (d, lH, J = 8 Hz), 6.89 (d, lH, J = 8 Hz) ), 2.30(s, 3H), 1.44(s, 9H). Example 113

[5-(5-氟 -7-甲酰胺基 -2-氧代 -1，2-二氢 -吲哚 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯 [5-(5-Fluoro-7-carboxamido-2-oxo-1,2-dihydro-indole-3-methylene)-2-methyl-4-trifluoromethyl-1H- Pyrrol-3-yl]-carbamic acid tert-butyl ester

重复本发明实施例 110第一步和第二步反应反应，不同的是使用上述第一歩中所得到的化合物 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸叔丁酯 110a 作原料，与 5-氟 -7-甲酰胺基 -1,3-二氢吲哚 -2-酮的反应，则得到标题产物 [5-(5-氟 -7-甲酰胺基 -2-氧代 -1,2-二氢』引哚 -3-亚甲基) -²-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯 113 ( 128mg，黄色固体)，产率： 88.9%。 The first step and the second step of the reaction of Example 110 of the present invention are repeated, except that the compound obtained in the above first oxime (5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole) is used. -3-yl)-tert-butyl carbamate 110a as a starting material, and the reaction with 5-fluoro-7-carboxamido-1,3-dihydroindol-2-one gives the title product [5-(5) -Fluoro-7-carboxamido-2-oxo-1,2-dihydro"anthracene-3-methylene) ^-2 -methyl-4-trifluoromethyl-1H-pyrrol-3-yl ]-tert-butyl carbamate 113 (128 mg, yellow solid), Yield: 88.9%.

MS m/z (ESI): 467.3(M-1) MS m/z (ESI): 467.3 (M-1)

1H NMR (400 MHz, DMSO-i ) δ 8.72(s，lH), 8.33(s，lH), 7.45(m,2H)， 2.30(s, 3H), 1.43(s,9H). 实施例 114 1H NMR (400 MHz, DMSO-i) δ 8.72 (s, lH), 8.33 (s, lH), 7.45 (m, 2H), 2.30 (s, 3H), 1.43 (s, 9H). Example 114

[5-(7-乙酰胺基 -5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯 [5-(7-Acetylamino-5-fluoro-2-oxo-1,2-dihydro-indole-3-methylene)-2-methyl-4-trifluoromethyl-1H- Pyrrol-3-yl]-carbamic acid tert-butyl ester

重复本发明实施例 110第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸叔丁酯 110a 作原料，与 7-乙酰胺基 -5-氟 -1,3-二氢吲哚 -2-酮的反应，则得到标题产物 [5-(7-乙酰胺基 -5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯 114( 134 mg，黄色固体)，产率： 90.5 %。 The first and second reaction reactions of Example 110 of the present invention were repeated except that the compound obtained in the above first step (5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole) was used. -3-yl)-tert-butyl carbamate 110a as a starting material, and the reaction with 7-acetamido-5-fluoro-1,3-dihydroindol-2-one gives the title product [5-(7) -acetamido-5-fluoro-2-oxo-1,2-dihydro-indol-3-methylene)-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl ]-tert-butyl carbamate 114 (134 mg, yellow solid), Yield: 90.5 %.

MS m/z (ESI): 481.6(M-1) MS m/z (ESI): 481.6 (M-1)

Ή NMR (400 MHz,

δ 8.46(s,lH), 7.44(m,2H), 2.32(s, 3H), 2.09(s, 3H),1.43(s,9H). 实施例 115 Ή NMR (400 MHz,

δ 8.46 (s, lH), 7.44 (m, 2H), 2.32 (s, 3H), 2.09 (s, 3H), 1.43 (s, 9H).

[₅_₍₇_溴 _5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] - 氨基甲酸叔丁酯 [ ₅ _ ₍₇ _Bromo- _5- fluoro-2-oxo-1,2-dihydro-indole-3-methylene)-2-methyl-4-trifluoromethyl-1H-pyrrole- 3-yl]-tert-butyl carbamate

重复本发明实施例 110第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸叔丁酯 110a 作原料，与 7-溴 -5-氟 --1，3-二氢吲哚 -2-酮的反应，则得到标题产物 [5-(7-溴 -5-氟 2-氧代 -1，2-二氢- 朵 -3-亚甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯 115(124 mg, 黄色固体)，产率： 88.6%。 The first and second reaction reactions of Example 110 of the present invention were repeated except that the compound obtained in the above first step (5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole) was used. -3-yl)-tert-butyl carbamate 110a is used as a starting material to react with 7-bromo-5-fluoro-1,3-dihydroindol-2-one to give the title product [5-(7- Bromo-5-fluoro 2-oxo-1,2-dihydro-mono-3-methylene)-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl]-carbamic acid Butyl ester 115 (124 mg, yellow solid), Yield: 88.6%.

MS m/z (ESI): 504.2(M+1) MS m/z (ESI): 504.2 (M+1)

1H NMR ( 400 MHz, OMSO-d6 ) 5 7.70(m,lH), 7.55(s,lH), 7.37(m,lH)， 2.24(s, 3H),1.44(s,9H). 实施例 116 1H NMR (400 MHz, OMSO-d6) 5 7.70 (m, lH), 7.55 (s, lH), 7.37 (m, lH), 2.24 (s, 3H), 1.44 (s, 9H). Example 116

(⁵-[⁵-氟 _⁶_(²-羟基 -乙酰胺基) - 2-氧代 -I,²-二氢 -吲哚 -3-亚甲基] -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯 ( ^5- [ ⁵ -Fluoro- ^6- ( ² -hydroxy-acetamido)-2-oxo-I, ² -dihydro-indole-3-methylene]-2-methyl-4-tri Fluoromethyl-1H-pyrrol-3-yl]-carbamic acid tert-butyl ester

重复本发明实施例 110第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸叔丁酯 110a作原料，与 N-(5-氟 -2-氧代 -2,3-二氢 -1H-吲哚 -6-基) -2-轻基-乙酰胺的反应，则得到标题产物 {5-[5-氟 -6-(2-羟基 -乙酰胺基) - 2-氧代 -1,2-二氢 -吲哚 -3-亚甲基] _₂-甲基 _₄_三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯 116( 120 mg, 黄色固体)，产率： 78.4% The first and second reaction reactions of Example 110 of the present invention were repeated except that the compound obtained in the above first step (5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole) was used. -3-yl)-tert-butyl carbamate 110a as starting material, and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-lightyl- The reaction of acetamide gives the title product {5-[5-fluoro-6-(2-hydroxy-acetamido)-2-oxo-1,2-dihydro-indole-3-methylene] _ ₂ - _ _ _{4-trifluoromethyl-methyl} -1H- pyrrol-3-yl] - (, as a yellow solid 120 mg), yield carbamate 116: 78.4%

MS m/z (ESI): 498.1(M+1) MS m/z (ESI): 498.1 (M+1)

1H MR ( 400 MHz, OMSO-d6 ) δ 7.78(m,lH),7.72(d,lH, J=2.8Hz), 7.42(d，lH, J=2.8Hz), 4.05(s,2H), 2.20(s， 3H)，1.43(s，9H) 实施例 117 1H MR ( 400 MHz, OMSO-d6 ) δ 7.78 (m, lH), 7.72 (d, lH, J = 2.8 Hz), 7.42 (d, lH, J = 2.8 Hz), 4.05 (s, 2H), 2.20 (s, 3H), 1.43 (s, 9H) Example 117

{5-[5-氟 -6-(2-甲氧基乙酰胺基) - 2-氧代 -1,2-二氢 -Π引哚 -3-亚甲基] -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯 ' {5-[5-Fluoro-6-(2-methoxyacetamido)-2-oxo-1,2-dihydro-indole 哚-3-methylene]-2-methyl-4 -trifluoromethyl-1H-pyrrol-3-yl]-carbamic acid tert-butyl ester

重复本发明实施例 110第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸叔丁酯 110a作原料，与 N-(5-氟 -2-氧代 -2，3-二氢 -1H-吲哚 -6-基) -2-甲氧基-乙酰胺的反应，则得到标题产物 {5-[5-氟 -6-(2-甲氧基乙酰胺基) - 2-氧代 -1,2-二氢』引哚 -3-亚甲基] _2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸叔丁酯 117( 120 mg，黄色固体)，产率： 78.9%。 The first and second reaction reactions of Example 110 of the present invention were repeated except that the compound obtained in the above first step (5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole) was used. -3-yl)-tert-butyl carbamate 110a as starting material, and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy - acetamide reaction, the title product {5-[5-fluoro-6-(2-methoxyacetamido)-2-oxo-1,2-dihydro] hydrazine-3-methylene ]- -2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl]-carbamic acid tert-butyl ester 117 (120 mg, yellow solid), yield: 78.9%.

MS m/z (ESI): 493.4(M-1) MS m/z (ESI): 493.4 (M-1)

1H NMR ( 400 MHz, DMSO- (5 ) δ 7.70(m,lH)，7.63(d,lH， J=6.4Hz), 7.44(s,lH), 4.07(s,2H), 3.38(s,3H), 2.20(s, 3H),1.43(s,9H) 实施例 118 1H NMR (400 MHz, DMSO-(5) δ 7.70 (m, lH), 7.63 (d, lH, J = 6.4 Hz), 7.44 (s, lH), 4.07 (s, 2H), 3.38 (s, 3H) ), 2.20(s, 3H), 1.43(s,9H) Example 118

[5-(5-氟 -2-氧代 -1,2-二氢 -Π引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-yl]-氨基甲酸 -2-二乙氨基乙酯 [5-(5-Fluoro-2-oxo-1,2-dihydro-indole 哚-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3-yl ]-carbamic acid-2-diethylaminoethyl ester

将实施例 1 中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸 1₈ (1.105 ₈, 5^1₀1)溶解于甲苯(251_¾1)中，搅拌下依次加入叠氮磷酸二苯酯（1.651 g， 6.0 mmol)>三乙胺 (0.808g， 8mmol)， 2-二乙胺基乙醇 (3.3 ml, 25 mmol)加热回流过夜，浓缩反应液，得到的残留物通过柱层析 (乙酸乙酯：正己烷 =3.: 20)进一步分离提纯，得到产物 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸 -2-乙氨基乙酯 118 a (1.153 g，黄色固体)，产率 68.8%。 The compound 5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid 1 ₈ (1.105 ₈ , 5^1 ₀ 1) obtained in Example 1 was dissolved in toluene (1. 251 _¾ 1), the stirring were successively added diphenylphosphoryl azide (1.651 g, 6.0 mmol)> triethylamine (0.808g, 8mmol), 2- diethylamino ethanol (3.3 ml, 25 mmol) was heated at reflux After the reaction mixture was concentrated, the residue obtained was purified by column chromatography (ethyl acetate:hexanehexanes::: 20) to afford product (5-formyl-2-methyl-4-trifluoromethyl) -1H-pyrrol-3-yl)-carbamic acid-2-ethylaminoethyl ester 118 a (1.153 g, yellow solid), yield 68.8%.

MS m/z (ESI): 336.7(M+1) MS m/z (ESI): 336.7 (M+1)

将上述步骤得到的化合物 llSa tmg, 0.20 mmol)溶于 2 ml无水乙醇中，加入 5-氟 -1,3-二氢 -H引哚 -2-酮（24 mg, 0.16 mmol)和 2滴哌啶， 120°C微波反应 5 分钟。将溶液在减压下浓缩，得到的残留物进一步通过柱层析 (乙酸乙酯：正己垸 =2: 1)得到标题产物 [5-(5-氟 -2-氧代 -1,2-二氢 -Π引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-yl]-氨基甲酸 -2-二乙氨基乙酯 118(25 mg，黄色固体)，产率 33.3%。 MS m/z (ESI): 469.3(M+1) The compound obtained in the above step llSa mg, 0.20 mmol) was dissolved in 2 ml of absolute ethanol, and 5-fluoro-1,3-dihydro-H-indol-2-one (24 mg, 0.16 mmol) and 2 drops were added. Piperidine, microwave reaction at 120 ° C for 5 minutes. The solution was concentrated under reduced pressure, and the obtained residue wasjjjjjjjjjjjjjj Hydrogen-Π 哚-3-methylmethyl)-2-methyl-4-trifluoromethyl-1H-pyrrole-3-yl]-carbamic acid-2-diethylaminoethyl ester 118 (25 mg, yellow Solid), yield 33.3%. MS m/z (ESI): 469.3 (M+1)

1H MR ( 400 MHz, DMSO- 6 ) δ 7.52(m,lH),7.48(s,lH), 6.93(m,2H), 4.13(s,2H), 2.58(s,2H)， 2.40(m,4H), 2.20(s， 3H)，0.86〜0.75(m，6H) 实施例 119 </ RTI> <RTIgt; 4H), 2.20 (s, 3H), 0.86 to 0.75 (m, 6H) Example 119

[5-(7-溴 -5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-yl]- 氨基甲酸 -2-二乙氮基乙酯 [5-(7-Bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole- 3-yl]-carbamic acid-2-diethylaminoethyl ester

重复本发明实施例 118第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸 -2-乙氨基乙酯 118a作原料，与 7-溴 -5-氟 -1,3-二氢 -B引哚 -2-酮的反应，则得到标题产物 [5-(7-溴 -5-氟 -2-氧代 -1,2-二氢 -Π引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-yl]- 氨基甲酸 -2-二乙氨基乙酯 119 ( 57 mg，黄色固体)，产率： 58.2%。

The first and second reaction reactions of Example 118 of the present invention were repeated except that the compound obtained in the above first step (5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole was used. -3-yl)-carbamic acid-2-ethylaminoethyl ester 118a is used as a starting material to react with 7-bromo-5-fluoro-1,3-dihydro-B-indol-2-one to give the title product. 5-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indole hydrazone-3-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrole- 3-yl]-carbamic acid-2-diethylaminoethyl ester 119 (57 mg, yellow solid), yield: 58.2%.

MS m/z (ESI): 547.5(Μ+1) " MS m/z (ESI): 547.5 (Μ +1) "

Ή NMR ( 400 MHz, DMSO- ) δ 7.62(m,lH),7.48(s,lH), 7.27(m,lH), 4.00(s,2H), 2.60(s,2H), 2.39(m,4H), 2.08(s, 3H), 0.90~0.73(m,6H) 实施例 120 NMR NMR (400 MHz, DMSO-) δ 7.62 (m, lH), 7.48 (s, lH), 7.27 (m, lH), 4.00 (s, 2H), 2.60 (s, 2H), 2.39 (m, 4H) ), 2.08(s, 3H), 0.90~0.73 (m, 6H) Example 120

{5-[4-(2,3-氟苯基 )-2-氧代 -1,2-二氢 -H引哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 {5-[4-(2,3-Fluorophenyl)-2-oxo-1,2-dihydro-H 哚-3-methylidene]-2-methyl-4-trifluoromethyl -1H-pyrrole

-3-基氨基甲酸 -2-二乙氨基乙酯 -3-ylcarbamic acid-2-diethylaminoethyl ester

重复本发明实施例 118第一步和第 I：步反应反应，不同的是使用上述第一步中所得到的化合物 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸 -2-乙氨基乙酯 118a 作原料，与 4-(2,3-二氟 ^基) -1,3-二氢 -吲哚 -2-酮的反应，则得到标题产物 {5-[4-(2,3-氟苯基 )-2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基} -氨基甲酸 -2-二乙氨基乙酯 120 ( 55 mg，黄色固体)，产率： 54.4 %。 The first step and the first step of the reaction of the present invention were repeated, except that the compound obtained in the above first step (5-formyl-2-methyl-4-trifluoromethyl-1H-) was used. Pyrrol-3-yl)-carbamic acid-2-ethylaminoethyl ester 118a as a starting material, reacting with 4-(2,3-difluoro)-1,3-dihydro-inden-2-one, The title product {5-[4-(2,3-fluorophenyl)-2-oxo-1,2-dihydro-indol-3-methyl]-2-methyl-4-tri Fluoromethyl-1H-pyrrol-3-yl}-carbamic acid-2-diethylaminoethyl ester 120 (55 mg, yellow solid), yield: 54.4%.

MS m/z (ESI): 563.3(M+1) MS m/z (ESI): 563.3 (M+1)

1H NMR ( 400 MHz, DMSO-c^) δ 7.46(m，lH)，7.27(m，lH), 7.22(m,lH), 1H NMR (400 MHz, DMSO-c^) δ 7.46 (m,lH), 7.27 (m,lH), 7.22 (m,lH),

6.95(dd,lH),6.78(dd，lH), 6.70(s,lH)， 3.95(s,2H)， 2.58(s,2H), 2.40(m,4H), 2.08(s, 3H),0.86〜0.75(m,6H) 实施例 121 6.95 (dd, lH), 6.78 (dd, lH), 6.70 (s, lH), 3.95 (s, 2H), 2.58 (s, 2H), 2.40 (m, 4H), 2.08 (s, 3H), 0.86 ~0.75 (m, 6H) Example 121

{5-[5-氟 -6-(2-轻基-酰胺基 )-2-氧代 -1,2-二氢 -B引哚 -3-次甲基 ]-2-甲基 -4- -1H-吡咯 -3-基氨基甲酸 -2-二乙氨基乙酯 {5-[5-Fluoro-6-(2-light-amino-amido)-2-oxo-1,2-dihydro-B 哚-3-methylidene]-2-methyl-4- -1H-pyrrol-3-ylcarbamic acid-2-diethylaminoethyl ester

重复本发明实施例 118第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸 -2-乙氨基乙酯 118a作原料，与 N-(5-氟 -2-氧代 -2，3-二氢 -1H-吲哚 -6-基) -2-羟基-乙酰胺的反应，则得到标题产物 {5-[5-氟 -6-(2-羟基-酰胺基 )-2-氧代 -1,2-二氢 -B引哚 -3-次甲基] -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基} -氨基甲酸 -2-二乙氨基乙酯 121 ( 56 mg, 黄色固体)，产率： 57.7%。

The first and second reaction reactions of Example 118 of the present invention were repeated except that the compound obtained in the above first step (5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole was used. -3-yl)-carbamic acid-2-ethylaminoethyl ester 118a as a starting material, and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2 -Hydroxy-acetamide reaction, the title product {5-[5-fluoro-6-(2-hydroxy-amido)-2-oxo-1,2-dihydro-B 哚-3- Methyl]-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl}-carbamic acid-2-diethylaminoethyl ester 121 (56 mg, yellow solid), yield: 57.7%.

MS m/z (ESI): 542.5(M+1) MS m/z (ESI): 542.5 (M+1)

'H NMR ( 400 MHz, DMSO-^ ) 57.70(m,lH),7.35(s,lH), 7.10(m,lH), 3.99(s,2H), 3.90(s,2H), 2.55(m，2H), 2.40(m,4H)， 2.20(s， 3H),0.86〜0.75(m,6H) 实施例 122 'H NMR (400 MHz, DMSO-^) 57.70 (m, lH), 7.35 (s, lH), 7.10 (m, lH), 3.99 (s, 2H), 3.90 (s, 2H), 2.55 (m, 2H), 2.40 (m, 4H), 2.20 (s, 3H), 0.86 to 0.75 (m, 6H). Example 122

{5-[5-氟 -6-(2-甲氧基-酰胺基) -2-氧代 -1，2-二氢 -吲哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基氨基甲酸 -2-二乙氨基乙酯 {5-[5-Fluoro-6-(2-methoxy-amido)-2-oxo-1,2-dihydro-indol-3-methyl]-2-methyl-4- Trifluoromethyl-1H-pyrrol-3-ylcarbamic acid-2-diethylaminoethyl ester

重复本发明实施例 118第一步和第二步反应反应，不同的是使用上述第一步中所得到的化合物 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸 -2-乙氨基乙酯 118a作原料，与 N-(5-氟 -2-氧代 -2,3-二氢 -1H-B引哚 -6-基) -2-甲氧基-乙酰胺的反应，则得到标题产物 {5-[5-氟 -6-(2-甲氧基-酰胺基) -2-氧代 -1，2-二氢 -吲哚 -3- 次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基氨基甲酸 -2-二乙氨基乙酯 122( 56 mg, 黄色固体)，产率： 56.0%。 The first and second reaction reactions of Example 118 of the present invention were repeated except that the compound obtained in the above first step (5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole was used. -3-yl)-carbamic acid-2-ethylaminoethyl ester 118a as starting material, and N-(5-fluoro-2-oxo-2,3-dihydro-1H-B fluoren-6-yl) The reaction of 2-methoxy-acetamide gives the title product {5-[5-fluoro-6-(2-methoxy-amido)-2-oxo-1,2-dihydro-indole 3-Methylmethyl]-2-methyl-4-trifluoromethyl-1H-pyrrol-3-ylcarbamic acid-2-diethylaminoethyl ester 122 (56 mg, yellow solid), yield: 56.0 %.

MS m/z (ESI): 556.2(M+1) MS m/z (ESI): 556.2 (M+1)

1H NMR ( 400 MHz, DMSO-c ) 57.72(m,lH),7.65(m,lH)， 7.45(s,lH), 4.07(m,2H), 3.90(s,2H), 3.40(s,3H), 2.63(m,2H), 2.40(m,4H), 2.2 l(s, 3H),0.86〜0.75(m,6H) 实施例 123 1H NMR (400 MHz, DMSO-c) 57.72 (m, lH), 7.65 (m, lH), 7.45 (s, lH), 4.07 (m, 2H), 3.90 (s, 2H), 3.40 (s, 3H) ), 2.63 (m, 2H), 2.40 (m, 4H), 2.2 l (s, 3H), 0.86 to 0.75 (m, 6H).

{5-[5-(2-甲氧基-酰胺基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H- 吡咯 -3-基} -氨基甲酸 -2-二乙氨基乙酯

{5-[5-(2-Methoxy-amido)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-2-methyl-4-trifluoromethyl -1H-pyrrol-3-yl}-carbamic acid-2-diethylaminoethyl ester

重复本发明实施例 118第一步和第二步反应.反应，不同的是使用上述第一步中所得到的化合物 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸 -2-乙氨基乙酯 118a作原料，与 N-(2-氧代 -2,3-二氢 -1H-吲哚 -5-基) -2-甲氧基 -乙酰胺的反应，则得到标题产物 {5-[5-(2-甲氧基-酰胺基) -2-氧代 -1，2-二氢 -H引哚 -3-次甲基 ]-2- 甲基 -4-三氟甲基 -1H-吡咚 -3-基氨基甲酸 -2-二乙氨基乙酯 123( 20 mg, 黄色固体)，产率： 18.9%。 The first step and the second step of the reaction of Example 118 of the present invention were repeated. The reaction was carried out except that the compound obtained in the above first step (5-formyl-2-methyl-4-trifluoromethyl-1H-) was used. Pyrrol-3-yl)-carbamic acid-2-ethylaminoethyl ester 118a as starting material, and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-2-methoxy The reaction of keto-acetamide gives the title product {5-[5-(2-methoxy-amido)-2-oxo-1,2-dihydro-H-indol-3-ylmethyl] 2-Methyl-4-trifluoromethyl-1H-pyridin-3-ylcarbamic acid-2-diethylaminoethyl ester 123 (20 mg, yellow solid), yield: 18.9%.

MS m/z (ESI): 538.8(M+1) MS m/z (ESI): 538.8 (M+1)

Ή NMR ( 400 MHz, OUSO-d6 ) 67.78(s₅lH)₅7.52(m,lH)₅ 7.28(s,lH), 6.79(d,lH, J=8.4Hz), 3.99(s，2H)， 3.90(s,2H), 3.22(s,3H), 2.55(m,2H), 2.40(m,4H), 2.19(s， 3H),0.89〜0.75(m,6H) 实施例 124 NMR NMR ( 400 MHz, OUSO-d6 ) 67.78 (s ₅ lH) ₅ 7.52 (m, lH) ₅ 7.28 (s, lH), 6.79 (d, lH, J = 8.4 Hz), 3.99 (s, 2H), 3.90 (s, 2H), 3.22 (s, 3H), 2.55 (m, 2H), 2.40 (m, 4H), 2.19 (s, 3H), 0.89 to 0.75 (m, 6H) Example 124

4-(4-{3-[5-(5-氟 -2-氧代 -1,2-二氢 -H引哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3- 基] -酰脲基} -苯氧基) -嘧啶 -2-羧酸甲酯 4-(4-{3-[5-(5-fluoro-2-oxo-1,2-dihydro-H-indolyl-3-methyl)-2-methyl-4-trifluoromethyl -1H-pyrrol-3-yl]-acylureido}-phenoxy)-pyrimidine-2-carboxylic acid methyl ester

氮气气氛下，在干燥的 50ml单口瓶中加入原料 5-甲酰基 -2-甲基 -4-三氟甲基 -1氢 -吡咯 -3-羧酸 lg (lg， 4.52 mmol),丙酮 (20 ml),三乙胺 (547 mg, 5.42 mmol)。在冰浴冷却下，缓慢加入氯甲酸乙酯 (588 mg， 5.42 mmol), 搅拌 30分钟后加入叠氮化钠 (520 mg, 8.0mmol)水溶液 (4 ml)在反应液中加入乙酸乙酯 (200 ml), 有机层用饱和氯化钠溶液洗涤 (50 mlx2), 保持体系温度为 0— 5Ό，继续搅拌 30分钟反应完毕。向反应液中加入乙酸乙酯 (60 ml)萃取，有机相用饱和氯化钠溶液 (25 ml)洗漆，干燥，减压浓缩，得到黄色固体 5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-羰基叠氮 124a(750 mg，褐色固体)， 67.4%。 The raw material 5-formyl-2-methyl-4-trifluoromethyl-1 hydrogen-pyrrole-3-carboxylic acid lg (lg, 4.52 mmol), acetone (20) was added to a dry 50 ml single-mouth flask under a nitrogen atmosphere. Ml), triethylamine (547 mg, 5.42 mmol). Ethyl chloroformate (588 mg, 5.42 mmol) was slowly added under ice-cooling. After stirring for 30 min, sodium azide (520 mg, 8.0 mmol) aqueous solution (4 ml) was added and ethyl acetate was added to the reaction mixture. 200 ml), the organic layer was washed with a saturated sodium chloride solution (50 ml×2), the temperature of the system was maintained at 0-5 Torr, and stirring was continued for 30 minutes. Ethyl acetate (60 ml) was added to the mixture and the mixture was evaporated. Trifluoromethyl-1H-pyrrole-3-carbonyl azide 124a (750 mg, brown solid), 67.4%.

MS m/z (ESI): 245.4(M-1) MS m/z (ESI): 245.4 (M-1)

将上述步骤得到的化合物 124a (101 mg， 0.41 mmol)溶于甲苯 (15 ml)中，加热回流 1小时降至室温，减压下蒸出溶剂甲苯，得到的残留物用四氢呋喃 (15 ml) 溶解，冰水浴下，缓慢加入 4-(4-氨基苯氧基) -嘧啶 -2-羧酸甲酯 (90 mg, 0.37 mmol) 四氢呋喃溶液 (2 ml)。室温条件下搅拌 ·2小时后反应完毕。减压浓缩反应液，得到的残留物进一步通过柱层析 (乙酸乙酯：正己烷 =2: 1)得到化合物 4-{4-[3-(5- 甲酰基 -2-甲基 -4-三氟甲基 -1Η-吡咯 -3-基) -酰脲基] -苯氧基} -嘧啶 -2-羧酸甲酯 124b(90 mg, 黄色固体)，产率 52.9%。 The compound 124a (101 mg, 0.41 mmol) obtained in the above step was dissolved in toluene (15 ml), and the mixture was heated to reflux for 1 hour to room temperature, and the solvent was distilled off under reduced pressure to give the residue to tetrahydrofuran (15 ml). The solution was dissolved in ice-water bath and a solution of methyl 4-(4-aminophenoxy)-pyrimidine-2-carboxylate (90 mg, 0.37 mmol) in tetrahydrofuran (2 ml). Stirring was carried out at room temperature. After 2 hours, the reaction was completed. The reaction mixture was concentrated under reduced pressure, and the residue was obtainedjjjjjjjjjjjjj Methyl trifluoromethyl-1 Η-pyrrol-3-yl)-acylureido]-phenoxy}-pyrimidine-2-carboxylate 124b (90 mg, yellow solid), yield 52.9%.

MS m/z (ESI): 462·2(Μ+1) MS m/z (ESI): 462·2 (Μ +1)

将上述步骤得到的化合物 124b(160 mg, 0.347 mmol) 溶于 12 ml无水甲醇中，加入 5-氟 -1,3-二氢 -吲哚 -2-酮（42 mg， 0.277 mmol)和 2滴哌啶, 120。C，微波条件下反应 5分钟。将体系在低温下结晶，过滤，用冰甲醇洗涤数次得到标题产物 4-(4-{3-[5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -酰脲基} -苯氧基) -嘧啶 -2-羧酸甲酯 124 (82.5 mg，黄色固体)，产率 50%。 MS m/z (ESI): 595.8(M+1) The compound 124b (160 mg, 0.347 mmol) obtained in the above step was dissolved in 12 ml of anhydrous methanol, and 5-fluoro-1,3-dihydro-indol-2-one (42 mg, 0.277 mmol) and 2 Pipette piperidine, 120. C, the reaction under microwave conditions for 5 minutes. The system was crystallized at low temperature, filtered, and washed with ice methanol several times to give the title product 4-(4-{3-[5-(5-fluoro-2-oxo-1,2-dihydro-indole-3) Methyl-methyl)-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl]-acylureido}-phenoxy)-pyrimidine-2-carboxylate 124 (82.5 mg, Yellow solid), yield 50%. MS m/z (ESI): 595.8 (M+1)

1HNMR ( 400 MHz, DMSO- 5 ) 58.50(m,lH),7.55(m,2H), 7.48(m,lH), 7.15〜 7.00(m, 4H), 6.95〜6.80(m,3H), 3.50(s,2H), 2.69(s,3H), 2.3(s, 3H) 实施例 125 1HNMR (400 MHz, DMSO- 5 ) 58.50 (m, lH), 7.55 (m, 2H), 7.48 (m, lH), 7.15 to 7.00 (m, 4H), 6.95 to 6.80 (m, 3H), 3.50 ( s, 2H), 2.69 (s, 3H), 2.3 (s, 3H) Example 125

4-[4-(3-{5-[5-氟 -6-(2-羟基酰胺基) -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基} -酰脲基} -苯氧基) -嘧啶 -2-羧酸甲酯 4-[4-(3-{5-[5-fluoro-6-(2-hydroxyamido)-2-oxo-1,2-dihydro-indol-3-methyl]-2- Methyl-4-trifluoromethyl-1H-pyrrol-3-yl}-acylureido}-phenoxy)-pyrimidine-2-carboxylate

重复本发明实施例 124第一步、第二步和第三步的反应，不同的是使用上述第二步中所得到的化合物 4-{4-[3-(5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) - 酰脲基] -苯氧基} -嘧啶 -2-羧酸甲酯 124b 作原料，与 N-(5-氟 -2-氧代 -2,3-二氢 -1H- 哚 -6-基) -2-轻基-乙'酰胺的反应，则得到标题产物 {5-[5-氟 -6-(2-轻基-酰胺基 )-2- 氧代 -1,2-二氢』引哚 -3-次甲基 ]-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基氨基甲酸 -2-二乙氨基乙酯 125 ( 25 mg, 褐色固体)，产率： 41.7%。 The reaction of the first step, the second step and the third step of Example 124 of the present invention was repeated except that the compound 4-{4-[3-(5-formyl-2-) obtained in the above second step was used. Methyl 4-trifluoromethyl-1H-pyrrol-3-yl)-acylureido]-phenoxy}-pyrimidine-2-carboxylate 124b as starting material, with N-(5-fluoro-2- The reaction of oxo-2,3-dihydro-1H-indol-6-yl)-2-carbyl-ethyl'amide gives the title product {5-[5-fluoro-6-(2-light-based) Amido)-2-oxo-1,2-dihydro"indol-3-ylmethyl]-2-methyl-4-trifluoromethyl-1H-pyrrol-3-ylcarbamate-2- Diethylaminoethyl ester 125 (25 mg, brown solid), Yield: 41.7%.

MS m/z (ESI): 668.5(M+1) MS m/z (ESI): 668.5 (M+1)

1H NMR ( 400 MHz, DMSO-i d" ) 58.38(d,lH),7.68(d,lH， J=9.8Hz), 7.60(m,lH), 7.47〜7.28(m， 4H), 7.04〜7.0(m,2H)， 3.95(s,2H), 2.69(s，3H), 2.17(s, 3H) 实施例 126 1H NMR (400 MHz, DMSO-i d") 58.38 (d, lH), 7.68 (d, lH, J = 9.8 Hz), 7.60 (m, lH), 7.47~7.28 (m, 4H), 7.04~7.0 (m, 2H), 3.95 (s, 2H), 2.69 (s, 3H), 2.17 (s, 3H) Example 126

[5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -⁴-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸 -2-fJ比略焼 -1-乙酉! [5-(5-Fluoro-2-oxo-1,2-dihydro-indol-3-methylmethyl)-2-methyl- ⁴ -trifluoromethyl-1H-pyrrol-3-yl] -amino Formic acid-2-fJ is slightly more than -1- 酉!

将实施例 1 中所得到的化合物 5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-羧酸 lg (221 mg, l mol)溶解于甲苯 (10 ml)中，搅拌下依次加入叠氮磷酸二苯酯（330 mg, 1.2 mmol)、三乙胺 (161mg， 1.6 mmol)， 2-吡咯烷 -1-乙醇 (345.6 mg， 3.0 mmol) 加热回流过夜。反应完毕后加厶乙酸乙酯 (50 mlx2)萃取,合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，浓缩得到黄色固体产物（5-甲酰基 -2-甲基 -4- 三氟甲基 -1H-吡咯 -3-基) -氨基甲酸 -2-吡咯烷 -1-乙酯 126a The compound 5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole-3-carboxylic acid lg (221 mg, 1 mol) obtained in Example 1 was dissolved in toluene (10 ml). Diphenylphosphoryl azide (330 mg, 1.2 mmol), triethylamine (161 mg, 1.6 mmol), 2-pyrrolidine-1-ethanol (345.6 mg, 3.0 mmol) were added to the mixture and the mixture was evaporated. After completion of the reaction, the mixture was extracted with EtOAc (EtOAc m. Trifluoromethyl-1H-pyrrol-3-yl)-carbamic acid-2-pyrrolidine-1-ethyl ester 126a

MS m z (ESI): 334.5(M+1) MS m z (ESI): 334.5 (M+1)

将上述步骤得到的化合物 126a(75m_g, 0.23 mmol) 溶于 5 ml无水乙醇中，加入 5-氟 -1，3-二氢 -H引哚 -2-酮（34 mg， 0.16 mmol)和 2滴哌啶，加热回流 2小时后反应完毕。将溶液在减压下浓缩，得到的残留物进一步通过柱层析 (乙酸乙酯：甲醇 =20: 1)得到标题产物 [5-(5-氟 -2-氧代 -1,2-二氢 -吲哚 -3-次甲基 )-2-甲基 -4-三氟甲基 -1H-吡咯 -3-基] -氨基甲酸 -2-吡咯烷 -1-乙酯 126(30 mg, 黄色固体)，产率 60% The compound obtained in the above step 126a (75m _g, 0.23 mmol) was dissolved in 5 ml absolute ethanol, was added 5-fluoro-1,3-dihydro-indol-2-one -H (34 mg, 0.16 mmol) and Two drops of piperidine were heated and refluxed for 2 hours and the reaction was completed. The solution was concentrated under reduced pressure, and the obtained residue was purified tojjjjjjjjjjjjj -吲哚-3-methine)-2-methyl-4-trifluoromethyl-1H-pyrrol-3-yl]-carbamic acid-2-pyrrolidine-1-ethyl ester 126 (30 mg, yellow Solid), yield 60%

MS m/z (ESI): 467.6(M+1) MS m/z (ESI): 467.6 (M+1)

1HNMR ( 400 MHz, DMSO-i¾ ) S7.59(s,lH)， 7.52(s,lH), 7.03(m, 1H), 6.92(m,lH), 4.14(s,2H), 2.67(s,2H),2.33(m,4H)₅2.20(s,3H), 1.68(m, 4H) 实施例 127 1HNMR (400 MHz, DMSO-i3⁄4) S7.59 (s, lH), 7.52 (s, lH), 7.03 (m, 1H), 6.92 (m, lH), 4.14 (s, 2H), 2.67 (s, 2H), 2.33 (m, 4H) ₅ 2.20 (s, 3H), 1.68 (m, 4H) Example 127

{5-[4-(2,3-二氟苯基 2-氧代 -1，2-二氢 -吲哚 -3-次甲基] -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基氨基甲酸 -2-吡咯烧 -1-乙酯 {5-[4-(2,3-Difluorophenyl 2-oxo-1,2-dihydro-indol-3-ylmethyl)-2-methyl-4-trifluoromethyl-1H -pyrrol-3-ylcarbamic acid-2-pyrrole-1 -ethyl ester

重复本发明实施例 126第一步、第二步的反应，不同的是使用上述第一步中所得到的化合物 (5-甲酰基 -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基) -氨基甲酸 -2-吡咯烷 -1-乙酯 126a作原料，与 4-(2, 3-二氟苯基) -1，3-二氢 -吲哚 -2-酮的反应，则得到标题产物 {5-[4-(2，3-二氟苯基) -2-氧代 -1,2-二氢 -U引哚 -3-次甲基] -2-甲基 -4-三氟甲基 -1H-吡咯 -3-基} -氨基甲酸 -2-吡咯烧小乙酯 127( 25 mg，褐色固体)，产率： 16.7 %。 The reaction of the first step and the second step of Example 126 of the present invention was repeated except that the compound obtained in the above first step (5-formyl-2-methyl-4-trifluoromethyl-1H-pyrrole was used. -3-yl)-carbamic acid-2-pyrrolidine-1-ethyl ester 126a as starting material, and 4-(2,3-difluorophenyl)-1,3-dihydro-inden-2-one Reaction, the title product {5-[4-(2,3-difluorophenyl)-2-oxo-1,2-dihydro-U-indol-3-methyl]-2-methyl -4-Trifluoromethyl-1H-pyrrol-3-yl}-carbamic acid-2-pyrrolidone ethyl ester 127 (25 mg, brown solid), yield: 16.7 %.

MS m/z (ESI): 561.5(M+1) MS m/z (ESI): 561.5 (M+1)

lH MR ( 400 MHz, DMSO- ） S7.47(m,lH)， 7.34(m，lH), 7.3 l(m, 1H)， 7.25(dd, lH)₅7.05(dd,lH),6.87(d,lH),4.07(t,2H),2.62(m,2H),2.33(m₅4H)_>2.17(s,3H), 1.68(m, 4H). 测试例： lH MR (400 MHz, DMSO-) S7.47 (m, lH), 7.34 (m, lH), 7.3 l (m, 1H), 7.25 (dd, lH) ₅ 7.05 (dd, lH), 6.87 (d , lH), 4.07 (t, 2H), 2.62 (m, 2H), 2.33 (m ₅ 4H) _> 2.17 (s, 3H), 1.68 (m, 4H). Test example:

生物学评价例 1: 抑制细胞增殖测试 Biological evaluation 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高表达 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 IC₅o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 medium)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 sulforhodamine 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 ₅ o value. The general protocol for such an experiment is as follows: first select human tumor cells with high expression of VEGFR, inoculate them in 96-well culture plates at a suitable cell concentration (exp 5000 cells/ml medium), and then culture the cells in a carbon dioxide incubator. When they grow to 85% confluence, the medium is changed to a medium containing a series of concentration (usually 6 to 7 concentrations) of the test compound solution, and the plate is 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. corning 96孔培养板（Corning Incorporated, 目录 3599号） d. Corning 96-well culture plate (Corning 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） g. 澳大利亚胎牛血清（Gibco, 目录 10099-141号） f. DMEM/F12 cell culture medium (Gibco, catalog 12400-024) 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. Sulforhodamine B (Sigma, 目录 3520-42-1号） j. Sulforhodamine B (Sigma, Table of Contents 3520-42-1)

k. 醋酸 (Sinophma chemical reagent company, 目录 T20060508号） k. Acetic acid (Sinophma chemical reagent company, catalog T20060508)

1. 三氯醋酸（Sinophma chemical reagent company, 目录 T20060305号） m. Tris碱（Amresco, 目录 0826号） 1. Trichloroacetic acid (Sinophma chemical reagent company, catalogue T20060305) m. Tris base (Amresco, catalogue 0826)

n. II级 A/B3 型生物学安全工作橱 (ThermoForma目录. HB0053-03号） n. Class II A/B3 Biological Safety Work Cabinet (ThermoForma 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, Catalogue ⁷ 00-0081)

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。 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. 将 HUVEC细胞殖于 100mm corning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 °C，5 % C0₂), 直至细胞充分汇合； ' 1. HUVEC cells were cultured in a 100 mm corning plate in a growth medium (DMEM/F12 + 10% fetal bovine serum as a medium) (37 ° C, 5 % C0 ₂ ) until the cells were fully confluent;

2. 在 100 mm培养板中用胎牛血清洗涤 HUVEC细胞，以 Tyipsin消化细胞后，再将细胞接在 corning 96孔细胞培养板上，浓度为 50000 cells/ml，每个板空 6 孔，作为对照孔.； 2. Wash HUVEC cells with fetal bovine serum in 100 mm culture plates, digest the cells with Tyipsin, and connect the cells to a corning 96-well cell culture plate at a concentration of 50000 cells/ml, 6 wells per plate. 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；3. Incubate the cells in 96-well plates at 37 ° C, 5 % C0 ₂ until approximately 85% confluence is reached;

4. 用 DMSO溶解受试化合物，配置 20 ΰιΜ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;4. Dissolve the test compound in DMSO, configure 20 ΰιΜ mother liquor, and then dilute the mother liquor with DMSO to obtain 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在第五歩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 HUVEC cells are adherent and the growth reaches 85% confluence, the medium is changed to DMEM/F12. A new medium of +10% fetal bovine serum broth was added to each well and 180 μl of the culture medium and 20 μ of the test compound solution prepared in the fifth mash were added. 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 4Ό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 for 1 hour at 4 ,, and then wash several times with water to remove TCA, serum protein, and the like. The plate is 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 % Sulforhodamine B溶液，并向每孔中加入 50 μΐ sulforhodamine B溶液； 11. Prepare 0.4% Sulforhodamine B solution in 10% acetic acid solution, and add 50 μM sulforhodamine B 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 Sulforhodamine B中，增溶溶液（10 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 volume of Sulforhodamine B. The solubilizing solution (10 mM Tris) is the same as the original volume of the medium. The plate is allowed to stand at room temperature for 5 minutes, and the mixture is slowly stirred with a shaker to accelerate the mixing with the dye. ;

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 nm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 nm 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= ΙΟΟχ (对照组吸光度值-用药组吸光度值 )/对照组吸光度值％. IR = ΙΟΟχ (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_£ 实施例编号 IC₅₀ (VEGFR/HL Biochemical activity of the compounds of the present invention measured by the above test, Example No. IC ₅₀ (VEGFR / HL measured by IC50 values in the table below _£ embodiment

1 1.53 1 1.53

2 1.1 2 1.1

3 1.19 3 1.19

6 3.03 6 3.03

13 0.32 13 0.32

14 1.7 14 1.7

15 1.39 15 1.39

17 4.1 17 4.1

18 3.88 18 3.88

19 1.63 19 1.63

20 0.86 20 0.86

22 2.75 22 2.75

26 6.31 26 6.31

29 0.89 29 0.89

30 2.67 30 2.67

31 1.27 31 1.27

32 0.34 32 0.34

33 ,. ' 1.15 33 ,. ' 1.15

36 ' 6.65 36 ' 6.65

37 1.05 37 1.05

40 1.37 40 1.37

41 2.29 41 2.29

42 2.63 42 2.63

43 1.05 43 1.05

44 2.68 44 2.68

47 1.62 47 1.62

48 0.94 48 0.94

57 2.35 57 2.35

60 1.85 60 1.85

61 1.84 61 1.84

68 1.5 77 0.8868 1.5 77 0.88

81 0.281 0.2

82 1.6382 1.63

83 1.5583 1.55

89 0.3689 0.36

92 0.2992 0.29

98 0.298 0.2

102 0.32102 0.32

108 0.456108 0.456

116 0.2 例 2: VEGF-R2激酶活性测定 116 0.2 Example 2: Determination of VEGF-R2 kinase activity

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 KCK 4.3 mMNa₂HP0₄、 1.4 mM KH₂P0₄, 调 pH至 7.2) 和 0.05 % Tween-20 a. Wash buffer (PBS-T buffer): lx PBS (137 mM NaCK 2.7 mM KCK 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, Calbiochem #136593)PBS-T缓沖液 b. 1% bovine serum albumin (BSA, Calbiochem #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® Streptavidin包 96孔黄板 ¾PerkinElmer 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谷酰基胱氨酰甘氨酸和 20 %甘油 (Cell signaling technology #7787) h. lO mMATP溶液（Cell signaling technology #9804) f. DELFIA® Streptavidin 96-well yellow plate 3⁄4 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 glutamylcysteine Glycine glycine and 20% glycerol (Cell signaling technology #7787) h. lO mMATP solution (Cell signaling technology #9804)

i. Biotin-Gastrin Precursor (Tyr87) Peptide (Cell signaling technology #1310) j. Phosp o-Tyrosine Mouse mAb (P-Tyr-100) (Cell signaling technology #9411) k. HTScanTM酪氨酸激酶缓冲液 (4x) i. Biotin-Gastrin Precursor (Tyr87) Peptide (Cell signaling technology #1310) j. Phosp o-Tyrosine Mouse mAb (P-Tyr-100) (Cell signaling technology #9411) k. HTScanTM Tyrosine Kinase Buffer (4x )

l 激酶缓冲液： l Kinase buffer:

60 mM HEPES 60 mM HEPES

5 mM-MgCl₂ 5 mM-MgCl ₂

5 mM MnCl₂ 5 mM MnCl ₂

3 μΜ Να₃νθ ' 3 μΜ Να ₃ νθ '

(Cell signaling technology #9805) 1. 1.25 M DTT (lOOOx) (Cell signaling technology) (Cell signaling technology #9805) 1. 1.25 M DTT (lOOOOx) (Cell signaling technology)

方案： Program:

使用如下方案进行试验： Experiment with the following scenario:

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 μΐ of the 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 in 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 ml 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 μ1 4χ反应液； 6. Transfer 0.75 ml DTT/kinase buffer to each of each test to prepare a 4x reaction mixture and add 7.5 μl 4 χ reaction solution to each test;

7.加入 2 μ1ΑΤΡ (10 ηιΜ)至 498 μ Η₂0中，并在每个测试中加入 7.5 μΐ; 30 μΐ反应最终测试条件为： 7. Add 2 μl ΑΤΡ (10 ηιΜ) to 498 μ Η ₂ 0 and add 7.5 μΐ to each test; 30 μΐ reaction The final test conditions are:

60 mM HEPES pH 7.5 60 mM HEPES pH 7.5

5 mM MgCl₂ 5 mM MgCl ₂

5 mM MnCl₂ 5 mM MnCl ₂

1.25 mM DTT 1.25 mM DTT

ΙΟ μΜΑΤΡ ΙΟ μΜΑΤΡ

1.5 μΜ多肽底物 . 1.5 μΜ peptide substrate.

22 n_g VEGF-R2激酶 22 n _g 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； 9. Stop the reaction by adding 30 μΐ reaction stop buffer (50 mM EDTA, pH 8.0) to each test.

10.在 96孔 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； 10. Add 25 μM reaction solution and 75 μΐ dH ₂ 0 to each well of a 96-well streptavidin-coated plate, and shake at room temperature for 60 minutes;

11.每孔用 200 l PBS-T缓冲液洗涤 3次，在纸巾上轻拍以除去剩余的液体； 11. Wash each well 3 times with 200 l PBS-T buffer and pat on a paper towel to remove the remaining liquid;

12.用 1 %牛血清白蛋白 PBS-T缓冲液 l:1000稀释主要抗体Phospho-酪氨酸mAb (P-Tyr-lOO), 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 1:100 bovine serum albumin PBS-T buffer 1:500 and add 100 μl of diluted antibody to each well;

16.室温下，振摇温育 30分钟； 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；16. Incubate for 30 minutes at room temperature with shaking; 17. Wash each well 5 times with PBS-T buffer 200 μΐ, tap on a paper towel to remove the remaining liquid;

18.每孔中加入 100 DELFIA®信号倍增液； 18. Add 100 DELFIA® 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 nm下，用合适的时间分辨板读取器读取荧光强度。 20. Read the fluorescence intensity at a wavelength of 615 nm using a suitable time-resolving plate reader.

计算抑制率比值： m (%) =100- 100*(X-B)/ (N-B) Calculate the inhibition ratio: m (%) =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 ic₅₀值见下表。实施例编号 IC₅₀ (VEGFR/bio)( M) The biochemical activity of the compounds of the present invention was determined by the above test, and the measured ic ₅₀ values are shown in the following table. Example No. IC ₅₀ (VEGFR/bio) (M)

1 0.36 1 0.36

3 0.14 3 0.14

18 0.17 20 0.35 31 0.12 32 2.27 70 0.73 例 3: 抑制胞殖测试 18 0.17 20 0.35 31 0.12 32 2.27 70 0.73 Example 3: Inhibition Cytogenetic test

下面的外验是用来测定发明化合物对于人类肿瘤细胞 A431 EGFR高表达的细胞抻制增殖活 ¾。； , ：下面所述的体外细胞试验可确定受试合物的对高奉达 EGFR的^瘤¾胞的抗血管生成活性和抑制增殖活性，其活性可用 IC_5Q值表示。此类试验的一般方案如下：首先选择髙表达 EGFR的人类肿瘤细胞，以适宜细胞浓度下 (exp 5000 个细胞 /ml medium)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，当它丰长至 ⁸⁵%汇合，更换：^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，将培板重新放回培养箱，连续培养 72个小时。 72小时后，'可用 sulforhodamine B(SRB)方法进行测试化合物对于抑制细胞增殖活性。 IC_5Q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 following external assay was used to determine the cell proliferation activity of the inventive compound for high expression of human tumor cell A431 EGFR. ; , : The in vitro cell assay described below can determine the anti-angiogenic activity and the proliferative activity of the test compound against the high-end EGFR tumor cell, 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 expressing EGFR, inoculate them in 96-well culture plates at a suitable cell concentration (exp 5000 cells/ml medium), and then culture the cells in a carbon dioxide incubator. When it is as long as ⁸⁵ % confluence, replace: ^ Nutrient is a medium with a series of concentration (usually 6 to 7 concentrations) of the test compound solution, put the culture board back into the incubator, and continuously culture 72 Hours. After 72 hours, the test compound was tested for inhibition of cell proliferation activity by the sulforhodamine B (SRB) method. The IC _5Q value can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations. Materials and Method:

s. 二甲基亚砜 (Sinophma chemical reagent company, 目录 T20050806号） t. A431 细胞（购于 Institute of biochemistry and cell biology) s. dimethyl sulfoxide (Sinophma chemical reagent company, catalog T20050806) t. A431 cells (purchased from the Institute of biochemistry and cell biology)

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

v. corning 96孔培养板 (Corning Incorporated, 目录 3599号) v. corning 96-well culture plate (Corning Incorporated, catalogue 3599)

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

x. DMEM/F12 细胞培养基（Gibco, 目录 12400-024号） x. DMEM/F12 Cell Culture Medium (Gibco, Catalog 12400-024)

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

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

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

bb. Sulforhodamine B (Sigma, 目录 3520-42-1号） Bb. Sulforhodamine B (Sigma, Table of Contents 3520-42-1)

cc.醋酸 (Sinophma chemical reagent company, 目录 T20060508号) Cc. acetic acid (Sinophma chemical reagent company, catalog T20060508)

dd.三氯醋酸（Sinophma chemical reagent company, 目录 T20060305号） ee. Tris碱（Amresco, 目录 0826号） Dd. Trichloroacetic acid (Sinophma chemical reagent company, catalogue T20060305) ee. Tris base (Amresco, catalogue 0826)

ff. II 级 A/B3 型生物学安全工作橱 (ThermoForma目录. HB0053-03号） gg.系列 Π水套式二氧化碳培养箱（ThermoForma模型： 3111) Ff. Class II A/B3 biological safety work cabinet (ThermoForma catalogue. HB0053-03) gg. Series Water jacketed carbon dioxide incubator (ThermoForma model: 3111)

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

ii. Novastar板读取器（BMG Labtech, 目录 ⁷00-0081号） Ii. Novastar Board Reader (BMG Labtech, Catalogue ⁷ 00-0081)

jj. 定轨摇床（Qilinbeier, 目录 TS-1号）方案： Jj. 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 A431细胞的抑制细胞增殖 IC₅o值。The following protocol was used to test the inhibitory cell proliferation IC ₅ o values of the test compounds of the invention against A431 cells.

1. 将 A431细胞殖于 100mm coming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； 1. A431 cells were cultured in a 100 mm forth plate 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 mm培养板中用胎牛血清洗涤 A431细胞，以 Tyrpsin消化细胞后，再将细胞接种在 corning 96孔细胞培养板上，浓度为 50000 cells/ml,每个板空 6孔，作为对照? μ; 2. Wash A431 cells with fetal bovine serum in 100 mm culture plates, digest the cells with Tyrpsin, and inoculate the cells on corning 96-well cell culture plates at a concentration of 50000 cells/ml, 6 wells per plate. Control? μ;

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；3. Incubate the cells in 96-well plates at 37 'C, 5 % C0 ₂ until approximately 85% confluence is reached;

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 —系列浓^的受试化合物的溶液，即 2 mM, 1 mM, 0.2 mM, 20 μΜ， 2 μΜ， 0.2 μΜ;4. Dissolve the test compound in DMSO, dispose the 20 mM mother liquor, and dilute the mother liquor with DMSO to obtain a series of concentrated test compound solutions, ie 2 mM, 1 mM, 0.2 mM, 20 μΜ, 2 μΜ, 0.2 μΜ. ;

5. 使用细胞： t音养基（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 A431细胞暴露在 DMSO溶液中的浓度不超过 0.5 %，用涡旋混合，； 5. Use cells: t-tone (DMEM/F12 +10% fetal bovine serum as culture) Dilute the compound solution configured above. 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 A431 cells were exposed to DMSO solution. The concentration in the medium does not exceed 0.5%, and is mixed by vortexing;

6. 当 A431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 μ1培养液，这样 A431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 A431 cells adhered to the 85% confluence, the medium was changed to a new medium supplemented with DMEM/F12 +10% fetal bovine serum, and 180 μl of the medium and 20 μM were added to each well. The test compound solution prepared in the fifth step. In the negative control cell group, 20 μl of the culture medium containing 0.5% DMSO was added, so that the final concentration of A431 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 O, 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 under conditions of 37 O, 5 % C0 ₂ ;

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;

11.用 10 %醋酸溶液制备 0.4 % Sulforhodamine B 溶液，并向每孔中加入 50 μΐ sulforhodamine B溶液； 11. Prepare 0.4% Sulforhodamine B solution in 10% acetic acid solution, and add 50 μM sulforhodamine B solution to each well;

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

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 nm下吸光度减去 690 nm下^ 6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 nm minus the absorbance at 690 nm for 6-well plate background;

16.使用如下方法计算制率比值： 16. Calculate the ratio of ratios using the following method:

IR= ιοοχ (对照组吸光值-用药组吸光度值 y对照组吸光度值％. IR= ιοοχ (absorbance of the control group - absorbance value of the drug group y absorbance value of the control group %.

本发明 ft 生化学活性通过以上的试验进行测定，寻的 IC50值见下表。 The chemical activity of the present invention was determined by the above test, and the IC50 values sought are shown in the following table.

实施例编号 IC_5Q (EGFR/A431)^M) Example number IC _5Q (EGFR/A431)^M)

1 0.94 1 0.94

2 3.162 3.16

3 2.01 13 3.16 14 3.163 2.01 13 3.16 14 3.16

15 3.16 15 3.16

17 3.16 17 3.16

29 3.26 29 3.26

32· 0.63 32· 0.63

33 3.39 33 3.39

36 1.49 36 1.49

37 3.34 37 3.34

39 0.78 39 0.78

43 1.38 43 1.38

44 0.75 44 0.75

47 1.4 47 1.4

48 2.18 48 2.18

57 1.51 57 1.51

76 3.52 76 3.52

89 0.06 89 0.06

91 3.49 91 3.49

94 0.65 94 0.65

96 2.46 96 2.46

98 0.50 98 0.50

102 0.1 102 0.1

109 1.72109 1.72

116 0.61 例 4: EGFR激酶洁性 «定 116 0.61 Example 4: EGFR kinase cleanliness «Definite

体外 EGFR激酶活性通过以下的方法进行测试。 In vitro EGFR kinase activity was tested by the following method.

材料与试剂.： Materials and reagents.:

a.洗涤缓冲液（PBS-T缓冲液)： lx PBS (137 mM NaCl, 2.7 mM KCl, 4.3 mM Na₂HP0 , 1.4 mM KH₂P0₄,调 pH至 7.2)和 0.05 % Tween-20 a. Wash buffer (PBS-T buffer): lx PBS (137 mM NaCl, 2.7 mM KCl, 4.3 mM Na ₂ HP0 , 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, Calbiochem #136593)PBS-T缓冲液 b. 1% bovine serum albumin (BSA, Calbiochem #136593) PBS-T buffer

c. 反应中止缓冲液： 50 mM EDTA，pH 8.0. c. Reaction stop buffer: 50 mM EDTA, pH 8.0.

d. DELFIA®铕标记抗 ί IgG (PerkinElmer Life Sciences #AD0124) d. DELFIA® 铕 mark anti-ί IgG (PerkinElmer Life Sciences #AD0124)

f. DELFIA® Streptavidin包 96孔黄板（PerkinElmer Life Sciences#AAAND-0005) g. EGFR激酶 (50 mM Tris-HCl (pH 8.0), 100 mM NaCl, 5 mM DTT, 15 mM谷酰基胱氨酰甘氨酸和 20 %甘油， Cell signaling technology #7908) h. lO mMATP溶液（Cell signaling technology #9804). f. DELFIA® Streptavidin 96-well yellow plate (PerkinElmer Life Sciences #AAAND-0005) g. EGFR kinase (50 mM Tris-HCl (pH 8.0), 100 mM NaCl, 5 mM DTT, 15 mM glutamyl) Cysteinyl glycine and 20% glycerol, Cell signaling technology #7908) h. lO mMATP solution (Cell signaling technology #9804).

i. PTP1B (Tyr66)生物素酰化蛋白（Cell signaling technology #1325). i. PTP1B (Tyr66) biotinylated protein (Cell signaling technology #1325).

j. Phospho-酪氨酸鼠 mAb (P-Tyr-100) (Cell signaling technology #9411). j. Phospho-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： Lx kinase buffer:

60 mM HEPES 60 mM HEPES

5 mM MgCl₂ 5 mM MgCl ₂

5 mM MnCl₂ 5 mM MnCl ₂

3 μΜΝα₃νθ₄ 3 μΜΝα ₃ νθ ₄

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

1. 1.25 M DTT (lOOOx) (Cell signaling technology). 方案： 1. 1.25 M DTT (lOOOOx) (Cell signaling technology).

使用如下方案进行测试： Use the following scenario to test:

1.用 DMSO稀释受试化合物达到最终浓度值； 1. Dilute the test compound with DMSO to a final concentration;

在每个试验中加入 1 i受试化合物、 P性对照和空白对照（不接受任何受试化合物），只加入 1 l DMSO; 1 i test compound, P-control and blank control (do not accept any test compound) were added to each test, only 1 l DMSO was added;

2.用 d¾01:l稀释 6 μΜ底物蛋白 (Tyr589)，并加 15 μΐ到每个测试； 2. Dilute 6 μΜ substrate protein (Tyr589) with d3⁄401:1 and add 15 μΐ to each test;

3.将酶从 -80°C直接转移到冰上， EGFR酶解冻在冰上； 3. Transfer the enzyme directly from -80 ° C to ice, and EGFR enzyme is thawed on ice;

4.取 3 EGFR酶到每个测试中； 4. Take 3 EGFR enzymes into each test;

5.加入 10 μΐ DTT (1.25 M)到 2.5 ml 4x HTScan™酪氨酸激酶缓液 (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 ml DTT/ ^[酶缓冲液到每个每个测试中，制得 4x反应混合液，并在每个¾¾中加入 7.5 μΐ 4χ反应 6. Transfer 0.75 ml DTT/^ [enzyme buffer to each test to prepare a 4x reaction mixture and add 7.5 μΐ 4χ to each 3⁄43⁄4

7.加入 2 μ1ΑΤΡ (10 ιηΜ)至 496 μ Η₂0中，并在每个观 !j试中加入 7.5 μΐ; 30 μΐ反应最终测试条件为： 7. Add 2 μl ΑΤΡ (10 ηηΜ) to 496 μ Η ₂ 0 and add 7.5 μΐ to each observation! j; 30 μΐ reaction The final test conditions are:

60 mM HEPES H 7.5 60 mM HEPES H 7.5

5 mM MgCl₂ 5 mM MgCl ₂

5 mM MnCl₂ 5 mM MnCl ₂

3 μΜΝα₃νθ₄ 3 μΜΝα ₃ νθ ₄

1.25 mM DTT 1.25 mM DTT

20 μΜΑΤΡ 20 μΜΑΤΡ

1.5 μΜ多肽底物 30 ng EGFR激酶 1.5 μΜ peptide substrate 30 ng EGFR kinase

8.在 25°C下，将反应管温育 45分钟； 8. Incubate the reaction tube at 25 ° C for 45 minutes;

9.每个测试中加入 30 μ1中止反应缓冲液 (50 mM EDTA, pH 8.0)中止反应； 9. Stop the reaction by adding 30 μl of stop reaction buffer (50 mM EDTA, pH 8.0) to each test;

10.在 96孔 streptavidin包被培养板每孔中加入 25 μΐ反应液和 75 μΐ d¾0，在室温下，并振摇 60分钟； 10. Add 25 μM reaction solution and 75 μΐ d3⁄40 to each well of a 96-well streptavidin-coated plate, shake at room temperature for 60 minutes;

11. 每孔用 20(^1 PBS-T缓冲液洗涤 3次，在纸巾上轻拍以除去剩余的液体； 11. Wash each well 3 times with 20 (^1 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稀释抗体 Phospho-酪氨酸 mAb (P-Tyr-100), 在每孔中加入 100 μΐ稀释的抗体； 12. Dilute the antibody Phospho-tyrosine mAb (P-Tyr-100) with 1% bovine serum albumin in PBS-T buffer 1:1000, and add 100 μL of diluted antibody to each well;

13.在室温下，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稀释铕标记抗鼠 IgG，并在每孔中加入 100 μΐ稀释抗体； 15. Dilute anti-mouse IgG with 1:5% dilution of 1% bovine serum albumin in PBS-T buffer, and add 100 μM diluted antibody to each well;

16.在室温下，振摇温育 30分钟； 16. Incubate for 30 minutes at room temperature with shaking;

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;

19.在室温下，振摇温育 5分钟； 19. Incubate for 5 minutes at room temperature with shaking;

20.在 615 nm处，用合适的时间分辨板读取器读取荧光强度。。 20. At 615 nm, 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=受试化合物荧光值 X = fluorescence value of test compound

N-阴性对照 N-negative control

B=空白 B=blank

IC₅₀值可通过受试化合物不同浓度递度下的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 inhibition rates at different concentrations of the test compound. 'The 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。 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.

实施例编号 ICso (EGFR/bio)( M) Example number ICso (EGFR/bio)( M)

1 1.07 2 1.59 1 1.07 2 1.59

29 1.06 31 1.6 32 0.96 76 3.52 29 1.06 31 1.6 32 0.96 76 3.52

Claims

权利要求 Rights request

种由通式 (I)表示的吡咯取代的 2-二氢吲哚酮衍生物或其药学上可接受的 a pyrrole-substituted 2-indanone derivative represented by the formula (I) or a pharmaceutically acceptable thereof

其中-among them-

R ，和分别选自氢原子、卤素、烷基、卤代烷基、卤代烷氧基、环烷基、烯基、炔基、芳基、杂芳基、杂环烷基、羟基、 -OR₈、 -0[CH₂CH₂0]_rR.n, -SR₈、 - ₈R₉、 -SOR₈、 -S。₂R₈、 -NS0₂R₈、 -S0₂N ₈R₉、 -(CH₂)_nCOOR_s、 -(CH₂)_nCO R₈R₉、 -C(=S)NR₈R₉、 -COR₈、 - R₈COR₉、 -NHC(=0)OR₉、 -OCOOR9, -OCONR₈R₉、 -CN或者 -N0₂，其中芳基、杂芳基、杂环垸基官能团进一步被一个或多个垸基或者卤素取代； R , and are respectively selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a halogenated alkoxy group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, a heterocycloalkyl group, a hydroxyl group, -OR ₈ , 0[CH ₂ CH ₂ 0] _r Rn, -SR ₈ , - ₈ R ₉ , -SOR ₈ , -S. _{_{_{_{2 R 8, -NS0 2 R 8}}}} , -S0 2 N 8 R 9, - (CH 2) n COOR s, - (CH 2) n CO R 8 R 9, -C (= S) NR 8 R 9, -COR ₈ , - R ₈ COR ₉ , -NHC(=0)OR ₉ , -OCOOR9, -OCONR ₈ R ₉ , -CN or -N0 ₂ , wherein the aryl, heteroaryl, heterocyclic thiol functional group is further Substituted by one or more sulfhydryl groups or halogens;

R₅和 R6至少有一个是三氟甲基； R₅和分别选自氢原子、垸基、芳基或三氟甲基； R ₅ and at least one R6 is trifluoromethyl; and R ₅ are independently selected from hydrogen, alkyl with, aryl, or trifluoromethyl;

R7选自氢原子、垸基、氨基、芳基、 -Ν(∞) 。或- (CO)R ，其中芳基进一步被一个或多个卤素所取代； R7 is selected from the group consisting of a hydrogen atom, a fluorenyl group, an amino group, an aryl group, and -Ν(∞). Or - (CO)R , wherein the aryl group is further substituted by one or more halogens;

R₈和 R₉分别选自氢原子、烷基、环垸基、芳基、杂芳基或者杂环烷基，其中烷基、环垸基、芳基、杂芳基或者杂环垸基进一步被一个或多个烷基、芳基、羟基、氨基、垸氨基、酰胺基、胺酰基、氰基、垸氧基、芳氧基、胺綜基、羟烷基、杂环垸基、羧酸或者羧酸酯所取代； R ₈ and R ₉ are each independently selected from a hydrogen atom, an alkyl group, a cyclodecyl group, an aryl group, a heteroaryl group or a heterocycloalkyl group, wherein an alkyl group, a cyclodecyl group, an aryl group, a heteroaryl group or a heterocyclic fluorenyl group is further By one or more alkyl, aryl, hydroxy, amino, decylamino, amide, aminyl, cyano, decyloxy, aryloxy, amine synthyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid Or substituted with a carboxylic acid ester;

同时， R₈和 R₉形成一个 4〜8元杂环基；其中 5〜8元杂环内进一步含有一个或多个 0或 S原子，并且 4〜8元杂环进一步被一个或多个选自垸基、芳基、杂芳基、卤代烷基、卤代烷氧基、羟基、氨基、烷氨基、酰胺基、胺酰基、氰基、烷氧基、芳氧基、胺垸基、羟烷基、杂环垸基、羧酸、羧酸酯、卤素或 - ¾R₉ 的取代基所取代；Meanwhile, R ₈ and R ₉ form a 4 to 8 membered heterocyclic group; wherein the 5 to 8 membered heterocyclic ring further contains one or more 0 or S atoms, and the 4 to 8 membered heterocyclic ring is further selected by one or more From fluorenyl, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, amide, aminyl, cyano, alkoxy, aryloxy, amidino, hydroxyalkyl, Substituted by a heterocyclic fluorenyl group, a carboxylic acid, a carboxylic acid ester, a halogen or a substituent of -3⁄4R ₉ ;

0选自羟基、垸氧基、芳氧基、杂环烷氧基、芳垸氧基、 -0(CH₂)_mR₁₂、 -NiRnXCHa R^、 -N _u[CH₂CH₂0]_rR_u、 -N¾R₉、 -N-Z-O-Z 或 -NR_u(C¾)_m [CH(OH)CH₂]_pZ ，其中 Z 是芳基、杂芳基、杂环烷基、 -NR₈R₉、 -COORn或 CO ¾R₉; 0 is selected from the group consisting of hydroxyl, decyloxy, aryloxy, heterocycloalkoxy, aryloxy, -0(CH ₂ ) _m R ₁₂ , -NiRnXCHa R^, -N _u [CH ₂ CH ₂ 0] _r R _u , -N3⁄4R ₉ , -NZOZ or -NR _u (C3⁄4) _m [CH(OH)CH ₂ ] _p Z , wherein Z is aryl, heteroaryl, heterocycloalkyl, -NR ₈ R ₉ , - COORn or CO 3⁄4R ₉ ;

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

R₁₂选自 - ¾R₉、羟基、芳基、杂环烷基，杂芳基、垸氧基、 -0[CH₂CH₂0]_rRn、 -N⁺(0-)R₈R9> -N(OH)R₈、 -NHC(0)R₁₃或 -COR₁₃，其中 Ri₃是未取代的垸基、卤代烷基或者垸基，其中芳基、杂环烷基，杂芳基进一步被一个或多个羟基， -COOR,^?取代； R _{12 is} selected from the group consisting of -3⁄4R ₉ , hydroxy, aryl, heterocycloalkyl, heteroaryl, decyloxy, -0[CH ₂ CH ₂ 0] _r Rn, -N ⁺ (0-)R ₈ R9> -N(OH)R ₈ , -NHC(0)R ₁₃ or -COR ₁₃ , wherein Ri ₃ is unsubstituted fluorenyl, haloalkyl or fluorenyl, wherein aryl a heterocycloalkyl group, the heteroaryl group being further substituted by one or more hydroxyl groups, -COOR, ^?

11是0〜4； 11 is 0~4;

r是 1~6； r is 1~6;

m是 1〜6； m is 1 to 6;

p是 1〜2。 p is 1 to 2.

2. 根据权利要求 1所述的吡咯取代的 2-二氢吲哚酮衍生物或其药学上可接受的盐，其中 R₅是三氟甲基； 2. The pyrrole-substituted 2-indanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₅ is a trifluoromethyl group;

3. 根据权利要求 1或 2所述的吡咯取代的 2-二氢吲哚酮衍生物或其药学上可接受的盐，其中包括： The pyrrole-substituted 2-indanone derivative or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which comprises:

CZC000/.00ZN3/X3d S0ZS80/.00Z OAV

CZC000/.00ZN3/X3d S0ZS80/.00Z OAV

931

CZC000/.00ZN3/X3d S0ZS80/.00Z OAV CZC000/.00ZN3/X3d S0ZS80/.00Z OAV

CZC000/.00ZN3/X3d S0ZS80/.00Z OAV 8ZI CZC000/.00ZN3/X3d S0ZS80/.00Z OAV 8ZI

£Z£000/L00Z l3/13d S0ZS80/.00Z OAV £Z£000/L00Z l3/13d S0ZS80/.00Z OAV

CZC000/.00ZN3/X3d S0ZS80/.00Z OAV CZC000/.00ZN3/X3d S0ZS80/.00Z OAV

CZC000/.00ZN3/X3d S0ZS80/.00Z OAV

CZC000/.00ZN3/X3d S0ZS80/.00Z OAV

4. 根据权利要求 1所述的吡咯取代的 2-二氢吲哚酮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 pyrrole-substituted 2-indanone derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is a compound formed from an acid selected from the group consisting of Salt: Malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid', phosphoric acid, citric acid, tartaric acid, acetic acid or trifluoroacetic acid.

5. 根据权利要求 1所述的吡咯取代的 2-二氢吲哚酮衍生物的制备方法，包括以下步骤- 将三氟甲基化合物 a 按下式环合生成三氟甲基化合物 e ;

The method for preparing a pyrrole-substituted 2-indanone derivative according to claim 1, comprising the steps of: cyclizing a trifluoromethyl compound a to form a trifluoromethyl compound e;

将所述的三氟甲基化合物 c由无机碱选择性水解成化合物 d;

The trifluoromethyl compound c is selectively hydrolyzed from the inorganic base to the compound d;

将三氟甲基化合物 e由 PCC氧化成化合物 f。 The trifluoromethyl compound e is oxidized from PCC to compound f.

6. 一种药物组合物，其包括药物有效剂量的权利要求 1〜4中任何一项所述的吡咯取代的 2-二氢吲哚酮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 pyrrole-substituted 2-indanone derivative according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof Acceptable carrier.

7. 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 1〜4中任何一项所述的吡咯取代的 2-二氢吲哚酮衍生物或其药学上可接受的盐接触。 A method for modulating catalytic activity of a protein kinase, which comprises the above-described protein kinase and the pyrrole-substituted 2-indanone derivative according to any one of claims 1 to 4, or a pharmaceutically acceptable compound thereof Accepted salt contact.

8. 根据权禾要求 7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。 8. The method of claim 7, 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.

9. 一种治疗患有与蛋白质激酶有关的疾病的哺乳动物的方法，所述方法包括对所述哺乳动物给药治疗有效剂量的根据权利要求 6所述的药物组合物。 9. A method of treating a mammal having a disease associated with a protein kinase, the method comprising administering to the mammal a therapeutically effective amount of the pharmaceutical composition of claim 6.

10. 根据权利要求 9 所述的方法，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。 ' 10. The method according to claim 9, 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. '

11. 根据权利要求 9所述的方法，其中所述的哺乳动物是人。 11. The method of claim 9 wherein the mammal is a human.

12. 根据权利要求 9所述的方法，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， Von-Heppel-Lindau氏病，炎症或纤维变性病。 12. The method according to claim 9, 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, Von-Heppel-Lindau's disease, inflammation or fibrosis.

13. 根据权利要求 9所述的方法，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， Kaposi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。 13. The method according to claim 9, wherein the protein kinase-related disease is cancer, selected from Squamous cell carcinoma, renal cell carcinoma, Kaposi 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.

14. 根据权利要求 13所述的方法，该方法进一歩包括同时向需要治疗的患者给药治疗有效量的其它抗癌药物。 14. The method of claim 13, further comprising administering a therapeutically effective amount of another anti-cancer drug to a patient in need of treatment.

15. 根据权利要求 14所述的方法，其中所述的其它抗癌药物选自紫杉酚或卡铂。 15. The method of claim 14, wherein the other anti-cancer drug is selected from the group consisting of taxol or carboplatin.

16. 一种权利要求 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。 16. Use of a compound of claim 1 for the manufacture of a medicament for the treatment of a disease associated with a protein kinase.

17. 根据权利要求 16 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。 17. The use according to claim 16, 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.

18. 根据权利要求 16所述的方法，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， Vgn-HePPei-Lindau氏病，炎症或纤维变性病。 18. The method according to claim 16, 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, Vgn-HePPei-Lindau's disease, inflammation or fibrosis.

19. 根据权利要求 16所述的方法，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， Kaposi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，！胱癌，生殖泌尿癌，胃肠癌，神经胶质癌，结肠直肠癌或卵巢癌。 19. The method according to claim 16, wherein the protein kinase-related disease is cancer, selected from the group consisting of squamous cell carcinoma, renal cell carcinoma, Kaposi sarcoma, non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid Cancer, breast cancer, head and neck cancer, uterine cancer, esophageal cancer, melanoma, ! Cyst cancer, genitourinary cancer, gastrointestinal cancer, glial cancer, colorectal cancer or ovarian cancer.