RU2473543C2 - Heterocyclic nitrogen pyrrole derivatives, producing them and pharmaceutical application - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrrole nitrogen-containing heterocyclic derivatives of formula (I) or their pharmaceutically acceptable salts:

,

wherein: X means C, N; each R₁,R₂ means H; R₃ means C_1-10alkyl; R₄ means -[CH₂CH(OH)]_rCH₂NR₉R₁₀, -(CH₂)_nNR₉R₁₀; provided X means N, R₅ is absent, each R₆, R₇, R₈ means H, halogen; provided X means C, each R₅, R₆, R₇, R₈ means H, halogen, hydroxyC_1-10alkyl, C_1-10alkyl, phenyl, 6-member heteroaryl with one N, -OH, -OR₉, -NR₉R₁₀, -(CH₂)_nCONR₉R₁₀, -NR₉COR₁₀, -SO₂R₉ and -NHCO₂R₁₀, wherein said phenyl is unsubstituted or additionally substituted by one or more group C_1-10alkyl, C_1-10alkoxyl, halogen; each R₉, R₁₀ means H, C_1-10alkyl wherein C_1-10alkyl is unsubstituted or additionally substituted by one or more group C_1-10alkyl, phenyl, halogenophenyl, -OH, C_1-10alkoxy, OH- C_1-10alkyl; or R₉ and R₁₀ together with an attached atom form a 5-6-member heteroring which may contain one O; n is equal to 2- 6; z is equal to 1-2; r is equal to 1-6;.

EFFECT: compounds may be used as protein kinase inhibitors.

14 cl, 2 tbl, 67 ex

Description

FIELD OF THE INVENTION

The invention provides new pyrrole-nitrogen-containing heterocyclic derivatives, their preparation, pharmaceutical compositions containing such derivatives, and the use of such derivatives as therapeutic agents, in particular as protein kinase inhibitors.

BACKGROUND OF THE INVENTION

Cellular signal transmission is the fundamental mechanism by which extracellular stimuli are transmitted inside the cells and then regulate a variety of cellular processes. These signals regulate a wide variety of physical responses in the cell, including proliferation, differentiation, apoptosis, and motility. Extracellular signals take the form of a number of diverse soluble factors, including both growth factors and paracrine, autocrine, and endocrine factors. By binding to specific transmembrane receptors, growth factor ligands transmit extracellular signals to intracellular signal transduction pathways, which provides an individual cell response to extracellular signals. Many of these signaling processes utilize a reversible protein phosphorylation process that involves specific protein kinases and phosphatases.

Protein kinases (PCs) are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine and threonine residues of proteins, while protein phosphatases hydrolyze phosphate groups on phosphorylated protein substrates. The opposite functions of protein kinases and protein phosphatases balance and regulate signal transduction in signal transduction processes. The state of protein phosphorylation, which can affect its conformation, enzymatic activity, and cellular localization, is modified through the reciprocal actions of protein kinases and protein phosphatases. Phosphorylation is an important regulatory mechanism in the process of signal transmission, and aberrations in this process result in abnormalities in cell differentiation, transformation and growth. For example, it was discovered that a cell can become cancerous as a result of the transformation of part of its DNA into an oncogen. Several of these oncogenes encode proteins that are receptors for growth factors, for example tyrosine kinases. Tyrosine kinases can also mutate to form active forms, resulting in the transformation of various human cells. Alternatively, overexpression of normal tyrosine kinase enzymes can also result in abnormal cell proliferation.

There are two classes of PK, protein tyrosine kinases (PTK - protein tyrosine kinases) and serine treonine kinases (STK - serine treonine kinases). PTK phosphorylates the tyrosine residue on the protein. STK phosphorylates serine and / or threonine on the protein. Tyrosine kinases can be not only of the receptor type (having extracellular, transmembrane and intracellular domains), but also of the non-receptor type (fully intracellular). One of the main aspects of PTK activity is their involvement in growth factor receptors, which are cell surface proteins. Growth factor receptors with PTK activity are known as receptor tyrosine kinases ("RTK"). About 90 tyrosine kinases have been identified in the human genome, of which about 60 are of the receptor type and about 30 are of the non-receptor type. They can be classified into 20 subfamilies of receptor tyrosine kinases in accordance with the families of growth factors that they bind, and into 10 subfamilies of non-receptor tyrosine kinases (Robinson et al., Onoogene, 2000, 19, 5548-5557).

The family of receptor tyrosine kinases (RTK - receptor tyrosine kinases) includes: (1) the family of tyrosine kinases of EGF receptors (epidermal growth factor - epidermal growth factors), such as EGF, TGFα receptors (tumor growth factor α - tumor growth factor α), Neu and erbB ; (2) a family of tyrosine kinases of insulin receptors, such as insulin receptors and IGF1 (insulin-like growth factor) and an insulin-related receptor (IRR); (3) a family of class III receptor tyrosine kinases, such as platelet derived growth factor receptor tyrosine kinases (PDGFs), e.g. PDGFα and PDGFβ receptors, SCF RTK stem cell receptor tyrosine kinase (stem cell factor receptor tyrosine kinase) (commonly known as c-Kit), fms-associated tyrosine kinase 3 (Flt3) and colony stimulating factor 1 receptor tyrosine kinase (CSF-1R - colony stimulating factor 1 receptor), and the like. They play a critical role in the regulation of cell growth and differentiation and are key mediators of cellular signals leading to the production of growth factors and cytokines (Schlessinger and Ullrich, Neuron 1992, 9, 383). A partial non-limiting list of such kinases includes Abl, ARaf, ATK, ATM, bcr-abl, Blk, BRaf, Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CHK, AuroraA, AuroraB , AuroraC, cfms, c-fms, c-Kit, c-Met, cRaf1, 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-IR, IKK, IKK1, IKK2, IKK3, INS -R, integrin-associated kinase, Jak, JAK1, JAK2, JAK3, JNK, JNK, Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKB1, PKB2, PKB3, PKC, PKCa, PKCb, PKCd , PKCe, PKCg, PKC1, PKCm, PKCz, PLK1, Polo-like kinase, PYK2, tie ₁ , tie ₂ , TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1, VEGF-R2, Yes and Zap70 and the like . Protein kinases are also targets in disorders of the central nervous system, such as Alzheimer's disease (Mandelkow, EM et al. FESS Lett. 1992, 314, 315; Sengupta, A. et al. Mol. Cell. Biochem. 1997, 167.99), sensation of pain (Yashpal, KJ Neurosci. 1995, 15, 3263-72), in inflammatory disorders such as arthritis (Badger, J. Pharmn Exp. Ther. 1996, 279, 1453), psoriasis (Dvir, et al. J. Cell Biol. 1991, 113, 857), for bone diseases such as osteoporosis (Tanaka et al., Nature, 1996, 383, 528), cancer (Hunter and Pines, Cell 1994, 79, 573), for atherosclerosis (Hajjar and Pomerantz, FASEB J. 1992, 6, 2933), with thrombosis (Salari, FEBS 1990, 263, 104), with metabolic disorders such as diabetes (Borthwick, A.C. et al. Biochem. Biophys. Res. Commun. 1995, 210, 738) for proliferative disorders of blood vessels such as angiogenesis (Strawn et al. Cancer Res. 1996, 56, 3540; Jackson et al. J. Phann. Exp. Then 1998, 284, 687) for autoimmune disorders and transplant rejection (Bolen and Brugge, Ann. Rev. Immunol. 1997, 15, 371) and in infectious diseases such as viral (Littler, E. Nature 1992, 358, 160) and fungal infections (Lum, R.T. PCT Int Appl., WO 9805335 A1 980212).

RTK-mediated signal transduction is initiated by intercellular interaction with a specific growth factor (ligand), followed by receptor dimerization, transit stimulation of intrinsic protein tyrosine kinase activity, and phosphorylation. As a result of this, binding sites are created for intracellular signal transmission molecules, which leads to the formation of complexes with a spectrum of cytoplasmic signal transmission molecules, which contribute to the correct cellular responses, for example, cell division (reproduction), and responses to the extracellular microenvironment.

With respect to receptor tyrosine kinases, it has also been shown that tyrosine phosphorylation sites function as binding sites with high affinity for the SH2 domains (homologous to src) of the signal transduction molecules. Several intracellular substrate proteins have been identified that bind to receptor tyrosine kinases. They can be divided into two main groups: (1) substrates that have a catalytic domain; and (2) substrates that lack such a domain, but which serve as adapters and bind to catalytically active molecules. The specificity of the interactions between receptors or proteins and the SH2 domains of their substrates is determined by the amino acid residues directly surrounding the phosphorylated tyrosine residue. Differences in binding affinity between SH2 domains and amino acid sequences surrounding phosphothyrosine residues at specific receptors are consistent with observed differences in the phosphorylation profiles of their substrates. These observations suggest that the function of each receptor tyrosine kinase is determined not only by its expression pattern and ligand availability, but also by the order of biochemical signal transduction pathways that are activated by a particular receptor. Thus, phosphorylation provides an important regulatory stage, which determines the selectivity of the biochemical signal transmission pathways recruited by specific growth factor receptors, as well as differentiation factor receptors. As shown, aberrant expression or mutations in tyrosine kinases of proteins leads either to uncontrolled cell proliferation (for example, malignant tumor growth), or to defects in key development processes.

It has been established that such mutated and overexpressed forms of tyrosine kinases are present in a large proportion of common types of cancer in humans, such as leukemia, breast cancer, prostate cancer, non-small cell lung cancer (NSCLC), including adenocarcinomas and squamous cell lung cancer, gastrointestinal cancer including cancer of the colon, rectum and stomach, cancer of the bladder, cancer of the esophagus, cancer of the ovary and cancer of the pancreas and the like. It is expected that with further testing of human tumor tissues, the widespread and importance of tyrosine kinases will be further established. For example, it has been shown that tyrosine kinase EGFR is mutated and its overexpression occurs in several types of cancer in humans, including tumors of the lung, head and neck, gastrointestinal tract, breast, esophagus, ovary, uterus, bladder and thyroid gland.

One of the subfamilies, designated as “HER” or “Erb” RTK, includes EGFR (Epithelial Growth Factor Receptor), HER2, HER3 and HER4. These RTKs consist of an extracellular glycosylated ligand binding domain, a transmembrane domain, and an intracellular cytoplasmic catalytic domain that can phosphorylate tyrosine residues on proteins. The enzymatic activity of receptor tyrosine kinases can be stimulated either by overexpression of the receptor or by ligand-mediated dimerization. The formation of both homodimers and heterodimers has been demonstrated for the HER2 receptor family. An example of homodimerization is the dimerization of HER1 (EGF receptor) mediated by ligands of the EGF family (which includes EGF, transforming growth factor alpha, betacellululin, heparin-binding EGF and epiregulin). Heterodimerization among the four HER receptor kinases can be stimulated by binding to members of the heregulin ligand family (also called neuregregin). Such heterodimerization, in which a combination of HER2 and HER3 or HER3 and HER4 is involved, leads to a significant stimulation of the tyrosine kinase activity of receptor dimers even though one of the receptors (HER3) is enzymatically inert. It was shown that the kinase activity of HER2 is also activated by overexpression of a single receptor in some types of cells. Activation of receptor homodimers and heterodimers results in phosphorylation of tyrosine residues at receptors and other intracellular proteins. This is followed by activation of intracellular biochemical signal transmission pathways, such as those involving the kinase of the protein associated with microtubules (MAP (microtubule associated protein) kinase) and phosphatidylinositol-3-kinase (PI3 (phosphatidylinositol-3 kinase). It has been shown that activation of these biochemical pathways leads to cell proliferation and inhibition of apoptosis.

Other RTK subfamilies include an insulin receptor (IR), an insulin-like growth factor receptor I (IGF-1R), and an insulin receptor-linked receptor (IRR). IR and IGF-1R interact with insulin, IGF-I and IGF-II to form a heterotetramer of two completely extracellular glycosylated α subunits and two β subunits that cross the cell membrane and which contain a tyrosine kinase domain.

The third RTK subfamily refers to the platelet growth factor receptor (PDGFR) group, which includes PDGFRα, PDGFRβ, CSFIR, c-Kit and c-fms. These receptors consist of glycosylated extracellular domains, consisting of variable members of immunoglobulin-like loops, and the intracellular domain, where the tyrosine kinase domain is interrupted by unrelated amino acid sequences.

Platelet growth factor receptors, such as PDGFRα and PDGFRβ, are also transmembrane tyrosine kinase receptors. Upon ligand binding, they form either homodimers (PDGF-AA, PDGF-BB) or heterodimers (PDGF-AB). After the receptor dimerizes, its tyrosine kinase is activated. This leads to signal transmission down the signaling pathway, which may support tumor growth. Mutations in this gene make it possible to activate the receptor regardless of ligand binding and are the driving forces in oncogenesis. The expression of PDGF, a growth factor that activates PDGFR, was observed in a number of different tumor cell lines, inter alia, in the cell lines of the breast, colon, ovary, prostate carcinoma, sarcoma and glioblast. Among the tumors, brain tumors and prostate carcinoma (including adenocarcinomas and bone metastases) were of particular interest. Interesting evidence also exists regarding malignant gliomas.

c-Kit is a tyrosine kinase receptor that belongs to the PDGF receptor family and is activated by binding to the SCF ligand (stem cell factor). The expression pattern of c-Kit was investigated, for example, in a set of different primary solid tumors. Strong c-Kit expression can be detected, among other things, in sarcoma, gastrointestinal stromal tumors (GIST - gastrointestinal stromal tumors), seminoma and carcinoids [Weber et al., J. Clin. Oncol. 22 (14S), 9642 (2004)]. GISTs are not epithelial tumors. They can be found in the stomach, they are less in the small intestine and even less in the esophagus. Dissemination into the liver, omentum and abdominal cavity may be observed. GISTs are likely to arise from interstitial intestinal Cajal cells (ICCs), which normally form part of the autonomic nervous system of the intestine and are involved in the regulation of peristalsis. Most (50 to 80%) GISTs result from mutations in the c-Kit gene. In the intestine, the region of positive staining on c-Kit / CD117 is probably GIST. Mutations of the c-Kit can make the functioning of the c-kit independent of SCF activation, which leads to high cell division rates and, possibly, genome instability. C-Kit aberrations can also be observed in mast cell tumors, as well as in mastocytosis and a combination of myeloproliferative syndrome and pigmented urticaria. Expression and / or aberrations of c-Kit can also be detected in acute myeloid leukemia (AML) and malignant lymphomas. Expression of c-Kit can also be indicated in small cell bronchial carcinoma, seminomas, dysgerminomas, testicular intraepithelial neoplasias, melanomas, breast carcinomas, neuroblastomas, Ewing's sarcoma, some soft tissue sarcomas, as well as papillary / follicular carcinoma. al., Innovartis 3/2001). For example, it is known that hereditary mutations of the RET proto-oncogen (rearrangement after transfection) are oncogenic in patients with multiple endocrine neoplasia type 2 (MEN 2 - multiple endocrine neoplasia), which can lead to pheochromocytoma, medullary thyroid carcinoma and hyperplasia / parathyroid adenoma ( see Huang et al., Cancer Res. 60, 6223-6 (2000)).

Another group, which due to similarities with the PDGFR subfamily is sometimes included in this last group, is the subfamily of the fetal liver kinase receptor (Flk - fetal liver kinase). It is believed that this group consists of the kinase domain of the kinase-1 insertion of the fetal liver receptor - (KDR / FLK-1, VEGFR2), Flk-1R, Flk-4 and Fms-like tyrosine kinase 1 (Fit-1).

The next member of the tyrosine kinase receptor family of growth factors is the subgroup of the fibroblast growth factor receptor (FGF-fibroblast growth factor). This group consists of four receptors, FGFR1-4, seven ligands, and FGF1-7. Although not yet well defined, it appears that receptors consist of a glycosylated extracellular domain containing a varying number of immunoglobulin-like chains, and an intracellular domain in which the tyrosine kinase sequence is interrupted by regions of unrelated amino acid sequences.

Another member of the tyrosine kinase family of growth factor receptors is the subgroup of the vascular endothelium growth factor receptor (VEGF), where VEGF is a dimeric glycoprotein similar to PDGF but with different biological functions and specificity for in vivo target cells. In particular, it is known that VEGFRs are involved in the regulation of the onset of angiogenesis. Since especially solid tumors depend on good blood supply, inhibition of VEGFR and, therefore, angiogenesis is the goal of clinical studies in the treatment of such tumors, and shows promising results. VEGF also plays a major role in leukemia and lymphomas and shows high expression in a number of solid malignant tumors, which correlates well with the progress of the malignant disease. Examples of tumor diseases expressing VEGFR-2 (KDR) are pulmonary carcinomas, breast carcinomas, non-Hodgkin lymphomas, ovarian carcinoma, pancreatic cancer, malignant pleural mesothelioma and melanoma. In addition to its angiogenic activity, the VEGFR ligand, VEGF, can stimulate tumor growth through effects directly promoting survival in tumor cells. PDGF is also involved in angiogenesis, the process of the formation of new blood vessels, which is critical for continued tumor growth. Normally, angiogenesis plays an important role in processes such as embryonic development, wound healing, and some components of female reproductive function. However, unwanted or pathological angiogenesis is associated with a number of painful conditions, including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi’s sarcoma, and hemangioma. Stimulation of angiogenesis occurs by stimulating the growth of endothelial cells. Several polypeptides with in vitro endothelial cell growth promoting activity have been identified, including acidic and basic fibroblast growth factors (aFGF and bFGF) and vascular endothelial growth factor (VEGF). Due to the limited expression of its receptors, VEGF activity as a growth factor, in contrast to such activity of aFGF and bFGF, is relatively specific for endothelial cells. Recent data indicate that VEGF is an important stimulant of both normal and pathological angiogenesis and vascular permeability. This cytokine induces the phenotype of blood vessel germination by inducing endothelial cell proliferation, protease expression and migration, which subsequently leads to the formation of capillary tubes, which contributes to the formation of a superpermeable, immature vascular network, which is characteristic of pathological angiogenesis. Accordingly, antagonism of VEGF activity is expected to be useful in the treatment of a number of disease states that are associated with angiogenesis or increased vascular permeability, such as cancer, in particular in inhibiting tumor development.

FLT3 (fms-like tyrosine kinase - fms-like tyrosine kinase) is a member of the family of receptor tyrosine kinases type III (RTK). Aberrant FLT3 gene expression has been documented, among other things, in leukemia in both adults and children, including acute myeloid leukemia (AML), AML with trilinear myelodysplasia (AML / TMD), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS) (a) also SLL (mixed linear leukemia). Activating mutations of the FLT3 receptor were found in approximately 35% of patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. The most common mutation involves framed duplication within the permembrane domain, with another 5-10% of patients having a point mutation in asparagine 835. Both of these mutations are associated with constitutive activation of the tyrosine kinase activity of FLT3 and, as a result, provoke triggering proliferation and survival signals in the absence of ligands . Patients expressing a mutant form of the receptor have been shown to have a reduced chance of cure. Thus, data are accumulating on the role of the overactive (mutated) activity of FLT3 kinase in leukemia and myelodysplastic syndrome in humans.

It has been shown that receptor tyrosine kinase (RTK) (c-MET or HGFR) of hepatocyte growth factor (HGF - hepatocyte growth factor) in many types of cancer in humans is involved in oncogenesis, tumor progression with increased mobility and cell invasion, as well as metastases (see . Ma, P.C. et al. (2003b), Cancer Metastasis Rev, 22, 309-25; Maulik, G. et al. (2002b), Cytokine Growth Factor Rev, 13, 41-59). c-MET (HGFR) can be activated by overexpression or mutations in various types of human cancer, including small cell lung cancer (SCLC) (Ma, P.C. et al. (2003a), Cancer Res, 63, 6272-6281).

c-MET is a receptor tyrosine kinase that is encoded by the Met proto-oncogen and transmits the biological effects of hepatocyte growth factor (HGF). It is a transmembrane glycoprotein with tyrosine kinase activity, which contributes to the multiplication and division of many cells. Overexpression of the c-Met proto-oncogen occurs with numerous malignant tumors in humans, in particular, with a thyroid tumor, which is closely associated with pathological staging, tumor invasion and metastases.

A more complete list of known RTK subfamilies is described in Plowman et al., DN&P 7 (6): 334-339 (1994), which is incorporated by reference, as if fully set forth herein.

In addition to RTK, there is another family of cellular enzymes called receptor tyrosine kinase inhibitors (abbreviated as "CTK"). Currently, more than twenty-four CTKs have been identified, comprising eleven subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes / Fps, Fak, Jak, Ack and LIMK). Currently, the Src STK subfamily consists of the largest number of RTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk. A subfamily of Src enzymes is associated with oncogenesis. A more detailed discussion of CTK is given in Bolen, 1993, Oncogen 8: 2025-2031, which is incorporated herein by reference, including all graphic materials.

Serine / threonine kinases, or STK, like STK, are predominantly intracellular, although there are several STK receptor kinases. STKs are the most common of cytosolic kinases; that is, kinases that perform their function in a different part of the cytoplasm than the cytoplasmic organelles and cytoskeleton. The cytosol is the region within the cell where a significant portion of the intermediate cellular metabolic and biosynthetic activity takes place; for example, it is in the cytosol that proteins on ribosomes are synthesized.

Another characteristic feature of hyperproliferative diseases, such as cancer, is damage to cellular biochemical pathways, which control the passage through the cell cycle, in which an ordered cascade of protein phosphorylation is involved in normal eukaryotic cells. Regarding signal transduction mechanisms, several families of protein kinases, as it turned out, play a critical role in the cascade of the cell cycle.

Regarding cancer, the two main hypotheses put forward to explain the excess cell proliferation that directs tumor development are related to functions that are known to be regulated by protein kinases. That is, there is an assumption that malignant cell growth is the result of the destruction of the mechanisms that control cell division and differentiation. It has been shown that protein products of a number of proto-oncogenes are involved in biochemical signal transmission pathways that regulate cell growth and differentiation. These protein products of proto-oncogenes include extracellular growth factors, PTK receptors of transmembrane growth factor (RTK), cytoplasmic PTK (STK) and cytosolic STK, which were discussed above.

There is a need for new viable low molecular weight inhibitors that have antitumor activity and activity against cell proliferation. These small molecules are expected to inhibit one or more than one RTK, CTK or STK and are useful in treating or alleviating mediated RTK, CTK or STK mediated by angiogenesis or hyperproliferative disorder.

Based on the structure of the tyrosine kinase inhibitor SU-11248 and the pyrrolocondensed heterocycle of formula (X), which showed the high biological activity reported in the patent (US-6599902 B2), the present invention is directed to the construction and synthesis of pyrrolocondensed polynomial aza-heterocyclic derivatives, and The best pharmacological data were obtained. In order to improve the pharmacokinetic profile of pyrrolocondensed polynomial aza-heterocyclic derivatives, the present invention is directed to the creation of compounds of formula (I). The compounds of the invention exhibit obvious structural differences from existing prior art compounds, and they also exhibit higher efficiency and better functioning.

SUMMARY OF THE INVENTION

In order to overcome the disadvantages of the prior art, the present invention is directed to the development of pyrrole-nitrogen-containing heterocyclic derivatives having the formula (I), their tautomers, enantiomers, diastereomers, racemates or their pharmaceutically acceptable salts and metabolites, their precursor or prodrug, where the specified tautomer includes Z configuration and E configuration,

Where:

X is selected from the group consisting of a carbon atom and a nitrogen atom;

R ₁ and R _{2 are} each independently selected from the group consisting of a hydrogen atom and an alkyl;

R _{3 is} selected from the group consisting of alkyl, trifluoromethyl, aryl and aralkyl, wherein said alkyl, aryl or aralkyl is additionally substituted with one or more halogen atoms;

R _{4 is} selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, - (CH ₂ ) _n (OCH ₂ CH ₂ ) _r R ₁₁ ,

- [(CH ₂ CH (OH)] _r CH ₂ NR ₉ R ₁₀ and - (CH ₂ ) _n NR ₉ R ₁₀ , wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further substituted by one or more than one group selected from the group consisting of aryl, hydroxyl, amino, amide group, aminocarbonyl, alkoxyl, aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester and —NR ₉ R ₁₀ ;

when X is a nitrogen atom, R _{5 is} absent, R ₆ , R ₇ , R _{8 are} each independently selected from the group consisting of a hydrogen atom and a halogen atom;

when X represents a carbon atom, R ₅ , R ₆ , R ₇ , R _{8 are} each independently selected from the group consisting of hydrogen atom, halogen atom, hydroxyalkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, cyano, nitro, -OR ₉ , -O [CH ₂ CH ₂ O] _r R ₁₁ , -NR ₉ R ₁₀ , - (CH ₂ ) _n CO ₂ R ₉ , - (CH ₂ ) _n CONR ₉ R ₁₀ , -COR ₉ ,

—NR ₉ COR ₁₀ , —SO ₂ R ₉ and —NHCO ₂ R ₁₀ , wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl is additionally substituted with one or more groups selected from the group consisting of alkyl, alkoxyl and a halogen atom;

R ₉ and R _{10 are} each independently selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, wherein said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is further substituted by one or more than one group selected from the group consisting of alkyl, aryl, haloaryl, hydroxyl, amino, cyano, alkoxyl, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester and —NR ₉ R ₁₀ ;

R ₉ and R ₁₀ together with the attached atom form 4-8 membered hetero rings, wherein said 4-8 membered hetero rings may contain one or more heteroatoms selected from the group consisting of N, O and S, and said 4 The 8-membered rings are further substituted by one or more than one group consisting of alkyl, halogen atom, aryl, heteroaryl, haloalkyl, hydroxyl, cyano, alkoxyl, aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester and -NR ₉ R ₁₀ ;

R _{11 is} selected from the group consisting of a hydrogen atom and an alkyl;

n is an integer from 2 to 6;

z is an integer from 1 to 4; and

r is an integer from 1 to 6;

or their pharmaceutically acceptable salts.

Compounds or their pharmaceutically acceptable salts of formula (I), where R ₃ preferably represents methyl.

The compounds or their pharmaceutically acceptable salts of formula (I), where R ₁ and R ₂ preferably represent a hydrogen atom.

In addition, the present invention includes compounds or pharmaceutically acceptable salts having the formula (IA):

Where:

X is selected from the group consisting of a carbon atom and a nitrogen atom;

R ₁ and R _{2 are} each independently selected from the group consisting of a hydrogen atom and an alkyl;

R _{3 is} selected from the group consisting of alkyl, trifluoromethyl, aryl and aralkyl, wherein said alkyl, aryl or aralkyl is additionally substituted with one or more halogen atoms;

R _{4 is} selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, - (CH ₂ ) _n (OCH ₂ CH ₂ ) _r R ₁₁ , - [CH ₂ CH (OH)] _r CH ₂ NR ₉ R ₁₀ and - (CH ₂ ) _n NR ₉ R ₁₀ , wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further substituted by one or more groups selected from the group consisting of aryl, hydroxyl, amino, amide group, aminocarbonyl, alkoxyl , aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester and —NR ₉ R ₁₀ ;

when X is a nitrogen atom, R _{5 is} absent, R ₆ , R ₇ , R _{8 are} each independently selected from the group consisting of a hydrogen atom and a halogen atom;

when X is a carbon atom, R ₅ , R ₆ , R ₇ , R _{8 are} each independently selected from the group consisting of hydrogen atom, halogen atom, hydroxyalkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, cyano, nitro, -OR ₉ , -O [CH ₂ CH ₂ O] _r R ₁₁ , -NR ₉ R ₁₀ , - (CH ₂ ) _n CO ₂ R ₉ , - (CH ₂ ) _n CONR ₉ R ₁₀ , -COR ₉ ,

—NR ₉ COR ₁₀ , —SO ₂ R ₉ and —NHCO ₂ R ₁₀ , wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl is additionally substituted with one or more groups selected from the group consisting of alkyl, alkoxyl and a halogen atom;

R ₉ and R _{10 are} each independently selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, wherein said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is further substituted by one or more than one group selected from the group consisting of alkyl, aryl, haloaryl, hydroxyl, amino, cyano, alkoxyl, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester and —NR ₉ R ₁₀ ;

R ₉ and R ₁₀ together with the attached atom form 4-8 membered hetero rings, wherein said 4-8 membered hetero rings may contain one or more heteroatoms selected from the group consisting of N, O and S, and said 4 The 8-membered rings are further substituted by one or more than one group consisting of alkyl, halogen atom, aryl, heteroaryl, haloalkyl, hydroxyl, cyano, alkoxyl, aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester and -NR ₉ R ₁₀ ;

R _{11 is} selected from the group consisting of a hydrogen atom and an alkyl;

n is an integer from 2 to 6; and

r is an integer from 1 to 6;

or their pharmaceutically acceptable salts.

In addition, the present invention includes compounds or pharmaceutically acceptable salts having the formula (IB):

Where:

X is selected from the group consisting of a carbon atom and a nitrogen atom;

R ₁ and R _{2 are} each independently selected from the group consisting of a hydrogen atom and an alkyl;

R _{3 is} selected from the group consisting of alkyl, trifluoromethyl, aryl and aralkyl, wherein said alkyl, aryl or aralkyl is additionally substituted with one or more halogen atoms;

R _{4 is} selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, - (CH ₂ ) _n (OCH ₂ CH ₂ ) _r R ₁₁ , - [CH ₂ CH (OH)] _r CH ₂ NR ₉ R ₁₀ and - (CH ₂ ) _n NR ₉ R ₁₀ , wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further substituted by one or more groups selected from the group consisting of aryl, hydroxyl, amino, amide group, aminocarbonyl, alkoxyl , aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester and —NR ₉ R ₁₀ ;

when X is a nitrogen atom, R _{5 is} absent, R ₆ , R ₇ , R _{8 are} each independently selected from the group consisting of a hydrogen atom and a halogen atom;

when X represents a carbon atom, R ₅ , R ₆ , R ₇ , R _{8 are} each independently selected from a hydrogen atom, halogen, hydroxyalkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, cyano, nitro, -OR ₉ ,

-O [CH ₂ CH ₂ O] _r R ₁₁ , -NR ₉ R ₁₀ , - (CH ₂ ) _n CO ₂ R ₉ , - (CH ₂ ) _n CONR ₉ R ₁₀ , -COR ₉ , -NR ₉ COR ₁₀ ,

—SO ₂ R ₉ and —NHCO ₂ R ₁₀ wherein said aryl, heteroaryl, cycloalkyl or heterocycloalkyl is further substituted by one or more than one group selected from the group consisting of alkyl, alkoxyl and halogen atom;

R ₉ and R _{10 are} each independently selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, wherein said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is further substituted by one or more than one group selected from the group consisting of alkyl, aryl, haloaryl, hydroxyl, amino, cyano, alkoxyl, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester and —NR ₉ R ₁₀ ;

R ₉ and R ₁₀ are taken together with the attached atom to form 4-8 membered hetero rings, where said 4-8 membered hetero rings may optionally contain one or more heteroatoms selected from the group consisting of N, O and S and said 4-8 membered rings are further substituted with one or more than one group consisting of alkyl, halogen atom, aryl, heteroaryl, haloalkyl, hydroxyl, cyano, alkoxyl, aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic ester acids and -NR ₉ R ₁₀ ;

R _{11 is} selected from the group consisting of a hydrogen atom and an alkyl;

n is an integer from 2 to 6; and

r is an integer from 1 to 6;

or their pharmaceutically acceptable salts.

Compounds of the invention include, but are not limited to, the following:

Another aspect of the present invention relates to a pharmaceutical composition comprising one or more than one compound of formula (I) or a pharmaceutically acceptable salt thereof, a prodrug thereof and pharmaceutically acceptable carriers.

Another aspect of the present invention is directed to a method for modulating the catalytic activity of a protein kinase, wherein said protein kinase is contacted with a compound of formula (I) or a pharmaceutically acceptable salt thereof. These protein kinases are selected from the group consisting of receptor tyrosine kinases (RTK), tyrosine kinases of non-receptor proteins (STK) and serine-threonine protein kinases (STK),

Where the pharmaceutically acceptable salts of the present invention are salts formed from the present compound with acids 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 and trifluoroacetic acid.

The invention also relates to compounds having the following formula (IC) or (ID) as intermediates in the synthesis of compounds of formula (I):

Where:

R ₂ selected from the group consisting of hydrogen atom and alkyl;

R _{3 is} selected from the group consisting of alkyl, trifluoromethyl, aryl and aralkyl, wherein said alkyl, aryl or aralkyl is additionally substituted with one or more halogen atoms;

R _{4 is} selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, - (CH ₂ ) _n (OCH ₂ CH ₂ ) _r R ₁₁ , - [CH ₂ CH (OH)] _r CH ₂ NR ₉ R ₁₀ and - (CH ₂ ) _n NR ₉ R ₁₀ , wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is further substituted by one or more groups selected from the group consisting of aryl, hydroxyl, amino, amide group, aminocarbonyl, alkoxyl , aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester and —NR ₉ R ₁₀ ;

R ₉ and R _{10 are} each independently selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, wherein said alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl is further substituted by one or more than one group selected from the group consisting of alkyl, aryl, haloaryl, hydroxyl, amino, cyano, alkoxyl, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester and —NR ₉ R ₁₀ ;

R ₉ and R ₁₀ together with the attached atom form 4-8 membered hetero rings, wherein said 4-8 membered hetero rings may additionally contain one or more heteroatoms selected from the group consisting of N, O and S, and 4-8 membered rings are additionally substituted with one or more than one group consisting of alkyl, halogen atom, aryl, heteroaryl, haloalkyl, hydroxyl, cyano, alkoxyl, aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester and - NR ₉ R ₁₀ ;

R _{11 is} selected from the group consisting of a hydrogen atom and an alkyl;

n is an integer from 2 to 6;

z is an integer from 1 to 4; and

r is an integer from 1 to 6.

In another aspect, the invention is directed to a method for treating or preventing a protein kinase related disorder in a mammal, wherein a therapeutically effective amount of a pharmaceutical composition of the invention, which comprises the compound (s) of the invention or their pharmaceutically acceptable salts, and pharmaceutically acceptable carriers, is administered to the mammal and excipients. Protein kinase related disorders are selected from the group consisting of disorders associated with VEGFR-2, EGFR, HER-2, HER-3, HER-4, PDGFR, c-Kit, c-Met, FGFR and Flt3. Protein kinase-related disorders also include leukemia, diabetes, autoimmune diseases, hyperplasia, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, cardiovascular disease, Hippel-Lindau disease, inflammatory diseases and fibrosis. More preferably, said protein kinase-related disorders are squamous cell carcinoma, renal cell carcinoma, Kaposi’s sarcoma, non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid adenocarcinoma, breast cancer, head and neck cancer, uterine cancer, cancer of the esophagus, melanoma, cancer of the bladder, carcinosarcoma in the urinary and reproductive system, gastrointestinal carcinoma, gliomas, cancer of the colon and rectum, ovarian cancer. Preferably, said mammal is a human.

Further, a method for treating a mammal for protein kinase related disorders according to the present invention is preferably a method for treating a mammal for cancer. The present method further comprises co-administering to the mammal a therapeutically effective amount of an antitumor agent selected from the group consisting of taxol or carboplatin. Preferably, said mammal is a human. In yet another aspect, the invention is directed to the use of a compound of the present invention in the manufacture of a medicament for the treatment of protein kinase related disorders. Protein kinase related disorders are selected from the group consisting of disorders associated with VEGFR-2, EGFR, HER-2, HER-3, HER-4, PDGFR, c-Kit, c-Met, FGFR and Flt3. Alternative protein kinase-related disorders are selected from the group consisting of leukemia, diabetes, autoimmune diseases, hyperplasia, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, cardiovascular disease, Hippel-Lindau disease, inflammatory disease and fibrosis. More preferably, said protein kinase related disorders are cancer selected from the group consisting of squamous cell carcinoma, renal cell carcinoma, Kaposi’s sarcoma, non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid adenocarcinoma, breast cancer, head and neck cancer, cancer of the uterus, cancer of the esophagus, melanoma, cancer of the bladder, carcinosarcoma in the urinary and reproductive system, gastrointestinal carcinoma, glioma, cancer of the colon and rectum and ovarian cancer.

In another aspect, the invention relates to a method for producing an intermediate of formula (IC), comprising the following steps:

the reaction of the starting material — pyrrolomethylcarboxylic acid diester IC-1 — in tetrahydrofuran in the presence of acetic acid with cerium ammonium nitrate at room temperature to give pyrrolaldehyde carboxylic acid diester IC-2; and

the reaction of the pyrrolaldehyde carboxylic acid diester IC-2 in anhydrous tetrahydrofuran with (carbethoxymethylene) triphenylphosphorane by means of the Wittig reaction to obtain the pyrrolethoxycarbonylethylenedicarboxylic acid ester IC-3;

reduction of the pyrrolethoxycarbonylethylenedicarboxylic acid ester IC-3 in anhydrous ethanol with hydrogen catalysis with palladium on carbon at room temperature to give the pyrrolethoxycarbonylethyldiethicarboxylic acid ester IC-4;

hydrolysis of the ester of pyrrolethoxycarbonylethyldicarboxylic acid IC-4 in an aqueous solution of lithium hydroxide to obtain a pyrrole carboxyethyl carboxylic acid diester IC-5;

recovering the pyrrole carboxyethyl dicarboxylic acid ester IC-5 in anhydrous tetrahydrofuran with a borane-tetrahydrofuran solution at -20 ~ -5 ° C (degrees Celsius) to obtain the pyrrole hydroxypropyl dicarboxylic acid ester IC-6;

mesylation of the pyrrole hydroxypropyl dicarboxylic acid ester IC-6 in anhydrous dichloromethane in the presence of triethylamine at -20 ~ -5 ° C to obtain the pyrrolemethylsulfonyloxypropyl dicarboxylic acid ester IC-7;

reacting the pyrrolmethylsulfonyloxypropyldicarboxylic acid ester IC-7 with various amines to produce the pyrroldicarboxylic acid ester amide IC-8;

the reaction of the amide of pyrrolidicarboxylic acid ester IC-8 with trimethylaluminum in toluene under reflux to obtain the pyrrolocondensed seven-membered aza-heterocyclic ether IC-9;

the reaction of pyrrolocondensed seven-membered aza-heterocyclic ether IC-9 with trifluoroacetic acid at 30 ~ 50 ° C in argon atmosphere to obtain pyrrolocondensed seven-membered aza-heterocyclic formaldehyde IC

Where:

R ₂ , R ₃ and R ₄ are as defined above.

In another aspect, the invention relates to a method for producing an intermediate of formula (ID), comprising the following steps:

the reaction of the pyrrolicarboxylic acid alyedide diester IC-2 with Grignard reagent - cyclopropyl magnesium bromide - in anhydrous tetrahydrofuran at room temperature under argon atmosphere to give the pyrrole cyclopropyl hydroxycarboxylic acid diester ID-1;

the reaction of the pyrrole cyclopropylhydroxycarboxylic acid diester ID-1 with hydrobromic acid in methanol to obtain the bromobutenylpyrrole diester ID-2;

reduction of the bromobutenylpyrrole diester ID-2 in anhydrous ethanol with hydrogen, catalyzed by palladium on carbon at room temperature to obtain the bromobutylpyrrole diester ID-3;

the reaction of bromobutylpyrrole diester ID-3 with various amines in dichloromethane under reflux to produce a pyrrolamide dicarboxylic acid diester ID-4;

reacting ID-4 pyrrolamide dicarboxylic acid diester with trimethylaluminum in toluene under reflux to obtain pyrrolocondensed eight-membered aza heterocyclic aldehyde ID;

Where:

R ₂ , R ₃ and R ₄ are as defined above.

In addition, another aspect of the present invention relates to a method for producing pyrrole-nitrogen-containing heterocyclic derivatives, comprising the step of reacting oxindole with an aldehyde in the presence of a base (such as triethylamine, piperidine) and heating the reaction mixture for 2 ~ 12 hours, wherein said aldehyde has the following the formula:

and said oxindole has the following formula:

Where:

X, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are as defined above.

In yet another aspect, the invention provides compounds by which protein kinase activity can be distinguished by contacting cells that express a protein kinase with a compound of the invention or a pharmaceutically acceptable salt thereof, and determining the effect on the cell.

In yet another aspect, the invention relates to compounds by which protein kinase activity can be distinguished by contacting an artificially produced recombinant protein kinase with a compound of the invention or a pharmaceutically acceptable salt thereof, and determining kinase activity by enzyme linked immunosorbent analysis (ELISA) analysis).

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise specified, the following terms used in the description and claims have the meanings discussed below.

“Alkyl” means a saturated aliphatic hydrocarbon radical comprising C ₁ -C ₂₀ straight and branched groups. Preferably, the alkyl group is medium-sized alkyl having from 1 to 10 carbon atoms, for example methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like. More preferably, it is lower alkyl having from 1 to 4 carbon atoms, for example methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl and the like. The alkyl group may be substituted or unsubstituted. In case this group is substituted, preferred substituent groups are halogen, hydroxyl, lower alkoxyl, aryl, aryloxyl, heteroaryl, heterocycloalkyl, —OR ₉ , —NR ₉ R ₁₀ , —COR ₉ ,

—O [CH ₂ CH ₂ O] _r R ₁₁ , —NR ₉ COR ₁₀ , —SO ₂ R _9, or —NHCO ₂ R ₁₀ .

“Cycloalkyl” means a 3-8 membered monocyclic ring, 5 membered / 6 membered or 6 membered / 6 membered fused bicyclic ring or polycyclic fused ring group (“fused” ring system means that each ring in the system has a common adjacent pair of carbon atoms with another ring in the system), consisting only of carbon atoms, where one or more than one ring may contain one or more than one double bond, but none of the rings has a fully conjugated pi-electron system tron. Examples of cycloalkyl groups are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene and the like. The cycloalkyl group may be substituted or unsubstituted. If this group is substituted, the substituent groups are preferably one or more than one group independently selected from the group consisting of lower alkyl, trihaloalkyl, halogen atom, hydroxyl, lower alkoxyl, aryl (possibly substituted by one or more than one group each of which independently represents a halogen atom, a hydroxyl, lower alkyl or lower alkoxy group), aryloxy (possibly substituted by one or more than one group, each of which is independent imo represents a halogen atom, a hydroxyl, lower alkyl or lower alkoxyl group), a 6-membered heteroaryl (having from 1 to 3 nitrogen atoms in the ring, where the carbon atoms in the ring can be replaced by one or more than one group, each independently represents a halogen atom, a hydroxyl, lower alkyl or lower alkoxyl group), a 5-membered heteroaryl (having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, where the carbon atoms and nitrogen atoms of this group could be substituted by one or more than one group, each of which independently represents a halogen atom, a hydroxyl, lower alkyl or lower alkoxy group), a 5- or 6-membered heterocycloalkyl (having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms, where carbon atoms and nitrogen atoms (if present) in this group can be substituted by one or more than one group, each of which independently represents a halogen atom, a hydroxyl, lower alkyl or lower alk strong groups), mercapto, cyano, nitro, carboxylic acid, carboxylic acid ester, -OR ₉ , -NR ₉ R ₁₀ , -COR ₉ , -O [CH ₂ CH ₂ O] _r R ₁₁ , -NR ₉ COR ₁₀ , -SO ₂ R ₉ and -NHCO ₂ R ₁₀ .

“Alkenyl” means an alkyl group as defined above having at least 2 carbon atoms and at least one carbon-carbon double bond. Non-limiting examples of alkenyls are illustratively derived from the following groups: ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl and the like. The specified alkenyl may be substituted by one or more than one group selected from the group consisting of a halogen atom, trihalogenomethyl, hydroxyl, nitro, cyano, alkoxyl, alkyl, carboxylic acid, carboxylic acid ester, -OR ₉ , -NR ₉ R ₁₀ , -COR ₉ ,

—O [CH ₂ CH ₂ O] _r R ₁₁ , —NR _g COR ₁₀ , —SO ₂ R _9, and —NHCO ₂ R ₁₀ .

"Alkynyl" means an alkyl group as defined above having at least 2 carbon atoms and at least one carbon-carbon triple bond. Illustrative non-limiting examples of alkynyls are derivatives of the following groups: ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl and the like. The specified alkynyl may be substituted by one or more than one group selected from the group consisting of a halogen atom, trihalomethyl, hydroxyl, nitro, cyano, alkoxyl, alkyl, carboxylic acid, carboxylic acid ester, -OR ₉ , -NR ₉ R ₁₀ , -COR ₉ ,

—O [CH ₂ CH ₂ O] _r R ₁₁ , —NR ₉ COR ₁₀ , —SO ₂ R _9, and —NHCO ₂ R ₁₀ .

“Aryl” means groups having at least one aromatic ring, that is, having a fully conjugated pi-electron system, including cyclic aryl of carbon atoms only, heteroaryl, polycyclic aryl with fused rings. The specified aryl may be optionally substituted by one or more than one group selected from the group consisting of a halogen atom, trihalo methyl, hydroxyl, nitro, cyano, alkoxyl, alkyl, carboxylic acid, carboxylic acid ester, -OR ₉ , -NR ₉ R ₁₀ , -COR ₉ ,

—O [CH ₂ CH ₂ O] _r R ₁₁ , —NR ₉ COR ₁₀ , —SO ₂ R _9, and —NHCO ₂ R ₁₀ .

“Heteroaryl” means an aryl having from 1 to 3 ring heteroatoms selected from the group consisting of O, S, and N, as ring atoms, where the remaining ring atoms are C. This ring is a 5- or 6-membered ring. Non-limiting examples of heteroaryl groups are furan, thiophene, pyridine, pyrrole, N-alkylpyrrole, pyrimidine, pyrazine, imidazole and the like. The specified heteroaryl may be substituted by one or more than one group independently selected from the group consisting of a halogen atom, trihalogenomethyl, hydroxyl, nitro, cyano, alkoxyl, alkyl, carboxylic acid, carboxylic acid ester, -OR ₉ , -NR ₉ R ₁₀ , -COR ₉ ,

—O [CH ₂ CH ₂ O] _r R ₁₁ , —NR ₉ COR ₁₀ , —SO ₂ R _9, and —NHCO ₂ R ₁₀ .

A “heterocycloalkyl” group refers to a monocyclic or fused ring group of 5 to 9 ring atoms, having in the ring (s) one or more than one atom selected from the group consisting of nitrogen, oxygen and S (O) _n (n is an integer from 0 to 2), where the remaining ring atoms are C. The rings may also have one or more than one double bond, however, these rings may or may not have a fully conjugated pi-electron system. Non-limiting examples of unsubstituted heterocycloalkyl groups are pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperazine and the like. Heterocycloalkyl may be substituted or unsubstituted. If it is substituted, the groups of substituents are preferably one or more than one group selected from a halogen atom, trihalogenomethyl, hydroxyl, nitro, cyano, alkoxyl, alkyl, carboxylic acid, carboxylic acid ester, -OR ₉ , -NR ₉ R ₁₀ , —COR ₉ , —O [CH ₂ CH ₂ O] _r R ₁₁ , —NR ₉ COR ₁₀ , —SO ₂ R _9, and —NHCO ₂ R ₁₀ .

“Hydroxyl” means a —OH group.

“Alkoxyl” means both the —O— (alkyl) group and the —O— (unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, for example, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like. The specified alkoxyl group may optionally be substituted with one or more than one group selected from the group consisting of a halogen atom, trihalo methyl, hydroxyl, nitro, cyano, alkoxyl, alkyl, carboxylic acid, carboxylic acid ester, -OR ₉ ,

—NR ₉ R ₁₀ , —COR ₉ , —O [CH ₂ CH ₂ O] _r R ₁₁ , —NR ₉ COR ₁₀ , —SO ₂ R _9, and —NHCO ₂ R ₁₀ .

“Haloalkoxy” means —O— (haloalkyl). Representative examples include, but are not limited to, trifluoromethoxy, tribromethoxy, and the like.

“Aryloxy” refers to both an —O-aryl and an —O-heteroaryl group as defined above. Representative examples include, but are not limited to, phenoxy, pyridynyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy and the like, and derivatives thereof. The specified aryloxy group may be substituted by one or more than one group selected from the group consisting of a halogen atom, trihalomethyl, hydroxyl, nitro, cyano, alkoxyl, alkyl, carboxylic acid, carboxylic acid ester, -OR ₉ , -NR ₉ R ₁₀ , -COR ₉ ,

—O [CH ₂ CH ₂ O] _r R ₁₁ , —NR ₉ COR ₁₀ , —SO ₂ R _9, and —NHCO ₂ R ₁₀ .

"Hydroxyalkyl" refers to the group - (CH ₂ ) _n OH.

“Halogen atom” means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.

“Trihalogenomethyl” refers to —CX ₃ , wherein X is as defined above.

“Possible” or “possible” means that the event or circumstance subsequently described may or may not occur, and that the description includes cases where the event or circumstance may or may not occur. For example, “a heterocyclic group optionally substituted with an alkyl group” means that alkyl may or may not be present, and situations where the heterocyclic group is substituted by an alkyl group and situations where the heterocyclic group is not substituted by an alkyl group are included in the description.

A “pharmaceutical composition” refers to a mixture of one or more than one compound described herein, or physiologically / pharmaceutically acceptable salts or prodrugs thereof, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the administration of a compound to the body.

METHOD FOR SYNTHESIS OF COMPOUND OF THE INVENTION

In order to fulfill the object of the invention, the following technical solution is applied in the invention:

Compounds of the invention may be prepared by methods known in the art. Suitable synthesis methods are provided in the examples below. Generally, compounds can be prepared according to the scheme below:

The starting material, diester of pyrrolemethylcarboxylic acid IC-1, is subjected to reaction in tetrahydrofuran in the presence of acetic acid with cerium ammonium nitrate at room temperature to obtain pyrroldicarboxylic acid aldehyde ester IC-2. The pyrrole carboxylic acid aldehyde diester IC-2 is reacted in anhydrous tetrahydrofuran with (carbethoxymethylene) triphenylphosphorane by means of the Wittig reaction to produce pyrrolethoxycarbonylethylenedicarboxylic acid ester IC-3; palladium-carbon-catalyzed reduction of the pyrrolethoxycarbonylethylene dicarboxylic acid ester IC-3 in anhydrous ethanol with hydrogen at room temperature to give the pyrrolethoxycarbonylethyldicarboxylic acid ester IC-4; hydrolysis of the pyrrolethoxycarbonylethyldicarboxylic acid ester IC-4 in an aqueous lithium hydroxide solution to produce the pyrrole carboxyethyl dicarboxylic ester IC-5; recovering the pyrrole carboxyethyl dicarboxylic acid ester IC-5 in anhydrous tetrahydrofuran with a borane-tetrahydrofuran solution at -20 - ~ -5 ° C to obtain the pyrrole hydroxypropyl dicarboxylic acid ester IC-6; then, pyrrole hydroxypropyl dicarboxylic acid ester IC-6 is mesylated in anhydrous dichloromethane in the presence of triethylamine at -20 ~ -5 ° C to obtain pyrrolemethylsulfonyloxypropyl dicarboxylic acid ester IC-7; reacting the pyrrolmethyl sulfonyloxypropyldicarboxylic acid ester IC-7 with various amines to produce the pyrroldicarboxylic acid ester amide IC-8; pyrroldicarboxylic acid ester amide IC-8 is reacted with trimethylaluminum in toluene under reflux to produce pyrrole-condensed seven-membered aza-bicyclic ether IC-9; reacting pyrrolocondensed seven-membered aza-bicyclic ether IC-9 with trifluoroacetic acid at 30-50 ° C under argon atmosphere to obtain pyrrolocondensed seven-membered aza-bicyclic formaldehyde IC; pyrrolocondensed seven-membered aza-bicyclic formaldehyde IC is reacted with indolinones in the presence of a base, such as triethylamine or piperidine, under reflux for 2-12 hours to obtain pyrrolocondensed seven-membered aza-heterocyclic derivatives (IA).

Pyrroldicarboxylic acid ester aldehyde IC-2 is reacted with Grignard reagent - cyclopropyl magnesium bromide - in anhydrous tetrahydrofuran at room temperature under argon atmosphere to obtain pyrrole cyclopropyl hydroxy carboxylic acid diester ID-1; reacting a pyrrole cyclopropylhydroxycarboxylic acid diester ID-1 with hydrobromic acid in methanol to obtain a bromobutenylpyrrole diester ID-2; recovering the bromobutenylpyrrole diester ID-2 in anhydrous ethanol with hydrogen, catalyzed by palladium on carbon at room temperature to obtain the bromobutylpyrrole diester ID-3; reacting the bromobutylpyrrole ID-3 diester with various amines in dichloromethane under reflux to obtain the dicarboxylic acid amide diester pyrrole ID-4; reacting the pyrrolidicarboxylic acid amide diester ID-4 with trimethylaluminum in toluene under reflux to obtain pyrrolocondensed eight-membered aza heterocyclic aldehyde ID; pyrrolocondensed eight-membered aza heterocyclic aldehyde ID is reacted with indolinones in the presence of a base such as triethylamine or piperidine under reflux for 2-12 hours to produce pyrrolocondensed eight-membered aza heterocyclic derivatives (IB).

In this case, the double bond of formula (I) is in the Z configuration (cis), which can be confirmed by NMR data. Generally, the chemical shift of pyrrole NH proton was about 9 million ^-1, but pyrrole NH proton shift of the obtained compounds is about 14 million ^-1. The shift of the NH proton towards a weak field took place mainly due to the intramolecular hydrogen bonding interaction between the NH proton of pyrrole and the neighboring carbonyl oxygen atom of oxindole, which was also described in patent WO 0160814 (Su-11248).

The present invention also relates to a pharmaceutical composition comprising the compounds or their salts of the present invention in an effective therapeutic dose, as well as a pharmaceutically acceptable carrier.

The invention also relates to the use of compounds of formula (I) or their salts in the manufacture of a medicament as tyrosine kinase inhibitors. In other words, the invention also provides a composition containing the above compound in an effective therapeutic dose, and the use of compounds and / or pharmaceutical compositions containing them in the manufacture of a medicament as tyrosine kinase inhibitors.

The following examples serve to illustrate the invention, but these examples should not be considered limiting the scope of the invention.

EXAMPLES

Compound structures were confirmed by nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR shifts (δ) were given in ppm (mn ^-1). NMR measurements were performed on Bmker AVANCE-400, using, as solvents, and tetramethylsilane (TMS) as the internal standard and chemical shifts are reported in parts per million (ppm ^-1) deuterated chloroform (CDCla) and deuterated dimethyl sulfoxide (DMSO-d _6).

MS measurements were performed on a FINNIGAN LCQAd mass spectrometer (ESI).

The average VEGFR kinase inhibition rate was determined using HTScan (Cell Signaling).

The mean EGFR / HER-2 kinase inhibition rate was determined using NovoStar (BMG LABTECH in Germany).

Thin layer silica gel was a Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.

Column chromatography typically used Yantai Huanghai 200-300 mesh silica gel as a carrier.

DMSO-d ₆ : deuterated dimethyl sulfoxide

CDCl ₃ : deuterated chloroform

PRODUCTION EXAMPLES

Example 1

(Z) -5- (2-Diethylaminoethyl) -2- (5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-3a, 5,6,7,8,8- hexahydro-1H-pyrrolo [3,2-c] azepin-4-one

Stage 1

5-Formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl

ether 4-ethyl ether

3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 1a (30 g, 0.113 mol) was dissolved in 300 ml of tetrahydrofuran and 360 ml of acetic acid and 300 ml of water were added at stirring at room temperature. After complete addition, the mixture was stirred so that it mixed well, and cerium ammonium nitrate (246 g, 0.449 mol) was added in one portion. The mixture was stirred at room temperature for 0.5 hours, and the color of the reaction solution changed from carmine to orange. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was poured into 800 ml of ice water and a yellow precipitate formed. The mixture was stirred for another 0.5 hour, filtered and dried in vacuo to give the title compound, 5-formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl 4-ethyl ester ether 1b (31.13 g, yield 98%) as a pale yellow solid.

MS m / z (ESI): 282.0 [M + 1]

Stage 2

5- (2-Ethoxycarbonylvinyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether

5-Formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 1b (23 g, 81.7 mmol) and (ethoxycarbonylmethylene) triphenylphosphorane (34.66 g, 99 , 4 mmol) was dissolved in 450 ml of tetrahydrofuran and stirred at room temperature overnight under argon. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was concentrated under reduced pressure to give a yellow oil. The residue was dissolved in a solvent mixture of n-hexane and ethyl acetate (v: v = 20: 1) and purified by column chromatography with decompression on a sand funnel to give the title compound 5- (2-ethoxycarbonylvinyl) -3-methyl-1H- pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 1c (24 g, 84% yield) as a pale yellow solid.

MS m / z (ESI): 352.1 [M + 1]

Stage 3

5- (2-Ethoxycarbonylethyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether

5- (2-Ethoxycarbonylvinyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 1c (24 g, 68.3 mmol) was dissolved in anhydrous ethanol (180 ml) with stirring and palladium on activated carbon (2.44 g, 10%) was added to the solution. The resulting solution was stirred at room temperature overnight in a hydrogen atmosphere. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was filtered to remove palladium on activated carbon and washed with a small amount of ethanol. The filtrate was concentrated under reduced pressure to obtain the title compound 5- (2-ethoxycarbonylethyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4d ethyl ester 1d (23 g, yield 95%) as a white solid.

MS m / z (ESI): 354.40 [M + 1]

Stage 4

5- (2-Carboxyethyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether

5- (2-Ethoxycarbonylethyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 1d (23.6 g, 66.8 mmol) was dissolved in 190 ml of tetrahydrofuran and 90 ml of methanol with stirring and an aqueous lithium hydroxide solution (80 ml, 10 mol / L, 0.8 mol) was added at room temperature. The color of the reaction solution gradually changed from light yellow to blue; stirring was carried out for another 1 hour. When thin layer chromatography showed the disappearance of the starting materials, the resulting mixture was concentrated under reduced pressure to evaporate the organic solvent. The pH of the residue was adjusted to 2 with a solution of hydrochloric acid (2 mol / L) in an ice bath with stirring. A white precipitate formed. The mixture was filtered and the filter cake was dried to obtain the title compound 5- (2-carboxyethyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4e ethyl ester 1e (24 g, yield 98%) as a white solid.

MS m / z (ESI): 326.1 [M + 1]

Stage 5

5- (3-Hydroxypropyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether

5- (2-Carboxyethyl) -3-methyl-1 H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 1e (9.75 g, 30 mmol) was dissolved in 90 ml of anhydrous tetrahydrofuran at while stirring, a solution of borane in tetrahydrofuran (90 ml, 1 mol / L, 90 mmol) was slowly added dropwise to the solution while maintaining the temperature at -10 - ~ -5 ° C in an ice and salt bath under argon atmosphere. After completion of the addition, the ice and salt bath was removed and the reaction mixture was allowed to warm to room temperature and was stirred for 2-3 hours. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was concentrated under reduced pressure to evaporate the solvent. To the residue were added 100 ml of a saturated solution of sodium bicarbonate and 100 ml of ethyl acetate and stirred until dissolved. The resulting mixture was extracted with ethyl acetate (100 ml × 3). The combined organic extracts were washed with 100 ml of saturated brine, dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure to obtain the title compound 5- (3-hydroxypropyl) -3-methyl-1H-pyrrole-2 , 4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 1f (9.2 g, yield 98%) as a pale yellow oil.

MS m / z (ESI): 312.3 [M + 1]

Stage 6

5- (3-Methanesulfonyloxypropyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether

5- (3-Hydroxypropyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-mpem-butyl ether 4f ethyl ester 1f (9.20 g, 30 mmol) was dissolved in 150 ml of dichloromethane with stirring, and triethylamine (7.0 ml, 50 mmol) was added to the solution while maintaining the temperature at about −10 ° C. in an ice and salt bath under argon. After complete addition, methanesulfonyl chloride (3.5 ml, 45 mmol) was slowly added to the mixture. After stirring to mix well, the reaction system was allowed to warm to room temperature and stirred for 4 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was quickly cooled with ice. The reaction mixture was washed successively with dilute hydrochloric acid (0.5 mol / L, 80 ml × 2) to remove triethylamine, saturated sodium carbonate solution (80 ml × 2) to remove excess hydrochloric acid and saturated brine (80 ml) and concentrated under reduced pressure with obtaining the title compound 5- (3-methanesulfonyloxypropyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1g (11.4 g, 99% yield) in the form of brown oil.

MC m / z (ESI): 390.5 [M + 1]

Stage 7

5- [3- (2-Diethylaminoethylamino) propyl] -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether

5- (3-Methanesulfonyloxypropyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 1g (8.24 g, 21 mmol) was dissolved in N, N-diethylethylenediamine ( 15 ml, 100 mmol) with stirring at room temperature and stirred overnight. When thin layer chromatography showed the disappearance of the starting materials, 100 ml of ethyl acetate and 100 ml of saturated brine were added to the reaction mixture, stirred for 5 minutes and separated into layers. The organic phase was washed with saturated brine (100 ml × 4), dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure to obtain a brown oil. This residue was purified by silica gel column chromatography to obtain the title compound 5- [3- (2-diethylaminoethylamino) propyl] -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4 ethyl ester 1h (8.2 g, 95% yield) as a colorless oil.

MC m / z (ESI): 410.2 [M + 1]

Stage 8

5- (2-Diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine-2-carboxylic acid tert-butyl ether

5- [3- (2-Diethylaminoethylamino) propyl] -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 1h (3.547 g, 8.67 mmol) was dissolved in 70 ml of toluene and stirred for 10 minutes at room temperature in argon atmosphere. A solution of trimethylaluminum in toluene (5.6 ml, 2 mol / L, 11.27 mmol) was added to the mixture and stirred for another 30 minutes at room temperature until the white smoke ceased to emit. The reaction mixture was heated to reflux for 4 hours in an oil bath. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was naturally cooled to room temperature, rapidly cooled with ethanol (10 ml, 95%) and anhydrous ethanol (60 ml) was added. The resulting mixture was filtered through a pad of celite, washed with anhydrous ethanol (200 ml × 4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-s] azepine-2-carboxylic acid tert-butyl ether 1i (0.413 g, 75.7% yield) as a white solid.

MS m / z (ESI): 364.1 [M + 1]

Stage 9

5- (2-Diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde

5- (2-Diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carboxylic acid tert-butyl ether 1i (0.413 g , 1.14 mmol) was dissolved in trifluoroacetic acid (1.5 ml, 20 mmol) with stirring, heated to 40 ° C for 5 minutes in an oil bath under argon atmosphere and cooled to -5 ° C in an ice and salt bath with stirring, triethoxymethane (0.34 ml, 1.7 mmol) was added and stirred for 2 minutes. Then, the ice salt bath was removed, and the reaction mixture was allowed to warm to room temperature and was stirred for another 2 hours. When thin layer chromatography showed the disappearance of the starting materials, 3 ml of ice water and 10 ml of dichloromethane were added to the reaction mixture, adjusted to pH 11 with an aqueous solution of sodium hydroxide (2 mol / L) and extracted with dichloromethane (10 ml × 3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure to give a yellow oil. This residue was purified by silica gel column chromatography to obtain the title compound 5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-s ] azepine-2-carbaldehyde 1j (0.271 g, 55% yield) as a light brown oil.

MS m / z (ESI): 292.3 [M + 1]

Stage 10

(Z) -5- (2-Diethylaminoethyl) -2- (5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-3a, 5,6,7,8,8- hexahydro-1H-pyrrolo [3,2-c] azepin-4-one

5- (2-Diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 1j (0.271 g, 0.93 mmol ) and 5-fluoro-1,3-dihydroindol-2-one (0.127 g, 0.84 mmol) were dissolved in 1.4 ml of anhydrous ethanol with stirring at room temperature, the resulting mixture was stirred for 10 minutes in the dark and piperidine (0.15 ml, 1.49 mmol) was added. The mixture was refluxed at 70 ° C. for about 1.5 hours in an oil bath under argon, and a lot of orange precipitate formed. When thin layer chromatography showed the disappearance of the starting materials, the ice salt bath was removed and the reaction mixture was naturally cooled to room temperature, filtered and dried to give the title compound, (Z) -5- (2-diethylaminoethyl) -2- (5 -fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl) -3-methyl-3a, 5,6,7,8,8a-hexahydro-1H-pyrrolo [3,2-c] azepine- 4-one 1 (0.288 g, yield 80.76%) as an orange solid.

MS m / z (ESI): 425.3 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.710 (s, 1H, pyrrole-NH), 10.903 (s, 1H, indole-NH), 7.753-7.782 (dd, 1H, -ArH), 7.744 (s , 1H, -CH = C), 6.914-6.965 (m, 1H, -ArH), 6.834-6.867 (m, 1H, -ArH), 3.483-3.518 (t, 2H, seven-membered ring intra-CH ₂ N) , 3.336-3.364 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.907-2.944 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.529-2.581 (m, 6H, 3 × - CH ₂ N), 2.455 (s, 3H, pyrrole-CH ₃ ), 2.040-2.079 (m, 2H, seven-membered ring-intra-CH2), 0.956-0.992 (t, 6H, 2 × -CH ₃ ).

Example 2

(Z) -2- (5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -5- (2-diethylaminoethyl) -3-methyl-5,6,7,8-tetrahydro-1H- pyrrolo [3,2-c] azepin-4-one

The title compound was obtained under the same conditions as described in step 10 of Example 1, c (Z) -5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7 , 8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 1j obtained in Step 9 of Example 1, and 5-chloro-1,3-dihydroindol-2-one as starting materials, to give 2- (5 -chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl) -5- (2-diethylaminoethyl) -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 2 (27 mg, 60.0% yield) as a carmine solid.

MS m / z (ESI): 441.1 [M + 1]

¹ H NMR (400 MHz, DMCO-d ₆ ) δ 13.663 (s, 1H, pyrrole-NH), 11.002 (s, 1H, indole-NH), 7.987-7.991 (d, 1H, -ArH), 7.798 (s , 1H, -CH = C), 7.132-7.158 (dd, 1H, -ArH), 6.867-6.888 (d, 1H, -ArH), 3.483-3.518 (t, 2H, seven-membered ring intra-CH ₂ N) , 3.336-3.364 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.907-2.944 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.529-2.581 (m, 6H, 3 × - CH ₂ N), 2.455 (s, 3H, pyrrole-CH ₃ ), 2.040-2.079 (m, 2H, seven-membered ring-intra-CH ₂ ), 0.956-0.992 (t. 6H, 2 × -CH ₃ ).

Example 3

(Z) -5- (2-Diethylaminoethyl) -2- [5-fluoro-6- (4-fluorobenzylamino) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5,6, 7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

Stage 1

(5-Fluoro-2,4-dinitrophenyl) -acetic acid

(3-Fluorophenyl) -acetic acid 3a (31.5 g, 0.204 mol) was dissolved in sulfuric acid (64 ml, 98%) with stirring at room temperature, and a mixture (v: v = 1: 1, 100 ml) was added dropwise. ) nitric acid (65% -68%) and sulfuric acid (98%), while maintaining the temperature at about 35 ° C. After complete addition, the mixture was stirred at 35 ° C. When thin layer chromatography showed the disappearance of the starting materials, ice was added to the reaction mixture and filtered after ice melted to give the title compound (5-fluoro-2,4-dinitrophenyl) -acetic acid 3b (49 mg) as a light yellow oils.

MS m / z (ESI): 243.5 [M-1]

Stage 2

(2,4-diamino-5-fluorophenyl) -acetic acid

(5-Fluoro-2,4-dinitrophenyl) -acetic acid 3b (10 g, 38.7 mmol) was dissolved in 150 ml of methanol with stirring and added to a solution of palladium on activated carbon (1.5 g, 5%) at room temperature. The reaction mixture was hydrogenated at a hydrogen pressure of 0.3 MPa. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was filtered twice and concentrated under reduced pressure to obtain the title compound (2,4-diamino-5-fluorophenyl) -acetic acid 3c (7.12 g) as a brown solid substances for the next stage.

Stage 3

5-fluoro-6-aminoindol-2-one

(2,4-Diamino-5-fluorophenyl) -acetic acid 3c (7.12 g, 38.7 mmol) was dissolved in hydrochloric acid (100 ml, 1 mol / l) with stirring at room temperature. This solution was heated to reflux for 1 hour. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was cooled to room temperature, neutralized with sodium hydroxide solution (100 ml, 1 mol / L) in an ice-water bath, and extracted with ethyl acetate (125 ml × 4). The combined organic extracts were washed with saturated brine (100 ml), dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure to obtain the title compound 5-fluoro-6-aminoindol-2-one 3d (5, 3 g, 82.8% yield) as a yellow solid.

MC m / z (ESI): 165.3 [M-1]

Stage 4

5-Fluoro-6- (4-fluorobenzylamino) -1,3-dihydroindol-2-one

6-amino-5-fluoro-1,3-dihydro-indol-2-one 3d (2.26 g, 13.6 mmol) was dissolved in 40 ml of ethanol with stirring at room temperature, the resulting solution was cooled to 0 ° C in an ice-water bath and 4-fluorobenzaldehyde (1.5 ml, 13.6 mmol) was added to the solution. After complete addition, the resulting solution was stirred for 1 hour at room temperature, sodium borohydride (1.08 g, 28.5 mmol) was added and heated to reflux for 18 hours. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was naturally cooled to room temperature, ice water was added, and a lot of precipitate formed, which was filtered and washed with water (50 ml × 3). The residue was purified by silica gel column chromatography to obtain the title compound 5-fluoro-6- (4-fluorobenzylamino) -1,3-dihydroindol-2-one 3e (1.67 g, 45% yield) as a white solid substances.

MS m / z (ESI): 275 [M + 1]

Stage 5

(Z) -5- (2-Diethylaminoethyl) -2- [5-fluoro-6- (4-fluorobenzylamino) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5,6, 7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described for Step 10 of Example 1, with 5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 1j obtained in Step 9 of Example 1 and 5-fluoro-6- (4-fluorobenzylamino) -1,3-dihydroindol-2-one 3e as starting materials to give (Z) -5- (2-diethylaminoethyl) -2- [5-fluoro-6- (4-fluorobenzylamino) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5,6, 7.8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 3 (61 mg, yield 62.2%) as a reddish-brown solid.

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.416 (s, 1H, pyrrole-NH), 10.520 (s, 1H, indole-NH), 7.573-7.602 (d, 1H, -ArH), 7.366-7.401 (m, 2H, -ArH), 7.350 (s, 1H, -CH = C), 7.141-7.185 (m, 2H, -ArH), 6.410-6.415 (m, 1H, -ArH), 6.038-6.057 (d , 1H, -ArH), 4.346-4.361 ( d, 2H, aniline-CH _2), 3.466-3.501 (t, 2H, seven-membered ring intra-CH ₂ M), 3.336-3.364 (t, 2H, amide N seven-membered ring-external CH ₂ ), 2.907-2.944 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.529-2.581 (m, 6H, 3 × -CH ₂ N), 2.388 (s, 3H, pyrrole -CH ₃ ), 2.011-2.039 (m, 2H, seven-membered ring-intra-CH ₂ ), 0.967-1.063 (t, 6H, 2 × -CH ₃ ).

Example 4

(Z) -2- (7-Bromo-5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -5- (2-diethylaminoethyl) -3-methyl-5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

Stage 1

7-bromo-5-fluoro-1,3-dihydroindol-2-one

5-Fluoro-1,3-dihydroindol-2-one 4a (1.5 g, 0.01 mol) was dissolved in 15 ml of acetonitrile with stirring and N-bromosuccinimide (1.8 g, 0.01 mol) was added dropwise. at room temperature. After complete addition, the mixture was stirred overnight, and a lot of precipitate formed. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was filtered to obtain 7-bromo-5-fluoro-1,3-dihydroindol-2-one 4b (2 g, 87% yield) as a gray solid.

MS m / z (ESI): 228.3 [M-1]

Stage 2

(Z) -2- (7-Bromo-5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -5- (2-diethylaminoethyl) -3-methyl-5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described for Step 10 of Example 1, with 5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 1j obtained in step 9 of Example 1 and 7-bromo-5-fluoro-1,3-dihydro-indol-2-one 4b as starting materials to give (Z ) -2- (7-bromo-5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -5- (2-diethylaminoethyl) -3-methyl-5,6,7,8-tetrahydro 1H-pyrrolo [3,2-c] azepin-4-one 4 (55 mg, 61.1% yield) as a yellow solid.

MS m / z (ESI): 503.6 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.653 (s, 1H, pyrrole-NH), 11.181 (s, 1H, indole-NH), 7.848-7.876 (dd, 1H, -ArH), 7.794 (s , 1H, -CH = C), 7.242-7.270 (dd. 1H, -ArH), 3.485-3.520 (t, 2H, seven-membered ring-intra-CH ₂ N), 3.338-3.366 (t, 2Н, amide N seven-membered ring-external CH ₂ ), 2.932-2.969 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.527-2.582 (m, 6H, 3 × -CH ₂ N), 2.470 (s, 3H, pyrrole -CH ₃ ), 2.031-2.093 (m, 2H, seven-membered ring-intra-CH ₂ ), 0.954-0.990 (t, 6H, 2 × -CH ₃ ).

Example 5

(Z) -2- (5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -5- (2-diethylaminoethyl) -3-methyl-5,6,7,8-tetrahydro-1H- pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described in Step 10 of Example 1, with 5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 1j obtained in Step 9 of Example 1 and 5-bromo-1,3-dihydroindol-2-one as starting materials to give (Z) -2- (5- bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl) -5- (2-diethylaminoethyl) -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepine -4-one 5 (59 mg, 67.8% yield) as a yellow solid.

MS m / z (ESI): 485.5 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.660 (s, 1H, pyrrole-NH), 11.008 (s, 1H, indole-NH), 8.113-8.117 (d, 1H, -ArH), 7.803 (s , 1H, -CH = C), 7.260-7.286 (dd, 1H, -ArH), 6.825-6.845 (d, 1H, -ArH), 3.482-3.516 (t, 2H, seven-membered ring-intra-CH ₂ N) , 3.336-3.364 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.907-2.944 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.490-2.578 (m, 6H, 3 × - CH ₂ N), 2.464 (s, 3H, pyrrole-CH ₃ ), 2.039-2.067 (m, 2H, seven-membered ring-intra-CH ₂ ), 0.954-0.990 (t. 6H, 2 × -CH ₃ ).

Example 6

(Z) -5- (2-Diethylaminoethyl) -2- [4- (2,3-difluorophenyl) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5,6,7, 8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

Stage 1

4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1 H-indole

4-Bromo-1H-indole 6a (29.4 g, 150 mmol) was dissolved in 600 ml of dimethyl sulfoxide with stirring and bis (pinacolato) dibor (41.9 g, 165 mmol), potassium acetate (44.1 g, 450 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (3.6 g, 4.8 mmol) in an argon atmosphere. After complete addition, the reaction mixture was stirred at 80 ° C in an oil bath for 22 hours. When thin layer chromatography showed the disappearance of the starting materials, water (2 L) was added to the reaction mixture and extracted with ethyl acetate (2 L × 3). The combined organic extracts were washed with saturated brine (2 L × 5), dried over anhydrous sodium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and recrystallized to give 4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-indole 6b (20 g, 60% yield) in as a white solid.

MS m / z (ESI): 243.9 [M + 1]

Stage 2

4- (2,3-difluorophenyl) -1H-indole

4- (4,4,5,5-Tetramethyl- [1,3,2] dioxaborolan-2-yl) -1H-indole 6b (1.22 g, 5 mmol) was dissolved in 20 ml of tetrahydrofuran with stirring and 1 -bromo-2,3-difluorobenzene (0.97 g, 5 mmol), tetrakis (triphenylphosphine) palladium (0.17 g, 0.15 mmol) and a solution of sodium hydroxide (7 ml, 2 mol / l) in argon atmosphere . After complete addition, the reaction system was stirred at 75 ° C in an oil bath overnight. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was naturally cooled to room temperature and extracted with ethyl acetate (20 ml × 3). The combined organic extracts were washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4- (2,3-difluorophenyl) -1H-indole 6c (800 mg, 70% yield) as a white solid.

MS m / z (ESI): 228.4 [M-1]

Stage 3

4- (2,3-difluorophenyl) -1,3-dihydroindol-2-one

4- (2,3-Difluorophenyl) -1H-indole 6c (744 mg, 3.25 mmol) was dissolved in 12 ml of ethanol with stirring, and tert-butanol (21 ml), glacial acetic acid (6.4 ml) were successively added. and pyridinium tribromide (3.12 g, 9.7 mmol) at room temperature. After complete addition, the reaction mixture was stirred for 3 hours, glacial acetic acid (16 ml) and zinc dust (1.1 g, 16.25 mmol) were added and stirred for another 1 hour. The reaction mixture was filtered and concentrated under reduced pressure. Ethyl acetate (30 ml) was added to the residue, washed successively with water (10 ml), saturated sodium bicarbonate solution (10 ml) and saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered to remove the drying agent, and concentrated under reduced pressure with obtaining 4- (2,3-difluorophenyl) -1,3-dihydroindol-2-one 6d (780 mg, 97% yield) as a white solid.

MS m / z (ESI): 246.6 [M + 1]

Stage 4

(Z) -5- (2-Diethylaminoethyl) -2- [4- (2,3-difluorophenyl) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5,6,7, 8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described in Step 10 of Example 1, with 5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 1j obtained in step 9 of Example 1 and 4- (2,3-difluorophenyl) -1,3-dihydroindol-2-one 6d as starting materials to give (Z ) -5- (2-diethylaminoethyl) -2- [4- (2,3-difluorophenyl) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 6 (43 mg, 61.4% yield) as a yellow solid.

MS m / z (ESI): 519.6 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.531 (s, 1H, pyrrole-NH), 11.133 (s, 1H, indole-NH), 7.617-7.640 (m, 1H, -ArH), 7.429-7.442 (m, 1H, -ArH), 7.305-7.340 (m, 1H, -ArH), 7.232-7.270 (m, 1H, -ArH), 6.997-7.017 (d, 1H, -ArH), 6.874-6.893 (d , 1H, -ArH), 6.710 (s, 1H, -CH = C), 3.445-3.478 (t, 2H, seven-membered ring-intra-CH ₂ N), 3.313 (m, 2H, amide N, seven-membered ring-external CH ₂ ), 2.868-3.904 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.465-2.542 (m, 6H, 3 × -CH ₂ N), 2.002-2.032 (m, 2H, seven-membered ring - intra-CH ₂ ), 1.794 (s, 3H, pyrrole-CH ₃ ), 0.930-0.965 (t, 6H, 2 × -CH ₃ ).

Example 7

(Z) -N- {3- [5- (2-Diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2- ilmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -2-methoxyacetamide

Stage 1

N- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl) -2-methoxyacetamide

6-amino-5-fluoro-1,3-dihydroindol-2-one 3d (2.028 g, 12.2 mmol) was dissolved in 30 ml of tetrahydrofuran with stirring and 1.3 ml of pyridine was added to the solution at room temperature. The reaction system was cooled to about −50 ° C. in a dry ice / ethanol bath. To the above reaction system was added dropwise a solution of methoxyacetyl chloride (1.35 g, 12.5 mmol) in tetrahydrofuran (20 ml). After the addition was complete, the ethanol ice bath was removed and the reaction mixture was allowed to warm to room temperature and was stirred overnight. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was filtered. The resulting solid was washed with water (10 ml × 3) and recrystallized with methanol to give N- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl) -2-methoxyacetamide 7a (1 , 18 mg, yield 40.6%) as a gray solid.

MS m / z (ESI): 239.3 [M + 1]

Stage 2

(Z) -N- {3- [5- (2-Diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2- ilmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -2-methoxyacetamide

The title compound was prepared under the same conditions as described in Step 10 of Example 1, with 5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 1j obtained in step 9 of Example 1 and N- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl) -2- methoxyacetamide 7a as starting materials to give (Z) -N- {3- [5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3, 2-c] azepin-2-ylmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -2-methoxyacetamide 7 (37 mg, 53.6% yield) as brown solid.

MC m / z (ESI): 512.5 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.605 (s, 1H, pyrrole-NH), 10.893 (s, 1H, indole-NH), 9.320 (s, 1H, amide-NH), 7.838-7.866 ( d, 1H, -ArH), 7.350 (s, 1H, -CH = C), 7.540-7.556 (d, 1H, -ArH), 4.064 (s, 2H, -CH ₂ O), 3.483-3.517 (t, 2H, seven-membered ring-intra-CH ₂ N), 3.336-3.362 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 3.314 (s, 3H, -CH ₃ O), 2.902-2.939 (t. 2H, seven-membered ring-intra-CH ₂ C = C), 2.530-2.562 (m, 6H, 3 × -CH ₂ N), 2.444 (s, 3H, pyrrole-CH ₃ ), 2.037-2.066 (m, 2H, seven-membered ring -intra-CH ₂ ), 0.958-0.993 (t, 6H, 2 × -CH ₃ ).

Example 8

(S, Z) -N- {3- [5- (2-Diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine- 2-ylmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxypropionamide

Stage 1

Acetic acid 1- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl) -ethyl ether

5-Fluoro-6-amino-1,3-dihydroindol-2-one 3d (450 mg, 2.71 mmol) was dissolved in 10 ml of tetrahydrofuran with stirring at room temperature. The mixture was cooled to −45 ° C. in a dry ice and acetone bath, and 364 μl piperidine was added. A solution of acetic acid 1-chloro-carbonyl ethyl ester (423 mg, 2.71 mmol) in 10 ml of tetrahydrofuran was added dropwise to the above reaction system. After complete addition, the bath of dry ice and acetone was removed, and the reaction mixture was allowed to warm to room temperature and was stirred overnight. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was filtered. The filter cake was washed with water, and the resulting solid was dried to obtain the title compound - 1- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl) ethyl acetate acid 8a (840 mg) as a white solid, which was used directly in the next step.

MC m / z (ESI): 281.5 [M + 1]

Stage 2

N- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl) -2-hydroxypropionamide

Acetic acid 1- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl) -ethyl ether 8a (1.86 g, 6.4 mmol) was dissolved in 20 ml of methanol with stirring and 10 ml of water and a sodium hydroxide solution (10 ml, 0.7 mol / L) were added to the solution and stirred for 4 hours at room temperature. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was neutralized with hydrochloric acid (1 mol / L) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and dried to obtain N- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl) -2-hydroxypropionamide 8b (1.0 g, 70% yield) in the form of a white solid.

MS m / z (ESI): 239.6 [M + 1]

Stage 3

(S, Z) -N- {3- [5- (2-Diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine- 2-ylmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxypropionamide

The title compound was prepared under the same conditions as described in Step 10 of Example 1, with 5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 1j obtained in Step 9 of Example 1 and (S, Z) -N- (5-fluoro-2-oxo-2,3-dihydro-1H-indole-6 -yl) -2-hydroxypropionamide 8b as starting materials to obtain N- {3- [5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [ 3,2-c] azepin-2-ylmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxypropionamide 8 (28 mg, 40.8% yield) in the form of a yellow solid.

MS m / z (ESI): 512.4 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.594 (s, 1H, pyrrole-NH), 10.902 (s, 1H, indole-NH), 9.245 (s, 1H, amide-NH), 7.856-7.884 ( d, 1H, -ArH), 7.725-7.741 (d, 1H, -ArH), 7.663 (s, 1H, -CH = C), 6.057-6.070 (d, 1H, -ArH), 4.206-4.236 (q, 1H, -CHO), 3.480-3.514 (t, 2H, seven-membered ring-intra-CH ₂ N), 3.336-3.362 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.902-2.939 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.530-2.562 (m, 6H, 3 × -CH ₂ N), 2.443 (s, 3H, pyrrole-CH ₃ ), 2.037-2.066 (m, 2H, seven-membered ring -intra-CH ₂ ), 1.328-1.345 (d, 3H, -CH ₃ ), 0.958-0.993 (t, 6H, 2 × -CH ₃ ).

Example 9

(Z) -N- {3- [5- (2-Diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2- Ilmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxy-2-methylpropionamide

Stage 1

1- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl) -1-methylethyl ester of acetic acid

5-Fluoro-6-amino-1,3-dihydroindol-2-one 3d (410 mg, 2.47 mmol) was dissolved in 10 ml of tetrahydrofuran with stirring at room temperature. The mixture was cooled to −45 ° C. in a dry ice / acetone bath and piperidine (322 μl) was added. A solution of acetic acid 1-chlorocarbonyl-1-methylethyl ether (423 mg, 2.71 mmol) in tetrahydrofuran (10 ml) was added dropwise to the above reaction system. After the addition was complete, the dry ice-acetone bath was removed and the reaction mixture was allowed to warm to room temperature and was stirred overnight. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was filtered. The filter cake was washed with water, and the resulting solid was dried to give 1- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl) -1-methylethyl ether 9a (792 mg) ) as a white solid for the next step.

MS m / z (ESI): 293.7 [M-1]

Stage 2

N- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl) -2-hydroxy-2-methylpropionamide

Acetic acid 1- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl) ethyl ester 9a (2.035 g, 6.9 mmol) was dissolved in 20 ml of methanol with stirring, added to a solution of sodium hydroxide solution (20 ml, 0.7 mol / L) (20 ml) and stirred for 4 hours at room temperature. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was neutralized with hydrochloric acid (1 mol / L) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography and dried to obtain N- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl) -2-hydroxy-2-methylpropionamide 9b (900 mg, yield 59 , 2%) as a white solid.

MS m / z (ESI): 253.6 [M + 1]

Stage 3

(Z) -N- {3- [5- (2-Diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2- Ilmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxy-2-methylpropionamide

The title compound was prepared under the same conditions as described for Step 10 of Example 1, with 5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 1j obtained in step 9 of Example 1, and (Z) -N- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl ) -2-hydroxy-2-methylpropionamide 9b as starting materials to give N- {3- [5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8- hexahydropyrrolo [3,2-c] azepin-2-ylmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxy-2-methylpropionamide 9 (39 mg, yield 62.4%) as a yellow solid.

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.591 (s, 1H, pyrrole-NH), 10.900 (s, 1H, indole-NH), 9.284 (s, 1H, amide-NH), 7.862-7.890 ( d, 1H, -ArH), 7.774-7.791 (d, 1H, -ArH), 7.661 (s, 1H, -CH = C). 6.052 (s, 1H, -OH), 3.480-3.514 (t, 2H, seven-membered ring-intra-CH ₂ N), 3.334-3.361 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.902-2.939 ( t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.530-2.562 (m, 6H, 3 × -CH ₂ N), 2.443 (s, 3H, pyrrole-CH ₃ ), 2.037-2.066 (m, 2H, seven-membered ring-intra-CH ₂ ), 1.377 (s, 6H, 2 × -CH ₃ ), 0.958-0.993 (t, 6H, 2 × -CH ₃ ).

Example 10

(Z) -2- (5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-morpholin-4-yl-ethyl) -5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

Stage 1

3-Methyl-5- [3- (2-morpholin-4-yl-ethylamino) -propyl] -1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether

5- (3-Methanesulfonyloxypropyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 1g (5.812 g, 15 mmol) obtained in Step 6 of Example 1 and 2 -morpholin-4-yl-ethylamine (10.725 g, 82.5 mmol) was dissolved in a water bath at 30 ° C and stirred for 5.5 hours at room temperature. When thin layer chromatography showed the disappearance of starting materials, ethyl acetate (100 ml) and saturated brine (100 ml) were added to the reaction mixture, stirred for 5 minutes and separated into layers. The organic phase was washed with saturated brine (100 ml × 4), dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3-methyl-5- [3- (2-morpholin-4-yl-ethylamino) -propyl] -1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl 4-ethyl ether 10a (2.238 g, 87% yield) as a pale yellow oil.

MS m / z (ESI): 424.9 [M + 1]

Stage 2

3-Methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carboxylic acid tert-butyl ether

3-Methyl-5- [3- (2-morpholin-4-yl-ethylamino) -propyl] -1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether 10a (2.238 g, 5.29 mmol) was dissolved in 50 ml of toluene with stirring, and a solution of trimethylaluminum in toluene (3.9 ml, 2 mol / L, 7.9 mmol) was slowly added under argon. The reaction system was stirred for 30 minutes at room temperature until the white smoke ceased to stand out and was refluxed for another 3 hours in an oil bath. When thin layer chromatography showed the disappearance of the starting materials, the oil bath was removed, and the reaction mixture was quickly cooled with a small amount of water, adjusted to pH 8-10 with a dilute sodium hydroxide solution (2 mol / L), saturated brine (50 ml) was added, and extracted with ethyl acetate (50 ml × 3). The combined organic extracts were filtered through a layer of celite, concentrated under reduced pressure to obtain the title compound 3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7, 8-hexahydro-pyrrolo [3,2-c] azepine-2-carboxylic acid tert-butyl ether 10b (1.218 g, 61% yield) as a pale yellow solid.

MS m / z (ESI): 378.2 [M + 1]

Stage 3

3-Methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde

3-Methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carboxylic acid tert-butyl ether 10b (725 mg, 1.92 mmol) was dissolved in trifluoroacetic acid (2.6 ml, 34.2 mmol) in an ice-water bath with stirring. The reaction mixture was stirred at 40 ° C in a water bath for 5 minutes, triethoxymethane (0.42 ml, 2.5 mmol) was added in one portion at

-5 ° C in a bath with ice and water and stirred for 2 minutes. Then the bath with salt and water was removed, and the reaction mixture was allowed to warm to room temperature, it turned brown, and it was stirred for another 2 hours. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was quickly cooled with a small amount of water, adjusted to pH 8 with a dilute sodium hydroxide solution (2 mol / L) and extracted with dichloromethane (50 ml × 3). The combined organic extracts were concentrated under reduced pressure to obtain a reddish-brown solid. This solid was purified by silica gel column chromatography to obtain the title compound 3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [ 3,2-c] azepine-2-carbaldehyde 10c (240 mg, 40% yield) as a pale yellow solid.

MS m / z (ESI): 306.3 [M + 1]

Stage 4

(Z) -2- (5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-morpholin-4-yl-ethyl) -5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

3-Methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 10c (53 mg, 0.174 mmol) and 5-chloro-1,3-dihydroindol-2-one (29 mg, 0.84 mmol) were dissolved in 0.9 ml of ethanol with stirring, and piperidine (0.1 ml, 1 was added to the solution , 0 mmol) at room temperature. The mixture was heated to reflux for 2 hours in an oil bath, and a lot of precipitate formed. Then the oil bath was removed and the reaction mixture was naturally cooled to room temperature and filtered to give the title compound, (Z) -2- (5-chloro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) - 3-methyl-5- (2-morpholin-4-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 10 (30 mg, 38% yield) in the form of a red solid.

MS m / z (ESI): 455.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.682 (s, 1H, pyrrole-NH), 11.009 (s, 1H, indole-NH), 7.992-7.997 (d, 1H, -ArH), 7.804 (s , 1H, -CH = C), 7.138-7.164 (dd, 1H, -ArH), 6.873-6.894 (d, 1H, -ArH), 3.572-3.583 (m, 6H, N seven-membered ring-CH ₂ , 2 × -CH ₂ O), 3.346-3.360 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.938-2.974 (t, 2H, -CH ₂ C = C), 2.463 (s, 3H, pyrrole-CH ₃ ), 2.438-2.510 (m, 6H, 2 × -CH ₂ N), 2.054-2.083 (m, 2H, seven-membered ring-intra-CH ₂ ).

Example 11

(Z) -2- (5-Fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-morpholin-4-yl-ethyl) -5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was obtained under the same conditions as described for Step 4 of Example 10, with 3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7 , 8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 10c obtained in step 3 of Example 10, and 5-fluoro-1,3-dihydroindol-2-one as starting materials to give (Z) -2 - (5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-morpholin-4-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 11 (29 mg, 51.5% yield) as a yellow solid.

MS m / z (ESI): 439.3 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.727 (s, 1H, pyrrole-NH), 10.908 (s, 1H, indole-NH), 7.756-7.785 (dd, 1H, -ArH), 7.746 (s , 1H, -CH = C), 6.917-6.968 (m, 1H, -ArH), 6.838-6.871 (m, 1H, -ArH), 3.571-3.600 (m, 6H, N seven-membered ring-СН ₂ , 2 × -CH ₂ O), 3.344-3.371 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.934-2.971 (t, 2H, -CH ₂ C = C), 2.454 (s, 3H, pyrrole-CH ₃ ), 2.438-2.510 (m, 6H, 2 × -CH ₂ N), 2.053-2.082 (m, 2H, seven-membered ring-intra-CH ₂ ).

Example 12

(Z) -2- [4- (2,3-Difluorophenyl) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5- (2-morpholin-4-yl-ethyl) -5, 6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was obtained under the same conditions as described for Step 4 of Example 10, with 3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7 , 8-hexahydro-pyrrolo [3,2-c] azepin-2-carbaldehyde 10c obtained in step 3 of Example 10, and 4- (2,3-difluorophenyl) -1,3-dihydroindol-2-one 6d obtained in step 3 of Example 6, as starting materials to obtain (Z) -2- [4- (2,3-difluorophenyl) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5- (2 -morpholin-4-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 12 (20 mg, 29% yield) as a yellow solid.

MS m / z (ESI): 533.3 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.546 (s, 1H, pyrrole-NH), 11.135 (s, 1H, indole-NH), 7.598-7.662 (m, 1H, -ArH), 7.409-7.461 (m, 1H, -ArH), 7.306-7.343 (m, 1H, -ArH), 7.234-7.273 (m, 1H, -ArH), 6.700-7.019 (d, 1H, -ArH), 6.875-6.894 (d , 1H, -ArH), 6.712 (s, 1H, -CH = C), 3.547-3.560 (m, 6H, N seven-membered ring-CH ₂ , 2 × -CH ₂ O), 3.295-3.310 (t, 2H, amide N seven-membered ring-external CH ₂ ), 2.897-2.933 (t, 2H, -CH ₂ C = С), 2.410-2.510 (m, 6H, 2 × -CH ₂ N), 1.999-2.061 (m, 2H, seven membered ring-intra-CH ₂ ), 1.794 (s, 3H, pyrrole-CH ₃ ).

Example 13

(Z) -2- (4-Bromo-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -5- (2-diethylaminoethyl) -3-methyl-5,6,7,8-tetrahydro-1H- pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described for Step 10 of Example 1, with 5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 1j obtained in Step 9 of Example 1 and 4-bromo-1,3-dihydroindol-2-one as starting materials to give (Z) -2- (4- bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl) -5- (2-diethylaminoethyl) -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepine -4-one 13 (30 mg, yield 45.5%) as an orange solid.

MS m / z (ESI): 585.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.634 (s, 1H, pyrrole-NH), 11.184 (s, 1H, indole-NH), 8.589 (s, 1H, -CH = C), 7.220-7.240 (d, 1H, -ArH), 7.056-7.096 (m, 1H, -ArH), 6.938-6.957 (d, 1H, -ArH), 3.491-3.524 (t, 2H, seven-membered ring-intra-CH ₂ N) , 3.346-3.373 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.930-2.966 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.508-2.569 (m, 6H, 3 × - CH ₂ N), 2.412 (s, 3H, pyrrole-CH ₃ ), 2.030-2.095 (m, 2H, seven-membered ring-intra-CH ₂ ), 0.959-0.994 (t, 6H, 2 × -CH ₃ ).

Example 14

(Z) -2- (5-Bromo-2-oxo-1,2-dihydropyrrolo [2,3-b] pyridin-3-ylidenemethyl) -5- (2-diethylaminoethyl) -3-methyl-5,6, 7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described for Step 10 of Example 1, with 5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 1j obtained in step 9 of Example 1 and 5-bromo-1,3-dihydropyrrolo [2,3-b] pyridin-2-one as starting materials to give ( Z) -2- (5-bromo-2-oxo-1,2-dihydropyrrolo [2,3-b] pyridin-3-ylidenemethyl) -5- (2-diethylaminoethyl) -3-methyl-5,6,7 , 8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 14 (23 mg, 33.8% yield) as an orange solid.

MS m / z (ESI): 486.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.472 (s, 1H, pyrrole-NH), 11.636 (s, 1H, indole-NH), 8.487 (s, 1H, pyridine-CH), 8.116 (s, 1H, pyridine-CH), 7.889 (s, 1H, -CH = C), 3.505 (t, 2H, seven-membered ring-intra-CH ₂ N), 3.354 (t, 2H, amide N, seven-membered ring-external CH ₂ ) , 2.930-2.966 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.508-2.569 (m, 6H, 3 × -CH ₂ N), 2.472 (s, 3H, pyrrole-CH ₃ ), 2.030 -2.095 (m, 2H, seven-membered ring-intra-CH ₂ ), 0.959-0.994 (t, 6H, 2 × -CH ₃ ).

Example 15

(Z) -5- (2-Diethylaminoethyl) -2- (6-methoxy-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5,6,7,8-tetrahydro-1H- pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described for Step 10 of Example 1, with 5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 1j obtained in Step 9 of Example 1 and 6-methoxy-1,3-dihydroindol-2-one as starting materials to give (Z) -5- (2- diethylaminoethyl) -2- (6-methoxy-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepine -4-one 15 (31 mg, yield 52.7%) as a red solid.

MS m / z (ESI): 437.4 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.466 (s, 1H, pyrrole-NH), 10.852 (s, 1H, indole-NH), 7.670-7.691 (d, 1H, -ArH), 7.496 (s , 1H, -CH = C), 6.575-6.596 (d, 1H, -ArH), 6.463 (s, 1H, -ArH), 3.769 (s, 3H, -CH ₃ ), 3.477-3.510 (t, 2H, seven-membered ring-intra-CH ₂ N), 3.316-3.347 (t, 2H, amide N seven-membered ring-external CH ₂ ), 2.888-2.924 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.489- 2.573 (m, 6H, 3 × -CH ₂ N), 2.416 (s, 3H, pyrrole-CH ₃ ), 2.030-2.095 (m, 2H, seven-membered ring-intra-CH ₂ ), 0.954-0.982 (t, 6H , 2 × -CH ₃ ).

Example 16

(Z) -5- (2-Diethylaminoethyl) -3-methyl-2- (4-methyl-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -5,6,7,8-tetrahydro-1H- pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described for Step 10 of Example 1, with 5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 1j obtained in Step 9 of Example 1 and 4-methyl-1,3-dihydroindol-2-one as starting materials to give (Z) -5- (2- diethylaminoethyl) -3-methyl-2- (4-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepine -4-one 16 (25 mg, 44.1% yield) as a yellow solid.

MS m / z (ESI): 421.5 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.710 (s, 1H, pyrrole-NH), 10.927 (s. 1H, indole-NH), 7.566 (s, 1H, -CH = C), 7.034-7.072 (m, 1H, -ArH), 6.768-6.835 (dd, 2H, -ArH), 3.483-3.517 (t, 2H, seven membered ring-intra-CH ₂ N), 3.339-3.366 (t, 2H, amide N seven ring-external CH ₂ ), 2.909-2.946 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.489-2.573 (m, 6H, 3 × -CH ₂ N), 2.590 (s, 3H, benzene -CH ₃ ), 2.386 (s, 3H, pyrrole-CH ₃ ), 2.041-2.069 (m, 2H, seven-membered ring-intra-CH ₂ ), 0.956-0.991 (t, 6H, 2 × -CH ₃ ).

Example 17

(Z) -5- (2-Diethylaminoethyl) -2- [4- (2-hydroxyethyl) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described for Step 10 of Example 1, with 5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 1j obtained in step 9 of Example 1 and 4- (2-hydroxyethyl) -1,3-dihydroindol-2-one as starting materials to give (Z) -5 - (2-diethylaminoethyl) -2- [4- (2-hydroxyethyl) -2-oxo-1,2-dihydro-indol-3-ylidenomethyl] -3-methyl-5,6,7,8-tetrahydro-1H -pyrrolo [3,2-c] azepin-4-one 17 (18 mg, yield 29.5%) as a yellow solid.

MC m / z (ESI): 451.5 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.722 (s, 1H, pyrrole-NH), 10.924 (s, 1H, indole-NH), 7.652 (s, 1H, -CH = C), 7.045-7.065 (m, 1H, -ArH), 6.772-6.847 (dd, 2H, -ArH), 4.871 (s, 1H, -OH), 3.726-3.739 (t, 2H, amide N, seven-membered ring-external CH ₂ O), 3.486-3.502 (t, 2H, seven-membered ring-intra-CH ₂ N), 3.342-3.556 (t, 2H, -CH ₂ ), 3.095 (t, 2H, benzene-CH ₂ ), 2.910-2.946 (t, 2H , seven-membered ring-intra-CH ₂ C = C), 2.504-2.566 (m, 6H, 3 × -CH ₂ N), 2.398 (s, 3H, pyrrole-CH ₃ ), 2.092 (m, 2H, seven-membered ring intra-CH ₂ ), 0.957-0.993 (t, 6H, 2 × -CH ₃ ).

Example 18

(Z) -N- {5-Fluoro-3- [3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3, 2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-methoxyacetamide

The title compound was obtained under the same conditions as described for Step 4 of Example 10, with 3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7 , 8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 10c obtained in step 3 of Example 10, and N- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl ) -2-methoxyacetamide 7a, obtained in step 1 of Example 7, as starting materials to give (Z) -N- {5-fluoro-3- [3-methyl-5- (2-morpholin-4-yl-ethyl) - 4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} - 2-methoxyacetamide 18 (47 mg, 60% yield) as a yellow solid Twa.

MS m / z (ESI): 526.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.608 (s, 1H, pyrrole-NH), 10.884 (s, 1H, indole-NH), 9.308 (s, 1H, -NHCO), 7.827-7.854 (d , 1H, -ArH), 7.659 (s, 1H, -CH = C), 7.534-7.550 (d, 1H, -ArH), 4.056 (s, 2H, -CH ₂ O), 3.561-3.571 (m, 6H , N seven-membered ring is CH ₂ , 2 × -CH ₂ O), 3.397 (s, 3H, -CH ₃ O), 3.331-3.345 (t, 2H, amide N is a seven-membered ring is external CH ₂ ), 2.918-2.954 ( t, 2H, -CH ₂ C = C), 2.432 (s, 3H, pyrrole-CH ₃ ), 2.431-2.500 (m, 6H, 2 × -CH ₂ N), 2.040-2.067 (m, 2H, seven-membered ring Intra-CH ₂ ).

Example 19

(Z) -2- [5-Fluoro-6- (4-fluorobenzylamino) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5- (2-morpholin-4-yl-ethyl) - 5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described in Step 4 of Example 10, with 3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7 , 8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 10c obtained in step 3 of Example 10, and 5-fluoro-6- (4-fluorobenzylamino) -1,3-dihydroindol-2-one 3e obtained in step 4 of Example 3, as starting materials, to give (Z) -2- [5-fluoro-6- (4-fluorobenzylamino) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl- 5- (2-morpholin-4-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 19 (57 mg, 69% yield) as a carmine solid substances.

MS m / z (ESI): 526.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.423 (s, 1H, pyrrole-NH), 10.515 (s, 1H, indole-NH), 7.565-7.595 (d, 1H, -ArH), 7.359-7.394 (m, 2H, -ArH), 7.343 (s, 1H, -CH = C), 7.134-7.177 (m, 1H, -ArH), 6.404 (m, 1H, -NH), 6.032-3.051 (d, 1H , -ArH), 4.399-4.353 (d, 2H, aniline-CH ₂ ), 3.544-3.555 (m, 6H, N seven-membered ring-CH ₂ , 2 × -CH ₂ O), 3.310-3.326 (t, 2H, amide N seven-membered ring-external CH ₂ ), 2.870-2.906 (t, 2H, -CH ₂ C = C), 2.378 (s, 3H, pyrrole-CH ₃ ), 2.416-2.500 (m, 6H, 2 × -CH ₂ N), 2.014-2.041 (m, 2H, seven membered ring-intra-CH ₂ ).

Example 20

(Z) -N- {5-Fluoro-3- [3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3, 2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-7-yl} -formamide

Stage 1

5-fluoro-7-nitroindol-2-one

5-Fluoro-1,3-dihydroindol-2-one 4a (5.0 g, 33 mmol) was dissolved in sulfuric acid (17.6 ml, 98%) with stirring at -5 ° C, and nitric acid was added to the solution (2.1 ml, 65% -68%), while maintaining the temperature below 0 ° C. After complete addition, the mixture was stirred at room temperature for 1 hour. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was poured into ice water and filtered after the ice had melted. The filter cake was washed three times with water, and the resulting solid was recrystallized to give the title compound 5-fluoro-7-nitro-1,3-dihydroindol-2-one 20a (4.0 g, yield 62.5 %) as an orange solid.

MC m / z (ESI): 196.3 [M + 1]

Stage 2

7-amino-5-fluoro-1,3-dihydroindol-2-one

5-Fluoro-7-nitro-1,3-dihydroindol-2-one 20a (4.0 g, 20 mmol) was dissolved in 200 ml of acetic acid with stirring and palladium on activated carbon (1.0 g, 5%) was added. at room temperature. The reaction system was stirred in a hydrogen atmosphere. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was filtered and concentrated under reduced pressure to obtain the title compound 7-amino-5-fluoro-1,3-dihydroindol-2-one 20b (3.2 g, yield 97 , 5%) as a white solid.

MC m / z (ESI): 167.4 [M + 1]

Stage 3

5-Fluoro-7-formamidoindol-2-one

A mixture of acetic anhydride (0.8 ml) and formic acid (0.6 ml) was stirred for 1 hour at room temperature, and 7-amino-5-fluoro-1,3-dihydroindol-2-one 20b was added to the above mixture. (2.0 g, 12 mmol) in 30 ml of tetrahydrofuran followed by piperidine (0.02 ml). The resulting mixture was stirred for 3 hours until a precipitate formed, filtered to give a crude product (1.95 g) and recrystallized from methanol to give the title compound, 5-fluoro-7-formamidoindol-2-one 20s (700 mg, yield 30.4%) as a white solid.

MC m / z (ESI): 195.1 [M + 1]

Stage 4

(Z) -N- {5-Fluoro-3- [3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3, 2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-7-yl} -formamide

The title compound was prepared under the same conditions as described in Step 4 of Example 10, with 3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7 , 8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 10c obtained in step 3 of Example 10, and N- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl ) -formamide 20c as starting materials to give (Z) -N- {5-fluoro-3- [3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4, 5,6,7,8-hexahydro-pyrrolo [3,2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-7-yl} -formamide 20 (37 mg, yield 52 %) as an orange solid.

MS m / z (ESI): 480.2 [M-1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.655 (s, 1H, pyrrole-NH), 10.424 (s, 1H, indole-NH), 9.801 (s, 1H, -NHCO), 8.330 (s, 1H , -CHO), 7.757 (s, 1H, -CH = C), 7.610-7.633 (d, 1H, -ArH), 7.428-7.461 (dd, 1H, -ArH), 3.562-3.592 (m, 6H, N seven-membered ring-CH ₂ , 2 × -CH ₂ O), 3.331-3.345 (t, 2H, amide N seven-membered ring-external CH ₂ ), 2.935-2.971 (t, 2H, -CH ₂ C = C), 2.451 ( s, 3H, pyrrole-CH ₃ ), 2.431-2.500 (m, 6H, 2 × -CH ₂ N), 2.046-2.074 (m, 2H, seven-membered ring-intra-CH ₂ ).

Example 21

(S, Z) -N- {5-Fluoro-3- [3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [ 3,2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxypropionamide

The title compound was obtained under the same conditions as described for Step 4 of Example 10, with 3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7 , 8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 10c obtained in step 3 of Example 10, and N- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl ) -2-hydroxypropionamide 8b obtained in step 2 of Example 8 as starting materials to give (S, Z) -N- {5-fluoro-3- [3-methyl-5- (2-morpholin-4-yl-ethyl) ) -4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl } -2-hydroxypropionamide 21 (44 mg, 58% yield) as an orange solid of a substance.

MS m / z (ESI): 526.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.599 (s, 1H, pyrrole-NH), 10.895 (s, 1H, indole-NH), 9.236 (s, 1H, -NHCO), 7.846-7.874 (d , 1H, -ArH), 7.718-7.734 (d, 1H, -ArH), 7.663 (s, 1H, -CH = C), 6.051-6.064 (d, 1H, -OH), 4.199-4.229 (t, 1H , -CHO), 3.560-3.586 (m, 6H, N seven-membered ring-CH ₂ , 2 × -CH ₂ O), 3.331-3.345 (t, 2H, amide N seven-membered ring-external CH ₂ ), 2.918-2.954 ( t, 2H, -CH ₂ C = C), 2.456 (s, 3H, pyrrole-CH ₃ ), 2.431-2.500 (m, 6H, 2 × -CH ₂ N), 2.048-2.077 (m, 2H, seven-membered ring -intra-CH ₂ ), 1.321-1.338 (d, 2H, -CH ₃ ).

Example 22

(Z) -2- (5-Bromo-2-oxo-1,2-dihydropyrrolo [2,3-b] pyridin-3-ylidenemethyl) -3-methyl-5- (2-morpholin-4-yl-ethyl) - 5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was obtained under the same conditions as described for Step 4 of Example 10, with 3-methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7 , 8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 10c obtained in step 3 of Example 10, and 5-bromo-1,3-dihydropyrrolo [2,3-b] pyridin-2-one as the starting materials substances to give (Z) -2- (5-bromo-2-oxo-1,2-dihydropyrrolo [2,3-b] pyridin-3-ylidenomethyl) -3-methyl-5- (2-morpholin-4- ilethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 22 (59 mg, 60% yield) as an orange solid.

MC m / z (ESI): 500.0 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.474 (s, 1H, pyrrole-NH), 11.004 (s, 1H, indole-NH), 8.475 (d, 1H, pyridine-CH), 8.102-8.107 ( d, 1H, pyridine-CH), 7.873 (s, 1H, -CH = C), 3.560-3.591 (m, 6H, N seven-membered ring-CH ₂ , 2 × -CH ₂ O), 3.336-3.364 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.946-2.983 (t, 2H, -CH ₂ C = C), 2.456 (s, 3H, pyrrole-CH ₃ ), 2.425-2.500 (m, 6H, 2 × -CH ₂ N), 2.048-2.077 (m, 2H, seven-membered ring-intra-CH ₂ ).

Example 23

(Z) -2- (5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -5- (2-dimethylaminoethyl) -3-methyl-5,6,7,8-tetrahydro-1H- pyrrolo [3,2-c] azepin-4-one

Stage 1

5- [3- (2-Dimethylaminoethylamino) propyl] -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester

5- (3-Methanesulfonyloxypropyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 1g (11.964 g, 25.7 mmol) obtained in step 6 of Example 1, dissolved in N, N-dimethylethylenediamine (12 ml, 97 mmol), the resulting solution was stirred for 5 hours at room temperature. When thin layer chromatography showed the disappearance of the starting materials, ethyl acetate (80 ml) and saturated brine (80 ml) were added to the reaction mixture, stirred for 5 minutes and separated into layers. The organic phase was washed with saturated brine (80 ml × 4) to remove N, N-dimethylethylenediamine, dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure to obtain a brown oil. This residue was purified by silica gel column chromatography to obtain the title compound 5- [3- (2-dimethylaminoethylamino) propyl] -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4 ethyl ester 23a (5.85 g, yield 45.9%) as a yellow oil.

MS m / z (ESI): 382.2 [M + 1]

Stage 2

5- (2-Dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine-2-carboxylic acid tert-butyl ether

5- [3- (2-Dimethylaminoethylamino) propyl] -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether 23a (5.85 g, 13.8 mmol) dissolved in 130 ml of toluene with stirring, and a solution of trimethylaluminum in toluene (12 ml, 2 mol / l, 24 mmol) under argon was slowly added to the solution. After complete addition, the reaction mixture was stirred for 10 minutes at room temperature until the white smoke ceased to stand out and heated to reflux for 3 hours in an oil bath. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was rapidly cooled with ice water. After naturally cooling the reaction system to room temperature, hydrochloric acid solution (50 ml, 2 mol / L) was added to the mixture and stirred for 10 minutes. The mixture was adjusted to pH 9 with an aqueous solution of sodium hydroxide (2 mol / L) and extracted with dichloromethane (50 ml × 4). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure to obtain the title compound 5- (2-dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6 , 7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carboxylic acid tert-butyl ester 23b (3.3 g, 71.4% yield) as a yellow solid.

MS m / z (ESI): 336.2 [M + 1]

Stage 3

5- (2-Dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde

5- (2-Dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carboxylic acid tert-butyl ether 23b (774 mg , 2.3 mmol) was dissolved in trifluoroacetic acid (3.1 ml, 20 mmol) with stirring, the resulting solution was heated at 40 ° C for 5 minutes in an oil bath under argon atmosphere. The reaction mixture was cooled to -5 ° C in an ice salt bath with stirring, triethoxymethane (0.5 ml, 3.0 mmol) was added and stirred for 2 minutes. Then the ice salt bath was removed, and the reaction mixture was allowed to warm to room temperature and was stirred for another 1 hour. When thin layer chromatography showed the disappearance of the starting materials, ice water (3 ml) and dichloromethane (10 ml) were added to the reaction mixture, adjusted to pH 11 with an aqueous solution of sodium hydroxide (2 mol / L) and extracted with dichloromethane (10 ml × 3). The combined organic extracts were dried over anhydrous mathium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure to give a reddish brown oil. This residue was purified by silica gel column chromatography to obtain the title compound 5- (2-dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-s ] azepine-2-carbaldehyde 23c (223 mg, 37% yield) as a yellow oil.

MC m / z (ESI): 264.2 [M + 1]

Stage 4

(Z) -2- (5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -5- (2-dimethylaminoethyl) -3-methyl-5,6,7,8-tetrahydro-1H- pyrrolo [3,2-c] azepin-4-one

5- (2-Dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 23c (53 mg, 0.2 mmol ) was dissolved in 1 ml of methanol with stirring, and 5-chloro-1,3-dihydroindol-2-one (34 mg, 0.2 mmol) and piperidine (0.1 ml) were added to the solution. After complete addition, the mixture was stirred to mix well in the dark, heated to reflux for 2 hours, and a lot of precipitate formed. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with ethanol and dried to give the title compound, (Z) -2- (5-chloro-2-oxo-1.2-dihydroindol-3-ylidenemethyl) -5- (2-dimethylaminoethyl) -3-methyl- 5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 23 (62 mg, 75% yield) as an orange powder.

MC m / z (ESI): 413.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.667 (s, 1H, pyrrole-NH), 11.004 (s, 1H, indole-NH), 7.990 (s, 1H, -ArH), 7.799 (s, 1H , -CH = C), 7.134-7.159 (m, 1H, -ArH), 6.869-6.890 (m, 1H, -ArH), 3.533-3.567 (t, 2H, N seven-membered ring-СН ₂ ), 3.336-3.364 (t, 2H, amide N seven-membered ring-external CH ₂ ), 2.909-2.945 (t, 2H, -CH ₂ C = C), 2.463 (s, 3H, pyrrole-CH ₃ ), 2.401-2.434 (t, 2H , -CH ₂ N), 2.204 (s, 6H, 2 × -CH ₂ N), 2.035-2.079 (m, 2H, seven-membered ring-intra-CH ₂ ).

Example 24

(Z) -2- (5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -5- (2-dimethylaminoethyl) -3-methyl-5,6,7,8-tetrahydro-1H- pyrrolo [3,2-c] azepin-4-one

The title compound was obtained under the same conditions as described for Step 4 of Example 23, with 5- (2-dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 23c obtained in step 3 of Example 23 and 5-bromo-1,3-dihydroindol-2-one as starting materials to give (Z) -2- (5- bromo-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -5- (2-dimethylaminoethyl) -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepine -4-one 24 (71 mg, 77% yield) as a red solid.

MS m / z (ESI): 457.0 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.663 (s, 1H, pyrrole-NH), 11.011 (s, 1H, indole-NH), 8.118 (s, 1H, -ArH), 7.804 (s, 1H , -CH = C), 7.262-7.287 (m, 1H, -ArH), 6.826-6.847 (m, 1H, -ArH), 3.533-3.567 (t, 2H, N seven-membered ring-СН ₂ ), 3.336-3.364 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.909-2.945 (t, 2H, -CH ₂ C = C), 2.465 (s, 3H, pyrrole-CH ₃ ), 2.401-2.434 (t, 2H , -CH ₂ N), 2.204 (s, 6H, 2 × -CH ₂ N), 2.035-2.079 (m, 2H, seven membered ring-intra-CH ₂ ).

Example 25

(Z) -5- (2-Dimethylaminoethyl) -2- (5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5,6,7,8-tetrahydro-1H- pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described for Step 4 of Example 23, with 5- (2-dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [ 3,2-c] azepin-2-carbaldehyde 23c obtained in step 3 of Example 23 and 5-fluoro-1,3-dihydroindol-2-one as starting materials to give (Z) -5- (2-dimethylaminoethyl ) -2- (5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepine- 4-one 25 (205 mg, 68% yield) as a red solid.

MS m / z (ESI): 397.0 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.714 (s, 1H, pyrrole-NH), 10.904 (s, 1H, indole-NH), 7.760-7.783 (m, 1H, -ArH), 7.744 (s , 1H, -CH = C), 6.915-6.943 (m, 1H, -ArH), 6.836-6.868 (m, 1H, -ArH), 3.533-3.567 (t, 2H, N seven-membered ring-CH ₂ ), 3.336 -3.364 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.909-2.945 (t, 2H, -CH ₂ С = С), 2.457 (s, 3Н, pyrrole-CH ₃ ), 2.401-2.434 (t , 2H, -CH ₂ N), 2.204 (s, 6H, 2 × -CH ₃ N), 2.035-2.079 (m, 2H, seven-membered ring-intra-CH ₂ ).

Example 26

(Z) -N- {3- [5- (2-Dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2- ilmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl} -formamide

The title compound was obtained under the same conditions as described for Step 4 of Example 23, with 5- (2-dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 23c obtained in step 3 of Example 23 and N- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl) -formamide 20c obtained in stage 3 of Example 20 as starting materials to give (Z) -N- {3- [5- (2-dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7, 8-hexahydro-pyrrolo [3,2-c] azepin-2-ylmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl} -formamide 26 (71 mg, 79% yield) in the form of a red solid.

MC m / z (ESI): 440.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.653 (s, 1H, pyrrole-NH), 10.437 (s, 1H, indole-NH), 9.814 (s, 1H, -NHCO), 8.339 (s, 1H , -CH = O), 7.768 (s, 1H, -CH = C), 7.621-7.649 (m, 1H, -ArH), 7.440-7.473 (m, 1H, -ArH), 3.533-3.567 (t, 2H , N seven-membered ring -CH ₂ ), 3.336-3.364 (t, 2H, amide N seven-membered ring-external CH ₂ ), 2.919-2.955 (t, 2H, -CH ₂ C = C), 2.463 (s, 3H, pyrrole -CH ₃ ), 2.403-2.436 (t, 2H, -CH ₂ N), 2.204 (s, 6H, 2 × -CH ₃ N), 2.035-2.079 (m, 2H, seven-membered ring-intra-CH ₂ ).

Example 27

(Z) -N- {3- [5- (2-Dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2- ilmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxyacetamide

Stage 1

Acetic acid (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl) methyl ether

6-amino-5-fluoro-1,3-dihydroindol-2-one 3d (500 mg, 3.0 mmol) was dissolved in 10 ml of tetrahydrofuran with stirring and 0.4 ml of pyridine was added to the solution at room temperature. After stirring to achieve good mixing, the mixture was cooled to -40 ° C in a dry ice-acetone bath. To the above reaction system was added dropwise acetic acid chlorocarbonyl methyl ether (420 mg, 3.0 mmol) in 10 ml of tetrahydrofuran. After the addition was complete, the dry ice-acetone bath was removed and the reaction mixture was allowed to warm to room temperature and was stirred overnight. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was filtered. The resulting solid was washed with water three times and dried to give the title compound, acetic acid (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl) methyl ether 27a (562 mg, yield 70.4%) as a gray solid.

MS: 265.3 [M-1]

Stage 2

N- (5-Fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl) -2-hydroxyacetamide

Acetic acid (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl) methyl ester 27a (58 mg, 0.22 mmol) was dissolved in 1 ml of methanol with stirring and added to solution 1 ml of water and sodium hydroxide (15 mg, 0.375 mmol) at room temperature. After complete addition, the reaction mixture was stirred for another 1 hour. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was filtered. The resulting solid was washed with water three times and dried to give the title compound, N- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl) -2-hydroxyacetamide 27b ( 46 mg, yield 93.8%) as a gray solid.

MS: 223.7 [M-1]

Stage 3

(Z) -N- {3- [5- (2-Dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2- ilmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxyacetamide

The title compound was obtained under the same conditions as described for Step 4 of Example 23, with 5- (2-dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 23c obtained in step 3 of Example 23 and N- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl) -2- hydroxyacetamide 27b as starting materials to give (Z) -N- {3- [5- (2-dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3, 2-c] azepin-2-ylmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxyacetamide 27 (80 mg, 83.4% yield) as orange solid.

MS m / z (ESI): 470.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.599 (s, 1H, pyrrole-NH), 10.893 (s, 1H, indole-NH), 9.233 (s, 1H, -NHCO), 7.854-7.879 (m , 1H, -ArH), 7.725 (s, 1H, -CH = C), 7.663-7.688 (m, 1H, -ArH), 5.950 (s, 1H, -OH), 4.053 (s, 2H, -CH ₂ O), 3.544 (t, 2H, N seven-membered ring-CH ₂ ), 3.315-3.340 (t, 2H, amide N seven-membered ring-external CH ₂ ), 2.924 (t, 2H, -CH ₂ C = C), 2.464 (t, 2H, -CH ₂ N), 2.442 (s, 3H, pyrrole-CH ₃ ), 2.199 (s, 6H, 2 × -CH ₃ N), 2.044 (m, 2H, seven-membered ring-intra-CH ₂ )

Example 28

(Z) -2- [4- (2,3-Difluorophenyl) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -5, 6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

Stage 1

3-Methyl-5- [3- (2-pyrrolidin-1-yl-ethylamino) -propyl] -1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether

5- (3-Methanesulfonyloxypropyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 1g (8.462 g, 21.75 mmol) was dissolved in 2-pyrrolidin-1- ilethylamine (6.3 ml, 49.79 mmol) with stirring and the resulting solution was stirred at room temperature overnight. When thin layer chromatography showed the disappearance of the starting materials, ethyl acetate (200 ml) and a small amount of methanol were added to the reaction mixture until a clear solution was obtained. The mixture was washed with water (30 ml × 3), saturated brine (40 ml × 2) and concentrated under reduced pressure to obtain a light brown oil. This oil was purified by silica gel column chromatography to obtain the title compound 3-methyl-5- [3- (2-pyrrolidin-1-yl-ethylamino) -propyl] -1H-pyrrole-2,4-dicarboxylic acid 2-tert 4-ethyl ester 28a-butyl ether (4.488 g, 63.5% yield) as a yellow oil.

MS m / z (ESI): 406.5 [M-1]

Stage 2

3-Methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carboxylic acid tert-butyl ether

3-Methyl-5- [3- (2-pyrrolidin-1-yl-ethylamino) -propyl] -1H-pyrrol-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether 28a (6.754 g, 16.6 mmol) was dissolved in 150 ml of toluene with stirring, and a solution of trimethylaluminum in toluene (16.6 ml, 2 mol / L, 33.2 mmol) was slowly added to the solution under argon atmosphere. The reaction mixture was stirred for 20 minutes at room temperature until the white smoke ceased to stand out and was refluxed for another 3.5 hours in an oil bath. When thin layer chromatography showed the disappearance of starting materials, the oil bath was removed. The reaction mixture was quickly cooled with a small amount of ethanol (95%), ethyl acetate (100 ml) was added, filtered through a pad of celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydropyrrolo [3, 2-c] azepine-2-carboxylic acid mpem-butyl ether 28b (3.894 g, yield 65%) as a yellow oil.

MS m / z (ESI): 362.2 [M + 1]

Stage 3

3-Methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde

3-Methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carboxylic acid tert-butyl ether 28b (3.562 g, 9.87 mmol) was dissolved in 50 ml of dichloromethane with stirring and trifluoroacetic acid (19.7 ml, 260 mmol) was added to the solution at room temperature. After complete addition, the mixture was heated to reflux for 30 minutes in an oil bath. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was cooled to -5 ° C in an ice salt bath, triethoxymethane (2.96 ml, 14.8 mmol) was added in one portion, stirred at

-5 ° C for 5 minutes, and for another 1 hour at room temperature. Water (25 ml) was added to the reaction system, adjusted to approximately pH 11 with a dilute sodium hydroxide solution (2 mol / L), and extracted with dichloromethane (100 ml × 3). The combined organic extracts were concentrated under reduced pressure to obtain a reddish brown oil. This oil was purified by silica gel column chromatography to obtain the title compound 3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3 , 2-c] azepine-2-carbaldehyde 28c (1.116 g, 49% yield) as a yellow solid.

MS m / z (ESI): 290.2 [M + 1]

Stage 4

(Z) -2- [4- (2,3-Difluorophenyl) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -5, 6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

3-Methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 28c (40 mg, 0.134 mmol) and 4- (2,3-difluorophenyl) -1,3-dihydroindol-2-one 6d obtained in step 3 of Example 6 were dissolved in 0.3 ml of methanol with stirring, and piperidine was added to the solution (0, 03 ml, 0.3 mmol). After complete addition, the mixture was stirred at room temperature overnight. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was concentrated under reduced pressure to obtain the title compound, (Z) -2- [4- (2,3-difluorophenyl) -2-oxo-1,2-dihydroindole-3 -ilidenmethyl] -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 28 (40 mg, yield 57%) as a yellow solid.

MC m / z (ESI): 517.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.532 (s, 1H, pyrrole-NH), 11.132 (s, 1H, indole-NH), 7.598-7.620 (m, 1H, -ArH), 7.421-7.434 (m, 1H, -ArH), 7.307-7.323 (m, 1H, -ArH), 7.232-7.271 (m, 1H, -ArH), 7.001-7.021 (d, 1H, -ArH), 6.865-6.884 (d , 1H, -ArH), 6.698 (s, 1H, -CH = C), 3.499-3.533 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 3.273-3.302 (t, 2H, N seven-membered ring-CH ₂ ), 2.854-2.891 (t, 2H, -CH ₂ C = C), 2.536-2.570 (t, 2H, -CH ₂ N), 2.498-2.515 (m, 4H, five-membered ring-CH ₂ N), 1.982 -2.012 (m, 2H, seven-membered ring-CH ₂ ), 1.777 (s, 3H, pyrrole-CH ₃ ), 1.657 (m, 4H, five-membered ring-CH ₂ ).

Example 29

(Z) -N- {5-Fluoro-3- [3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3, 2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-7-yl} -formamide

The title compound was prepared under the same conditions as described for Step 4 of Example 28, with 3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 28c, obtained in step 3 of Example 28, and N- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl ) -formamide 20c obtained in step 3 of Example 20 as starting materials to give (Z) -N- {5-fluoro-3- [3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) ) -1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-7-yl} -formamide 29 (59 mg, 95% yield) as a yellow solid.

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.679 (s, 1H, pyrrole-NH), 10.868 (s, 1H, indole-NH), 8.324 (s, 1H, -HCO), 7.796 (s, 1H , -ArH), 7.747 (s, 1H, -CH = C), 7.601-7.629 (dd, 1H, -ArH), 7.424-7.454 (dd, 1H, -ArH), 3.543-3.577 (t, 2H, amide N seven-membered ring-external CH ₂ ), 3.330-3.357 (t, 2H, N seven-membered ring-CH ₂ ), 2.907-2.944 (t, 2H, -CH ₂ C = C), 2.576-2.610 (t, 2H, - CH ₂ N), 2.498-2.515 (m, 4H, five-membered ring-CH ₂ N), 2.449 (s, 3H, pyrrole-CH ₃ ), 2.026-2.055 (m, 2H, seven-membered ring-CH ₂ ), 1.679 ( m, 4H, five-membered ring —CH ₂ ).

Example 30

(Z) -N- {3- [3-Methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydropyrrolo [3,2-s] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} -acetamide

Stage 1

5-nitroindol-2-one

1,3-Dihydroindol-2-one 30a (20.0 g, 150 mmol) was dissolved in sulfuric acid (100 ml, 98%) in a bath with ice and water with stirring, and nitric acid (10 ml, 65%) was added dropwise. -68%), keeping the temperature below 0 ° C. After complete addition, the mixture was stirred for 1 hour at 0 ° C. When thin layer chromatography showed the disappearance of the starting materials, ice was added to the reaction mixture and filtered after the ice melted. The filter cake was washed with water (20 ml × 3), and the resulting solid was recrystallized to give the title compound 5-nitroindol-2-one 30b (25.3 g, yield 92.4%) as an orange solid substances.

MC m / z (ESI): 177.3 [M-1]

Stage 2

5-amino-1,3-dihydroindol-2-one

5-Nitro-1,3-dihydroindol-2-one 30b (3.56 g, 20 mmol) was dissolved in 200 ml of acetic acid with stirring and added to a solution of palladium on activated carbon (1.0 g, 5%) at room temperature. The reaction mixture was stirred in a hydrogen atmosphere. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was filtered and concentrated under reduced pressure to obtain the title compound 5-amino-1,3-dihydroindol-2-one 30c (2.04 g, 68.9% yield) in the form of a white solid.

MS m / z (ESI): 149.4 [M + 1]

Stage 3

N- (2-oxo-2,3-dihydro-1H-indol-5-yl) -acetamide

5-amino-1,3-dihydroindol-2-one 30c (3.5 g, 23.6 mmol) was dissolved in 20 ml of tetrahydrofuran with stirring and triethylamine (3.6 ml, 26 mmol) was added to the solution at room temperature. After completion of the addition, the mixture was cooled to −30 ° C. in a dry ice / acetone bath and acetyl chloride (1.8 ml, 24.8 mmol) was slowly added, keeping the temperature below -20 ° C. After the addition was complete, the dry ice and acetone bath was removed and the reaction mixture was allowed to warm to room temperature and was stirred for 20 minutes. When thin layer chromatography showed the disappearance of starting materials, ethyl acetate (20 ml) was added to the reaction mixture, gray solids formed, and the mixture was filtered. The filter cake was washed with water (70 ml × 3) to give 2.5 g of solids. The filtrate was extracted with ethyl acetate (200 ml × 3). The combined organic extracts were concentrated under reduced pressure, combined with the above solids to give the title compound, N- (2-oxo-2,3-dihydro-1H-indol-5-yl) -acetamide 30d (4.0 g yield 89%) as a gray solid.

MC m / z (ESI): 191.2 [M + 1]

Stage 4

(Z) -N- {3- [3-Methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydropyrrolo [3,2-s] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} -acetamide

The title compound was prepared under the same conditions as described for Step 4 of Example 28, with 3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 28c obtained in step 3 of Example 28 and N- (2-oxo-2,3-dihydro-1H-indol-5-yl) -acetamide 30d as starting materials, to obtain (Z) -N- {3- [3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [ 3,2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} -acetamide 30 (50 mg, 80% yield) as a yellow solid.

MS m / z (ESI): 462.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.679 (s, 1H, pyrrole-NH), 10.868 (s, 1H, indole-NH), 9.806 (s, 1H, -NHCO), 7.796 (s, 1H , -ArH), 7.447 (s, 1H, -CH = C), 7.231-7.256 (dd, 1H, -ArH), 6.789-6.710 (s, 1H, -ArH), 3.513-3.547 (t, 2H, amide N seven-membered ring-external CH ₂ ), 3.303-3.330 (t, 2H, N seven-membered ring-CH ₂ ), 2.866-2.903 (t, 2H, -CH ₂ C = C), 2.540-2.574 (t, 2H, - CH ₂ N), 2.461-2.513 (m, 4H, five-membered ring-CH ₂ N), 2.388 (s, 3H, pyrrole-CH ₃ ), 2.002-2.024 (m, 2H, seven-membered ring-CH ₂ ), 2.024 ( s, 3H, -CH ₃ ), 1.648 (m, 4H, five-membered ring-CH ₂ ).

Example 31

(Z) -N- {5-Fluoro-3- [3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3, 2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxyacetamide

The title compound was prepared under the same conditions as described in Step 4 of Example 28, with 3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 28c, obtained in step 3 of Example 28, and N- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl ) -2-hydroxyacetamide 27b obtained in step 2 of Example 27 as starting materials to give (Z) -N- {5-fluoro-3- [3-methyl-4-oxo-5- (2-pyrrolidin-1 -ylethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} - 2-hydroxyacetamide 31 (50 mg, 76% yield) as a yellow solid eschestva.

MS m / 2 (ESI): 496.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.658 (s, 1H, pyrrole-NH), 10.857 (s, 1H, indole-NH), 9.426 (s, 1H, -NHCO), 7.826-7.854 (d , 1H, -ArH), 7.694-7.710 (d, 1H, -ArH), 7.640 (s, 1H, -CH = C), 5.717 (s, 1H, -HO), 4.035 (d, 2H, -CH ₂ O), 3.536-3.570 (t, 2H, N seven-membered ring-CH ₂ ), 3.339 (t, 2H, amide N seven-membered ring-external CH ₂ ), 2.889-2.926 (t, 2H, -CH ₂ C = C) 2.562-2.596 (t, 2H, -CH ₂ N), 2.483-2.513 (m, 4H, five-membered ring-CH ₂ N), 2.427 (s, 3H, pyrrole-CH ₃ ), 2.034 (m, 2H, seven-membered ring-CH ₂ ), 1.673 (m, 4H, five-membered ring-CH ₂ ).

Example 32

(Z) -2- (5-Fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) -5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

Stage 1

3-Methyl-5- [3- (2-piperidin-1-yl-ethylamino) -propyl] -1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether

5- (3-Methanesulfonyloxypropyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 1g (10.64 g, 27.3 mmol) was dissolved in 2-piperidine- 1-yl-ethylamine (7 ml, 49.2 mmol), the reaction solution was stirred at room temperature overnight. When thin layer chromatography showed the disappearance of the starting materials, ethyl acetate (200 ml) and a small amount of methanol were added to the reaction mixture until a clear solution was obtained. The mixture was washed with water (30 ml × 3), the organic phase was washed with saturated brine (40 ml × 2) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 3-methyl-5- [3- (2-piperidin-1-yl-ethylamino) -propyl] -1H-pyrrole-2,4-dicarboxylic acid 2-tert- 4-ethyl ester 32a butyl ether (5.35 g, 46.5% yield) as a yellow oil.

MC m / z (ESI): 422.3 [M + 1]

Stage 2

3-Methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carboxylic acid tert-butyl ether

3-Methyl-5- [3- (2-piperidin-1-yl-ethylamino) -propyl] -1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 32a (225 mg, 0.534 mmol) dissolved in 5 ml of dry toluene with stirring, the reaction system was cooled in an ice-water bath and a solution of trimethylaluminum in toluene (0.534 ml, 2 mol / L, 1.07 mmol) was added in an argon atmosphere. After complete addition, the reaction system was stirred for 20 minutes at room temperature until the white smoke ceased to stand out, and was refluxed for another 3 hours in an oil bath. When thin layer chromatography showed the disappearance of the starting materials, the oil bath was removed, saturated brine (10 ml) and ethyl acetate (20 ml) were added to the reaction mixture, stirred for 15 minutes at room temperature and filtered. The filter cake was washed with ethyl acetate (10 ml × 3). The filtrate was extracted with ethyl acetate (10 ml × 2). The combined organic extracts were washed with saturated brine (10 ml × 2), dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure to obtain the title compound 3-methyl-4-oxo-5- (2- piperidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carboxylic acid tert-butyl ether 32b (105 mg) as a colorless oil, which was directly used in the next stage.

MC m / z (ESI): 376.2 [M + 1]

Stage 3

3-Methyl-5- (2-piperidin-1-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

3-Methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carboxylic acid tert-butyl ether 32b (953 mg, 2.54 mmol) was dissolved in 3 ml of ethanol with stirring, and hydrochloric acid (3.2 ml, 12 mol / L) was added dropwise in an ice and water bath under argon. After complete addition, the ice and water bath was removed, and the reaction mixture was stirred at 60 ° C in an oil bath for 1 hour. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was adjusted to approximately pH 7 with an aqueous solution of sodium hydroxide (10 mol / L) and concentrated under reduced pressure to evaporate ethanol. The residue was adjusted to approximately pH 10 with an aqueous solution of sodium hydroxide (10 mol / L) and extracted with dichloromethane (20 ml × 3). The combined organic extracts were washed with saturated brine (20 ml), dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 3-methyl-5- (2-piperidin-1-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-s] azepin-4-one 32 s (395 mg, 57% yield) as a white solid.

MS m / z (ESI): 276.1 [M + 1]

Stage 4

3-Methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde

Dichloromethane (36 ml, 559 mmol) and N, N-dimethylformamide (1,637 ml, 20.9 mmol) were stirred for 5 minutes at -15 ° C in an ice salt bath under argon atmosphere. Phosphorus oxychloride (1.07 ml, 11.5 mmol) was added dropwise to the solution and stirred for 15 minutes while maintaining the temperature at -10 ° C. 3-Methyl-5- (2-piperidin-1-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 32c (1.26 g, 4, 58 mmol) was dissolved in 10 ml of dichloromethane, the resulting solution was added dropwise to the above solution. After complete addition, the ice salt bath was removed and the reaction mixture was stirred for 3 hours at room temperature. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was rapidly cooled with ice water, adjusted to approximately pH 10 with sodium hydroxide solution (10 mol / L) and stirred for 30 minutes, extracted with dichloromethane (30 ml × 3). The combined organic extracts were washed with saturated brine (30 ml), dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3, 2-c] azepine-2-carbaldehyde 32d (993 mg, 71.4% yield) as a pale yellow solid.

MC m / z (ESI): 304.1 [M + 1]

Stage 5

(Z) -2- (5-Fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) -5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

3-Methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 32d (50 mg, 0.165 mmol) and 5-fluoro-1,3-dihydroindol-2-one (22.4 mg, 0.15 mmol) were dissolved in 0.3 ml of ethanol with stirring, and piperidine (0.05 ml, 0) was added to the solution. 5 mmol) at room temperature. After complete addition, the mixture was stirred at 40-50 ° C. in an oil bath for 5 hours. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was filtered to give a yellow solid. This solid was dissolved in ethanol (2 ml), heated to reflux for 30 minutes, cooled to room temperature and filtered to give the title compound, (Z) -2- (5-fluoro-2-oxo-1 , 2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4- she 32 (38 g, yield 58%) as a yellow solid.

MS m / z (ESI): 437.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.720 (s, 1H, pyrrole-NH), 10.900 (s, 1H, indole-NH), 7.749-7.779 (dd, 1H, -ArH), 7.740 (s , 1H, -CH = C), 6.912-6.963 (m, 1H, -ArH), 6834-6.867 (d, 1H, -ArH), 3.539-3.572 (t, 2H, seven-membered ring intra-CH ₂ N) , 3.326-3.354 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.922-2.958 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.452 (s, 3H, pyrrole-CH ₃ ) , 2.386-2.431 (m, 6H, 3 × -CH ₂ N), 2.027-2.091 (t, 2H, seven-membered ring-intra-CH ₂ ), 1.474-1.499 (m, 4H, six-membered ring-2 × -CH ₂ ), 1.379-1.391 (m, 2H, seven-membered ring-CH ₂ ).

Example 33

(Z) -2- [4- (2,3-Difluorophenyl) -2-oxo-1,2-dihydro-indol-3-ylidenomethyl] -3-methyl-5- (2-piperidin-1-yl-ethyl) - 5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was obtained under the same conditions as described for Step 5 of Example 32, with 3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydro-pyrrolo [3,2-c] azepin-2-carbaldehyde 32d obtained in step 4 of Example 32, and 4- (2,3-difluorophenyl) -1,3-dihydro-indol-2-one 6d obtained at the stage 3 of Example 6, as starting materials to obtain (Z) -2- [4- (2,3-difluorophenyl) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5- (2-piperidin-1-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 33 (51 mg, 80.9% yield) as a yellow solid substances.

MS m / z (ESI): 531.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.540 (s, 1H, pyrrole-NH), 11.130 (s, 1H, indole-NH), 7.618-7.640 (m, 1H, -ArH), 7.429-7.461 (m, 1H, -ArH), 7.306-7.360 (m, 1H, -ArH), 7.232-7.2710 (m, 1H, -ArH), 6.998-7.017 (d, 1H, -ArH), 6.874-6.893 (d , 1H, -ArH), 6.709 (s, 1H, -CH = C), 3.504-3.536 (t, 2H, seven-membered ring-intra-CH ₂ N), 3.289-3.312 (t, 2H, amide N, seven-membered ring external CH ₂ ), 2.887-2.923 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.365-2.417 (m, 6H, 3 × -CH ₂ N), 2.009-2.038 (t, 2H, - CH ₂ ), 1.792 (s, 3H, pyrrole-CH ₃ ), 1.456-1.468 (m, 4H, seven-membered ring-2 × -CH ₂ ), 1.368-1.377 (m, 2H, seven-membered ring-CH ₂ ).

Example 34

(Z) -2- [5- (4-Methoxyphenyl) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5- (2-piperidin-1-yl-ethyl) -5,6, 7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was obtained under the same conditions as described for Step 5 of Example 32, with 3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 32d obtained in step 4 of Example 32, and 5- (4-methoxyphenyl) -1,3-dihydroindol-2-one as starting materials to give ( Z) -2- [5- (4-methoxyphenyl) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5- (2-piperidin-1-yl-ethyl) -5,6,7 , 8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 34 (68 mg, 68.7% yield) as a yellow solid.

MS m / z (ESI): 525.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.653 (s, 1H, pyrrole-NH), 11.003 (s, 1H, indole-NH), 7.930-7.850 (d, 1H, -ArH), 7.668 (s , 1H, -CH = C), 7.583-7.605 (d, 2H, -ArH), 7.251-7.274 (d, 1H, -ArH), 7.017-7.071 (m, 3H, -ArH), 3.804 (s, 3H , -CH ₃ O), 3.541-3.574 (t, 2H, seven-membered ring-intra-CH ₂ N), 3.343 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.926-2.962 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.386-2.449 (m, 9H, pyrrole-CH ₃ , 3 × -CH ₂ N), 2.062 (m, 2H, seven-membered ring-intra-CH ₂ ), 1.475-1.487 (m, 4H, six-membered ring-2 × -CH ₂ ), 1.379-1.391 (m, 2H, six-membered ring-CH ₂ ).

Example 35

(Z) -2- (5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) -5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was obtained under the same conditions as described for Step 5 of Example 32, with 3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6, 7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 32d obtained in step 4 of Example 32 and 5-chloro-1,3-dihydroindol-2-one as starting materials to give (Z) - 2- (5-chloro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) -5,6,7,8-tetrahydro-1H- pyrrolo [3,2-c] azepin-4-one 35 (44 mg, 64.8% yield) as a yellow solid.

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.674 (s, 1H, pyrrole-NH), 11.003 (s, 1H, indole-NH), 7.989 (s, 1H, -ArH), 7.799 (s, 1H , -CH = C), 7.135-7.155 ( d, 1H, -ArH), 6869-6.890 (d, 1H, -ArH), 3.545-3.576 (t, 2H, seven-membered ring intra-CH ₂ N), 3.313 -3.342 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.925-2.962 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.399-2.459 (m, 9H, pyrrole-CH ₃ , 3 × -CH ₂ N), 2.047-2.074 (t, 2H, seven-membered ring-intra-CH ₂ ), 1.490 (m, 4H, six-membered ring-2 × -CH ₂ ), 1.385 (m, 2H, six-membered ring - CH ₂ ).

Example 36

(Z) -2- (5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) -5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was obtained under the same conditions as described for Step 5 of Example 32, with 3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 32d obtained in step 4 of Example 32, and 5-bromo-1,3-dihydroindol-2-one as starting materials to give (Z) -2 - (5-bromo-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 36 (43 mg, yield 57.6%) as a yellow solid.

MS m / z (ESI): 497.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.670 (s, 1H, pyrrole-NH), 11.010 (s, 1H, indole-NH), 8.114 (s, 1H, -ArH), 7.802 (s, 1H , -CH = C), 7.262-7.283 ( d, 1H, -ArH), 6.826-6.846 (d, 1H, -ArH), 3.542-3.574 (t, 2H, seven-membered ring intra-CH ₂ N), 3.315 -3.339 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.924-2.960 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.389-2.460 (m, 9H, pyrrole-CH ₃ , 3 × -CH ₂ N), 2.045-2.074 (t, 2H, seven-membered ring-intra-CH ₂ ), 1.476-1.489 (m, 4H, six-membered ring-2 × -CH ₂ ), 1.381 (m, 2H, six-membered ring-CH ₂ ).

Example 37

(Z) -N- {5-Fluoro-3- [3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3, 2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-methoxyacetamide

The title compound was obtained under the same conditions as described for Step 5 of Example 32, with 3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 32d obtained in step 4 of Example 32, and N- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl ) -2-methoxyacetamide 7a, obtained in step 1 of Example 7, as starting materials to give (Z) -N- {5-fluoro-3- [3-methyl-4-oxo-5- (2-piperidin-1 -ylethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} - 2-methoxyacetamide 37 (59 mg, 75% yield) as a yellow solid Properties.

MS m / z (ESI): 524.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.613 (s, 1H, pyrrole-NH), 10.890 (s, 1H, indole-NH), 9.316 (s, 1H, -NHCO), 7.835-7.863 (d , 1H, -ArH), 7.668 (s, 1H, -CH = C), 7.542-7.558 (d, 1H, -ArH), 4.064 (s, 2H, -CH ₂ O), 3.540-3.572 (t, 2H , seven-membered ring-intra-CH ₂ N), 3.406 (s, 3H, CH ₃ O), 3.315-3.340 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.918-2.954 (t, 2H, seven-membered ring -intra-CH ₂ C = C), 2.390-2.467 (m, 9H, pyrrole-CH ₃ , 3 × -CH ₂ N), 2.043-2.072 (t, 2H, seven-membered ring-intra-CH ₂ ), 1.478- 1.490 (m, 4H, six-membered ring-2 × -CH ₂ ), 1.382-1.393 (m, 2H, six-membered ring-CH ₂ ).

Example 38

(S, Z) -N- {5-Fluoro-3- [3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [ 3,2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-hydroxypropionamide

The title compound was obtained under the same conditions as described for Step 5 of Example 32, with 3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 32d obtained in step 4 of Example 32, and N- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl ) -2-hydroxypropionamide 8b obtained in step 2 of Example 8 as starting materials to give (S, Z) -N- {5-fluoro-3- [3-methyl-4-oxo-5- (2-piperidine -1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl } -2-hydroxypropionamide 38 (49 mg, yield 62.5%) as a yellow solid rdogo substances.

MS m / z (ESI): 524.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.603 (s, 1H, pyrrole-NH), 10.900 (s, 1H, indole-NH), 9.246 (s, 1H, -NH), 7.853-7.881 (d , 1H, -ArH), 7.726-7.743 (d, 1H, -ArH), 7.659 (s, 1H, -CH = C), 6.058-6.070 (d, 1H, -OH), 4.207-4.237 (m, 1H , -CHO), 3.541-3.573 (t, 2H, seven-membered ring-intra-CH ₂ N), 3.326-3.354 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.917-2.954 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.392-2.440 (m, 9H, pyrrole-CH ₃ , 3 × -CH ₂ N), 2.025-2.089 (t, 2H, seven-membered ring-intra-CH- ₂ ), 1.478 -1.490 (m, 4H, six-membered ring-2 × -CH ₂ ), 1.383 (m, 2H, six-membered ring-CH ₂ ), 1.330-1.347 (d, 3H, CH ₃ O).

Example 39

(Z) -N- {3- [5- (2-Dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2- ilmethylene] -5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl} -2-methoxyacetamide

The title compound was prepared under the same conditions as described in Step 4 of Example 23, with 5- (2-dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 23c obtained in step 3 of Example 23 and N- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl) -2- methoxyacetamide 7a obtained in step 1 of Example 7 as starting materials to give (Z) -N- {3- [5- (2-dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6, 7,8-hexahydro-pyrrolo [3,2-c] azepin-2-ylmethylene] -5-fluoro-2-oxo-2,3-dihydro-1 H-indol-6-yl} -2-methoxyacetamide 39 (75 mg yield 76.5%) as a brown solid eschestva.

MS m / z (ESI): 484.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.607 (s, 1H, pyrrole-NH), 10.894 (s, 1H, -NH), 9.320 (s, 1H, -NHCO), 7.840-7.868 (d, 1H, -ArH), 7.673 (s, 1H, -CH = C), 7.540-7.557 (d, 1H, -ArH), 4.064 (s, 2H, -CH ₂ O), 3.531-3.564 (t, 2H, N seven-membered ring-CH ₂ ), 3.406 (s, 3H, -CH ₃ O), 3.333-3.359 (t, 2H, amide N seven-membered ring-external CH ₂ ), 2.904-2.941 (t, 2H, -CH ₂ C = C), 2.445 (s, 3H, pyrrole-CH ₃ ), 2.404-2.420 (t, 2H, -CH ₂ N), 2.206 (s, 6H, 2 × -CH ₃ N), 2.029-2.057 (m, 2H, seven membered ring-intra-CH ₂ ).

Example 40

(Z) -2- [4- (2,6-Difluorophenyl) -2-oxo-1,2-dihydroindol-3-ylidenemethyl] -5- (2-dimethylaminoethyl) -3-methyl-5,6,7, 8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was obtained under the same conditions as described for Step 4 of Example 23, with 5- (2-dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 23c obtained in step 3 of Example 23 and 4- (2,6-difluorophenyl) -1,3-dihydroindol-2-one as starting materials to give (Z) -2- [4- (2,6-difluorophenyl) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -5- (2-dimethylaminoethyl) -3-methyl-5,6,7,8-tetrahydro -1H-pyrrolo [3,2-c] azepin-4-one 40 (36 mg, 36.4% yield) as an orange solid.

MC m / z (ESI): 491.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.552 (s, 1H, pyrrole-NH), 11.075 (s, 1H, indole-NH), 7.661 (m, 1H, -ArH), 7.338-7.378 (m , 2H, -ArH), 7.238-7.277 (m, 1H, -ArH), 7.008-7.027 (m, 1H, -ArH), 6.895-6.914 (d, 1H, -ArH), 6.652 (s, 1H, - CH = C), 3.488-3.522 (t, 2H, N seven-membered ring-CH ₂ ), 3.280-3.316 (t, 2H, amide N seven-membered ring-external CH ₂ ), 2.868-2.904 (t, 2H, -CH ₂ C = C), 2.355-2.388 (t, 2H, -CH ₂ N), 2.171 (s, 6H, 2 × -CH ₃ N), 1.992-2.021 (m, 2H, seven-membered ring-intra-CH ₂ ), 1.764 (s, 3H, pyrrole-CH ₃ ).

Example 41

(Z) -5- (2-Dimethylaminoethyl) -2- [4- (3-fluorophenyl) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was obtained under the same conditions as described for Step 4 of Example 23, with 5- (2-dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 23c obtained in step 3 of Example 23 and 4- (3-fluorophenyl) -1,3-dihydroindol-2-one as starting materials to give (Z) -5 - (2-dimethylaminoethyl) -2- [4- (3-fluorophenyl) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 41 (37 mg, 38.9% yield) as a yellow solid.

MS m / z (ESI): 473.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.533 (s, 1H, pyrrole-NH), 11.075 (s, 1H, indole-NH), 7.595-7.610 (m, 1H, -ArH), 7.286-7.343 (m, 3H, -ArH), 7.191-7.229 (m, 1H, -ArH), 6.942-6.962 (d, 1H, -ArH), 6.830-6.844 (d, 1H, -ArH), 6.811 (s, 1H , -CH = C), 3.488-3.521 (t, 2H, N seven-membered ring-CH ₂ ), 3.277-3.315 (t, 2H, amide N seven-membered ring-external CH ₂ ), 2.859-2.896 (t, 2H, - CH ₂ C = C), 2.361-2.394 (t, 2H, -CH ₂ N), 2.176 (s, 6H, 2 × -CH ₃ N), 1.989-2.018 (m, 2H, seven-membered ring-intra-CH ₂ ), 1.774 (s, 3H, pyrrole-CH ₃ ).

Example 42

(Z) -2- [4- (2,3-Difluorophenyl) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -5- (2-dimethylaminoethyl) -3-methyl-5,6,7, 8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described for Step 4 of Example 23, where 5- (2-dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepin-2-carbaldehyde 23c obtained in step 3 of Example 23 and 4- (2,3-difluorophenyl) -1,3-dihydroindol-2-one 6d obtained in step 3 of Example 6, used as starting materials, to obtain (Z) -2- [4- (2,3-difluorophenyl) -2-oxo-1,2-dihydroindol-3-ylidenemethyl] -5- (2-dimethylaminoethyl) -3- methyl 5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 42 (25 mg, 25.2% yield) as a yellow solid.

MC m / z (ESI): 491.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.532 (s, 1H, pyrrole-NH), 11.132 (s, 1H, indole-NH), 7.618-7.640 (m, 1H, -ArH), 7.429-7.442 (m, 1H, -ArH), 7.306-7.340 (m, 1H, -ArH), 7.232-7.271 (m, 1H, -ArH), 6.998-7.017 (d, 1H, -ArH), 6.874-6.893 (d , 1H, -ArH), 6.712 (s, 1H, -CH = C), 3.491-3.525 (t, 2H, N seven-membered ring -CH ₂ ), 3.292-3.315 (t, 2H, amide N seven-membered ring-external CH ₂ ), 2.869-2.905 (t, 2H, -CH ₂ C = C), 2.362-2.395 (t, 2H, -CH ₂ N), 2.176 (s, 6H, 2 × -CH ₃ N), 1.993-2.018 (m, 2H, seven membered ring-intra-CH ₂ ), 1.795 (s, 3H, pyrrole-CH ₃ ).

Example 43

(Z) -5- (2-Dimethylaminoethyl) -2- [5-fluoro-6- (4-fluorobenzylamino) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5,6, 7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described for Step 4 of Example 23, where 5- (2-dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepin-2-carbaldehyde 23c obtained in step 3 of Example 23 and 5-fluoro-6- (4-fluorobenzylamino) -1,3-dihydroindol-2-one 3e obtained in step 4 of Example 3, used as starting materials, to obtain (Z) -5- (2-dimethylaminoethyl) -2- [5-fluoro-6- (4-fluorobenzylamino) -2-oxo-1,2-dihydro-indole-3 -ylidenemethyl] -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 43 (50 mg, 43.7% yield) as a red solid Twa.

MS m / z (ESI): 520.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.421 (s, 1H, pyrrole-NH), 10.523 (s, 1H, indole-NH), 7.574-7.603 (d, 1H, -ArH), 7.367-7.402 (m, 2H, -ArH), 7.513 (s, 1H, -CH = C), 7.142-7.186 (m, 2H, -ArH), 6.41 (t, 1H, -NH), 6.041-6.059 (d, 1H , -ArH), 4.348-4.362 (d, 2H, aniline-CH ₂ ), 3.982-3.996 (d, 2H, -CH ₂ O), 3.531-3.564 (t, 2H, N seven-membered ring-СН ₂ ), 3.316 -3.344 (t, 2H, amide N, seven-membered ring-external СН ₂ ), 2.856-2.893 (t, 2H, -CH ₂ С = С), 2.398-2.415 (t, 2H, -CH ₂ N), 2.390 (s , 3H, pyrrole-CH ₃ ), 2.192 (s, 6H, 2 × -CH ₃ N), 2.002-2.030 (m, 2H, seven-membered ring-intra-CH ₂ ).

Example 44

(Z) -N- {3- [5- (2-Dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2- ilmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} -2-hydroxyacetamide

Stage 1

Acetic acid (2-oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl) methyl ether

5-amino-1,3-dihydroindol-2-one 30c (500 mg, 3.38 mmol) was dissolved in 10 ml of dichloromethane with stirring at room temperature, and pyridine (470 μl, 5 mmol) was added to the solution at -40 ° C in a bath with dry ice and acetone. Acetic acid, chlorocarbonylmethyl ether (473 mg, 3.48 mmol) was dissolved in 10 ml of dichloromethane, the resulting solution was added dropwise to the above solution. After complete addition, dry ice and acetone were removed, and the reaction mixture was allowed to warm to room temperature and was stirred overnight. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was filtered. The filter cake was washed with water (10 ml × 3) and recrystallized to give the title compound, acetic acid (2-oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl) methyl ester 44a (510 mg, yield 60.7%) as a yellow solid.

MS m / z (ESI): 247.7 [M-1]

Stage 2

2-Hydroxy-N- (2-oxo-2,3-dihydro-1H-indol-5-yl) -acetamide

Acetic acid (2-oxo-2,3-dihydro-1H-indol-5-ylcarbamoyl) methyl ester 44a (2.43 g, 10 mmol) was dissolved in 60 ml of methanol with stirring, and a solution of sodium hydroxide ( 20 ml, 2 mol / L) and stirred at room temperature overnight. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was neutralized with a solution of hydrochloric acid (6 mol / L) in an ice-water bath and concentrated under reduced pressure. The resulting solid was purified by silica gel column chromatography to obtain the title compound 2-hydroxy-N- (2-oxo-2,3-dihydro-1 H-indol-5-yl) -acetamide 44b (402 mg yield 19.5%) as a yellow solid.

MS m / z (ESI): 205.3 [M-1]

Stage 3

(Z) -2-Hydroxy-N- {3- [3-methyl-5- (2-methylaminoethyl) -4-oxo-1,4,5,6,7,8-hexahydropyrrolo13,2-c] azepine- 2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} -acetamide

The title compound was obtained under the same conditions as described for Step 4 of Example 23, with 5- (2-dimethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and 2-hydroxy-N- (2-oxo-2,3-dihydro-1H-indol-5-yl) -acetamide 44b as starting materials, to obtain (Z) -2-hydroxy-N- {3- [3-methyl-5- (2-methylaminoethyl) -4-oxo-1,4,5,6,7,8-hexahydropyrrolo [ 3,2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} -acetamide 44 (52 mg, yield 50.5%) as an orange solid.

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.658 (s, 1H, pyrrole-NH), 10.857 (s, 1H, -NH), 9.426 (s, 1H, - NHCO), 7.939-7.942 (d, 1H, -ArH), 7.513 (s, 1H, -CH = C), 7.485-7.489 (d, 1H, -ArH), 6.820-6.841 (d, 1H, -ArH), 5.717 (s, 1H, -HO ), 3.982-3.996 (d, 2H, -CH ₂ O), 3.531-3.564 (t, 2H, N seven-membered ring-CH ₂ ), 3.337-3.365 (t, 2H, amide N seven-membered ring-external CH ₂ ), 2.908-2.944 (t, 2H, -CH ₂ C = C), 2.433 (s, 3H, pyrrole-CH ₃ ), 2.394-2.411 (t, 2H, -CH ₂ N), 2.199 (s, 6H, 2 × -CH ₃ N), 2.031-2.059 (m, 2H, seven membered ring-intra-CH ₂ ).

Example 45

(Z) -2- (5-Fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was obtained under the same conditions as described for Step 4 of Example 28, with 3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6, 7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 28c obtained in step 3 of Example 28 and 5-fluoro-1,3-dihydroindol-2-one as starting materials to give (Z) - 2- (5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -5,6,7,8-tetrahydro-1H- pyrrolo [3,2-c] azepin-4-one 45 (61 mg, yield 80.8%) as an orange solid.

MS m / z (ESI): 423.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.715 (s, 1H, pyrrole-NH), 10.902 (s, 1H, indole-NH), 7.752-7.782 (m, 1H, -ArH), 7.743 (s , 1H, -CH = C), 6.937-6.965 (m, 1H, -ArH), 6.835-6.867 (d, 1 H, -ArH), 3.548-3.582 (t, 2H, seven-membered ring-intra-CH ₂ N ), 3.337-3.365 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 3.314 (m, 4H, five-membered ring-2 × -CH ₂ N), 2.990-3.027 (t, 2H, seven-membered ring-intra- CH ₂ C = C), 2.573-2.607 (t, 2H, -CH ₂ N), 2.473 (s, 3H, pyrrole-CH ₃ ), 2.101-2.129 (m, 2H, seven-membered ring-intra-CH ₂ ), 1.751 (m, 4H, five-membered ring-CH ₂ ).

Example 46

(Z) -2- (5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described for Step 4 of Example 28, with 3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 28c, obtained in step 3 of Example 28, and 5-bromo-1,3-dihydroindol-2-one as starting materials to give (Z) -2 - (5-bromo-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3.2-c] azepin-4-one 46 (61 mg, yield 70.4%) as a yellow solid.

MS m / z (ESI): 485.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.664 (s, 1H, pyrrole-NH), 11.007 (s, 1H, indole-NH), 8.113-8.114 (d, 1H, -ArH), 7.803 (s , 1H, -CH = C), 7.261-7.286 (m, 1H, -ArH), 6.825-6.846 (d, 1H, -ArH), 3.548-3.582 (t, 2H, seven-membered ring intra-CH ₂ N) , 3.337-3.364 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 3.312 (m, 4H, five-membered ring-2 × -CH ₂ N), 2.905-2.942 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.573-2.606 (t, 2H,

-CH ₂ N), 2.462 (s, 3H, pyrrole-CH ₃ ), 2.028-2.057 (m, 2H, seven-membered ring-intra-CH ₂ ), 1.751 (m, 4H, five-membered ring-CH ₂ ).

Example 47

(Z) -2- (5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described for Step 4 of Example 28, with 3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 28c, obtained in step 3 of Example 28, and 5-chloro-1,3-dihydroindol-2-one as starting materials to give (Z) -2 - (5-chlorop-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3.2-s] azepin-4-one 47 (61 ms, yield 77.7%) as a yellow solid.

MS m / z (ESI): 439.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.714 (s, 1H, pyrrole-NH), 11.046 (s, 1H, indole-NH), 8.038 (s, 1H, -CH = C), 7.838-7.845 (d, 1H, -ArH), 7.179-7.205 (dd, 1H, -ArH), 6.915-6.935 (d, 1H, -ArH), 3.612-3.629 (t, 2H, seven-membered ring-intra-CH ₂ N) , 3.384-3.412 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 3.337-3.384 (m, 4H, five-membered ring-2 × -CH ₂ N), 2.990-3.027 (t, 2H, seven-membered ring-intra -CH ₂ C = C), 2.650-2.684 (t, 2H,

-CH ₂ N), 2.473 (s, 3H, pyrrole-CH ₃ ), 2.101-2.129 (m, 2H, seven-membered ring-intra-CH ₂ ), 1.751 (m, 4H, five-membered ring-CH ₂ ).

Example 48

(Z) -3-Methyl-2- (2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenomethyl) -5- (2-pyrrolidin-1-yl-ethyl) -5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described for Step 4 of Example 28, with 3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 28c, obtained in step 3 of Example 28, and 5-phenyl-1,3-dihydroindol-2-one as starting materials to give (Z) -3 -methyl-2- (2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenomethyl) -5- (2-pyrrolidin-1-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3.2-c] azepin-4-one 48 (41 mg, yield 62.3%) as a yellow solid.

MC m / z (ESI): 481.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.706 (s, 1H, pyrrole-NH), 10.070 (s, 1H, indole-NH), 8.174 (s, 1H, -CH = C), 7.843 (s , 1H, -ArH), 7.722-7.741 (d, 2H, -ArH), 7.443-7.480 (m, 3H, -ArH), 7.314-7.351 (t, 1H, -ArH), 6.961-6.981 (d, 1H , -ArH), 3.554-3.588 (t, 2H, seven-membered ring-intra-CH ₂ N), 3.362-3.376 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 3.289-3.347 (m, 4H, five-membered ring-2 × -CH ₂ N), 2.990-3.027 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.650-2.684 (t, 2H, -CH ₂ N), 2.473 (s, 3H, pyrrole-CH ₃ ), 2.101-2.129 (m, 2H, seven-membered ring-intra-CH ₂ ), 1.751 (m, 4H, five-membered ring-2 × -CH ₂ ).

Example 49

(Z) -2- (4-Bromo-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described for Step 4 of Example 28, with 3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 28c, obtained in step 3 of Example 28, and 4-bromo-1,3-dihydroindol-2-one as starting materials to give (Z) -2 - (4-bromo-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 49 (40 mg, 60.5% yield) as a yellow solid.

MS m / z (ESI): 483.2 [M-1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.697 (s, 1H, pyrrole-NH), 11.244 (s, 1H, indole-NH), 8.650 (s, 1H, -CH = C), 7.281-7.301 (d, 1H, -ArH), 7.118-7.158 (m, 1H, -ArH), 7.000-7.190 (d, 1H, -ArH), 3.618-3.652 (t, 2H, seven-membered ring intra-CH ₂ N) , 3.410-3.438 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 3.356-3.378 (m, 4H, five-membered ring-2 × -CH ₂ N), 2.990-3.027 (t, 2H, seven-membered ring-intra -CH ₂ C = C), 2.650-2.684 (t, 2H,

-CH ₂ N), 2.473 (s, 3H, pyrrole-CH ₃ ), 2.101-2.129 (m, 2H, seven-membered ring-intra-CH ₂ ), 1.751 (m, 4H, five-membered ring-CH ₂ ).

Example 50

(Z) -2- (7-Bromo-5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -5,6, 7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described for Step 4 of Example 28, with 3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydro-pyrrolo [3,2-c] azepin-2-carbaldehyde 28c, obtained from stage 3 of Example 28, and 7-bromo-5-fluoro-1,3-dihydroindol-2-one 4b, obtained from stage 1 of Example 4, as starting materials, to obtain (Z) -2- (7-bromo-5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-pyrrolidin-1 -ylethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 50 (51 mg, 73.2% yield) as an orange solid.

MC m / z (ESI): 501.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.660 (s, 1H, pyrrole-NH), 11.177 (s, 1H, indole-NH), 7.857-7.875 (d, 1H, -ArH), 7.798 (s , 1H, -CH = C), 7.251-7.269 (d, 1H, -ArH), 3.556-3.590 (t, 2H, seven membered ring-intra-CH ₂ N), 3.317-3.359 (t, 2H, amide N seven outer ring CH ₂ ), 3.294-3.359 (m, 4H, five-membered ring-2 × -CH ₂ N), 2.935-2.971 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.587-2.620 ( t, 2H, -CH ₂ N), 2.473 (s, 3H, pyrrole-CH ₃ ), 2.059 (m, 2H, seven-membered ring-intra-CH ₂ ), 1.751 (m, 4H, five-membered ring-CH ₂ ).

Example 51

(Z) -N- {3- [5- (2-Diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2- ilmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} -acetamide

The title compound was prepared under the same conditions as described for Step 10 of Example 1, with 5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepin-2-carbaldehyde 1j obtained in step 9 of Example 1 and N- (2-oxo-2,3-dihydro-1H-indol-5-yl) -acetamide 30d obtained in step 3 of Example 30, as starting materials to obtain (Z) -N- {3- [5- (2-diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [ 3,2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-5-yl} -acetamide 51 (12 mg, yield 18.9%) as an orange solid.

MC m / z (ESI): 464.2 [M + 1]

¹ H NMR (400 MHz, HMCO-d ₆ ) δ 13.679 (s, 1H, pyrrole-NH), 10.868 (s, 1H, indole-NH), 9.806 (s, 1H, amide-NH), 7.841 (s, 1H, -ArH), 7.472 (s, 1H, -CH = C), 7.251-7.256 (d, 1H, -ArH), 6.806-6.827 (s, 1H, -ArH), 3.499 (t, 2H, seven-membered ring -intra-CH ₂ N), 3.322-3.347 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.902-2.939 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.530-2.562 ( m, 6H, 3 × -CH ₂ N), 2.423 (s, 3H, pyrrole-CH ₃ ), 2.029-2.051 (m, 2H, seven-membered ring-intra-CH ₂ ), 2.029 (s, 3H, -CH ₃ СО), 0.958-0.993 (t, 6Н, 2 × -CH ₃ ).

Example 52

(Z) -N- {5-Fluoro-3- [3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3, 2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} -2-methoxyacetamide

The title compound was prepared under the same conditions as described for Step 4 of Example 28, with 3-methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 28c, obtained in step 3 of Example 28, and N- (5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl ) -2-methoxyacetamide 7a, obtained in step 1 of Example 7, as starting materials to give (Z) -N- {5-fluoro-3- [3-methyl-4-oxo-5- (2-pyrrolidin-1 -ylethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepin-2-ylmethylene] -2-oxo-2,3-dihydro-1H-indol-6-yl} - 2-methoxyacetamide 52 (45 mg, 63.7% yield) as a yellow solid substances.

MC m / z (ESI): 510.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.652 (s, 1H, pyrrole-NH), 10.936 (s, 1H, indole-NH), 9.362 (s, 1H, -NHCO), 7.882-7.910 (d , 1H, -ArH), 7.714 (s, 1H, -CH = C), 7.582-7.598 (d, 1H, -ArH), 4.110 (s, 2H, -CH ₂ O), 3.597-3.631 (t, 2H , seven-membered ring-intra-CH ₂ N), 3.447 (s, 3H, -CH ₃ O), 3.381-3.408 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 3.331-3.355 (m, 4H, five-membered ring-2 × -CH ₂ N), 2.945-2.981 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.660 (m, 2H, -CH ₂ N), 2.489 (s, 3H, pyrrole - CH ₃ ), 2.069-2.099 (m, 2H, seven-membered ring-intra-CH ₂ ), 1.731 (m, 4H, five-membered ring-CH ₂ ).

Example 53

(R, Z) -2- (5-Fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -5- (2-hydroxy-3-morpholin-4-yl-propyl) -3-methyl- 5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

Stage 1

4-oxiranylmethylmorpholine

Morpholine 53a (8.712 ml, 0.1 mol) was dissolved in tert-butanol (4.5 ml) with stirring at room temperature, and (R) - (-) - 1-chloro-2,3-epoxypropane was slowly added to the solution. (8.05 ml, 0.1 mol) at 0 ° C in a bath with ice and water. After complete addition, the ice and water bath was removed and the reaction mixture was allowed to warm to room temperature and was stirred for 24 hours. When thin layer chromatography showed the disappearance of the starting materials, a solution of potassium tert-butoxide in tetrahydrofuran (60 ml, 1.67 mol / l, 100 mmol) was added dropwise to the reaction mixture, keeping the temperature below 10 ° C, in an ice and water bath, the solution gradually turned from light yellow to a white cloudy, and it was stirred for 30 minutes. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was concentrated under reduced pressure, water (50 ml) was added, and extracted with dichloromethane (100 ml × 2). The combined organic extracts were washed with saturated brine (100 ml), dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure to obtain the title compound 4-oxiranylmethylmorpholine 53b (12.7 g, 88.8% yield) ) as a yellow oil.

MC m / z (ESI): 144.4 [M + 1]

Stage 2

1-amino-3-morpholin-4-ylpropan-2-ol

Ammonia (450 ml, 25%, 6.6 mol) was slowly added to 4-oxiranylmethylmorpholine 53b (6.3 g, 44 mmol), keeping the temperature below 0 ° C in an ice-water bath. After complete addition, the reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was concentrated under reduced pressure to obtain the title compound 1-amino-3-morpholin-4-ylpropan-2-ol 53c (7 g, 99% yield) as a white solid substances.

MC m / z (ESI): 161.1 [M + 1]

Stage 3

5- [3- (2-Hydroxy-3-morpholin-4-ylpropylamino) propyl] -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether

5- (3-Methanesulfonyloxypropyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 1g (1.13 g, 2.9 mmol) was dissolved in 5.6 ml dichloromethane with stirring, and 1-amino-3-morpholin-4-ylpropan-2-ol 53c (0.93 g, 5.8 mmol) was added to the solution at room temperature. After complete addition, the reaction mixture was stirred at room temperature overnight and heated for 14 hours at 45 ° C in an oil bath. When thin layer chromatography showed the disappearance of starting materials, saturated brine (15 ml) was added to the reaction mixture and extracted with dichloromethane (20 ml × 3). The combined organic extracts were concentrated under reduced pressure, purified by column chromatography on silica gel to give the title compound 5- [3- (2-hydroxy-3-morpholin-4-ylpropylamino) propyl] -3-methyl-1H-pyrrole -2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 53d (600 mg, 72.5% yield) as a colorless oil.

MS m / z (ESI): 454.2 [M + 1]

Stage 4

5- (2-Hydroxy-3-morpholin-4-ylpropyl) -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

5- [3- (2-Hydroxy-3-morpholin-4-ylpropylamino) propyl] -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether 53d (580 mg , 1.28 mmol) was dissolved in 6 ml of toluene with stirring, and trimethylaluminum in toluene (1.9 ml, 2 mol / L, 3.84 mmol) was added dropwise in an ice-water bath under argon atmosphere. After completion of the addition, the ice and water bath was removed and the reaction mixture was heated to reflux for 24 hours. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was concentrated under reduced pressure, hydrochloric acid solution (20 ml, 6 mol / L) was added and stirred for 20 minutes at room temperature. The mixture was adjusted to approximately pH 12 with an aqueous solution of sodium hydroxide (12 mol / L) in an ice-water bath and was extracted with dichloromethane (50 ml × 2). The combined organic extracts were concentrated under reduced pressure, purified by silica gel column chromatography to obtain the title compound 5- (2-hydroxy-3-morpholin-4-ylpropyl) -3-methyl-5,6,7,8-tetrahydro -1H-pyrrolo [3,2-c] azepin-4-one 53e (300 mg, yield 57.6%) as a white solid.

MS m / z (ESI): 308.2 [M + 1]

Stage 5

5- (2-Hydroxy-3-morpholin-4-ylpropyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde

(Chloromethylene) dimethylammonium chloride (130 mg, 0.977 mmol) was dissolved in 3 ml of dichloromethane with stirring, the resulting solution was cooled to 0 ° C in an ice and water bath under argon atmosphere. 5- (2-Hydroxy-3-morpholin-4-ylpropyl) -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 53e (300 mg, 0.977 mmol) was dissolved in 2 ml of dichloromethane, the resulting solution was added dropwise to the above reaction system, maintaining the temperature below 0 ° C, and stirred for 20 minutes. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was quickly cooled with an aqueous solution of sodium hydroxide (12 mol / L), saturated brine (10 ml) was added and extracted with a solvent mixture (v: v = 10: 1, 100 ml × 3) of dichloromethane and methanol. The combined organic extracts were washed with saturated brine (100 ml), dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5- (2-hydroxy-3-morpholin-4-ylpropyl) -3-methyl-4-oxo-1,4,5,6,7,8- hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 53f (200 mg, 61% yield) as a white solid.

MS m / z (ESI): 336.2 [M + 1]

Stage 6

(R, Z) -2- (5-Fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -5- (2-hydroxy-3-morpholin-4-ylpropyl) -3-methyl-5, 6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

5- (2-Hydroxy-3-morpholin-4-ylpropyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 53f (50 mg, 0.149 mmol) was dissolved in 261 μl of ethanol with stirring, and 5-fluoro-1,3-dihydroindol-2-one (20.28 mg, 0.134 mmol) and piperidine (7.3 μl, 0.074) were added to the solution. mmol) at room temperature. After complete addition, the reaction mixture was stirred for 2 hours in the dark at 80 ° C in an oil bath. When thin layer chromatography showed the disappearance of the starting materials, the oil bath was removed and the reaction mixture was naturally cooled to room temperature, filtered and dried to give the title compound, (R, Z) -2- (5-fluoro-2-oxo- 1,2-dihydroindol-3-ylidenomethyl) -5- (2-hydroxy-3-morpholin-4-ylpropyl) -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [3,2-s ] azepin-4-one 53 (40 g, yield 57%) as a yellow solid.

MS m / z (ESI): 469.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.725 (s, 1H, pyrrole-NH), 10.907 (s, 1H, indole-NH), 7.760-7.783 (m, 1H, -ArH), 7.747 (s , 1H, -CH = C), 6.914-6.939 (m, 1H, -ArH), 6.835-6.867 (m, 1H, -ArH), 4.719-4.731 (d, 1H, -OH), 3.897 (m, 1H , -CHO), 3.749-3.792 (dd, 1H, amide N, seven-membered ring-external CH ₂ ), 3.570-3.592 (t, 4H, morpholin-2 × -CH ₂ O), 3.384-3.351 (t, 2H, N seven-membered ring-CH ₂ ), 3.138-3.191 (dd, 1H, amide N; seven-membered ring-external CH ₂ ), 2.917-2.953 (t, 2H, -CH ₂ C = C), 2.457 (s, 3H, pyrrole-CH ₃ ), 2.418-2.507 (m, 4H, -CH ₂ N, morpholine-CH ₂ N), 2.289-2.313 (t, 2H, morpholine-CH ₂ M), 2.076 (m, 2H, seven-membered ring-CH ₂ ) .

Example 54

(Z) -3-Methyl-2- (2-oxo-4-pyridin-4-yl-1,2-dihydroindol-3-ylidenomethyl) -5- (2-piperidin-1-yl-ethyl) -5,6, 7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was obtained under the same conditions as described for Step 5 of Example 32, with 3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydro-pyrrolo [3,2-c] azepin-2-carbaldehyde 32d obtained in step 4 of Example 32, and 4-pyridin-4-yl-1,3-dihydroindol-2-one as starting materials to give ( Z) -3-methyl-2- (2-oxo-4-pyridin-4-yl-1,2-dihydroindol-3-ylidenemethyl) -5- (2-piperidin-1-yl-ethyl) -5,6,7 , 8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 54 (40 mg, 54% yield) as a yellow solid.

MS m / z (ESI): 496.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.530 (s, 1H, pyrrole-NH), 11.115 (s, 1H, indole-NH), 8.738-8.753 (d, 2H, -CH = N), 7.498 (s, 2H, pyridine-CH = C), 7.219-7.258 (m, 1H, -ArH), 6.976-6.996 (d, 1H, -ArH), 6.808-6.830 (d. 1H, -ArH), 6.808 ( s, 1H, -CH = C), 3.499-3.532 (t, 2H, seven-membered ring-intra-CH ₂ N), 3.270-3.298 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.879-2.916 ( t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.361-2.413 (m, 6H, 3 × -CH ₂ N), 2.055-2.084 (t, 2H, seven-membered ring-intra-CH- ₂ ), 1.732 (s, 3H, pyrrole-CH ₃ ), 1.453-1.478 (m, 4H, six-membered ring-2 × -CH ₂ ), 1.365-1.377 (m, 2H, six-membered ring-CH ₂ ).

Example 55

(Z) -2- [5-Fluoro-6- (4-fluorobenzylamino) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5- (2-piperidin-1-yl-ethyl) - 5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was obtained under the same conditions as described for Step 5 of Example 32, with 3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 32d obtained in step 4 of Example 32, and 5-fluoro-6- (4-fluorobenzylamino) -1,3-dihydroindol-2-one 3e obtained in step 4 of Example 3, as starting materials, to give (Z) -2- [5-fluoro-6- (4-fluorobenzylamino) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl- 5- (2-piperidin-1-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 55 (77 mg, 90.8% yield) as yellow solid.

MS m / z (ESI): 560.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.425 (s, 1H, pyrrole-NH), 10.520 (s, 1H, -NH), 7.572-7.602 (d, 1H, -ArH), 7.349 (s, 1H, -CH = C), 7.367-7.402 (m, 2H, -ArH), 7.141-7.186 (m, 2H, -ArH), 6.398-6.422 (m, 1H, -NH), 6.040-6.059 (m, 1H, -ArH), 4.347-4.361 (d, 2H, aniline-CH ₂ ), 3.524-3.557 (t, 2H, seven-membered ring-intra-CH ₂ N), 3.314-3.337 (t, 2H, amide N, seven-membered ring -external CH ₂ ), 2.869-2.906 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.390-2.467 (m, 9H, pyrrole-CH ₃ , 3 × -CH ₂ N), 1.999-2.063 (t, 2H, seven-membered ring-intra-CH ₂ ), 1.476-1.489 (m, 4H, six-membered ring-2 × -CH ₂ ), 1.383-1.393 (m, 2H, six-membered ring-CH ₂ ).

Example 56

(Z) -2- (7-Bromo-5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) -5,6, 7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was obtained under the same conditions as described for Step 5 of Example 32, with 3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydro-pyrrolo [3,2-c] azepin-2-carbaldehyde 32d obtained in step 4 of Example 32, and 7-bromo-5-fluoro-1,3-dihydroindol-2-one 4b obtained in step 1 of Example 4, as starting materials, to give (Z) -2- (7-bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5- (2-piperidine -1-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 56 (63 mg, 76.44% yield) as a yellow solid.

MC m / z (ESI): 515.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.661 (s, 1H, pyrrole-NH), 11.184 (s, 1H, indole-NH), 7.848-7.876 (dd, 1H, -ArH), 7.794 (s , 1H, -CH = C), 7.242-7.240 (dd, 1H, -ArH), 3.545-3.571 (t, 2H, amide N, seven-membered ring-intra-CH ₂ ), 3.331-3.358 (t, 2H, amide N seven-membered ring-external CH ₂ ), 2.950-2.986 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.390-2.467 (m, 9H, pyrrole-CH ₃ , 3 × -CH ₂ N), 2.055 -2.084 (t, 2H, seven-membered ring-intra-CH ₂ ), 1.476-1.489 (m, 4H, six-membered ring-2 × -CH ₂ ), 1.383-1.393 (m, 2H, six-membered ring-CH ₂ ).

Example 57

(Z) -2- (4-Bromo-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) -5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was obtained under the same conditions as described for Step 5 of Example 32, with 3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 32d, obtained from step 4 of Example 32, and 4-bromo-1,3-dihydroindol-2-one as starting materials to give (Z) -2 - (4-bromo-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5- (2-piperidin-1-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 57 (68 mg, 91.2% yield) as a yellow solid.

MS m / z (ESI): 499.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.682 (s, 1H, pyrrole-NH), 11.232 (s, 1H, indole-NH), 8.634 (s, 1H, -CH = C), 7.267-7.287 (m, 1H, -ArH), 7.105-7.144 (m, 1H, -ArH), 6.988-7.007 (d, 1H, -ArH), 3.595-3.627 (t, 2H, seven-membered ring-intra-CH ₂ N) , 3.402 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.991-3.028 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.454-2.556 (m, 9H, pyrrole-CH ₃ , 3 × -CH ₂ N), 2.102-2.131 (t, 2H, seven-membered ring-intra-CH ₂ ), 1.523-1.550 (m, 4H, six-membered ring-2 × -CH ₂ ), 1.429-1.441 (m, 2H six-membered ring-CH ₂ ).

Example 58

(Z) -3-Methyl-2- (4-methyl-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -5- (2-piperidin-1-yl-ethyl) -5,6,7,8- tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was obtained under the same conditions as described in Step 5 of Example 32, with 3-methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7 , 8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 32d, obtained from step 4 of Example 32, and 4-methyl-1,3-dihydroindol-2-one as starting materials to give (Z) -3 -methyl-2- (4-methyl-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -5- (2-piperidin-1-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 58 (46 mg, 70.9% yield) as a yellow solid.

MS m / z (ESI): 433.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.703 (s, 1H, pyrrole-NH), 10.926 (s, 1H, indole-NH), 7.567 (s, 1H, -CH = C), 7.035-7.074 (m, 1H, -ArH), 6.769-6.838 (dd, 2H, -ArH), 3.544-3.576 (t, 2H, seven membered ring-intra-CH ₂ N), 3.331-3.359 (t, 2H, amide N seven ring-external CH ₂ ), 2.926-2.962 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.591 (s, 3H, benzene-CH ₃ ), 2.383-2.437 (m, 9H, -CH ₃ , pyrrole-3 × -CH ₂ N), 2.030-2.092 (t, 2H, seven-membered ring-intra-CH- ₂ ), 1.479-1.491 (m, 4H, six-membered ring-2 × -CH2), 1.383-1.394 (m , 2H, six-membered ring-CH ₂ ).

Example 59

(R, Z) -2- (5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -5- (2-hydroxy-3-morpholin-4-ylpropyl) -3-methyl-5, 6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

The title compound was prepared under the same conditions as described for Step 6 of Example 53, with 5- (2-hydroxy-3-morpholin-4-ylpropyl) -3-methyl-4-oxo-1,4,5 , 6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 53f obtained in step 5 of Example 53, and 5-bromo-1,3-dihydroindol-2-one as starting materials to give ( R, Z) -2- (5-bromo-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -5- (2-hydroxy-3-morpholin-4-ylpropyl) -3-methyl-5,6 , 7.8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 59 (30 mg, 63% yield) as a yellow solid.

MS m / z (ESI): 529.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.674 (s, 1H, pyrrole-NH), 11.014 (s, 1H, indole-NH), 8.116-8.120 (d, 1H, -ArH), 7.807 (s , 1H, -CH = C), 7.262-7.287 (dd, 1H, -ArH), 6.826-6.846 (d, 1H, -ArH), 4.719.4.731 (d, 1H, -OH), 3.897 (m, 1H , -CHO), 3.748-3.758 (dd, 1H, amide N, seven-membered ring-external CH ₂ ), 3.570-3.593 (t, 4H, morpholin-2 × -CH ₂ O), 3.433 (t, 2H, N seven-membered ring -CH ₂ ), 3.159 (dd, 1H, amide N, seven-membered ring-external CH ₂ ), 2.917-2.954 (t, 2H, -CH ₂ C = C), 2.465 (s, 3H, pyrrole-CH ₃ ), 2.418 -2.465 (m, 4H, -CH ₂ N, morpholine-CH ₂ N), 2.290-2.314 (t, 2H, morpholine-CH ₂ N), 2.061-2.092 (m, 2H, seven-membered ring-CH ₂ ).

Example 60

(Z) -5- (2-Diethylaminoethyl) -2- (5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-6,7,8,9-tetrahydro-1H, 5H-1,5-diazacyclopentacycloocten-4-one

Stage 1

5- (Cyclopropylhydroxymethyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether

Cyclopropyl magnesium bromide (15 mg, 0.5 mol / L) was cooled to -10 ° C in an ice salt bath in an argon atmosphere. 5-Formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether 1b (1.26 g, 4.5 mmol) was dissolved in 10 ml of tetrahydrofuran with stirring, obtained in as a result, the solution was added dropwise to the above solution, maintaining the temperature at

-10 ° C. After complete addition, the ice salt bath was removed and the reaction mixture was stirred for 1 hour at room temperature. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was rapidly cooled with water, a solution of sulfuric acid (20 ml, 10%) was added, stirred for 30 minutes and extracted with ethyl acetate (50 ml × 3). The combined organic extracts were washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5- (cyclopropylhydroxymethyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 60a (576 mg, yield 39.6%) as a white solid.

MS m / z (ESI): 322.2 [M-1]

Stage 2

5- (4-Bromobut-1-enyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether

5- (Cyclopropylhydroxymethyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether 60a (323 mg, 1 mmol) was dissolved in 4 ml of ethanol with stirring, and was added to the solution hydrobromic acid (2.8 ml, 40%) and stirred for 30 minutes at room temperature. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was extracted with ethyl acetate (10 ml × 5). The combined organic extracts were washed with saturated brine (15 ml), dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5- (4-bromobut-1-enyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-ethyl tert-butyl 4-ethyl ester 60b (345 mg, 89.5% yield) as a white solid.

MS m / z (ESI): 329.4 [M + 1]

Stage 3

5- (4-Bromobutyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether

5- (4-Bromobut-1-enyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether 60b (30 mg, 0.08 mmol) was dissolved in 3 ml ethanol with stirring, and palladium on activated carbon (6 mg, 5%) was added to the solution at room temperature. The reaction mixture was stirred for 45 minutes in a hydrogen atmosphere. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was filtered and concentrated under reduced pressure to obtain the title compound 5- (4-bromobutyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert- 4-ethyl ester butyl ether 60c (21 mg, 70% yield) as a colorless oil.

MS m / z (ESI): 388.0 [M + 1]

Stage 4

5- (4-Diethylaminobutyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether

5- (4-Bromobutyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether 60c (220 mg, 0.57 mmol) was dissolved in 5 ml of dichloromethane with stirring, and N, N-diethylethylenediamine (164 μl, 1.13 mmol) was added to the solution, and refluxed for 30 minutes in an oil bath. The reaction mixture was concentrated to evaporate the solvent and refluxed for another hour. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was concentrated under reduced pressure, purified by silica gel column chromatography to obtain the title compound 5- (4-diethylaminobutyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 4-ethyl ester 2-tert-butyl ether 60d (187 mg, 78% yield) as a white solid.

MS m / z (ESI): 424.3 [M + 1]

Stage 5

5- (2-Diethylaminoethyl) -3-methyl-4-oxo-4,5,6,7,8,9-hexahydro-1H-1,5-diazacyclopentacyclooctene-2-carbaldehyde

Trimethylaluminum (489 μl, 2 mol / L) was dissolved in 3 ml of toluene with stirring, and a solution of 5- (4-diethylaminobutyl) -3-methyl-1H-pyrrol-2,4-dicarboxylic acid 2-tert- was added to the above solution. 4-ethyl ester 60d butyl ether (345 mg, 0.82 mmol) in 6 ml of toluene at room temperature. After complete addition, the reaction mixture was stirred for 30 minutes at room temperature, heated to reflux for 2 hours in an oil bath, an additional amount of trimethylaluminium (900 μl, 2 mol / L) was added and refluxed for another 7 hours. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was rapidly cooled with water, a solution of hydrochloric acid (1 ml, 2 mol / L) was added and stirred for 30 minutes at room temperature. The mixture was adjusted to approximately pH 10 with an aqueous solution of sodium hydroxide (10%) and extracted with ethyl acetate (25 ml × 3). The combined organic extracts were washed with saturated brine (25 ml), dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5- (2-diethylaminoethyl) -3-methyl-4-oxo-4,5,6,7,8,9-hexahydro-1H-1,5- diazacyclopentacyclooctene-2-carbaldehyde 60e (60 mg, 26.7% yield) as a white solid.

MS m / z (ESI); 278.2 [M + 1]

Stage 6

(Z) -5- (2-Diethylaminoethyl) -2- (5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-6,7,8,9-tetrahydro-1H, 5H-1,5-diazacyclopentacycloocten-4-one

5- (2-Diethylaminoethyl) -3-methyl-4-oxo-4,5,6,7,8,9-hexahydro-1H-1,5-diazacyclopentacyclooctene-2-carbaldehyde 60e (20 mg, 0.066 mmol) was dissolved in 1 ml of ethanol with stirring, and 5-fluoro-1,3-dihydroindol-2-one (9.9 mg, 0.066 mmol) was added to the solution at room temperature. The reaction mixture was stirred in the dark until dissolved, 0.1 ml of piperidine was added and heated to reflux for 2 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered to give the title compound, (Z) -5- (2-diethylaminoethyl) -2- (5-fluoro-2-oxo-1 , 2-dihydroindol-3-ylidenomethyl) -3-methyl-6,7,8,9-tetrahydro-1H, 5H-1,5-diazacyclopentacycloocten-4-one 60 (14 mg, 48.8% yield) as yellow solid.

MS m / z (ESI): 439.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.462 (s, 1H, pyrrole-NH), 10.874 (s, 1H, indole-NH), 7.739-7.758 (d, 1H, -ArH), 7.715 (s , 1H, -CH = C), 6.832-6.933 (m, 2H, -ArH), 3.406 (m, 4H, 2 × -CH ₂ NCO), 2.874 (t, 2H, -CH ₂ C = C), 2.597 -2.630 (t, 2H, -CH ₂ N), 2.486-2.538 (q, 4H, ethyl 2 × -CH ₂ N), 2.322 (s, 3H, pyrrole-CH ₃ ), 1.733 (m, 4H, eight-membered ring -intra-2 × -CH ₂ ), 0.963-0.968 (t, 6H, 2 × -CH ₃ ).

Example 61

(Z) -2- (5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl) -5- (2-diethylaminoethyl) -3-methyl-6,7,8,9-tetrahydro-1H, 5H-1,5-diazacyclopentacycloocten-4-one

The title compound was prepared under the same conditions as described for Step 6 of Example 60 with 5- (2-diethylaminoethyl) -3-methyl-4-oxo-4,5,6,7,8,9-hexahydro -1H-1,5-diazacyclopentacyclooctene-2-carbaldehyde 60e obtained in step 5 of Example 60, and 5-bromo-1,3-dihydroindol-2-one as starting materials to give (Z) -2- (5- bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl) -5- (2-diethylaminoethyl) -3-methyl-6,7,8,9-tetrahydro-1H, 5H-1,5-diazacyclopentacycopocten-4 -one 61 (16 mg, 68% yield) as a yellow solid.

MS m / z (ESI): 499.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.660 (s, 1H, pyrrole-NH), 11.008 (s, 1H, indole-NH), 8.113-8.117 (d, 1H, -ArH), 7.803 (s , 1H, -CH = C), 7.260-7.286 (dd, 1H, -ArH), 6.825-6.845 (d, 1H, -ArH), 3.406 (m, 4H, 2 × -CH ₂ NCO), 2.874 (t , 2H, -CH ₂ C = C), 2.597-2.630 (t, 2H, -CH ₂ N), 2.486-2.538 (q, 4H, ethyl 2 × -CH ₂ N), 2.322 (s, 3H, pyrrole - CH ₃ ), 1.733 (m, 4H, eight-membered ring-intra-2 × -CH ₂ ), 0.963-0.968 (t, 6H, 2 × -CH ₃ ).

Example 62

(Z) -5- (2-Ethylaminoethyl) -2- (5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-5,6,7,8-tetrahydro-1H- pyrrolo [3,2-c] azepin-4-one

Stage 1

5- [2- (2-Acetylaminoethylcarbamoyl) ethyl] -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester

5- (2-Carboxyethyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 1e (9.85 g, 30.3 mmol) obtained from stage 4 of Example 1, was dissolved in acetonitrile (50 ml) with stirring, and 1-hydroxy-1H-benzotriazole (8.2 g, 60.6 mmol) and N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide (11, 6 g, 60.6 mmol) at room temperature. After complete addition, the reaction mixture was stirred at room temperature overnight. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was concentrated under reduced pressure, water (200 ml) was added and extracted with ethyl acetate (200 ml × 4). The combined organic extracts were washed with saturated brine (100 ml), dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 5- [2- (2-acetylaminoethylcarbamoyl) ethyl] -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4- ethyl ether 62a (8 g, yield 65%) as a white solid.

MC m / z (ESI): 410.1 [M + 1]

Stage 2

2- [2- (2-Acetylaminoethylcarbamoyl) ethyl] -4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester

5- [2- (2-Acetylaminoethylcarbamoyl) ethyl] -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 62a (818 mg, 2 mmol) was dissolved in 5 ml ethanol with stirring and a solution of hydrochloric acid (5 ml, 12 mol / l) was added to this solution at room temperature. After complete addition, the reaction mixture was heated at 60 ° C in an oil bath for 2 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure to evaporate ethanol, adjusted to approximately pH 12 with an aqueous sodium hydroxide solution (10%), and extracted with ethyl acetate (20 ml × 3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered to remove a drying agent and concentrated under reduced pressure to obtain the title compound, 2- [2- (2-acetylaminoethylcarbamoyl) ethyl] -4-methyl-1H-pyrrole-3 -carboxylic acid ethyl ester 62b (600 mg, 97% yield) as a white solid.

MC m / z (ESI): 310.1 [M + 1]

Stage 3

2- [3- (2-Ethylaminoethylamino) propyl] -4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester

2- [2- (2-Acetylaminoethylcarbamoyl) ethyl] -4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 62b (600 mg, 1.94 mmol) was dissolved in 4 ml of tetrahydrofuran with stirring and a solution was added to the solution borane in tetrahydrofuran (7.79 ml, 1 mol / l, 7.79 mmol) in an ice-water bath under argon atmosphere. After complete addition, the reaction mixture was heated to reflux for 2 hours. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was rapidly cooled with hydrochloric acid, stirred for 30 minutes at room temperature, adjusted to about 12 with aqueous sodium hydroxide solution (10%) and extracted with ethyl acetate (30 ml × 3). The combined organic extracts were washed with saturated brine (30 ml), dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2- [3- (2-ethylaminoethylamino) propyl] -4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 62c (170 mg, 31% yield) ) as a white solid.

MS m / z (ESI): 282.2 [M + 1]

Stage 4

5- (2-Ethylaminoethyl) -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

2- [3- (2-Ethylaminoethylamino) propyl] -4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 62c (350 mg, 1.245 mmol) and trimethylaluminum (1.25 ml, 2.49 mmol) were dissolved in 75 ml of toluene with stirring and the resulting mixture was heated to reflux at 140 ° C in an oil bath for 24 hours. When thin-layer chromatophafia showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure, adjusted to approximately pH 3 with hydrochloric acid (6 mol / L), and stirred for 30 minutes. The mixture was adjusted to pH 14 with an aqueous solution of sodium hydroxide (12 mol / L) and extracted with dichloromethane (100 ml × 4). The combined organic extracts were washed with saturated brine (150 ml), dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure to obtain the title compound 5- (2-ethylaminoethyl) -3-methyl-5, b , 7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 62d (450 mg) as a yellow oil, which was used directly in the next step.

MS m / z (ESI): 236.0 [M + 1]

Stage 5

Ethyl [2- (3-methyl-4-oxo-4,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-5-yl) ethyl] carbamic acid tert-butyl ether

5- (2-Ethylaminoethyl) -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 62d (450 mg, 1.91 mmol) was dissolved in 20 ml of dichloromethane with stirring and di-tert-butyl dicarbonate (834 mg, 3.83 mmol), potassium carbonate (528 mg, 3.83 mmol) and tetrahydrofuran (30 ml) were added to the solution. After complete addition, the reaction mixture was stirred at room temperature overnight. When thin layer chromatography showed the disappearance of the starting materials, water (50 ml) was added to the reaction mixture and extracted with ethyl acetate (50 ml × 3). The combined organic extracts were washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound, ethyl- [2- (3-methyl-4-oxo-4,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepine- 5-yl) ethyl] carbamic acid tert-butyl ether 62e (40 mg, 6% yield) as a yellow solid.

MS m / z (ESI): 336.2 [M + 1]

Stage 6

Ethyl [2- (2-formyl-3-methyl-4-oxo-4,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-5-yl) ethyl] carbamic acid tert-butyl ether

Ethyl [2- (3-methyl-4-oxo-4,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-5-yl) ethyl] carbamic acid tert-butyl ether 62e (40 mg, 0.119 mmol) was dissolved in 25 ml of dichloromethane with stirring, and (chloromethylene) dimethylammonium chloride (15.92 mg, 0.12 mmol) was added to the solution. After complete addition, the reaction mixture was stirred at room temperature for 10 minutes. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was quickly cooled with an aqueous solution of sodium hydroxide (12 mol / L), stirred for another 15 minutes at room temperature and extracted with dichloromethane (20 ml × 3). The combined organic extracts were washed with saturated brine (20 ml), dried over anhydrous magnesium sulfate, filtered to remove a drying agent, and concentrated under reduced pressure to obtain the title compound, ethyl- [2- (2-formyl-3-methyl-4) -oxo-4,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-5-yl) ethyl] carbamic acid tert-butyl ether 62f (54 mg) as a yellow solid, which was used directly in the next step.

MC m / z (ESI): 364.1 [M + 1]

Stage 7

5- (2-Ethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde

Ethyl [2- (2-formyl-3-methyl-4-oxo-4,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-5-yl) ethyl] carbamic acid 62f tert-butyl ether (43 mg, 0.118 mmol) was dissolved in 10 ml of dichloromethane with stirring, and trifluoroacetic acid (272 μl, 3.55 mmol) was added to the solution and stirred for 15 minutes in an ice and water bath. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was concentrated under reduced pressure to obtain the title compound 5- (2-ethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8- hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 62j, which was used directly in the next step.

MC m / z (ESI): 264.1 [M + 1]

Stage 8

(Z) -5- (2-Ethylaminoethyl) -2- (5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-5,6,7,8-tetrahydro- 1H-pyrrolo [3,2-c] azepin-4-one

5- (2-Ethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 62j (45 mg, 0.118 mmol) was dissolved in 5 ml of ethanol with stirring, and 5-fluoro-1,3-dihydroindol-2-one (16 mg, 0.106 mmol) and piperidine (0.15 ml, 1.49 mmol) were added to the solution. After complete addition, the reaction mixture was refluxed at 90 ° C in an oil bath for 1 hour. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was concentrated under reduced pressure, a small amount of ethanol was added and filtered to obtain the title compound, (Z) -5- (2-ethylaminoethyl) -2- (5-fluoro-2- oxo-1,2-dihydroindol-3-ylidenemethyl) -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 62 (34 mg, 76% yield ) as a yellow solid.

MS m / z (ESI): 397.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ (s, 1H, pyrrole-NH), 10.920 (s, 1H, indole-NH), 7.781-7.788 (d, 1H, -ArH), 7.759 (s, 1H, -CH = C), 6.925-6.976 (td, 1H, -ArH), 6.845-6.877 (dd, 1H, -ArH), 3.637-3.688 (t, 2H, N seven-membered ring-CH ₂ ), 3.371- 3.398 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.959-3.026 (m, 4H, -CH ₂ C = C, -CH ₂ N), 2.864-2.918 (q, 2H, ethyl-CH ₂ ) 2.488 (s, 3H, pyrrole-CH ₃ ), 2.056-2.083 (m, 2H, seven-membered ring-CH ₂ ), 1.136-1.172 (t, 3H, ethyl-CH ₃ ).

Example 63

(Z) -5- (2-Diethylaminoethyl) -2- (5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenomethyl) -3-methyl-3a, 5,6,7,8, 8a-hexahydro-1H-pyrrolo [3,2-c] azepin-4-one malate

(Z) -5- (2-Diethylaminoethyl) -2- (5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenomethyl) -3-methyl-3a, 5,6,7,8,8- hexahydro-1H-pyrrolo [3,2-c] azepin-4-one 1 (2.01 g, 4.75 mmol) obtained according to Example 1 was dissolved in 279 ml of methanol with stirring, and 2-hydroxy succinic was added to the solution acid (0.953 g, 7.11 mmol) in one portion. The orange solution was concentrated under reduced pressure, 45 ml of acetonitrile was added, and heated to reflux for 30 minutes in an oil bath. Then the oil bath was removed and the reaction mixture was naturally cooled to room temperature, filtered and dried to give the title compound, (Z) -5- (2-diethylaminoethyl) -2- (5-fluoro-2-oxo-1 , 2-dihydro-indol-3-ylidenomethyl) -3-methyl-3a, 5,6,7,8,8a-hexahydro-1H-pyrrolo [3,2-c] azepin-4-one malate 63 (2, 02 g, yield 76.2%) as an orange solid.

MC m / z (ESI): 425.1 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.742 (s, 1H, pyrrole-NH), 10.925 (s, 1H, indole-NH), 7.784-7.790 (dd, 1H, -ArH), 7.755 (s , 1H, -CH = C), 6.922-6.951 (m, 1H, -ArH), 6.840-6.873 (m, 1H, -ArH), 3.631-3.665 (t, 2H, seven-membered ring-intra-CH- ₂ N) , 3.374-3.401 (t, 2H, amide N, seven-membered ring-external CH ₂ ), 2.911-2.958 (t, 2H, seven-membered ring-intra-CH ₂ C = C), 2.536-2.575 (m, 6H, 3 × - CH ₂ N), 2.471 (s, 3H, pyrrole-CH ₃ ), 2.053-2.079 (m, 2H, seven-membered ring-intra-CH ₂ ), 1.137 (t, 6H, 2 × -CH ₃ ).

Example 64

(Z) -2 - ((5- (2,6-Dichlorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) -3-methyl-5- (2-morpholinoethyl) -5,6,7,8-tetrahydropyrrolo [3,2-s] azepin-4 (1H) -one

Stage 1

5-chlorosulfonylindol-2-one

Chlorosulfonic acid (26.6 ml, 400 mmol) was slowly added to 1,3-dihydroindol-2-one 64a (13.3 g, 100 mmol) in an ice and water bath. After complete addition, the reaction mixture was stirred for 1 hour in an ice-water bath, for another 1 hour at room temperature and heated to 68 ° C for 1 hour. The reaction mixture was cooled to room temperature, water (400 ml) was added slowly, stirred, and yellow precipitates formed. After standing for 1 hour at room temperature, the filter cake was washed with water (20 ml × 4) and dried to give the title compound 5-chlorosulfonylindol-2-one 64b (15.0 g, yield 65%) as yellow solid matter.

Link: Acta Pharmacol Sin .; 2007, 28 (1), 140-152.

Stage 2

5- (2,6-Dichlorophenylmethanesulfonyl) -1,3-dihydroindol-2-one

Sodium monohydrogen phosphate dodecahydrate (142 g, 1.0 mol) and sodium sulfite (252 g, 2.0 mol) were dissolved in 2 L of water at room temperature, heated to 30 ° C and 2-oxo-2,3-dihydro- was added 1H-indole-5-sulfonyl chloride 64b (232 g, 1.0 mol). After complete addition, the reaction mixture was stirred at 60 ° C for 16 hours. To the above solution was added a solution of 2,6-dichlorobenzyl bromide (240 g, 1.0 mol) in acetone (1.8 L), stirred at 60 ° C for 1 hour, additional acetone (200 ml) was added and mixed in within 2 hours. The reaction mixture was rapidly cooled with water (5 L), stirred at room temperature for 1 hour and filtered. The filter cake was washed with water (1 L) and acetone (1 L) and dried in vacuo to give the title compound 5- (2,6-dichlorophenylmethanesulfonyl) -1,3-dihydroindol-2-one 64c (314 g, yield 88%) as a white solid.

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H, indole-NH), 7.56 (m, 4H, -ArH), 7.43 (m, 1H, -ArH), 6.99 (d, 1H, -ArH), 4.59 (s, 2H, -ArCH ₂ ).

Link: Organic Process Research &Development; 2003, 7, 313-317.

Stage 3

(Z) -2 - ((5- (2,6-Dichlorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) -3-methyl-5- (2-morpholinoethyl) -5,6,7,8-tetrahydropyrrolo [3,2-s] azepin-4 (1H) -one

3-Methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 10c (100 mg, 0.325 mmol) and 5- (2,6-dichlorophenylmethanesulfonyl) -1,3-dihydroindol-2-one 64 s (104 mg, 0.293 mmol) were dissolved in 3 ml of ethanol and 52 μl of piperidine was added to the solution at room temperature. After complete addition, the reaction mixture was heated to reflux for 2 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (3 ml × 2) and dried to obtain the title compound, (Z) -2 - ((5- (2,6-dichlorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) - 3-methyl-5- (2-morpholinoethyl) -5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 64 (166 mg, 88% yield) as an orange solid .

MS m / z (ESI): 643.3 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.63 (s, 1H, pyrrole-NH), 11.42 (s, 1H, indole-NH), 8.28 (s, 1H, -ArH), 7.90 (s, 1H , -ArH), 7.51 (m, 3H, -ArH), 7.42 (s, 1H, -CH = C), 7.06 (m, 1H, -ArH), 4.88 (s, 2H, -ArCH ₂ ), 3.58- 2.08 (m, 18H, aliphatic H); 2.44 (s, 3H, pyrrole-CH ₃ ).

Example 65

(Z) -2- [5- (4-Fluorophenylmethanesulfonyl) -2-oxo-1,2-dihydroindol-3-ylidenemethyl] -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -5,6, 7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

about

Stage 1

5- (4-Fluorophenylmethanesulfonyl) -1,3-dihydroindol-2-one

Sodium monohydrogen phosphate dodecahydrate (3.58 g, 10 mmol) and sodium sulfite (2.52 g, 20 mmol) were dissolved in 20 ml of water, heated to 30 ° C and 2-oxo-2,3-dihydro-1H-indole was added -5-sulfonyl chloride 64b (2.32 g, 10 mmol). After complete addition, the reaction mixture was stirred at 60 ° C for 16 hours. To the above solution, a solution of 5-fluorobenzyl bromide (1.9 g, 10 mmol) in acetone (18 ml) was slowly added and stirred at 60 ° C for 2 hours. The reaction mixture was rapidly cooled with water (50 ml) and a lot of precipitate formed. The mixture was stirred at room temperature for another hour, filtered, washed with a solvent mixture (20 ml, v: v = 1: 1) of water and acetone, and dried in vacuo to give the title compound, 5- (4-fluorophenylmethanesulfonyl) -1,3-dihydroindol-2-one 65a (1.8 g, 59% yield) as a pale yellow solid.

MS m / z (ESI): 304.1 [M-1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.85 (s, 1H, indole-NH), 7.42 (m, 2H, -ArH), 7.21 (m, 3H, -ArH), 6.95 (d, 1H, -ArH), 4.59 (s, 2H, -ArCH ₂ ).

Link: Organic Process Research &Development; 2003, 7, 313-317.

Stage 2

2- [5- (4-Fluorophenylmethanesulfonyl) -2-oxo-1,2-dihydroindol-3-ylidenomethyl] -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -5,6,7, 8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

3-Methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 28c (60.2 mg, 0.21 mmol) and 5- (4-fluorophenylmethanesulfonyl) -1,3-dihydroindol-2-one 65a (57.6 mg, 0.19 mmol) were dissolved in 2 ml of ethanol and 50 μl of piperidine was added to the solution at room temperature. After complete addition, the reaction mixture was heated to reflux for 3 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (3 ml × 2) and dried to give the title compound, (Z) -2- [5- (4-fluorophenylmethanesulfonyl) -2-oxo-1,2-dihydroindol-3-ylidenemethyl] -3-methyl-5- (2-pyrrolidin-1-yl-ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 65 (90 mg, yield 81, 8%) as an orange solid.

MS m / z (ESI): 577.3 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.133 (s, 1H, indole-NH), 8.99 (s, 1H, -ArH), 8.61 (s, 1H, -ArH), 7.88 (s, 1H, -CH = C), 8.14-7.76 (m, 4H, -ArH), 7.75 (d, 1H, -ArH), 5.39 (s, 2H, -ArCH ₂ ), 4.33 (m, 2H, -NCH ₂ ), 4.11-3.25 (m, 12H, aliphatic H), 3.70 (m, 2H,

-NCH ₂ ), 2.81 (m, 2H, -NCH ₂ ), 2.46 (s, 3H, pyrrole-CH ₃ ).

Example 66

(Z) -2 - ((5- (2,6-Dichlorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) -3-methyl-5- (2- (pyrrolidin-1-yl) ethyl) -5, 6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one

3-Methyl-4-oxo-5- (2-pyrrolidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 28c (75 mg, 0.262 mmol) and 5- (2,6-dichlorophenylmethanesulfonyl) -1,3-dihydroindol-2-one 64c (84 mg, 0.236 mmol) were dissolved in 2.5 ml of ethanol and 42 μl of piperidine was added to the solution at room temperature. After complete addition, the reaction mixture was heated to reflux for 3 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (3 ml × 2) and dried to obtain the title compound, (Z) -2 - ((5- (2,6-dichlorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) - 3-methyl-5- (2- (pyrrolidin-1-yl) ethyl) -5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 66 (117 mg, yield 79 , 6%) as an orange solid.

MS m / z (ESI): 627.3 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.18 (s, 1H, indole-NH), 9.04 (s, 1H, -ArH), 8.66 (s, 1H, -ArH), 8.25 (s, 1H, -CH = C), 8.23-8.16 (m, 3H, -ArH), 7.99 (d, 1H, -ArH), 5.64 (s, 2H, -ArCH ₂ ), 4.34 (m, 2H, -NCH ₂ ), 4.12-3.26 (m, 12H, aliphatic H), 3.70 (m, 2H,

-NCH ₂ ), 2.81 (m, 2H, -NCH ₂ ), 2.46 (s, 3H, pyrrole-CH ₃ ).

Example 67

(Z) -2 - ((5- (4-Fluorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) -3-methyl-5- (2- (piperidin-1-yl) ethyl) -5.6, 7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one

3-Methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 32d (57.6 mg, 0.21 mmol) and 5- (4-fluorophenylmethanesulfonyl) -1,3-dihydroindol-2-one 65a (57.6 mg, 0.19 mmol) were dissolved in 2 ml of ethanol and 42 μl of piperidine was added to the solution at room temperature. After complete addition, the reaction mixture was heated to reflux for 3 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (3 ml × 2) and dried to give the title compound, (Z) -2 - ((5- (4-fluorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) -3- methyl 5- (2- (piperidin-1-yl) ethyl) -5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 67 (84 mg, 76% yield) in the form of an orange solid.

MC m / z (ESI): 591.3 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.61 (s, 1H, pyrrole-NH), 11.39 (s, 1H, indole-NH), 8.24 (s, 1H, -HCO), 7.86 (s, 1H , -ArH), 7.17 (s, 1H, -CH = C), 7.39-7.13 (m, 4H, -ArH), 6.99 (d, 1H, -ArH), 4.64 (s, 2H, -ArCH ₂ ), 3.58 (m, 2H, -NCH ₂ ), 3.29-2.40 (m, 11H, aliphatic H), 2.97 (m, 2H, -NCH ₂ ), 2.08 (m, 2H, -NCH ₂ ), 1.49 (s, 3H , pyrrole-CH ₃ ).

Example 68

(Z) -2 - ((5- (2,6-Dichlorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) -3-methyl-5- (2- (piperidin-1-yl) ethyl) -5, 6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one

3-Methyl-4-oxo-5- (2-piperidin-1-yl-ethyl) -1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 32d (57 6 mg, 0.21 mmol) and 5- (2,6-dichlorophenylmethanesulfonyl) -1,3-dihydroindol-2-one 64c (67.2 mg, 0.19 mmol) were dissolved in 2.5 ml of ethanol and added to a solution of 42 μl of piperidine at room temperature. After complete addition, the reaction mixture was heated to reflux for 3 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (3 ml × 2) and dried to obtain the title compound, (Z) -2 - ((5- (2,6-dichlorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) - 3-methyl-5- (2- (piperidin-1-yl) ethyl) -5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 68 (93 mg, yield 77 , 5%) as an orange solid.

MC m / z (ESI): 641.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.79 (s, 1H, -ArH), 7.90 (s, 1H, -CH = C), 7.51-7.41 (m, 3H, -ArH), 7.05 (d , 1H, -ArH), 4.89 (m, 2H, -ArCH ₂ ), 3.57 (m, 2H, -NCH ₂ ), 3.35 (m, 2H,

-NCH ₂ ), 2.97 (m, 2H, -NCH ₂ ), 3.31-2.39 (m, 15H, aliphatic H), 2.07 (m, 2H, -NCH ₂ ).

Example 69

(Z) -2 - ((5- (4-Fluorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) -3-methyl-5- (2-morpholinoethyl) -5,6,7,8-tetrahydropyrrolo [3 , 2-c] azepin-4 (1H) -one

3-Methyl-5- (2-morpholin-4-yl-ethyl) -4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 10c (80 mg, 0.26 mmol) and 5- (4-fluorophenylmethanesulfonyl) -1,3-dihydroindol-2-one 65a (72 mg, 0.24 mmol) were dissolved in 2.5 ml of ethanol and 42 μl of piperidine was added to the solution at room temperature . After complete addition, the reaction mixture was heated to reflux for 3 hours. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (3 ml × 2) and dried to give the title compound, (Z) -2 - ((5- (4-fluorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) -3- methyl 5- (2-morpholinoethyl) -5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 69 (120 mg, 85.7% yield) as an orange solid .

MS m / z (ESI): 593.5 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.61 (s, 1H, pyrrole-NH), 11.39 (s, 1H, indole-NH), 8.24 (s, 1H, -ArH), 7.86 (s, 1H , -ArH), 7.40 (m, 1H, -ArH), 7.24 (m, 3H, 3 × -ArH), 7.21 (s, 1H,

-CH = C), 7.01 (d, 1H, -ArH), 4.64 (s, 2H, -ArCH ₂ ), 3.58-2.07 (m, 18H, aliphatic H), 2.44 (s, 3H, pyrrole-CH ₃ ) .

Example 70

(Z) -2 - ((5- (2,6-Dichlorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) -5- (2- (diethylamino) ethyl) -3-methyl-5,6,7, 8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one

5- (2-Diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 1j (60 mg, 0.21 mmol ) and 5- (2,6-dichlorophenylmethanesulfonyl) -1,3-dihydroindol-2-one 64c (67 mg, 0.19 mmol) were dissolved in 3 ml of ethanol and 52 μl of piperidine was added to the solution at room temperature. After complete addition, the reaction mixture was heated to reflux for 2 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (3 ml × 2) and dried to obtain the title compound, (Z) -2 - ((5- (2,6-dichlorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) - 5- (2- (diethylamino) ethyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 70 (95 mg, 79% yield) as orange solid.

MS m / z (ESI): 629.3 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.62 (s, 1H, pyrrole-NH), 11.42 (s, 1H, indole-NH), 8.29 (s, 1H, -ArH), 7.90 (s, 1H , -ArH), 7.49 (s, 1H, -CH = C), 7.52 (m, 2H, -NCH ₂ ), 7.06 (s, 1H, -ArH), 4.89 (s, 2H, -ArCH ₂ ), 3.52 -2.07 (m, 14H, aliphatic H), 2.50 (s, 3H, pyrrole-CH ₃ ), 1.00 (m, 6H, 2 × -CH ₃ ).

Example 71

(Z) -2 - ((5- (4-Fluorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) -5- (2- (diethylamino) ethyl) -3-methyl-5,6,7,8- tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one

5- (2-Diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-c] azepine-2-carbaldehyde 1j (60 mg, 0.21 mmol ) and 5- (4-fluorophenylmethanesulfonyl) -1,3-dihydroindol-2-one 65a (58 mg, 0.19 mmol) were dissolved in 2 ml of ethanol and 34 μl of piperidine was added to the solution at room temperature. After complete addition, the reaction mixture was heated to reflux for 3 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (3 ml × 2) and dried to give the title compound, (Z) -2 - ((5- (4-fluorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) -5- (2- (diethylamino) ethyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 71 (73 mg, 66% yield) as an orange solid substances.

MS m / z (ESI): 579.3 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.59 (s, 1H, pyrrole-NH), 11.39 (s, 1H, indole-NH), 8.24 (s, 1H, -ArH), 7.86 (s, 1H , -ArH), 7.21 (s, 1H, -CH = C), 7.24-7.13 (m, 3H, -ArH), 7.01 (d, 1H, -ArH), 4.64 (s, 2H, -ArCH ₂ ), 3.52-2.06 (m, 14H, aliphatic H), 2.50 (s, 3H, pyrrole-CH ₃ ), 1.00 (m, 6H, 2 × -CH ₃ ).

Example 72

(R, Z) -2 - ((5- (2,6-Dichlorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) -5- (2-hydroxy-3-morpholinopropyl) -3-methyl-5,6 , 7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one

5- (2-Hydroxy-3-morpholin-4-ylpropyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 53f (80 mg, 0.24 mmol) and 5- (2,6-dichlorophenylmethanesulfonyl) -1,3-dihydroindol-2-one 64c (75 mg, 0.21 mmol) were dissolved in 3 ml of ethanol and 30 μl was added to the solution piperidine at room temperature. After complete addition, after stirring for 4 minutes, the reaction mixture was allowed to interact at 120 ° C for 4 minutes under microwave radiation, and an orange hazy solution formed. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (2 ml × 2) and dried to give the title compound, (R, Z) -2 - ((5- (2,6-dichlorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl ) -5- (2-hydroxy-3-morpholinopropyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 72 (120 mg, 85% yield) ) as a yellow solid.

MS m / z (ESI): 673.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.63 (s, 1H, pyrrole-NH), 11.42 (s, 1H, indole-NH), 8.29 (d, 1H, -ArH), 7.90 (s, 1H , -ArH), 7.52 (m, 4H, -ArH), 7.42 (s, 1H, -CH = C), 7.06 (d, 1H, -ArH), 4.89 (s, 2H, -ArCH ₂ ), 4.74 ( m, 1H, -CHO), 3.92-2.33 (m, 18H, aliphatic H), 2.44 (s, 3H, pyrrole-CH ₃ ).

Example 73

(R, Z) -2 - ((5- (4-Fluorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) -5- (2-hydroxy-3-morpholinopropyl) -3-methyl-5,6,7 , 8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one

5- (2-Hydroxy-3-morpholin-4-ylpropyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 53f (80 mg, 0.24 mmol) and 5- (4-fluorophenylmethanesulfonyl) -1,3-dihydroindol-2-one 65a (64 mg, 0.21 mmol) were dissolved in 3 ml of ethanol and 30 μl of piperidine was added to the solution at room temperature. After complete addition, after stirring for 4 minutes, the reaction mixture was allowed to interact at 120 ° C for 4 minutes under microwave radiation, and an orange hazy solution formed. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (2 ml × 2) and dried to obtain the title compound, (R, Z) -2 - ((5- (4-fluorobenzylsulfonyl) -2-oxoindolin-3-ylidene) methyl) - 5- (2-hydroxy-3-morpholinopropyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 73 (100 mg, 76% yield) in as a yellow solid.

MC m / z (ESI): 621.3 [M-1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.61 (s, 1H, pyrrole-NH), 11.38 (s, 1H, indole-NH), 8.24 (d, 1H, -ArH), 7.86 (s, 1H , -ArH), 7.40 (m, 1H, -ArH), 7.24 (m, 1H, -ArH), 7.17 (m, 1H, -ArH), 7.13 (s, 1H, -CH = C), 7.01 (d , 1H, -ArH), 4.74 (m, 1H, -CHO), 4.64 (s, 2H, -ArCH ₂ ), 3.92-2.32 (m, 18H, aliphatic H), 2.44 (s, 3H, pyrrole-CH ₃ )

Example 74

(Z) -5- (2- (Diethylamino) ethyl) -2 ((4- (2,3-difluorophenyl) -5-fluoro-2-oxoindolin-3-ylidene) methyl) -3-methyl-5,6 , 7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one

Stage 1

1-iodine-2-methyl-3-nitrobenzene

2-Methyl-3-nitrophenylamine 74a (21.28 g, 0.14 mol) was dissolved in 70 ml of concentrated hydrochloric acid in an ice and water bath, water (40 ml) was added, stirred at 0-5 ° C, whereby yellow-green precipitate. A solution of nitric acid (40 ml, 3.6 M) was added dropwise to the reaction mixture, stirred for 15 minutes and filtered. The filtrate was added dropwise to a solution of potassium iodide (280 ml, 5.25 M) at 0-5 ° C. After complete addition, the reaction mixture was stirred for 1 hour. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was filtered. The filter cake was dissolved in ethyl acetate and washed with an aqueous solution of sodium hydroxide (10%), water, sodium thiosulfate (5%), saturated brine. The organic phase was dried over anhydrous magnesium sulfate to give a brown oil (34.4 g). This crude product was purified by silica gel column chromatography to give the title compound 1-iodo-2-methyl-3-nitrobenzene 74b (30.1 g, 81.7% yield) as a white solid.

Stage 2

3- (2-Iodo-6-nitrophenyl) -2-oxopropionic acid

To a solution of sodium ethoxide (35 ml, 44 mmol) in an ice-water bath was added dropwise a solution of 1-iodo-2-methyl-3-nitrobenzene 74b in ethanol (35 ml, 40 mmol) in an argon atmosphere. After complete addition, the reaction mixture was stirred until a large amount of brown precipitation formed and diethyl oxalate (6 ml, 44 mmol) was added in one portion. The reaction mixture was refluxed at 100 ° C. in an oil bath for half an hour, water (70 ml) was added and refluxed for another hour. The reaction mixture was concentrated under reduced pressure to evaporate ethanol, washed with ethyl acetate (50 ml) under basic conditions, adjusted to pH 3 with hydrochloric acid (1 M) and extracted with ethyl acetate (30 ml × 3). The combined organic extracts were washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound, 3- (2-iodo-6-nitrophenyl) -2-oxopropionic acid 74 s ( 2.94 g) as a brown oil, which was used directly in the next step.

MS: 334.2 [M-1].

Stage 3

(2-Iodine-6-nitrophenyl) -acetic acid

3- (2-Iodo-6-nitrophenyl) -2-oxopropionic acid 74c (2.086 g, 6.2 mmol) was dissolved in 6 ml of methanol with stirring, and 20 ml of water and 7 ml of hydrogen peroxide were added to the solution at room temperature. After complete addition, the reaction mixture was stirred at room temperature for 1 hour. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was filtered, extracted with ethyl acetate (20 ml × 2). The combined organic extracts were concentrated under reduced pressure, combined with the above filter cake and dried to give the title compound (2-iodo-6-nitrophenyl) -acetic acid 74d (1.77 g, 70% yield) as a brown solid substances.

Stage 4

1-Hydroxy-4-iodo-1,3-dihydroindol-2-one

(2-Iodo-6-nitrophenyl) acetic acid 74d (0.91 g, 3 mmol) was dissolved in ethanol (30 ml, 95%) and added to a solution of palladium on activated carbon (30 mg, 3%). After complete addition, the reaction mixture was stirred for 2 hours in a hydrogen atmosphere. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 1-hydroxy-4-iodo-1,3-dihydroindol-2-one 74e (516 mg, 63.4% yield) as a white solid.

MS: 274.1 [M-1]

Stage 5

5-fluoro-4-iodo-1,3-dihydroindol-2-one

1-Hydroxy-4-iodo-1,3-dihydroindol-2-one 74e (326 mg, 1.19 mmol) was dissolved in 24 ml of dichloromethane in a bath with dry ice and acetone, and sulfur trifluoride (diethylamino) (0, 16 ml, 1.19 mmol), maintaining the temperature at -25 ° C. After complete addition, the reaction mixture was stirred at -25 ° C for 15 minutes until it became transparent. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was quickly cooled with saturated sodium bicarbonate solution, saturated brine (30 ml) was added and extracted with dichloromethane (30 ml × 3). The combined organic extracts were washed with saturated brine (30 ml) and dried over anhydrous sodium sulfate to give a yellow solid (284 mg). This crude product was purified by silica gel column chromatography to give the title compound 5-fluoro-4-iodo-1,3-dihydroindol-2-one 74f (114 mg, 34.7% yield) as a white solid.

MS: 276.6 [M-1]

Stage 6

4- (2,3-difluorophenyl) -5-fluoro-1,3-dihydroindol-2-one

5-Fluoro-4-iodo-1,3-dihydroindol-2-one 74f (277 mg, 1 mmol) was dissolved in 10 ml of N, N-dimethylformamide and 2,3-fluorophenylboronic acid (158 mg, 1 mmol) was added to the solution. ), sodium bicarbonate (168 mg, 2 mmol) and water (10 ml) in an argon atmosphere. After complete addition, the mixture was stirred to achieve good mixing, tetrakis (triphenylphosphine) palladium (109 mg, 0.15 mmol) was added and heated to reflux overnight. When thin layer chromatography showed the disappearance of the starting materials, the reaction mixture was concentrated under reduced pressure, hydrochloric acid solution (10 ml, 1 M) was added, and extracted with ethyl acetate (10 ml × 3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 4- (2,3-difluorophenyl) -5-fluoro-1,3-dihydroindol-2-one 74g (42 mg, 16% yield) as a gray solid substances.

MS: 262.0 [M + 1]

Stage 7

(Z) -5- (2- (Diethylamino) ethyl) -2 - ((4- (2,3-difluorophenyl) -5-fluoro-2-oxoindolin-3-ylidene) methyl) -3-methyl-5, 6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one

5- (2-Diethylaminoethyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 1j (73 mg, 0.25 mmol ) and 4- (2,3-difluorophenyl) -5-fluoro-1,3-dihydro-indol-2-one 74g (60 mg, 0.23 mmol) were dissolved in 2 ml of ethanol, and 35 μl of piperidine was added to the solution at room temperature. After complete addition, the mixture was heated to reflux for 2 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (3 ml × 2) and dried to give the title compound, (Z) -5- (2- (diethylamino) ethyl) -2 - ((4- (2,3-difluorophenyl) - 5-fluoro-2-oxoindolin-3-ylidene) methyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 74 (23 mg, yield 19 %) as an orange solid.

MS m / z (ESI): 537.2 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.58 (s, 1H, pyrrole-NH), 11.178 (s, 1H, indole-NH), 8.24 (s, 1H, -HCO), 7.70-6.998 (m , 5H, -ArH), 6.65 (s, 1H, -CH = C), 4.36 (m, 2H, -NCH ₂ ), 2.91 (m, 2H, -NCH ₂ ), 2.54 (s, 3H, pyrrole-CH ₃ ), 1.2-3.4 (m, 14H, aliphatic H), 2.20 (m, 2H, -NCH ₃ ).

Example 75

2 - ((Z) - (4- (2,3-Difluorophenyl) -5-fluoro-2-oxoindolin-3-ylidene) methyl) -5 - ((R) -2-hydroxy-3-morpholinopropyl) -3 methyl 5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one

5- (2-Hydroxy-3-morpholin-4-ylpropyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 53f (84 mg, 0.25 mmol) and 4- (2,3-difluorophenyl) -5-fluoro-1,3-dihydroindol-2-one 74g (60 mg, 0.23 mmol) were dissolved in 2 ml of ethanol, and 35 μl of piperidine was added to the solution at room temperature. After complete addition, the mixture was heated to reflux for two hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (3 ml × 2) and dried to obtain the title compound 2 - ((Z) - (4- (2,3-difluorophenyl) -5-fluoro-2-oxoindolin-3-ylidene ) methyl) -5 - ((R) -2-hydroxy-3-morpholinopropyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 75 ( 100 mg, 78% yield) as an orange solid.

MC m / z (ESI): 581.3 [M + 1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.57 (s, 1H, pyrrole-NH), 11.12 (s. 1H, indole-NH), 7.704-6.98 (m, 5H, -ArH), 6.65 (s , 1H, -CH = C), 4.69 (m, 1H, -CHOH), 3.86 (m, 2H, -NCH ₂ ), 2.89 (m, 2H, -NCH ₂ ), 2.33 (m, 2H, -NCH ₂ ), 3.86-2.28 (m, 12H, aliphatic H).

Example 76

(R, Z) -5- (2-Hydroxy-3-morpholinopropyl) -3-methyl-2 - ((4-methyl-2-oxoindolin-3-ylidene) methyl) -5,6,7,8-tetrahydropyrrolo [3,2-s] azepin-4 (1H) -one

5- (2-Hydroxy-3-morpholin-4-ylpropyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 53f (30 mg, 0.09 mmol) and 4-methyl-1,3-dihydroindol-2-one (12 mg, 0.08 mmol) were dissolved in 156 μl of ethanol, and 4.4 μl of piperidine was added to the solution at room temperature . After complete addition, the reaction mixture was stirred at 45 ° C for 16 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (1 ml × 2) and dried to give the title compound, (R, Z) -5- (2-hydroxy-3-morpholinopropyl) -3-methyl-2 - ((4-methyl -2-oxoindolin-3-ylidene) methyl) -5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 76 (12 mg, 30% yield) as an orange solid .

MC m / z (ESI), 465.2 (M + 1)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.71 (s, 1H, pyrrole-NH), 10.92 (s, 1H, indole-NH), 7.57 (s, 1H, -CH = C), 7.07-6.77 (m, 3H, -ArH), 4.72 (d, 1H, -OH), 3.90 (m, 1H, -CHOH), 3.78 (dd, 1H, seven-membered ring external amide-NCH ₂ ), 3.58 (t, 4H, morpholine-intra-2 × -CH ₂ O), 3.40 (m, 2H, seven-membered ring-NCH ₂ ), 3.17 (dd, 1H, seven-membered ring external amide-NCH ₂ ), 2.94 (t, 2H, pyrrole-CH ₂ ), 2.59 (s, 3H, benzylmethyl), 2.44 (m, 4H, morpholine-intra-2 × CH ₂ N), 2.39 (s, 3H, pyrrole-CH ₃ ), 2.29 (m, 2H, morpholine-external NCH _2), 2.08 (m, 2H, seven-membered ring-CH ₂ -CH ₂ -CH _2).

Example 77

(R, Z) -5- (2-Hydroxy-3-morpholinopropyl) -2 - ((6-methoxy-2-oxoindolin-3-ylidene) methyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-s] azepin-4 (1H) -one

5- (2-Hydroxy-3-morpholin-4-ylpropyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine-2-carbaldehyde 53f (30 mg, 0.09 mmol) and 6-methoxy-1,3-dihydroindol-2-one (13 mg, 0.08 mmol) were dissolved in 156 μl of ethanol and 4.4 μl of piperidine was added to the solution at room temperature. After complete addition, the reaction mixture was stirred at 45 ° C for 16 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (1 ml × 2) and dried to obtain the title compound, (R, Z) -5- (2-hydroxy-3-morpholinopropyl) -2 - ((6-methoxy-2-oxoindoline -3-ylidene) methyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 77 (22 mg, 51% yield) as a yellow solid .

MC m / z (ESI), 481.2 (M + 1)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.47 (s, 1H, pyrrole-NH), 10.94 (s, 1H, indole-NH), 7.68 (d, 1H, -ArH), 7.40 (s, 1H , -CH = C), 6.60 (d, 1H, -ArH), 6.46 (s, 1H, -ArH), 4.70 (d, 1H,

-OH), 3.89 (m, 1H, -CHOH), 3.77 (dd, 1H, seven-membered ring external amide-NCH ₂ ), 3.58 (t, 4H, morpholine-intra-2 × -CH ₂ O), 3.41 (m , 2H, seven-membered ring-NCH ₂ ), 3.17 (dd, 1H, seven-membered ring external amide-NCH ₂ ), 2.93 (t, 2H, pyrrole-CH ₂ ), 2.41 (s, 3H, pyrrole-CH ₃ ), 2.34 (m, 4H, morpholin intra-2 × -CH ₂ N), 2.29 (m, 2H, morpholin outer NCH _2), 2.07 (m, 2H, seven-membered ring-CH ₂ -CH ₂ -CH _2).

Example 78

(S, Z) -2 - ((5-Fluoro-2-oxoindolin-3-ylidene) methyl) -5- (2-hydroxy-3-morpholinopropyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-s] azepin-4 (1H) -one

Stage 1

(S) -4-oxiranylmethylmorpholine

Morpholine 78a (4.356 ml, 50 mmol) was dissolved in 2.5 ml of tert-butyl alcohol at room temperature, the solution was cooled to 0 ° C, and (S) - (+) - 2-chloromethyloxyran (4.02 ml, 50 mmol). After complete addition, the reaction system was naturally warmed to room temperature and stirred overnight. When thin layer chromatography showed the disappearance of the starting materials, the reaction system was cooled to 10 ° C in an ice-water bath, a solution of potassium tert-butoxide in tetrahydrofuran (30 ml, 1.67 mol / L, 50 mmol) was added, the color of the solution changed from light yellow to a white suspension. After complete addition, the reaction mixture was stirred for another 30 minutes. When thin layer chromatography showed the disappearance of the starting materials, the reaction was stopped. The reaction mixture was concentrated under reduced pressure, 20 ml of water was added, and extracted with dichloromethane (100 ml × 3). The combined organic phase was washed with saturated brine (100 ml × 1), dried with anhydrous magnesium sulfate, filtered to remove a drying agent, the filtrate was concentrated to obtain the title compound, (S) -4-oxiranylmethylmorpholine 78b (5.52 g, yield 77 , 2%) as a yellow solid.

MC m / z (ESI): 144.4 (M + 1)

Stage 2

(R) -1-amino-3-morpholin-4-ylpropan-2-ol

To (S) -4-oxiranylmethylmorpholine 78b (5.52 g, 38.6 mmol), 395 ml of aqueous ammonia (25%, 5.8 mol) was slowly added in an ice and water bath, keeping the temperature below 0 ° C. After complete addition, the reaction mixture was naturally warmed to room temperature and stirred for another 18 hours. When thin layer chromatography showed the disappearance of the starting materials, the reaction was stopped. The reaction solution was concentrated under reduced pressure to remove the reaction solvent, and the title compound (R) -1-amino-3-morpholin-4-ylpropan-2-ol 78c (6.1 g, 99% yield) was obtained as light yellow oil.

MC m / z (ESI): 161.3 (M + 1)

Stage 3

(S) -5- [3- (2-Hydroxy-3-morpholin-4-ylpropylamino) propyl] -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester

5- (3-Methanesulfonyloxypropyl) -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 1-ethyl ester 1e (1.13 g, 2.9 mmol) was dissolved in 5.6 ml dichloromethane with stirring, and (R) -1-amino-3-morpholin-4-ylpropan-2-ol 78c (0.93 g, 5.8 mmol) was added to the solution at room temperature. After complete addition, the reaction mixture was heated to 45 ° C for 14 hours in an oil bath. When thin layer chromatography showed the disappearance of the starting materials, the reaction was stopped. 15 ml of saturated brine was added to the reaction solution, extracted with dichloromethane (20 ml × 3), the combined organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (S) -5- [3- (2-hydroxy-3-morpholin-4-ylpropylamino) propyl] -3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ester 78d (600 mg, yield 72.5 %) as a yellow oil.

MC m / z (ESI): 454.2 (M + 1)

Stage 4

(S) -5- (2-Hydroxy-3-morpholin-4-ylpropyl) -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one

(S) -5- [3- (2-Hydroxy-3-morpholin-4-ylpropylamino) propyl] -3-methyl-1H-pyrrol-2 and 4-dicarboxylic acid 2-tert-butyl ether 4-ethyl ether 78d (580 mg, 1.28 mmol) was dissolved in 6 ml of toluene in an argon atmosphere, the reaction mixture was cooled in an ice-water bath, at which time a solution of trimethyl aluminum in toluene (1.9 ml, 2 mol / L, 3) was added. 84 mmol). After the addition was complete, the bath was removed from ice and water, and the reaction solution was heated to reflux for 24 hours. When thin layer chromatography showed the disappearance of the starting materials, the reaction was stopped. The reaction solution was concentrated under reduced pressure to remove the reaction solvent, 20 ml of hydrochloric acid (6 mol / L) was added and stirred for 20 minutes, adjusted to approximately pH 12 with a solution of sodium hydroxide (12 mol / L) in an ice bath and water. The resulting mixture was extracted with dichloromethane (50 ml × 2), the combined organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound, (S) -5- (2-hydroxy-3-morpholine -4-ylpropyl) -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 78e (300 mg, yield 57.6%) as a white solid substances.

MC m / z (ESI): 308.2 (M + 1)

Stage 5

(S) -5- (2-Hydroxy-3-morpholin-4-ylpropyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine- 2-carbaldehyde

(Chloromethylene) dimethylammonium chloride (130 mg, 0.977 mmol) was dissolved in 3 ml of dichloromethane with stirring in an argon atmosphere, the solution was cooled to 0 ° C in an ice and water bath. (S) -5- (2-Hydroxy-3-morpholin-4-ylpropyl) -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo [3,2-c] azepin-4-one 78e (300 mg, 0.977 mmol) was dissolved in 2 ml of dichloromethane with stirring, the resulting solution was added to the above solution, keeping the temperature below 0 ° C. After complete addition, the reaction mixture was stirred for 20 minutes at room temperature. When thin layer chromatography showed the disappearance of starting materials, sodium hydroxide solution (12 mol / L) was added to the reaction solution to quickly cool the reaction mixture. 10 ml of saturated brine was added to the reaction solution, extracted with a mixture of dichloromethane and methanol solvents (v: v = 10: 1) (100 ml × 3), the combined organic phase was washed with saturated brine (100 ml × 1), dried over anhydrous magnesium sulfate, filtered to remove a drying agent, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound, (S) -5- (2-hydroxy-3-morpholin-4-ylpropyl) -3-methyl- 4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo [3,2-s] azepi -2-carbaldehyde 78f (200 mg, 61% yield) as a white solid.

MS m / z (ESI): 336.2 (M + 1)

Stage 6

(S, Z) -2 - ((5-Fluoro-2-oxoindolin-3-ylidene) methyl) -5- (2-hydroxy-3-morpholinopropyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-s] azepin-4 (1H) -one

(S) -5- (2-Hydroxy-3-morpholin-4-ylpropyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine- 2-carbaldehyde 78f (50 mg, 0.149 mmol) was dissolved in 261 μl of ethanol with stirring, and 5-fluoro-1,3-dihydroindol-2-one (20.28 mg, 0.134 mmol) and piperidine were added to the solution (7, 3 μl, 0.074 mmol) at room temperature. After complete addition, the reaction mixture was stirred for 2 hours in the dark at 80 ° C in an oil bath. When thin layer chromatography showed the disappearance of the starting materials, the reaction was stopped and the oil bath was removed. The reaction system was cooled to room temperature, the reaction solution was filtered, and the filter cake was dried to obtain the title compound, (S, Z) -2 - ((5-fluoro-2-oxoindolin-3-ylidene) methyl) -5- (2-hydroxy-3-morpholinopropyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 78 (40 mg, 57% yield) as yellow solid matter.

MS m / z (ESI): 469.2 (M + 1)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.73 (s, 1H, pyrrole-NH), 10.91 (s, 1H, indole-NH), 7.79-6.84 (m, 3H, -ArH), 7.56 (s , 1H, -CH = C), 4.73 (d, 1H, -OH), 3.90 (m, 1H, -CHOH), 3.76 (dd, 1H, seven-membered ring external amide-NCH ₂ ), 3.58 (t, 4H, morpholine-2 × -CH ₂ O), 3.42 (m, 2H, seven-membered ring-NCH ₂ ), 3.15 (dd, 1H, seven-membered ring external amide-NCH ₂ ), 2.94 (t, 2H, -CH ₂ C = C ), 2.457 (s, 3H, pyrrole-CH ₃ ), 2.413 (m, 4H, morpholine-intra-2 × -CH ₂ N), 2.306 (m, 2H, external morpholine NCH ₂ ), 2.08 (m, 2H, the seven-membered ring is CH ₂ —CH ₂ —CH ₂ ).

Example 79

(S, Z) -2 - ((5-Chloro-2-oxoindolin-3-ylidene) methyl) -5- (2-hydroxy-3-morpholinopropyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-s] azepin-4 (1H) -one

(S) -5- (2-Hydroxy-3-morpholin-4-ylpropyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine- 2-carbaldehyde 78f (40 mg, 0.12 mmol / L) and 5-chloro-1,3-dihydroindol-2-one (20 mg, 0.12 mmol) were dissolved in 1.5 ml of ethanol, and to the solution was added 6 μl piperidine at room temperature. After complete addition, the reaction mixture was stirred at 45 ° C for 16 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (1 ml × 2) and dried to give the title compound, (S, Z) -2 - ((5-chloro-2-oxoindolin-3-ylidene) methyl) -5- (2 -hydroxy-3-morpholinopropyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 79 (46 mg, 79% yield) as a yellow solid .

MC m / z (ESI): 485.2 (M + 1)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.679 (s, 1H, pyrrole-NH), 11.008 (s, 1H, indole-NH), 7.994 (s, 1H, -ArH), 7.803 (s, 1H , -CH = C), 7.159-6.869 (m, 2H, -ArH), 4.727 (d, 1H, -OH), 3.90 (m, 1H, -CHOH), 3.76 (dd, 1H, seven-membered ring, external amide- NCH ₂ ), 3.58 (t, 4H, morpholine-2 × -CH ₂ O), 3.418 (m, 2H, seven-membered ring-NCH ₂ ), 3.15 (m, 1H, seven-membered ring external amide-NCH ₂ ), 2.937 ( t, 2H, -CH ₂ C = C), 2.464 (s, 3H, pyrrole-CH ₃ ), 2.428 (m, 4H, morpholine-intra-2 × -CH ₂ N), 2.299 (m, 2H, external morpholine -NCH _2), 2.076 (m, 2H, seven-membered ring-CH ₂ -CH ₂ -CH _2).

Example 80

(S, Z) -2 - ((5-bromo-2-oxoindolin-3-ylidene) methyl) -5- (2-hydroxy-3-morpholinopropyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-s] azepin-4 (1H) -one

(S) -5- (2-Hydroxy-3-morpholin-4-yl-propyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-s] azepin-2-carbaldehyde 78f (40 mg, 0.12 mmol) and 5-bromo-1.3-dihydroindol-2-one (25 mg, 0.12 mmol) were dissolved in 1.5 ml of ethanol, and 6 μl was added to the solution piperidine at room temperature. After complete addition, the reaction mixture was stirred at 45 ° C for 16 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (1 ml × 2) and dried to give the title compound, (S, Z) -2 - ((5-bromo-2-oxoindolin-3-ylidene) methyl) -5- (2 -hydroxy-3-morpholinopropyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 80 (51 mg, 81% yield) as a yellow solid .

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.673 (s, 1H, pyrrole-NH), 11.014 (s, 1H, indole-NH), 8.120-8.115 (s, 1H, -ArH), 7.807 (s , 1H, -CH = C), 7.287-7.262 (dd, 1H, -ArH), 6.847-6.826 (d, 1H, -ArH), 4.734-4.722 (d, 1H, -OH), 3.90 (m, 1H , -CHOH), 3.792-3.748 (dd, 1H, seven-membered ring-external amide-NCH ₂ ), 3.58 (t, 4H, morpholin-2 × -CH ₂ O), 3.437-3.398 (m, 2H, seven-membered ring NCH ₂ ), 3.193-3.140 (m, 1H, seven-membered ring-external amide-NCH ₂ ), 2.936 (t, 2H, -CH ₂ C = C), 2.465 (s, 3H, pyrrole-CH ₃ ), 2.431- 2.420 (m, 4H, morpholine-intra-2 × -CH ₂ N), 2.315 (m, 2H, morpholine-external NCH ₂ ), 2.09 (m, 2H, seven-membered ring —CH ₂ —CH ₂ —CH ₂ ).

Example 81

(S, Z) -2 - ((4-Bromo-2-oxoindolin-3-ylidene) methyl) -5- (2-hydroxy-3-morpholinopropyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-s] azepin-4 (1H) -one

(S) -5- (2-Hydroxy-3-morpholin-4-ylpropyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine- 2-carbaldehyde 78f (40 mg, 0.12 mmol) and 4-bromo-1,3-dihydroindol-2-one (25 mg, 0.12 mmol) were dissolved in 1.5 ml of ethanol, and 6 μl was added to the solution piperidine at room temperature. After complete addition, the reaction mixture was stirred at 45 ° C for 16 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (1 ml × 2) and dried to give the title compound, (S, Z) -2 - ((4-bromo-2-oxoindolin-3-ylidene) methyl) -5- (2 -hydroxy-3-morpholinopropyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 81 (34 mg, 54% yield) as a yellow solid .

MS m / z (ESI): 529.3 (M + 1)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.647 (s, 1H, pyrrole-NH), 11.185 (s, 1H, indole-NH), 8.588 (s, 1H, -CH = C), 7.238-7.218 (d, 1H, -ArH), 7.095-7.055 (t, 1H, -ArH), 6.956-6.936 (d, 1H, -ArH), 4.739-4.726 (d, 1H, -OH), 3.90 (m, 1H , -CHOH), 3.800-3.757 (dd, 1H, seven-membered ring-external amide-NCH ₂ ), 3.593-3.570 (t, 4Н, morpholine-2 × -CH ₂ O), 3.446 (m, 2H, seven-membered ring - NCH ₂ ), 3.192 (dd, 1H, seven-membered ring-external amide-NCH ₂ ), 2.956 (t, 2H, -CH ₂ C = C), 2.447-2.428 (m, 4H, morpholine-intra-2 × -CH ₂ N), 2.411 (s, 3H, pyrrole-CH ₃ ), 2.301 (m, 2H, morpholine-external NCH ₂ ), 2.08 (m, 2H, seven-membered ring-CH ₂ -CH ₂ -CH ₂ ).

Example 82

(S, Z) -2 - ((7-Bromo-5-fluoro-2-oxoindolin-3-ylidene) methyl) -5- (2-hydroxy-3-morpholinopropyl) -3-methyl-5,6,7 , 8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one

(S) -5- (2-Hydroxy-3-morpholin-4-ylpropyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine- 2-carbaldehyde 78f (40 mg, 0.12 mmol) and 7-bromo-5-fluoro-1,3-dihydroindol-2-one 4b (27 mg, 0.12 mmol) were dissolved in 1.5 ml of ethanol, and 6 μl piperidine was added to the solution at room temperature. After complete addition, the reaction mixture was reacted at 45 ° C. for 16 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (1 ml × 2) and dried to give the title compound, (S, Z) -2 - ((7-bromo-5-fluoro-2-oxoindolin-3-ylidene) methyl) - 5- (2-hydroxy-3-morpholinopropyl) -3-methyl-5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 82 (48 mg, yield 73.8% ) as a yellow solid.

MC m / z (ESI): 547.5 (M + 1)

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.665 (s, 1H, pyrrole-NH), 11.188 (s, 1H, indole-NH), 7.876-7.848 (dd, 1H, -ArH), 7.797-7.055 (s, 1H, -ArH), 7.270-7.241 (dd, 1H, -ArH), 4.74 (m, 1H, -OH), 3.93 (m, 1H, -CHOH), 3.75 (dd, 1H, seven-membered ring external amide-NCH ₂ ), 3.583 (t, 4H, morpholin-2 × -CH ₂ O), 3.480-3.415 (m, 2H, seven-membered ring-NCH ₂ ), 3.15 (dd, 1H, seven-membered ring - external amide- NCH ₂ ), 2.471 (s, 3H, pyrrole-CH ₃ ), 2.430 (m, 4H, morpholine-int-2 × -CH ₂ N), 2.310 (t, 2H, morpholine-external NCH ₂ ), 2.086 (m , 2H, seven-membered ring-CH ₂ -CH ₂ -CH _2).

Example 83

(S, Z) -5- (2-Hydroxy-3-morpholinopropyl) -3-methyl-2 - ((4-methyl-2-oxoindolin-3-ylidene) methyl) -5,6,7,8-tetrahydropyrrolo [3,2-s] azeline-4 (1H) -one

(S) -5- (2-Hydroxy-3-morpholin-4-ylpropyl) -3-methyl-4-oxo-1,4,5,6,7,8-hexahydropyrrolo [3,2-c] azepine- 2-carbaldehyde 78f (40 mg, 0.12 mmol / L) and 4-methyl-1.3-dihydroindol-2-one (18 mg, 0.12 mmol) were dissolved in 1.5 ml of ethanol, and 6 μl was added to the solution piperidine at room temperature. After complete addition, the reaction mixture was stirred at 45 ° C for 16 hours. When thin layer chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (1 ml × 2) and dried to give the title compound, (S, Z) -5- (2-hydroxy-3-morpholinopropyl) -3-methyl-2 - ((4-methyl -2-oxoindolin-3-ylidene) methyl) -5,6,7,8-tetrahydropyrrolo [3,2-c] azepin-4 (1H) -one 83 (35 mg, 63.6% yield) as yellow solid matter.

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.715 (s, 1H, pyrrole-NH), 10.934 (s, 1H, indole-NH), 7.572 (s, 1H, -CH = C), 7.057 (t , 1H, -ArH), 6.840-6.821 (d, 1H, -ArH), 6.790-6.771 (d, 1H, -ArH), 4.737-4.725 (d, 1H, -OH), 3.92 (m, 1H, - CHOH), 3.75 (dd, 1H, seven-membered ring-intra-amide-NCH ₂ ), 3.58 (t, 4H, morpholine-2 × -CH ₂ O), 3.441 (m, 2H, seven-membered ring-NCH ₂ ), 3.15 (m, 1H, seven-membered ring-external amide-NCH ₂ ), 2.939 (t, 2H, -CH ₂ CH = C), 2.594 (s, 3H, pyrrole-CH ₃ ), 2.426 (m, 4H, morpholine-intra -2 × -CH ₂ N), 2.388 (s, 3H, pyrrole-CH ₃ ), 2.309-2.293 (m, 2H, morpholine-external NCH ₂ ), 2.078 (m, 2H, seven-membered ring-CH ₂ -CH ₂ -CH ₂ ).

BIOLOGICAL ANALYSIS SYSTEMS

EXAMPLE 1: Cell Proliferation Inhibition Aealysis System

To determine the level of activity and effect of various compounds of the present invention on the inhibition of proliferation (cellular toxicity) of human cancer cells with high expression of the endothelial growth factor receptor (VEGFR) - HUVEC cells (human umbilicial vein endothelium cells - human umbilical vein endothelial cells), the following in vitro assay system.

The cell analysis described herein is intended to test VEGFR-mediated activity of compounds against angiogenesis and the effect of inhibiting cancer cell proliferation in vitro. The effect and activity are expressed by an IC ₅₀ value that destroys a cancer cell. General assay techniques are described below: Human cells with high VEGFR expression are selected and seeded in a 96-well cell culture plate at a suitable concentration (exponential 5000 cells / ml medium). The cells are then cultured in an incubator with carbon dioxide (CO ₂ ) until their confluence is approximately 85%. The cell culture medium is then replaced with fresh medium with the addition of test compounds in a series of concentrations (usually 6 to 7 concentrations). Then the cells are again placed in an incubator and cultured continuously for 72 hours. After 72 hours, the cells exposed to the compounds and control cells were analyzed for their proliferation using the sulforodamine B (SRB) method. IC ₅₀ compounds in relation to the test cells are calculated based on the data of the inhibition of serial concentrations of the tested compounds.

Material and methods:

(a) Dimethyl sulfoxide (Sinophma reagent company, Catalog No. T20050806)

(b) HUVEC cells (acquired at the Institute of Biochemistry and Cell Biology)

(c) 100 mm Falcon Cell Culture Plates (Baton Dickison Labware, Baton Dickison and company, catalog number 18677)

(d) 96-well Corning Culture Kit (Corning Incorporated, 3599)

(e) Fisher pipette (Fisher scientific, Cat. No. 03-692-164)

(f) Cellular medium DMEM / F12 (Gibco, Cat. No. 12400-024)

(g) Fetal bovine serum, Australian origin (Gibco, Catalog No. 10099-141)

(h) Phosphate-buffered saline (Gibco, catalog No. 10010-072)

(i) 0.25% Trypsin-EDTA (Gibco, Catalog No. 25200-056)

(j) Sulforodamine B (Sigma, Cat. No. 3520-42-1)

(l) Acetic acid (reagent company Sinophma, catalog number T20060508)

(m) Trichloroacetic acid (Sinophma reagent company, Catalog No. T20060305)

(n) Tris base (Amresco, Catalog No. 0826)

(o) Class II A / B3 biological laminar box (ThermoForma, catalog number HB0053-03)

(p) CO ₂ incubator with a water jacket of a series II (ThermoForma, Model: 3111)

(p) Centrifuge (Fisher Scientific Marathon 8 k, Part No. 0027-02)

(c) Novastar Tablet Reader (BMG Labtech, Catalog No. 700-0081)

(t) Orbital Shaker (Qilinbeier, TS-1 Catalog No.)

Protocol:

The following protocol is used to analyze the cellular toxicity activity of the IC ₅₀ values of the test compounds of the invention for HUVEC cells:

1. HUVEC cells were grown in growth medium (DMEM / F12 supplemented with 10% Fetal bovine serum - PBS) in 100 mm Corning culture plates until confluence at 37 ° C, 5% CO ₂ .

2. HUVEC cells were washed in 100 mm PBS plates, then the cells were trypsinized and plated in Corning 96-well cell culture plates at a concentration of 50,000 cells / ml, leaving 6 wells per plate empty as a background.

3. Cells were grown in 96-well plates at 37 ° C, 5% CO ₂ , up to 85% confluency.

4. A stock solution of the compounds was prepared using DMSO to dissolve the candidate compounds to a concentration of 20 mM. Then, DMSO was used to dilute the stock solution to a series of concentrations of the solutions of the tested compounds (namely, 2 mM, 1 mM, 0.2 mM, 20 μM, 2 μM, 0.2 μM).

5. A cell culture medium (in this case DMEM / F12 supplemented with 10% PBS) was used to dilute a solution of the compound prepared above. Each serial concentration of a solution of the compound in DMSO was diluted 20 times with culture medium by adding 5 μl of a solution of the compound in DMSO to 95 μl of culture medium, then the vortex was well mixed. This ensured that the concentration of DMSO to which HUVEC cells were exposed would not exceed 0.5%.

6. After attaching HUVEC cells to the bottom of the dish and achieving confluence, approximately 85% of the culture medium was replaced with fresh DMEM / F12 medium supplemented with 10% PBS. 180 μl of medium was added to each well, then 20 μl of a solution of the test compounds in the medium prepared in step 5 was added to each well. For the wells of the negative control group, 20 μl of culture medium containing 0.5% pure DMSO was added. Thus, HUVEC cells were exposed to each test compound at a serial final concentration of 100 μM, 10 μM, 5 μM, 1 μM, 0.1 μM, 0.01 μM and 0.001 μM.

7. The culture plates were placed back into the incubator and cultured for 72 hours at 37 ° C, 5% CO ₂ .

8. After 72 hours, cultures were removed from the incubator into a sterile work area.

9. A fixative (50% trichloroacetic acid — TCA) was prepared by adding pure analysis water to TCA, fixing the cells by carefully layering 50 μl of a cold TCA solution on the surface of the growth medium.

10. The plates were incubated for 1 hour at 4 ° C, and then washed several times with water to remove TCA, whey proteins, etc. The tablets were air dried and stored until use. The optical density of the pure background control was measured in wells incubated with cell-free growth medium.

11. 0.4% Sulforodamine B solution was prepared using 10% acetic acid solution. To each well of 96-well plates, 50 μl of sulphorodamine B solution was added.

12. The cells were allowed to stain for 30 minutes.

13. Prepared a washing solution of 10% acetic acid. At the end of the staining period, the dye was removed and the cells were rinsed quickly with 1% acetic acid. Repeated until the included dye was removed. The washing time was kept to a minimum to reduce the desorption of the dye associated with the protein. After rinsing, the cultures were dried in air.

14. Then, the included dye was dissolved in the volume of sulforodamine B. The solubilization solution (10 mM Tris) was equal to the initial volume of the culture medium. Then the cultures were allowed to stand for 5 minutes at room temperature, and the mixing of the dye was enhanced by gentle mixing in a rotary shaker.

15. The absorption was measured using spectrophotometry at a wavelength of 565 nm. The background absorbance of 96-well plates at 690 nm was measured and subtracted from the measurement results at 565 nm.

16. The inhibition rate (IR - inhibition rate) was calculated as described below:

IR = 100 × (uptake of control cells — uptake of cells exposed to test compounds at various concentrations) / uptake of control cells%.

The IC ₅₀ value can be derived from IR compounds at various concentration gradients.

The activity of the compounds of the invention

The biological activity of the compounds of the invention is tested using the analysis system described above. IC ₅₀ values are measured and shown in the table below:

Example No. IC ₅₀ (VEGFR / HUVEC) (μM) one 0.09 2 0.288 3 0.1 four 0.404 5 0.1 6 0.28 8 0,308 9 0,068 10 0.123 eleven 0,207 12 0.3 13 0.804 fourteen 0.457 fifteen 1.2 16 0.21 17 0.129 19 0.146

EXAMPLE 2: VEGF-R2 Kinase Assay System

This assay system is used to measure the in vitro kinase activity of recombinant human VEGF-R2 in an ELISA assay.

Materials and reagents:

but. Wash buffer (FSB-T buffer): 1 × FSB (137 mM NaCl, 2.7 mM KCl, 4.3 mM Na ₂ HPO ₄ , 1.4 mM KH ₂ PO ₄ , pH adjusted to 7.2) and 0 .05% Tween-20.

b. 1% Bovine serum albumin (BSA, Calbiochem # 136593) in FSB-T buffer.

at. Stop buffer: 50 mM EDTA, pH 8.0.

d. DELFIA ^® europium-labeled IgG against mouse (PerkinElmer Life Sciences # AD0124).

D. DELFIA ^® Strengthening Solution (PerkinElmer Life Sciences # 1244-105).

e. DELFIA ^® Streptavidin-coated 96-well yellow plate (PerkinElmer Life Sciences # AAAND-0005).

g. Recombinant human VEGF-R2 kinase (supplied in 50 mM Tris-HCl (pH 8.0), 100 mM NaCl, 5 mM DTG, 15 mM reduced glutathione and 20% glycerin) (Cell signaling technology # 7787).

h. 10 mM ATP solution (Cell signaling technology # 9804).

and. Biotin-gastrin precursor peptide (Tyr87) (Cell signaling technology # 1310).

K. Phosphotyrosine-mouse mAb (P-Tyr-100) (Cell signaling technology # 9411).

l HTScan ™ Tyrosine Kinase Buffer (4 ×)

1x kinase buffer:

60 mM HEPP

5 mM MgCl ₂

5 mM MnCl ₂

3 μm Na ₃ VO ₄

(Cell signaling technology # 9805).

M. 1.25 M DTT (1000 ×) (Cell signaling technology).

Methodology:

Used the protocol below:

1. The test compound was diluted with DMSO to the desired final analytical concentration. 1 μl of test compound, negative control (sample to which no test compound was added), 1 μl of DMSO was added to each assay system.

2. 6 μM substrate peptide (Tyr87) was diluted with dH ₂ O (1: 1), and 15 μl was added to each assay.

3. The VEGF-R2 enzyme was immediately transferred from -80 ° C to ice, and the enzyme was allowed to thaw on ice.

4. 2.2 μg of VEGF-R2 enzyme was taken into the enzyme tube.

5. 10 μl of DTT (1.25 M) was added in 2.5 ml of 4x tyrosine kinase buffer

HTScan ™ (240 mM HEPES pH 7.5, 20 mM MgCl ₂ , 20 mM MnCl ₂ , 12 μM Na ₃ VO ₄ ) for the preparation of DTT / kinase buffer.

6. 0.75 ml of DTT / kinase buffer was transferred to each enzyme tube to prepare a 4 × reaction mixture, and 7.5 μl of the 4 × reaction mixture was added to each assay system.

7. 2 μl of ATP (10 mM) was added to 498 μl of dH ₂ O and 7.5 μl was added to each assay system.

Final analytical concentrations for 30 μl of the reaction mixture

60 mM HEPP pH 7.5

5 mM MgCl ₂

5 mM MnCl ₂

3 μm Na ₃ VO ₄

1.25 mm DTT

10 μM ATP

1.5 μM substrate peptide

22 ng VEGF-R2 kinase

8. The reaction tube was incubated at 25 ° C for 30 minutes.

9. To stop the reaction, 30 μl / analytical stop buffer (50 mM EDTA, pH 8.0) was added.

10. 25 μl of each reaction mixture and 75 μl of dH ₂ O / well were transferred to a 96-well streptavidin-coated plate with shaking at room temperature for 60 minutes.

11. Each well was washed three times with 200 μl of FSB-T buffer. The tablet was tapped on a paper towel to remove excess fluid.

12. The first antibody, phosphotyrosine mAb (P-Tyr-100) was diluted 1: 1000 in PBS-T buffer with 1% BSA, and 100 μl of the diluted first antibody was added to each well.

13. The reaction tube was incubated with shaking at room temperature for 60 minutes.

14. Washed, as described above for stage 11.

15. Europium-labeled anti-mouse IgG was diluted at 1: 500 in FSB-T buffer with 1% BSA, 100 μl of diluted antibody was added to each well.

16. The reaction tube was incubated with shaking at room temperature for 30 minutes.

17. Each well was washed five times with 200 μl of FSB-T buffer. The tablet was tapped on a paper towel to remove excess fluid.

18. Added 100 μl / well of DELFIA ^® Enhancing Solution.

19. The reaction tube was incubated with shaking at room temperature for 5 minutes.

20. Fluorescence emission was measured at 615 nm using a suitable time resolution tablet reader.

Calculation of Inhibition Index: IR (%) = 100-100 * (X-B) / (N-B)

X = fluorescence value of the well containing the test compound

N = negative control

B = pure control

The IC ₅₀ value can be deduced from IR compounds at various concentration gradients.

The activity of the compounds of the invention

The biochemical activity of the compounds of the invention is tested using the analysis systems described above. IC ₅₀ values are measured and shown in the table below:

Example No IC ₅₀ (VEGFR / bio) (μM) one 0.014 2 0,021 3 0.28 four 0,041 5 0.0085 6 0,023 7 0.69 8 0.115 9 0.49 10 0.014 eleven 0.001 12 0.001 13 0.003 fourteen 0.004 fifteen 0.002 16 0.0013 17 0.001 eighteen 0.01 19 0.012 twenty 0,072 21 0.16

PHARMACODYNAMIC IN VIVO ANALYSIS SYSTEMS

The therapeutic effect of the compound of Example 63 in relation to HT-29 human colon cancer xenografts in mice lacking hair

1. Summary:

The therapeutic effects of the compound of Example 63 against xenografts of human colon cancer NT-29 in mice lacking hair were evaluated. Prolonged oral administration of the compound from Example 63 markedly inhibited the growth of NT-29 human colon cancer and reduced tumor volume; mice can tolerate this compound well.

2. Purpose:

The therapeutic effects of the compound of Example 63 against xenografts of human colon cancer NT-29 in mice lacking hair were evaluated.

3. Test drug:

Name and lot of drug: the compound of Example 63 is a yellow powder.

Production method: the compound of Example 63 was diluted to the appropriate concentration with distilled water.

4. Test animals:

Female BALB / cA-nude mice aged six to seven weeks were purchased from the Slaccas Experimental Animal. Certificate Number: SCXK (Shanghai) 2003-0003. Dilution conditions: SPF level.

5. Test report:

Mice lacking hair were subcutaneously infected with NT-29 human colon cancer cells. After the tumors grew to 100-300 mm ³ , the mice were randomly divided into groups (d0). Doses and dosage regimens are shown in table 1. The volume of tumors and the mass of mice were measured 2-3 times a week. The formula for calculating the tumor volume (V) is the formula: V = 1/2 × a × b ² , a: tumor length, b: tumor width.

Table 1 The therapeutic effect of the compound of Example 63 against HT-29 human colon cancer xenografts in mice lacking hair Group Dose (mg / kg) Introduction The number of animals d0 / dn TV (X ± SD, mm ³ ) RTV T / C (%) d0 dn X ± SD The control p o 9/9 291 ± 66 729 ± 298 2.54 ± 1.01 Compound 40 d0-12 5/5 364 ± 46 300 ± 154 0.80 ± 0.42 31.5 * Example 63 d0: time of the first dosage; dn: 13th day after the first dosage; TV (tumor volume): tumor volume; RTV (relative tumor volume): relative tumor volume * P <0.01 versus control.

6. Conclusion:

Example 63 apparently inhibited the growth of human colon cancer HT-29 and reduced tumor volume; mice can tolerate this compound well without apparent toxicity.

The test compound was a compound obtained in accordance with example 53.

Supplementary Example 1: Cancer Cell Proliferation Inhibition Assay

The cell analysis described herein is intended to test the activity of the compound of Example 53 with respect to inhibition of cancer cell proliferation in vitro using the sulforodamine B (CPB) method. Cancer cells include HUVEC (human umbilical vein endothelial cells), HT-29 (human colorectal cancer cells), Mo7e (human megakaryoblastic leukemia cell line), A431 (human epidermal carcinoma cells), NCI-H526 (small cell lung cancer cells) and SK -BR-3 (breast cancer cells). Activity data are shown in table 1.1.

Table 1.1 In vitro cancer cell proliferation inhibition activity for the compound of Example 53 Example No. IC50 (µM, average ± SD) Huvec NT-29 Mo7e A431 NCI-H526 SK-BR-3 53 1,1 2.4 ± 1.6 0.8 ± 0.2 2.0 ± 0.5 8.3 ± 0.3 7.8 ± 1.5

The results show that the compound of Example 53 unexpectedly inhibits the proliferation of HUVEC, Mo7e, which express highly receptor tyrosine kinase VEGFR and c-kit. IC ₅₀ values are 1.1 μM and 0.8 μM, respectively. Additionally, the compound of Example 53 inhibits the proliferation of A431, SK-BR-3 expressing highly EGFR, HER2, and inhibits the proliferation of NCI-H526 cells expressing highly c-kit.

This analysis proves that the claimed compounds of the invention can inhibit protein kinases VEGFR, c-kit, EGFR, HER2. Moreover, the claimed compounds of the invention clearly inhibit the proliferation of colorectal cancer cells, leukemia cells, squamous cell carcinoma cells, small cell lung cancer cells, breast cancer cells.

Supplementary Example 2: In vivo Anticancer Pharmacodynamic Analysis

The test procedure and steps are the same as indicated in the "PHARMACODYNAMIC IN VIVO ANALYSIS SYSTEMS" section of the present invention. The therapeutic effects of the compound of Example 53 with respect to xenografts of colon and rectal cancer, non-small cell lung cancer, liver cancer, melanoma, and kidney cancer were evaluated in mice lacking hair. The test results are shown in table 2.1.

Table 2.1 The anticancer activity of the compounds of example 53 in vivo Cancer cells Medicine Dose (mg / kg) Introduction The initial tumor volume (mm ³ ) T / S (%) Note NT-29 (colorectal cancer) The control solvent n / a d0-20 146 ± 8 Example 53 fifteen n / a d0-20 147 ± 7 49.4 Example 53 thirty n / a d0-20 151 ± 4 48.5 Example 53 60 poststation d0-20 156 ± 18 31.6 Calu-3 (small cell lung cancer) The control solvent poststation d0-20 227 ± 27 Example 53 fifteen poststation d0-20 223 ± 29 26.3 Example 53 thirty poststation d0-20 252 ± 44 14.7 3/6 (PR) Example 53 60 poststation d0-20 200 ± 37 16.1 3/6 (PR) NCI-H460 (small cell lung cancer) The control solvent poststation d0-13 184 ± 37 Example 53 fifteen poststation d0-13 185 ± 27 41.1 * Example 53 thirty poststation d0-13 181 ± 21 46.3 * Example 53 60 poststation d0-13 176 ± 28 58.4 * Bel-7402 (liver cancer) The control solvent poststation d0-17 119 ± 20 Example 53 fifteen poststation d0-17 114 ± 15 39.8 Example 53 thirty poststation d0-17 120 ± 21 29.2 Example 53 60 poststation d0-17 119 ± 12 13.3 A 375 (melano ma) The control solvent poststation d0-16 160 ± 10 Example 53 fifteen poststation d0-16 147 ± 25 82.5 Example 53 thirty poststation d0-16 146 ± 7 58.5 Example 53 60 poststation d0-16 155 ± 6 46,4 Caki-1 (kidney cancer) The control solvent poststation d0-22 242 ± 68 Example 53 fifteen poststation d0-22 292 ± 78 73.0 Example 53 thirty poststation d0-22 303 ± 58 45.5 Example 53 60 poststation d0-22 212 ± 62 36.8 * P <0.01 against control; control: n = 12; processing group: n = 6; PR: partial regression; n / a: orally; d0-17: from 0 day to 17 days; T / C (%): relative tumor volume (%).

The results show the anticancer activity of the compound according to Example 53 against xenografts of colon cancer (NT-29), non-small cell lung cancer (NCI-H460, Calu-3), liver cancer (Bel-7402), melanoma (A375), kidney cancer (Caki- 1) in mice lacking hair, in vivo. The compound of example 53 has a pronounced anticancer activity against the xenografts listed above, reduces tumor volume and has a wide range of uses in anticancer medicine.

The compounds of the present invention as VEGFR inhibitors are useful for treating non-small cell lung cancer, liver cancer, melanoma, kidney cancer, and not just colon cancer.

Claims (19)

1. The compound having the formula (I), or its pharmaceutically acceptable salts:

where X represents carbon or nitrogen;
R ₁ and R ₂ each independently represents hydrogen;
R ₃ represents C _1-10 alkyl;
R ₄ represents - [CH ₂ CH (OH)] _r CH ₂ NR ₉ R ₁₀ or - (CH ₂ ) _n NR ₉ R ₁₀ ;
when X is nitrogen, R _{5 is} absent, R ₆ , R ₇ , R _{8 are} each independently selected from the group consisting of a hydrogen atom and a halogen atom;
when X is carbon, R ₅ , R ₆ , R ₇ , R _{8 are} each independently selected from the group consisting of hydrogen atom, halogen atom, hydroxyC _1-10 alkyl, C _1-10 alkyl, phenyl, six-membered heteroaryl with one atom nitrogen, hydroxyl, —OR ₉ , —NR ₉ R ₁₀ , - (CH ₂ ) _n CONR ₉ R ₁₀ , —NR ₉ COR ₁₀ , —SO ₂ R ₉ and —NHCO ₂ R ₁₀ , wherein said phenyl is unsubstituted or additionally substituted by one or more than one group selected from the group consisting of C _1-10 alkyl, C _1-10 alkoxyl and a halogen atom;
R ₉ and R _{10 are} each independently selected from the group consisting of a hydrogen atom, C _1-10 alkyl, wherein said C _1-10 alkyl is unsubstituted or is optionally substituted with one or more than one group selected from the group consisting of C _{1- 10} alkyl, phenyl, halogenophenyl, hydroxyl, C _1-10 alkoxyl, hydroxyC _1-10 alkyl;
R ₉ and R ₁₀ together with the attached atom form a 5-6 membered hetero ring, wherein said 5-6 membered hetero ring may contain one O heteroatom;
n is an integer from 2 to 6;
z is an integer from 1 to 2; and r is an integer from 1 to 6. 2. The compound, which is a pyrrolo-nitrogen-containing heterocyclic derivative or its pharmaceutically acceptable salts according to claim 1, where R ₃ represents methyl. 3. The compound, which is a pyrrole-nitrogen-containing heterocyclic derivative or its pharmaceutically acceptable salts according to claim 1, where R ₁ and R ₂ represent a hydrogen atom. 4. The compound, which is a pyrrole-nitrogen-containing heterocyclic derivative or its pharmaceutically acceptable salts according to claim 1, including compounds having the following formula (IA), or their pharmaceutically acceptable salts:

where X represents carbon or nitrogen;
R ₁ and R ₂ each independently represents hydrogen;
R ₃ represents C _1-10 alkyl;
R ₄ represents - [CH ₂ CH (OH)] _r CH ₂ NR ₉ R ₁₀ or - (CH ₂ ) _n NR ₉ R ₁₀ ;
when X is nitrogen, R _{5 is} absent, R ₆ , R ₇ , R _{8 are} each independently selected from the group consisting of a hydrogen atom and a halogen atom;
when X is carbon, R ₅ , R ₆ , R ₇ , R _{8 are} each independently selected from the group consisting of hydrogen atom, halogen atom, hydroxyC _1-10 alkyl, C _1-10 alkyl, phenyl, six-membered heteroaryl with one atom nitrogen, hydroxyl, —OR ₉ , —NR ₉ R ₁₀ , - (CH ₂ ) _n CONR ₉ R ₁₀ , —NR ₉ COR ₁₀ , —SO ₂ R ₉ and —NHCO ₂ R ₁₀ , wherein said phenyl is unsubstituted or additionally substituted by one or more than one group selected from the group consisting of C _1-10 alkyl, C _1-10 alkoxylal of the halogen atom;
R ₉ and R ₁₀ are each independently selected from the group consisting of hydrogen, C _1-10 alkyl, wherein said C _1-10 alkyl is unsubstituted or further substituted by one or more than one group selected from the group consisting of C _{1- 10} alkyl, phenyl, halogenophenyl, hydroxyl, C _1-10 alkoxyl, hydroxyC _1-10 alkyl;
R ₉ and R ₁₀ together with the attached atom form a 5-6 membered hetero ring, wherein said 5-6 membered hetero ring may contain one O heteroatom;
n is an integer from 2 to 6; and
r is an integer from 1 to 2. 5. The compound or its pharmaceutically acceptable salts according to claim 1, including compounds having the following formula (IB), or their pharmaceutically acceptable salts:

where X represents carbon or nitrogen;
R ₁ and R ₂ each independently represents hydrogen;
R ₃ represents C _1-10 alkyl;
R ₄ represents - [CH ₂ CH (OH)] _r CH ₂ NR ₉ R ₁₀ or - (CH ₂ ) _n NR ₉ R ₁₀ ;
when X is nitrogen, R _{5 is} absent, R ₆ , R ₇ , R _{8 are} each independently selected from the group consisting of a hydrogen atom and a halogen atom;
when X is carbon, R ₅ , R ₆ , R ₇ , R _{8 are} each independently selected from the group consisting of hydrogen atom, halogen atom, hydroxyC _1-10 alkyl, C _1-10 alkyl, phenyl, six-membered heteroaryl with one atom nitrogen, hydroxyl, —OR ₉ , —NR ₉ R ₁₀ , - (CH ₂ ) _n CONR ₉ R ₁₀ , —COR ₉ , —NR ₉ COR ₁₀ , —SO ₂ R ₉ and —NHCO ₂ R ₁₀ , where phenyl is indicated is unsubstituted or further substituted by one or more than one group selected from the group consisting of C _1-10 alkyl, C _1-10 alkoxyl and a halogen atom;
R ₉ and R _{10 are} each independently selected from the group consisting of a hydrogen atom, C _1-10 alkyl, wherein said C _1-10 alkyl is unsubstituted or is optionally substituted with one or more than one group selected from the group consisting of C _{1- 10} alkyl, phenyl, halophenyl, hydroxyl, C _1-10 alkoxy, hydroxyC _1-10 alkyl;
R ₉ and R ₁₀ together with the attached atom form a 5-6 membered hetero ring, wherein said 5-6 membered hetero ring may contain one O heteroatom;
n is an integer from 2 to 6; and
r is an integer from 1 to 2. 6. The compound, which is a pyrrole-nitrogen-containing heterocyclic derivative, or its pharmaceutically acceptable salts according to claim 1 or 2, including:

7. The compound, which is a pyrrolo-nitrogen-containing heterocyclic derivative or its pharmaceutically acceptable salts according to claim 1, where these pharmaceutically acceptable salts are salts formed with acids 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 and trifluoroacetic acid. 8. A pharmaceutical composition that inhibits protein kinase, containing a compound representing a pyrrolo-nitrogen-containing heterocyclic derivative or its pharmaceutically acceptable salts according to any one of claims 1 to 6 in an effective therapeutic dose, as well as a pharmaceutically acceptable carrier. 9. A compound having the following formula (IC) or (ID), which is an intermediate in the synthesis of a compound of formula (I):

where R ₂ represents hydrogen;
R ₃ represents C _1-10 alkyl;
R ₄ represents - [CH ₂ CH (OH)] _r CH ₂ NR ₉ R ₁₀ or - (CH ₂ ) _n NR ₉ R ₁₀ ;
R ₉ and R ₁₀ each independently represents hydrogen, C _1-10 alkyl, wherein said C _1-10 alkyl is unsubstituted or further substituted by one or more groups selected from the group consisting of C _1-10 alkyl, phenyl, halogenophenyl, hydroxyl, C _1-10 alkoxyl, hydroxyC _1-10 alkyl;
R ₉ and R ₁₀ together with the attached atom form a 5-6 membered hetero ring, wherein said 5-6 membered hetero ring may contain one O heteroatom;
n is an integer from 2 to 6;
r is an integer from 1 to 6. 10. The method of obtaining the intermediate compounds of formula (IC) according to claim 9, comprising the following stages:
the reaction of the starting material — diester of pyrrolemethylcarboxylic acid IC-1 in tetrahydrofuran in the presence of acetic acid with cerium ammonium nitrate at room temperature to obtain diester of pyrrolaldehyde carboxylic acid IC-2; and

the reaction of the pyrrolaldehyde carboxylic acid diester IC-2 in anhydrous tetrahydrofuran with (carbethoxymethylene) triphenylphosphorane by means of the Wittig reaction to obtain the pyrrolethoxycarbonylethylenedicarboxylic acid ester IC-3;

reduction of the pyrrolethoxycarbonylethylenedicarboxylic acid ester IC-3 in anhydrous ethanol with hydrogen, catalysed with palladium on carbon at room temperature to give the pyrrolethoxycarbonylethyldicarboxylic acid ester IC-4;

hydrolysis of the pyrrolethoxycarbonylethyldicarboxylic acid ester IC-4 in an aqueous lithium hydroxide solution to obtain the pyrrolecarboxyethyl dicarboxylic acid ester IC-5;

recovering the pyrrole carboxyethyl dicarboxylic acid ester IC-5 in anhydrous tetrahydrofuran with a borane-tetrahydrofuran solution at (-20) - (-5) ° C to obtain the pyrrole hydroxypropyl dicarboxylic acid ester IC-6;

mesylation of pyrrolehydroxypropyl dicarboxylic acid ester IC-6 in anhydrous dichloromethane in the presence of triethylamine at (-20) - (-5) ° C to give pyrrolemethylsulfonyloxypropyldicarboxylic acid ester IC-7;

reacting the pyrrolmethylsulfonyloxypropyldicarboxylic acid ester IC-7 with various amines of the formula R ₄ NH ₂ to give the pyrroldicarboxylic acid ester amide IC-8;

the reaction of the amide of pyrrolidicarboxylic acid ester IC-8 with trimethylaluminum in anhydrous toluene under reflux to obtain pyrrole-condensed seven-membered aza-heterocyclic ether IC-9;

the reaction of pyrrolocondensed seven-membered aza-heterocyclic ether IC-9 with trifluoroacetic acid at 30-50 ° C under argon atmosphere to obtain pyrrolocondensed seven-membered aza-heterocyclic formaldehyde IC;

11. The method of obtaining the compounds of intermediate formula (ID) according to claim 9, comprising the following stages:
the reaction of the pyrrole carboxylic acid aldehyde diester IC-2 with Grignard reagent - cyclopropyl magnesium bromide - in anhydrous tetrahydrofuran at room temperature under argon atmosphere to give the pyrrole cyclopropyl hydroxycarboxylic acid diester ID-1;

the reaction of the pyrrole cyclopropylhydroxycarboxylic acid diester ID-1 with hydrobromic acid in methanol to obtain the bromobutenylpyrrole diester ID-2;

reduction of bromobutenylpyrrole diester ID-2 in anhydrous ethanol with hydrogen, catalyzed by palladium on carbon at room temperature to obtain bromobutylpyrrole diester ID-3;

the reaction of bromobutylpyrrole diester ID-3 with various amines of the formula R ₄ NH ₂ in dichloromethane under reflux to obtain a pyrrolamide dicarboxylic acid diester ID-4;

reacting ID-4 pyrrolamide dicarboxylic acid diester with trimethylaluminum in toluene under reflux to obtain pyrrolocondensed eight-membered aza heterocyclic aldehyde ID;

12. The method of producing pyrrole-nitrogen-containing heterocyclic derivatives according to claims 1-6, comprising the step of reacting oxindole with an aldehyde in the presence of triethylamine or piperidine and heating the reaction mixture to form a compound of formula (I) for 2-12 hours, wherein said aldehyde has the formula below:

and said oxindole has the following formula:

where R ₁ -R ₈ are the same as defined in claim 1. 13. A method of inhibiting the catalytic activity of a protein kinase, wherein said protein kinase is contacted with said pyrrolo-nitrogen-containing heterocyclic derivatives or their pharmaceutically acceptable salts according to any one of claims 1 to 6. 14. The method of claim 13, wherein said protein kinases are selected from the group consisting of receptor tyrosine kinases. 15. The use of the compounds according to claim 1 for the manufacture of a drug that inhibits protein kinase. 16. The application of clause 15, where these disorders associated with protein kinases are selected from the group consisting of disorders associated with VEGFR-2, EGFR, HER-2 and c-Kit. 17. The application of clause 15, where these disorders associated with protein kinases are selected from the group consisting of leukemia. 18. The use of claim 15, wherein said protein kinase-related disorders are cancer selected from squamous cell carcinoma, renal cell carcinoma, Kaposi’s sarcoma, non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid adenocarcinoma, cancer breast, head and neck cancer, cancer of the uterus, cancer of the esophagus, melanoma, cancer of the bladder, carcinosarcoma in the urinary and reproductive system, gastrointestinal carcinoma, gliomas, colorectal cancer and ovarian cancer. 19. A method of inhibiting the catalytic activity of a protein kinase, wherein said protein kinase is contacted with the composition of claim 8.