Heterocyclic nitrogen pyrrole derivatives, producing them and pharmaceutical application

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 C1-10alkyl; 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, hydroxyC1-10alkyl, C1-10alkyl, 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 C1-10alkyl, C1-10alkoxyl, halogen; each R9, R10 means H, C1-10alkyl wherein C1-10alkyl is unsubstituted or additionally substituted by one or more group C1-10alkyl, phenyl, halogenophenyl, -OH, C1-10alkoxy, OH- C1-10alkyl; 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

 

The SCOPE of the INVENTION

According to the invention proposed new pyrrolo-nitrogen-containing heterocyclic derivative, receive them, pharmaceutical compositions containing such derivatives, and the use of such derivatives as therapeutic agents, in particular as inhibitors of protein kinases.

PRIOR art

Cellular signal transduction is a fundamental mechanism by which extracellular stimuli are transferred into 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 variety of soluble factors such as growth factors and paracrine, autocrine and endocrine factors. By binding to specific transmembrane receptors ligands are growth factors transmit extracellular signals to intracellular transmission signal, which provides the response of individual cells to extracellular signals. Many of these processes the transmission signal using the reversible phosphorylation of proteins, which involves specific protein kinases and phosphatases.

Protein kinase (PK) are enzymes that catalinabootstrap.java hydroxyl groups on tyrosine, serine and treoninove residues of proteins, whereas proteinopathy hydrolyzing the phosphate group in the phosphorylated protein substrates. The opposite function of protein kinases and proteinopathies balance and regulate the transmission signal in the processes of signal transduction. The state of phosphorylation of the protein, which may affect its conformation, enzyme activity and cellular localization, modified by the reciprocal action of protein kinases and proteinopathies. Phosphorylation is an important regulatory mechanism in the transmission signal, and aberrations in this process result in abnormalities in cell differentiation, transformation and growth. For example, made the discovery that the cell can become cancerous as a result of transformation of a portion of its DNA into an oncogene. Several of these oncogenes encode proteins that are receptors for growth factors, for example, tyrosinekinase. Tyrosine kinase can also mutate with the formation of active forms that result in the transformation of different human cells. Alternatively, the overexpression of normal enzymes tyrosinekinase can also result in abnormal cell proliferation.

There are two classes of PC, proteincontaining (PTK - protein tyrosine kinases) and sprintringtones (STK - serine treonine knases). PTK phosphorylate the tyrosine residue in the protein. STK phosphorylate serine and/or threonine in the protein. Tyrosine kinase may not be the only receptor type (with extracellular, transmembrane and intracellular domains), but also precepting type (fully intracellular). One of the main aspects of the activity of PTK is their involvement in the receptors of growth factors, which are proteins on the cell surface. The receptors of growth factors with PTK activity known as receptor tyrosine kinase ("RTK"). In the human genome identified approximately 90 tyrosinekinase, of which about 60 belong to the receptor type and about 30 belong to preceptored type. They can be classified into 20 subfamilies of receptor tyrosinekinase in accordance with the families of growth factors, which they bind, and 10 subfamilies preceptory tyrosinekinase (Robinson et al., Onoogene, 2000, 19, 5548-5557).

The family of receptor tyrosinekinase (RTK - receptor tyrosine kinases) includes: (1) the collection tyrosinekinase receptors EGF (epidermal growth factor - epidermal growth factors), such as the receptors for EGF, TGFα (tumor growth factor α - factor of tumor growth α), Neu and erbB; (2) the collection tyrosinekinase insulin receptors, such as receptors for insulin and IGF1 (insulin-like growth factor - insulin-like growth factor and receptor, is associated with insulin (IRR - insuline related receptor); (3) the family t is sinkins receptor class III, such as tyrosine kinase receptors, platelet-derived growth factors (PDGF - platelled derived growth factor), for example, PDGFα receptor and PDGFβ, tyrosinekinase receptor of stem cell factor (SCF) RTK (stem cell factor receptor tyrosine kinase) (commonly known as c-Kit), fms-associated tyrosinekinase 3 (Flt3) and tyrosinekinase receptor colony stimulating factor 1 (CSF-1R - colony stimulating factor 1 receptor), and so They play a critical role in the regulation of growth and differentiation of cells and are key mediators of cellular signals leading to the production of growth factors and cytokines (Schlessinger and Ullrich, Neuron 1992, 9, 383). Partial non-limiting list of such kinases includes Abl, ARaf, ATK, ATM, bcr-abl, Blk, skin disease, 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, a kinase that is associated with integrin, Jak, JAK1, JAK2, JAK3, JNK, JNK, Lck, Lyn, MEK, MEK1, MEK2, p38, DERIVED, PIK, PKB1, PKB2, PKB3, PKC, PKCa, PKCb, PKCd, PKCe, PKCg, PKC1, PKCm, PKCz, PLK1, Polo-like kinase, PYK2, tie1, tie2, TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1, VEGF-R2, Yes, and Zap70, and the like. Protein kinases are targets for disorders of the Central nervous system such as Alzheimer's disease (Mandelkow, E.M. et al. FESS Lett. 1992, 314, 315; Sengupta, A. et al. Mol. Cell. Biochem. 1997, 167,99), pain (Yashpal, K.J. Neurosci. 1995, 15, 3263-72), inflammatory disorders such as art is it (Badger, J. Pharmn Exp. Ther. 1996, 279, 1453), psoriasis (Dvir, et al. J. Cell Biol. 1991, 113, 857), bone diseases such as osteoporosis (Tanaka et al., Nature, 1996, 383, 528), cancer (Hunter and Pines, Cell 1994, 79, 573), atherosclerosis (Hajjar and Pomerantz, FASEB J. 1992, 6, 2933), thrombosis (Salari, FEBS 1990, 263, 104), metabolic disorders such as diabetes (Borthwick, A.S. et al. Biochem. Biophys. Res. Commun. 1995, 210, 738), proliferative disorders of the blood vessels, such as angiogenesis (Strawn et al. Cancer Res. 1996, 56, 3540; Jackson et al. J. Phann. Exp. Then in 1998, 284, 687), 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.. PCT Int Appl., WO 9805335 A1 980212).

Mediated RTK signaling is initiated by extracellular interaction with a specific growth factor (ligand), followed by dimerization of the receptor, transit stimulation of their activity protein tyrosine kinase and phosphorylation. As a result of this creates binding sites for molecules of intracellular signal transduction, which leads to the formation of complexes with a spectrum of cytoplasmic molecules transmission signal, which promote proper cellular responses, for example, division (reproduction) cells, and responses to extracellular microenvironment.

In relation to the receptor tyrosinekinase also shows that the site FOS is arilirovaniya tyrosine function as binding sites with high affinity for the SH2 domains (src homologous molecules signal transmission. Identified several intracellular protein substrates that bind to receptor tyrosine kinases. They can be divided into two main groups: (1) substrates, which have catalytic domain; and (2) substrates that do not have a domain, but which serve as adapters and contacted with a catalytically active molecules. The specificity of interactions between receptors or proteins SH2 their substrates determine the amino acid residues immediately surrounding the phosphorylated tyrosine residue. Differences in the affinity of binding between SH2 domains and amino acid sequences surrounding the remains of phosphotyrosine on specific receptors, are consistent with the observed differences in the profiles of phosphorylation of their substrates. These observations suggest that the function of each receptor tyrosine kinase is determined not only by its pattern of expression and accessibility of the ligand, but also the order of the biochemical signal transduction pathways during transcription, which are activated by a specific receptor. Thus, phosphorylation provides important regulatory stage, which determines the selectivity of biochemical signal transduction pathways, rekrutierung specific receptors of growth factors and receptors of the factor is in differentiation. As shown, the aberrant expression or mutations in the protein tyrosine kinases leads either to uncontrolled cell proliferation (e.g., malignant tumor growth)or to defects in key development processes.

It is established that such mutated and hyperexpression form tyrosinekinase present at a major share of common types of cancer in humans, such as leukemia, breast cancer, prostate cancer, non-small cell lung cancer (nmcrl), including adenocarcinoma and squamous cell lung cancer, gastrointestinal cancer, including cancer of the colon, rectum and stomach cancer, bladder cancer, esophageal cancer, ovarian cancer and pancreatic cancer and the like. It is expected that with further testing of tumor tissues will be installed prevalence and importance of tyrosinekinase. For example, it is shown that tyrosinekinase EGFR is mutated and its overexpression is carried out with several types of cancer in humans, including tumors of the lung, head and neck, gastrointestinal tract, breast, esophagus, ovary, uterus, urinary bladder and thyroid gland.

One of the subfamilies, designated as "HER" or "Erb" RTK includes EGFR (receptor epithelial growth factor), HER2, her3, and HER4. These RTK consist of extracellular glycosylate the nogo ligand-binding domain, transmembrane domain and an intracellular cytoplasmic catalytic domain, which can fosforilirovanii tyrosine residues on proteins. The enzymatic activity of the receptor tyrosinekinase can be stimulated either by overexpression of the receptor, either mediated by ligand dimerization. Education as homodimers and heterodimers demonstrated for a family of receptor HER2. An example of homodimerization is dimerization of HER1 (EGF receptor)mediated by ligands of the EGF family (which includes EGF, transforming growth factor alpha, betacellulin, heparin-binding EGF and epiregulin). Heterodimerization among the four receptor kinases HER it is possible to stimulate the binding of members of a family of ligands heregulin (also called neuregulins). This heterodimerization, which involves the combination of HER2 and HER3, or her3, and HER4, leads to a significant stimulation tyrosinekinase activity of receptor dimers even though one of the receptor (HER3,) enzymatic inert. It is shown that the kinase activity of HER2 is also activated by the overexpression of this gene one receptor in some types of cells. Activation of receptor homodimers and heterodimers results in the phosphorylation of tyrosine residues on the receptors and other intracellular proteins is H. This is followed by activation of intracellular biochemical signal transduction pathways, such as those involving protein kinase associated with microtubules (MAP (microtubule associated protein) kinase, and phosphatidylinositol-3-kinase (PI3 (phosphatidylinositol-3) kinase). It is shown that the activation of these biochemical pathways leading to cell proliferation and inhibition of apoptosis.

Another RTK subfamily includes the insulin receptor (IR), the receptor for insulin-like growth factor I (IGF-1R) and the receptor associated with the insulin receptor (IRR). IR and IGF-1R interact with insulin, IGF-I and IGF-II with the formation of heterotetramer of two entirely extracellular glycosylated α subunits and two β subunits which cross the cell membrane and which contain tyrosinekinase domain.

The third RTK subfamily is a group of receptors, platelet-derived growth factor (DERIVED), which includes PDGFRα, PDGFRβ, CSFIR, c-Kit and c-fms. These receptors consist of a glycosylated extracellular domain consisting of flexible members immunoglobulinovogo loops, and an intracellular domain, where tyrosinekinase domain is interrupted by an unrelated amino acid sequences.

The receptors for platelet-derived growth factor, such as PDGFRα and PDGFRβ are transmembrane tyrosinekinase receptors. Upon ligand binding, they form is either homodimer (PDGF-AA, PDGF-BB), or heterodimer (PDGF-AB). After receptor dimerizes, tyrosinekinase is activated. This leads to the transmission signal further along the way of signaling that can support tumor growth. Mutations in this gene give the ability to activate the receptor, regardless of the binding of the ligand and are driving forces in oncogenesis. The expression of PDGF, a growth factor, which activates the DERIVED observed in a number of different lines of tumor cells, among other cell lines of the breast, colon, ovary, prostate cancer, sarcoma and glioblastoma. Among tumors of particular interest was caused by a brain tumor and carcinoma of the prostate (including adenocarcinoma and bone metastases). Interesting data also exist for malignant gliomas.

c-Kit is tyrosinekinase receptor, which belongs to the family of PDGF receptors and activiues upon binding its ligand SCF (stem cells factor (stem cell factor). The pattern of expression of c-Kit investigated, for example, set different primary solid tumors. Strong expression of c-Kit can be found inter alia in sarcoma, gastrointestinal stromal tumors (GIST - gastrointestinal stromal tumors), seminoma and carcinoids [Weber et al., J. Clin. Oncol. 22(14S), 9642 (2004)]. GIST are not epithelially tumors. They can occur in the stomach, IU is the more in the small intestine and even less in the esophagus. May be spread to the liver, omentum and the abdominal cavity. GIST probably arise from intestinal interstitial cells of Cajal (ICC - interstitial Cajal cells)that normally form part of the Autonomous nervous system of the intestine and participate in the regulation of motility. The majority (50 to 80%) GIST arise due to mutations in a gene called c-Kit. In the intestine positive staining for c-Kit/CD117, probably represents the GIST. Mutations of c-Kit can do the operation of c-Kit-independent activation of the SCF, which leads to a high rate of cell division and possibly to genomic instability. Aberration c-Kit can also be observed in the tumors of mastocytes, and when mastocytosis and combination myeloproliferative syndrome and pigmentary urticaria. Expression and/or aberration of c-Kit can also be found in acute myeloid leukemia (AML) and malignant lymphoma. Expression of c-Kit can also be shown by small cell bronchial carcinoma, seminoma, dysgerminoma, testicular intraepithelial the neoplasms, melanomas, carcinomas of the breast, neuroblastoma, Ewing sarcoma, some soft tissue sarcomas, as well as papillary/follicular carcinoma of the thyroid gland (see Schutte et al., Innovartis 3/2001). For example, it is known that hereditary mutations of the RET proto-oncogene (rebuilding after transfect is) are oncogenic in patients with multiple endocrine neoplasia type 2 (MEN 2 - multiple endocrine neoplasia), which can lead to pheochromocytoma, medullary the thyroid carcinoma and hyperplasia/adenoma of the parathyroid gland (see Huang et al., Cancer Res. 60, 6223-6 (2000)).

Another group, which due to the similarity to the DERIVED subfamily sometimes include in this latter group represents a subfamily of kinase receptor fetal liver (Flk - fetal liver kinase). It is believed that this group consists of the kinase domain insert kinase-1 receptor fetal liver - (KDR/FLK-1, VEGFR2), Flk-1R, Flk-4 and Fms-like tyrosine kinase 1 (Fit-1).

The next member of the family tyrosinekinase receptors of growth factors is a subgroup of receptor fibroblast growth factor (FGF-fibroblast growth factor). This group consists of four receptors, FGFR1-4, seven ligands and FGF1-7. Although it is still not very well defined, it appears that the receptors consist of a glycosylated extracellular domain, containing varying number immunoglobulinovogo circuits, and intracellular domain, which tyrosinekinase sequence interrupted by areas unrelated amino acid sequences.

Another member of the family tyrosinekinase receptors of growth factors is the subgroup factor receptor vascular endothelial growth (VEGF - vascular endothelium growth facktor), where VEGF is a dimeric glycoprotein that is similar to PDGF, but with other b the ideological function and specificity to target cells in vivo. In particular, it is known that VEGFR involved in the regulation of early angiogenesis. Especially since solid tumors are dependent on good blood flow, inhibition of VEGFR and, therefore, angiogenesis is the goal of clinical research in the treatment of such tumors, and shows promising results. VEGF also plays a major role in leukemia and lymphoma and shows high expression in several solid malignancies, which correlates well with the progress of malignant disease. Examples of neoplastic diseases with the expression of VEGFR-2 (KDR) are lung carcinoma, breast carcinoma, non-Hodginsii lymphoma, carcinoma, ovarian cancer, pancreatic cancer, malignant pleural mesothelioma and melanoma. In addition to its angiogenic activity, VEGFR ligand, VEGF may stimulate tumor growth through effects, directly contributing to the survival of the tumor cells. PDGF is also involved in angiogenesis, the formation of new blood vessels, which is critical for continued tumor growth. Normal angiogenesis plays an important role in processes such as embryonic development, wound healing, and some components of female reproductive function. However, undesirable or pathological angiogenesis is associated with a number of painful the situation of the deposits, including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and hemangioma. Stimulation of angiogenesis occurs through stimulation of endothelial cell growth. Identified several polypeptides with an activity of stimulating the growth of endothelial cells in vitro, including acidic and basic fibroblast growth factors (aFGF and bFGF) and vascular endothelial growth (VEGF). Due to the limited expression of its receptors VEGF activity as a growth factor, in contrast to such an activity of aFGF and bFGF, relatively specific endothelial cells. Recent evidence indicates that VEGF is an important stimulator of both normal and pathological angiogenesis and vascular permeability. This cytokine induces the phenotype of sprouting angiogenesis through the induction of proliferation of endothelial cells, the expression of proteases and migration, which subsequently leads to the formation of capillary tubes, which leads to the formation overpronates, immature vascular network, which is characteristic of pathological angiogenesis. Accordingly, it is expected that the antagonism of VEGF activity will be useful in the treatment of a number of illnesses that are associated with angiogenesis or increased vascular permeability such as cancer, in particular, when ing is the repression of tumor development.

FLT3 (fms-like tyrosine kinase - fms-like tyrosinekinase) is a member of a family of receptor tyrosinekinase type III RTK. Aberrant expression of FLT3, among other things, documented with leukemia in adults and in children, including acute myeloid leukemia (AML), AML with three-myelodysplasia (AML/TMW), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS), and SL (mixed-linear leukemia). Activating mutations of the FLT3 receptor is detected in approximately 35% of patients with acute myeloblastic leukemia (AML) and are associated with poor prognosis. In the most common mutation involved duplication in a frame within kolomanbrunnen domain, and another 5-10% of patients have point mutations in the asparagine 835. Both of these mutations are associated with constitutive activation tyrosinekinase activity of FLT3 and prepare to launch signals to cell proliferation and survival in the absence of ligands. It was shown that patients expressing mutant form of the receptor, have reduced the chance of a cure. Thus, the accumulated data on the role of hyperactivemenu (mutated) kinase activity FLT3 with leukemia and myelodysplastic syndrome in humans.

It is shown that the receptor tyrosinekinase (RTK) (C-MET or HGFR) growth factor hepatocyte (HGF - hepatocyte growth factor) in many types of cancer in humans involved in the PMC is the Genesis, the progression of the tumor with increased motility and invasion of cells, and metastases (see MA, R.S. 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 of this gene or mutations in various human cancers, including small cell lung cancer (mcrl) (MA, R.S. et al. (2003a), Cancer Res, 63, 6272-6281).

C-MET is a receptor tyrosinekinase, which is encoded by protooncogene Met and transmits the biological effects of growth factor hepatocyte (HGF). It is a transmembrane glycoprotein with tyrosinekinase activity, which contributes to the multiplication and division multiple cells. Overexpression of the proto-oncogene c-Met occurs when multiple malignant tumors in humans, in particular, tumors of the thyroid gland, which is closely associated with pathological staging, tumor invasion and metastasis.

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

In addition to the RTC there is another family of cellular enzymes, called inhibitors, receptor tyrosinekinase (commonly referred to as the "CTK"). Currently identified more than twenty-four CTK comprising eleven subfamilies (Src, Frk, Btk, sk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK). Currently, the Src subfamily JCC consists of the greatest number of RTC and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. Subfamily enzymes Src is associated with oncogenesis. A more detailed discussion of CTK cited in the article Bolen, 1993, Oncogen 8: 2025-2031, which is incorporated here by reference, including all graphical materials.

Serine/threonine kinase, or STK, like JCC, are predominantly intracellular, although there are several receptor kinases type STK. STK are the most common of cytosolic kinases; i.e. kinases that perform their function in a different part of the cytoplasm than cytoplasmic organelles and the cytoskeleton. The cytosol is the area inside the cell, where a significant part of the intermediate cellular metabolic and biosynthetic activity; for example, in the cytosol proteins are synthesized on ribosomes.

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

As for cancer, two main hypotheses put forward to explain the excessive cell proliferation, which directs the development of tumors are functions that are known to be regulated by protein kinases. That is, there is an assumption that malignant cell growth is a result of the destruction of the mechanisms that control cell division and differentiation. It is shown that the protein products of several proto-oncogene involved in the biochemical pathway of signal transmission, which regulate growth and differentiation of cells. These protein products of proto-oncogene include extracellular growth factors, RTK receptors transmembrane growth factor (RTK), cytoplasmic RTC (JCC) and cytosolic STK discussed above.

There is a need for new viable low molecular weight inhibitors, which possess antitumor activity and activity against cell proliferation. It is expected that these small molecules inhibit one or more than one RTK, CTK or STK and useful in the treatment or relief mediated RTK, CTK or STK-mediated angiogenesis or hyperproliferative disorders.

Based on the structure of the tyrosine kinase inhibitor SU-11248 and pyrroloquinoline heterocycle of formula (X), which showed high biological activity, the which was reported in the patent (US-6599902 B2), the present invention is directed to the design and synthesis pyrroloquinoline polynomial Aza-heterocyclic derivatives, and received the best pharmacological data. To improve the pharmacokinetic profile pyrroloquinoline polynomial Aza-heterocyclic derivatives of the present invention is directed to the creation of compounds of formula (I). Compounds according to the invention have obvious structural differences from the existing connections of the prior art, and they also exhibit higher efficiency and best performance.

SUMMARY of the INVENTION

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

where:

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

R1and R2each independently selected from the group consisting of the volumes of hydrogen and alkyl;

R3selected from the group consisting of alkyl, trifloromethyl, aryl and aralkyl, where specified, the alkyl, aryl or aralkyl optionally substituted by one or more than one halogen atom;

R4selected from the group consisting of alkyl, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, -(CH2)n(OCH2CH2)rR11,

-[(CH2CH(OH)]rCH2NR9R10and -(CH2)nNR9R10where the specified alkyl, cycloalkyl, heteroseksualci, aryl or heteroaryl optionally substituted by one or more than one group selected from the group consisting of aryl, hydroxyl, amino, amide group, aminocarbonyl, alkoxyl, aryloxy, aminoalkyl, hydroxyalkyl, geterotsiklicheskie, carboxylic acid, ether carboxylic acids and-NR9R10;

when X represents a nitrogen atom, R5no, R6, R7, R8each independently selected from the group consisting of hydrogen atom and halogen atom;

when X represents a carbon atom, R5, R6, R7, R8each independently selected from the group consisting of hydrogen atom, halogen atom, hydroxyalkyl, alkyl, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, hydroxyl, cyano, nitro, -OR9, -O (CH2CH2O]rR11, -NR9R10, -(CH2 nCO2R9, -(CH2)nCONR9R10, -COR9,

-NR9COR10, -SO2R9and-NHCO2R10where specified aryl, heteroaryl, cycloalkyl or heteroseksualci optionally substituted by one or more than one group selected from the group consisting of alkyl, alkoxyl and halogen atom;

R9and R10each independently selected from the group consisting of hydrogen atom, alkyl, cycloalkyl, aryl, geterotsiklicheskie and heteroaryl where the specified alkyl, cycloalkyl, aryl, heteroseksualci or heteroaryl optionally substituted by one or more than one group selected from the group consisting of alkyl, aryl, halogenoarenes, hydroxyl, amino, cyano, alkoxyl, aryloxy, hydroxyalkyl, geterotsiklicheskie, carboxylic acid, ether carboxylic acids and-NR9R10;

R9and R10together with the attached atom to form 4 to 8 membered heterokonta where these 4-8-membered heterokonta can contain one or more than one heteroatom selected from the group consisting of atoms N, O and S, and these 4-8-membered ring optionally substituted by one or more than one group consisting of alkyl, halogen atom, aryl, heteroaryl, halogenoalkane, hydroxyl, cyano, alkoxyl, aryloxy, aminoalkyl, hydroxyalkyl, geterotsiklicheskie, carboxylic acid is you, ether carboxylic acids and-NR9R10;

R11selected from the group consisting of hydrogen atom and 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 R3preferably represents methyl.

Compounds or their pharmaceutically acceptable salts of formula (I), where R1and R2preferably 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 carbon atom and nitrogen atom;

R1and R2each independently selected from the group consisting of hydrogen atom and alkyl;

R3selected from the group consisting of alkyl, trifloromethyl, aryl and aralkyl, where specified, the alkyl, aryl or aralkyl optionally substituted by one or more than one halogen atom;

R4selected from the group consisting of alkyl, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, -(CH2)n(OCH2CH2)rR11, -[CH2CH(OH)]rCH2NR9R10and -(CH2)nNR9R1 where the specified alkyl, cycloalkyl, heteroseksualci, aryl or heteroaryl optionally substituted by one or more than one group selected from the group consisting of aryl, hydroxyl, amino, amide group, aminocarbonyl, alkoxyl, aryloxy, aminoalkyl, hydroxyalkyl, geterotsiklicheskie, carboxylic acid, ether carboxylic acids and-NR9R10;

when X represents a nitrogen atom, R5no, R6, R7, R8each independently selected from the group consisting of hydrogen atom and halogen atom;

when X represents a carbon atom, R5, R6, R7, R8each independently selected from the group consisting of hydrogen atom, halogen atom, hydroxyalkyl, alkyl, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, hydroxyl, cyano, nitro, -OR9, -O (CH2CH2O]rR11, -NR9R10, -(CH2)nCO2R9, -(CH2)nCONR9R10, -COR9,

-NR9COR10, -SO2R9and-NHCO2R10where specified aryl, heteroaryl, cycloalkyl or heteroseksualci optionally substituted by one or more than one group selected from the group consisting of alkyl, alkoxyl and halogen atom;

R9and R10each independently selected from the group consisting of hydrogen atom, alkyl, cyclo is Lila, aryl, geterotsiklicheskie and heteroaryl where the specified alkyl, cycloalkyl, aryl, heteroseksualci or heteroaryl optionally substituted by one or more than one group selected from the group consisting of alkyl, aryl, halogenoarenes, hydroxyl, amino, cyano, alkoxyl, aryloxy, hydroxyalkyl, geterotsiklicheskie, carboxylic acid, ether carboxylic acids and-NR9R10;

R9and R10together with the attached atom to form 4 to 8 membered heterokonta where these 4-8-membered heterokonta can contain one or more than one heteroatom selected from the group consisting of atoms N, O and S, and these 4-8-membered ring optionally substituted by one or more than one group consisting of alkyl, halogen atom, aryl, heteroaryl, halogenoalkane, hydroxyl, cyano, alkoxyl, aryloxy, aminoalkyl, hydroxyalkyl, geterotsiklicheskie, carboxylic acid, ether carboxylic acids and-NR9R10;

R11selected from the group consisting of hydrogen atom and 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, with the standing from the carbon atom and nitrogen atom;

R1and R2each independently selected from the group consisting of hydrogen atom and alkyl;

R3selected from the group consisting of alkyl, trifloromethyl, aryl and aralkyl, where specified, the alkyl, aryl or aralkyl optionally substituted by one or more than one halogen atom;

R4selected from the group consisting of alkyl, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, -(CH2)n(Och2CH2)rR11, -[CH2CH(OH)]rCH2NR9R10and -(CH2)nNR9R10where the specified alkyl, cycloalkyl, heteroseksualci, aryl or heteroaryl optionally substituted by one or more than one group selected from the group consisting of aryl, hydroxyl, amino, amide group, aminocarbonyl, alkoxyl, aryloxy, aminoalkyl, hydroxyalkyl, geterotsiklicheskie, carboxylic acid, ether carboxylic acids and-NR9R10;

when X represents a nitrogen atom, R5no, R6, R7, R8each independently selected from the group consisting of hydrogen atom and halogen atom;

when X represents a carbon atom, R5, R6, R7, R8each independently selected from a hydrogen atom, halogen, hydroxyalkyl, alkyl, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, hydroxyl, cyano, nitro, -OR9 ,

-O[CH2CH2O]rR11, -NR9R10, -(CH2)nCO2R9, -(CH2)nCONR9R10, -COR9, -NR9COR10,

-SO2R9and-NHCO2R10where specified aryl, heteroaryl, cycloalkyl or heteroseksualci optionally substituted by one or more than one group selected from the group consisting of alkyl, alkoxyl and halogen atom;

R9and R10each independently selected from the group consisting of hydrogen atom, alkyl, cycloalkyl, aryl, geterotsiklicheskie and heteroaryl where the specified alkyl, cycloalkyl, aryl, heteroseksualci or heteroaryl optionally substituted by one or more than one group selected from the group consisting of alkyl, aryl, halogenoarenes, hydroxyl, amino, cyano, alkoxyl, aryloxy, hydroxyalkyl, geterotsiklicheskie, carboxylic acid, ether carboxylic acids and-NR9R10;

R9and R10taken together with the attached atom with the formation of a 4-8-membered heterotopic where these 4-8-membered heterokonta can optionally contain one or more than one heteroatom selected from the group consisting of atoms N, O and S, and these 4-8-membered ring optionally substituted by one or more than one group consisting of alkyl, halogen atom, aryl, heteroaryl, halogeno the Qila, hydroxyl, cyano, alkoxyl, aryloxy, aminoalkyl, hydroxyalkyl, geterotsiklicheskie, carboxylic acid, ether carboxylic acids and-NR9R10;

R11selected from the group consisting of hydrogen atom and alkyl;

n is an integer from 2 to 6; and

r is an integer from 1 to 6;

or their pharmaceutically acceptable salts.

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

Another aspect of this invention relates to pharmaceutical compositions containing one or more than one compound of formula (I) or its pharmaceutically acceptable salt, its prodrug and pharmaceutically acceptable carriers.

Another aspect of the present invention is directed to a method of modulating the catalytic activity of protein kinases, which lead to the contact specified protein kinase with the compound of the formula (I) or the th pharmaceutically acceptable salt. These protein kinases selected from the group consisting of receptor tyrosinekinase (RTK), tyrosinekinase preceptory proteins (JCC) and the serine-treoninove protein kinases (STK),

Where the pharmaceutically acceptable salt according to the present invention are salts formed from the present compounds 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 triperoxonane acid.

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

where:

R2selected from the group consisting of hydrogen atom and alkyl;

R3selected from the group consisting of alkyl, trifloromethyl, aryl and aralkyl, where specified, the alkyl, aryl or aralkyl optionally substituted by one or more than one halogen atom;

R4selected from the group consisting of alkyl, cycloalkyl, geterotsiklicheskie, aryl, heteroaryl, -(CH2)n(Och2CH2)rR11, -[CH2CH(OH)]rCH2NR9R10and -(CH2)nNR9R10, the state Duma of the specified alkyl, cycloalkyl, heteroseksualci, aryl or heteroaryl optionally substituted by one or more than one group selected from the group consisting of aryl, hydroxyl, amino, amide group, aminocarbonyl, alkoxyl, aryloxy, aminoalkyl, hydroxyalkyl, geterotsiklicheskie, carboxylic acid, ether carboxylic acids and-NR9R10;

R9and R10each independently selected from the group consisting of hydrogen atom, alkyl, cycloalkyl, aryl, geterotsiklicheskie and heteroaryl where the specified alkyl, cycloalkyl, aryl, heteroseksualci or heteroaryl optionally substituted by one or more than one group selected from the group consisting of alkyl, aryl, halogenoarenes, hydroxyl, amino, cyano, alkoxyl, aryloxy, hydroxyalkyl, geterotsiklicheskie, carboxylic acid, ether carboxylic acids and-NR9R10;

R9and R10together with the attached atom to form 4 to 8 membered heterokonta where these 4-8-membered heterokonta can optionally contain one or more than one heteroatom selected from the group consisting of atoms N, O and S, and these 4-8-membered ring optionally substituted by one or more than one group consisting of alkyl, halogen atom, aryl, heteroaryl, halogenoalkane, hydroxyl, cyano, alkoxyl, aryloxy, aminoalkyl, hydroxyalkyl, heterocycle is Lila, carboxylic acid, ester of carboxylic acid and-NR9R10;

R11selected from the group consisting of hydrogen atom and 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 this invention is directed to a method of treatment or prevention in a mammal of disorders associated with protein kinases, wherein the mammal is administered a therapeutically effective amount of a pharmaceutical composition according to the invention which contains a compound(I) according to the invention or their pharmaceutically acceptable salts, and pharmaceutically acceptable carriers and excipients. Disorders associated with protein kinases, selected from the group consisting of disorders associated with VEGFR-2, EGFR, HER-2, HER-3, HER-4, DERIVED, c-Kit, c-Met, FGFR, and Flt3. Disorders associated with protein kinases, are also leukemia, diabetes, autoimmune disease, hyperplasia, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, cardiovascular disease, disease Hippel-Lindau, inflammatory diseases and fibrosis. More preferably the said disorder associated with protein kinases, are squamous cell carcinoma, renal cell cancer, Kaposi's sarcoma, non-small cell lung cancer, malkoc mocny lung cancer, lymphoma, adenocarcinoma of the thyroid gland, breast cancer, head and neck cancer, uterine cancer, esophageal cancer, melanoma, bladder cancer, carcinosarcoma in the urinary and reproductive system, gastrointestinal carcinoma, glioma, cancer of the colon and rectum, cancer of the ovary. Preferably specified mammal is a human.

Next, a method of treatment of a mammal from disorders associated with protein kinases, according to the present invention preferably is a method of treating a mammal with cancer. The present method further includes a joint introduction to the mammal a therapeutically effective amount of an antitumor agent selected from the group consisting of Taxol or carboplatin. Preferably specified mammal is a human. In one another aspect, this invention is directed to the use of compounds according to the present invention in the manufacture of a medicinal product for the treatment of disorders associated with protein kinases. Disorders associated with protein kinases, selected from the group consisting of disorders associated with VEGFR-2, EGFR, HER-2, HER-3, HER-4, DERIVED, c-Kit, c-Met, FGFR, and Flt3. Alternative disorders associated with protein kinases, selected from the group consisting of leukemia, diabetes, autoimmune diseases, hyperplasia, p is Oriana, osteoarthritis, rheumatoid arthritis, angiogenesis, cardiovascular disease, diseases of Hippel-Lindau, inflammatory diseases and fibrosis. More preferably the said disorder associated with protein kinases represent a cancer selected from the group consisting of squamous cell carcinoma, renal cell cancer, Kaposi's sarcoma, non-small cell lung cancer, small-cell lung cancer, lymphoma, adenocarcinoma of the thyroid gland, cancer of the breast, head and neck cancer, uterine cancer, esophageal cancer, melanoma, bladder cancer, carcinosarcoma in the urinary and reproductive system, gastrointestinal carcinoma, glioma, colon cancer, rectum and cancer of the ovary.

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

the reaction educt - diapir pyrrolidinylcarbonyl acid IC-1 in tetrahydrofuran in the presence of acetic acid with cerium ammonium nitrate at room temperature with obtaining diapir personaldevelopment acid IC-2; and

reaction diapir personaldevelopment acid IC-2 in anhydrous tetrahydrofuran (carletonville)triphenylphosphorane by Wittig reaction with obtaining ether pyrrolidonecarboxylic soldierboy acid IC-3;

recovery of ether pyrrolidinedithiocarbamate acid IC-3 in anhydrous ethanol with hydrogen, catalyzed by palladium on carbon at room temperature to obtain ether pyrrolidinedithiocarbamate acid IC-4;

hydrolysis of the ester pyrrolidinedithiocarbamate acid IC-4 in aqueous solution of lithium hydroxide getting diapir errorcorrection acid IC-5;

recovery of ether errorcorrection acid IC-5 in anhydrous tetrahydrofuran solution of borane-tetrahydrofuran at -20 ° ~-5°C (degrees Celsius) to give the ether pyrrolidinylcarbonyl acid IC-6;

metilirovaniya ether pyrrolidinylcarbonyl acid IC-6 in anhydrous dichloromethane in the presence of triethylamine at -20 ° ~-5°C with obtaining ether pyrrolidinylthiosemicarbazone acid IC-7;

the reaction of the ether pyrrolidinylthiosemicarbazone acid IC-7 with various amines to obtain amide ether pyrrolocarbazols acid IC-8;

reaction of amide ether pyrrolocarbazols acid IC-8 with trimethylaluminum in toluene at boiling the situation under reflux with getting pyrroloquinoline semichasnoho Aza-heterocyclic ester IC-9;

the reaction pyrroloquinoline semichasnoho Aza-heterocyclic ester IC-9 triperoxonane acid at 30~50°C in argon atmosphere to obtain pyrroloquinoline semichasnoho Aza-heterocyclic formaldehyde IC

where:

R2, R3and R4are as defined above.

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

reaction diapir of aleida terracarbon acid IC-2 with a Grignard reagent - bromide cyclopropylamine in anhydrous tetrahydrofuran at room temperature in an argon atmosphere to obtain diapir parallelprogramming acid ID-1;

reaction diapir parallelprogramming acid ID-1 with Hydrobromic acid in methanol to obtain diapir of bromoaniline ID-2;

recovery diapir of bromoaniline ID-2 in anhydrous ethanol by hydrogen catalyzed by palladium on carbon at room temperature to obtain diapir of bambuterol ID-3;

reaction diapir of bambuterol ID-3 with various amines in dichloromethane at which ipacarai under reflux with obtaining diapir pyrrolidinecarbonyl acid ID-4;

reaction diapir pyrrolidinecarbonyl acid ID-4 with trimethylaluminum in toluene at boiling under reflux with getting pyrroloquinoline eight-membered Aza-heterocyclic aldehyde ID;

where:

R2, R3and R4are as defined above.

In addition, another aspect of this invention relates to a method for pyrrole-nitrogen-containing heterocyclic derivative, comprising the step of the reaction of oxindole with aldehyde in the presence of a base (such as triethylamine, piperidine) and heating the reaction mixture for 2~12 hours, where the indicated aldehyde has the formula below:

and the specified oxindol has the following formula:

where:

X, R1, R2, R3, R4, R5, R6, R7and R8are as defined above.

In another aspect this invention relates to compounds with which it is possible to distinguish proteinkinase activity by bringing into contact of cells that Express the protein kinase with a compound according to the invention or its pharmaceutically acceptable salt, and determine the effect on the cell

In another aspect this invention relates to compounds with which it is possible to distinguish proteinkinase activity by bringing into contact artificially derived recombinant protein kinase with a compound according to the invention or its pharmaceutically acceptable salt, and determination of kinase activity using ELISA method (enzyme linked measurement sorbent analysis enzyme - linked immunosorbent assay).

DETAILED description of the INVENTION

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

"Alkyl" means a saturated aliphatic hydrocarbon radical, including C1-C20remotemachine and branched groups. Preferably the alkyl group is an alkyl of medium size, 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 represents a lower alkyl having from 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl and the like. The alkyl group may be substituted or unsubstituted. In the event that the group is substituted, the preferred groups of the substituents are halogen, hydroxyl, lower alkoxyl, aryl, aryloxy, heteroaryl is, heteroseksualci, -OR9, -NR9R10, -COR9,

-O[CH2CH2O]rR11, -NR9COR10, -SO2R9or-NHCO2R10.

"Cycloalkyl" denotes a 3-8-membered monocyclic ring, 5-membered/6-membered or 6-membered/6-membered condensed bicyclic ring or a polycyclic condensed ring group of a condensed ring system means that each ring in the system contains a pair of carbon atoms with another ring 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 completely conjugated system of PI electrons. Examples cycloalkyl groups are cyclopropane, CYCLOBUTANE, cyclopentane, cyclopentene, cyclohexane, cyclohexadiene, adamantane, Cycloheptane, cycloheptatrien and the like. Cycloalkyl group can be substituted or unsubstituted. If this group is substituted, the group of substituents preferably comprise one or more than one group independently selected from the group consisting of lower alkyl, trialogical, halogen atom, hydroxyl, lower alkoxyl, aryl (possibly substituted by one or more than one group, each of which is independently researched the performance represents a halogen atom, hydroxyl, lower alkyl or lower CNS group), aryloxy (possibly substituted by one or more than one group, each of which independently represents a halogen atom, hydroxyl, lower alkyl or lower CNS group), 6-membered heteroaryl (having from 1 to 3 nitrogen atoms in the ring, where the carbon atoms in the ring can be substituted by one or more than one group, each of which independently represents a halogen atom, hydroxyl, lower alkyl or lower CNS group), a 5-membered heteroaryl (having from 1 to 3 heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulfur, where the carbon atoms and the nitrogen atom of this group may be substituted by one or more than one group, each of which independently represents a halogen atom, hydroxyl, lower alkyl or lower CNS group), 5 - or 6-membered geterotsiklicheskie (having from 1 to 3 heteroatoms selected from the group consisting of nitrogen atoms, oxygen and sulfur, where the carbon atoms and nitrogen atoms (if present) in this group may be substituted by one or more than one group, each of which independently represents a halogen atom, hydroxyl, lower alkyl or lower CNS group), mercapto, cyano, nitro, carboxylic acid, e is Ira carboxylic acid, -OR9, -NR9R10, -COR9, -O (CH2CH2O]rR11, -NR9COR10, -SO2R9and-NHCO2R10.

"Alkenyl" refers to an alkyl group as defined above having at least 2 carbon atoms and at least one carbon-carbon double bond. Are given to illustrate non-limiting examples of alkenyl derive the following groups: Attila, 1-propenyl, 2-propenyl, 1-, 2 - or 3-butenyl and the like. Specified alkenyl 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, ester of carboxylic acid, -OR9, -NR9R10, -COR9,

-O[CH2CH2O]rR11, -NRgCOR10, -SO2R9and-NHCO2R10.

"Quinil" means an alkyl group as defined above having at least 2 carbon atoms and at least one carbon-carbon triple bond. Are given to illustrate non-limiting examples of alkinyl derive the following groups: ethinyl, 1-propinyl, 2-propinyl, 1-, 2 - or 3-butynyl and the like. Specified quinil may be substituted by one or more than one group selected from the group consisting of a halogen atom, Tagalog is nametil, hydroxyl, nitro, cyano, alkoxyl, alkyl, carboxylic acid, ester of carboxylic acid, -OR9, -NR9R10, -COR9,

-O[CH2CH2O]rR11, -NR9COR10, -SO2R9and-NHCO2R10.

"Aryl" means a group having at least one aromatic ring, that is, having a fully conjugate system of PI electrons, including cyclic aryl solely of carbon atoms, heteroaryl, polycyclic aryl condensed with rings. Specified aryl can be substituted one or more than one group selected from the group consisting of a halogen atom, trihalomethyl, hydroxyl, nitro, cyano, alkoxyl, alkyl, carboxylic acid, ester of carboxylic acid, -OR9, -NR9R10, -COR9,

-O[CH2CH2O]rR11, -NR9COR10, -SO2R9and-NHCO2R10.

"Heteroaryl" denotes 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. the Specified ring represents a 5 - or 6-membered ring. Non-limiting examples of heteroaryl groups are furan, thiophene, pyridine, pyrrole, N-acylpyrrole, pyrimidine, pyrazin, imidazole and the like. The specified heteroaryl can b shall be substituted one or more than one group, independently selected from the group consisting of a halogen atom, trihalomethyl, hydroxyl, nitro, cyano, alkoxyl, alkyl, carboxylic acid, ester of carboxylic acid, -OR9, -NR9R10, -COR9,

-O[CH2CH2O]rR11, -NR9COR10, -SO2R9and-NHCO2R10.

"Heterocytolysine" group refers to monocyclic or condensed ring group of 5-9 ring atoms with the ring(rings) one or more than one atom selected from the group consisting of nitrogen atom, oxygen and S(O)n(n is an integer from 0 to 2), where the remaining ring atoms are C. Ring may also have one or more than one double bond, however, these rings may or may not be fully conjugate system of PI electrons. Non-limiting examples of the unsubstituted geterotsiklicheskikh groups are pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperazine and the like. Heteroseksualci may be substituted or unsubstituted. If it is substituted, the group of substituents preferably comprise one or more than one group selected from a halogen atom, trihalomethyl, hydroxyl, nitro, cyano, alkoxyl, alkyl, carboxylic acid, ester of carboxylic acid, -OR99R10, -COR9, -O (CH2CH2O]rR11, -NR9COR10, -SO2R9and-NHCO2R10.

"Hydroxyl" refers to the group-HE.

"Alkoxyl" means as a group-O-(alkyl), or a group-O-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, for example, methoxy, ethoxy, propoxy, butoxy, cyclopropylamine, cyclobutylamine, cyclopentyloxy, cyclohexyloxy and the like. Specified CNS group can be possibly 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, ester of carboxylic acid, -OR9,

-NR9R10, -COR9, -O (CH2CH2O]rR11, -NR9COR10, -SO2R9and-NHCO2R10.

"Halogenoalkane" means-O-(halogenated). Representative examples include, but are not limited to, triptoreline, tribromide and the like.

"Aryloxy" refers to-O-aryl and-O-heteroaryl group, as defined above. Representative examples include, but are not limited to, phenoxy, pyridyloxy, furanose, titilate, pyrimidinone, pyrazinone and the like, and their derivatives. Specified arrochela group can be for esena one or more than one group, selected from the group consisting of a halogen atom, trihalomethyl, hydroxyl, nitro, cyano, alkoxyl, alkyl, carboxylic acid, ester of carboxylic acid, -OR9, -NR9R10, -COR9,

-O[CH2CH2O]rR11, -NR9COR10, -SO2R9and-NHCO2R10.

"Hydroxyalkyl" denotes the group -(CH2)nOH.

"Halogen atom" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

"Trihalomethyl" refers to-CX3where X is as defined above.

"Probable" or "possible" means that the described subsequently, the event or circumstance may or may not take place, and that the description includes instances where the event or circumstance may or may not take place. For example, "heterocyclic group possibly substituted alkyl group" means that the alkyl may be present or not be present, and the description includes situations where the heterocyclic group is substituted by an alkyl group and situations where the heterocyclic group is not substituted by an alkyl group.

"Pharmaceutical composition" refers to mixtures of one or more than one compound described herein, or physiologically/pharmaceutically acceptable salts or prodrugs with other chemical components, such as physiologists who Eski/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate the introduction of compounds into the body.

The METHOD of SYNTHESIS of the COMPOUNDS ACCORDING to the INVENTION

In order to perform the task of the invention, the invention is applied to the following technical solution:

Compounds according to the invention can be obtained by methods known in the art. Suitable methods of synthesis proposed in the examples below. As a rule, the compounds can be obtained in accordance with the following scheme:

The original substance - W pyrrolidinylcarbonyl acid IC-1 is subjected to the reaction in tetrahydrofuran in the presence of acetic acid with cerium ammonium nitrate at room temperature with obtaining ether aldehyde pyrrolocarbazols acid IC-2. Fluids aldehyde terracarbon acid IC-2 is subjected to the reaction in anhydrous tetrahydrofuran (carletonville)triphenylphosphorane by Wittig reaction with obtaining ether pyrrolidinedithiocarbamate acid IC-3; spend catalyzed by palladium on carbon recovery ether pyrrolidinedithiocarbamate acid IC-3 in anhydrous ethanol with hydrogen at room temperature with the floor is the group of ether pyrrolidinedithiocarbamate acid IC-4; carry out the hydrolysis of the ester pyrrolidinedithiocarbamate acid IC-4 in aqueous solution of lithium hydroxide with obtaining ether errorcorrection acid IC-5; carry out the restoration of ether errorcorrection acid IC-5 in anhydrous tetrahydrofuran solution of borane-tetrahydrofuran at -20 - ~-5°C with obtaining ether pyrrolidinylcarbonyl acid IC-6; next, conduct metilirovanie ether pyrrolidinylcarbonyl acid IC-6 in anhydrous dichloromethane in the presence of triethylamine at -20 ° ~-5°C with obtaining ether pyrrolidinylthiosemicarbazone acid IC-7; carry out the reaction of the ether pyrrolidyl sulfonylureatolerant acid IC-7 with various amines to obtain amide ester pyrrolocarbazols acid IC-8; carry out the reaction of the amide ester pyrrolocarbazols acid IC-8 with trimethylaluminum in toluene at boiling under reflux with getting pyrroloquinoline semichasnoho Aza-bicyclic ester IC-9; carry out the reaction pyrroloquinoline semichasnoho Aza-bicyclic ester IC-9 triperoxonane acid at 30-50°C in argon atmosphere to obtain pyrroloquinoline semichasnoho Aza-bicyclic formaldehyde IC; carry out the reaction pyrroloquinoline semichasnoho Aza-bicyclic is anyone formaldehyde IC with indolinone in the presence of a base, such as triethylamine or piperidine, boiling under reflux for 2-12 hours with obtaining pyrroloquinoline semichronic Aza-heterocyclic derivatives (IA).

The aldehyde ester pyrrolocarbazols acid IC-2 is subjected to reaction with a Grignard reagent - cyclopropylamine bromide in anhydrous tetrahydrofuran at room temperature in an argon atmosphere to obtain diapir parallelprogramming acid ID-1; carry out the reaction diapir parallelprogramming acid ID-1 with Hydrobromic acid in methanol to obtain diapir of bromoaniline ID-2; carry out the restoration of diapir of bromoaniline ID-2 in anhydrous ethanol by hydrogen catalyzed by palladium on carbon at room temperature to obtain diapir of bambuterol ID-3; carry out the reaction diapir of bambuterol ID-3 with various amines in dichloromethane at boiling under reflux with getting pyrrol diapir amide dicarboxylic acid ID-4; carry out the reaction diapir amide pyrrolocarbazols acid ID-4 with trimethylaluminum in toluene at boiling under reflux with getting pyrroloquinoline eight-membered azaheterocyclic aldehyde ID; carry out the reaction pyrroloquinoline eight-membered Aza-heterocyclic aldehyde ID with indolinone in the presence of a base such as triethylamine or piperidine, boiling under reflux for 2-12 hours with obtaining pyrroloquinoline eight-membered Aza-heterocyclic derivatives (IB).

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

This invention also relates to pharmaceutical compositions containing the compounds or their salts according to this invention in an effective therapeutic dose, as well as pharmaceutically acceptable carrier.

Also, this invention relates to the use of compounds of formula (I) or their salts in the manufacture of a medicinal product as tyrosine kinase inhibitors. In other words, the present invention also suggested the song, containing the above compound in an effective therapeutic dose, and the use of the compounds and/or pharmaceutical compositions thereof, in the manufacture of a medicinal product as tyrosine kinase inhibitors.

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

EXAMPLES

Structures of compounds were confirmed by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR shifts (δ) were given in ppm (m-1). NMR measurements were performed on a Bmker AVANCE-400, using deuterated chloroform (CDCla) and deuterated dimethylsulfoxide (DMSO-d6) as solvent and tetramethylsilane was (TMS) as internal standard, chemical shifts are given in ppm (m-1).

The MS measurement was performed on a mass spectrometer FINNIGAN LCQAd (ESI).

The average speed of the inhibition of VEGFR kinase were determined using HTScan (Cell Signaling).

The average speed of inhibiting kinase EGFR/HER-2 was determined using the NovoStar (BMG LABTECH in Germany).

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

In column chromatography, as a rule, used silica gel Yantai Huanghai 200-300 mesh as a carrier.

DMSO-d6 : deuterated dimethyl sulfoxide

CDCl3: deuterated chloroform

EXAMPLES RETRIEVE

Example 1

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

Stage 1

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

ester 4-ethyl ester

3,5-Dimethyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1A (30 g, 0,113 mol) was dissolved in 300 ml of tetrahydrofuran was added 360 ml of acetic acid and 300 ml of water under stirring at room temperature. After complete addition, the mixture was stirred so that it is well mixed, and added nitrate ammonium cerium (246 g, 0,449 mol) in one portion. The mixture was stirred at room temperature for 0.5 hours, and the color of the reaction solution changed from red to orange. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was poured into 800 ml of ice water, and the formed yellow precipitate. The mixture was stirred for 0.5 hour, filtered and dried in vacuum to obtain the connection specified in the header, 5-formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1b (31,13 g, yield 98%) as a pale yellow solid.

M is m/z (ESI): 282,0 [M+1]

Stage 2

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

5-Formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1b (23 g, to 81.7 mmol) and (ethoxycarbonylmethylene)triphenylphosphorane (34,66 g, and 99.4 mmol) was dissolved in 450 ml of tetrahydrofuran and stirred at room temperature overnight in an argon atmosphere. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was concentrated under reduced pressure to obtain a yellow oil. The residue was dissolved in a mixture solvent of n-hexane and ethyl acetate (about:about=20:1) and purified column chromatography with decompression on the sandy funnel with getting the connection specified in the header, 5-(2-ethoxycarbonylphenyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1C (24 g, yield 84%) 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 ester 4-ethyl ester

5-(2-Ethoxycarbonylphenyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1C (24 g, to 68.3 mmol) was dissolved in anhydrous ethanol (180 ml) under stirring, and added to a solution of palladium on activated carbon (2,44 g, 10%. The resulting solution was stirred at room temperature overnight in a hydrogen atmosphere. When thin layer chromatography showed the disappearance of starting compounds, 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 get the connection specified in the header, 5-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1d (23 g, yield 95%) as a white solid.

MC m/z (ESI): 354,40 [M+1]

Stage 4

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

5-(2-Ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1d (23,6 g, to 66.8 mmol) was dissolved in 190 ml of tetrahydrofuran and 90 ml of methanol under stirring, and added an aqueous solution of lithium hydroxide (80 ml, 10 mol/l, 0.8 mol) at room temperature. The color of the reaction solution gradually changed from light yellow to blue; the stirring was carried out for another 1 hour. When thin layer chromatography showed the disappearance of starting substances, the resulting mixture was concentrated under reduced pressure to evaporate the organic solvent. pH ostad is brought to 2 with hydrochloric acid (2 mol/l) in an ice bath with stirring. White precipitate appeared. The mixture was filtered, and the filter cake was dried to obtain the connection specified in the header, 5-(2-carboxyethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1E (24 g, yield 98%) as a white solid.

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

Stage 5

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

5-(2-Carboxyethyl)-3-methyl-1 H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1E (9.75 g, 30 mmol) was dissolved in 90 ml of anhydrous tetrahydrofuran with stirring and slowly added to the solution dropwise a solution of borane in tetrahydrofuran (90 ml, 1 mol/l, 90 mmol) while maintaining the temperature at -10 - ~-5°C in a bath of ice and salt in the atmosphere of argon. After adding a bath of ice and salt 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 starting compounds, the reaction mixture was concentrated under reduced pressure to evaporate the solvent. To the residue was added 100 ml of saturated sodium bicarbonate solution and 100 ml of ethyl acetate and stirred until dissolution. The resulting mixture was extracted with ethyl acetate (100 ml×3). The combined organic ek the tracts were washed with 100 ml saturated brine, was dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to get the connection specified in the header, 5-(3-hydroxypropyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1f (9,2 g, yield 98%) as a pale yellow oil.

MC m/z(ESI): 312,3 [M+1]

Stage 6

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

5-(3-Hydroxypropyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-mpem-butyl ester 4-ethyl ester 1f (9,20 g, 30 mmol) was dissolved in 150 ml of dichloromethane under stirring, and to the solution was added triethylamine (7.0 ml, 50 mmol) while maintaining the temperature at about -10°C in a bath of ice and salt in the atmosphere of argon. After adding to the mixture was slowly added methanesulfonamide (3.5 ml, 45 mmol). After stirring for good mixing of the reaction system was allowed to warm to room temperature and was stirred for 4 hours. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was quickly cooled with ice. The reaction mixture was successively washed with diluted hydrochloric acid (0.5 mol/l, 80 MLH) to remove triethylamine, a saturated solution of sodium carbonate (80 ml×2) removed the I excess hydrochloric acid and saturated brine (80 ml) and concentrated under reduced pressure to obtain compound, specified in the header, 5-(3-methanesulfonylaminoethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1g (11.4 g, yield 99%) as a brown oil.

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

Stage 7

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

5-(3-Methanesulfonylaminoethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1g (8,24 g, 21 mmol) was dissolved in N,N-diethylethylenediamine (15 ml, 100 mmol) under stirring at room temperature and was stirred overnight. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was added 100 ml of ethyl acetate and 100 ml saturated brine, was 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 the drying agent and concentrated under reduced pressure to obtain brown oil. This residue was purified column chromatography on silica gel with getting the connection specified in the header, 5-[3-(2-diethylaminoethylamine)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1h (8,2 g, yield 95%) as a colourless oil.

MC m/z (ESI): 410,2 [M+1]

Stage 8/p>

5-(2-Diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carboxylic acid tert-butyl methyl ether

5-[3-(2-Diethylaminoethylamine)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 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. To the mixture was added a solution of trimethylaluminum in toluene (5.6 ml, 2 mol/l, 11,27 mmol) and stirred for 30 minutes at room temperature before until white smoke did not cease to stand out. The reaction mixture was heated up to the formation of phlegmy for 4 hours in an oil bath. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was naturally cooled to room temperature, was rapidly cooled ethanol (10 ml, 95%) was added anhydrous ethanol (60 ml). The resulting mixture was filtered through a layer of cellite, washed with anhydrous ethanol (200 ml×4) and concentrated under reduced pressure. The residue was purified column chromatography on silica gel with getting the connection specified in the header, 5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carboxylic acid tert-butyl ester 1i (0,413 g, yield 75,7%) as a white solid.

MS m/z (ESI): 364,1 [M+1]

Stage 9

5-(2-what ethylaminomethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde

5-(2-Diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carboxylic acid tert-butyl ether 1i (0,413 g to 1.14 mmol) was dissolved in triperoxonane acid (1.5 ml, 20 mmol) under stirring, was heated to 40°C for 5 minutes in an oil bath in an argon atmosphere and cooled to -5°C in a bath of ice and salt under stirring, was added triethoxysilane (0,34 ml, 1.7 mmol) and was stirred for 2 minutes. Then the ice-salt bath was removed, and the reaction mixture was allowed to warm to room temperature and stirred for about 2 hours. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was added 3 ml of ice water and 10 ml of dichloromethane, was brought to pH 11 with aqueous solution of sodium hydroxide (2 mol/l) and was extracted with dichloromethane (10 ml×3). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain a yellow oil. This residue was purified column chromatography on silica gel with getting the connection specified in the header, 5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j (0,271 g, yield 55%) as a light brown oil.

MS m/z (ESI): 292,3 [M+1]

Stage 10

(Z)-5-(2-Diethylaminoethyl)-2-(5-fluoro-2-the CSR-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-3a,5,6,7,8,8A-hexahydro-1H-pyrrolo[3,2-C]azepin-4-one

5-(2-Diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j (0,271 g of 0.93 mmol) and 5-fluoro-1,3-dihydroindol-2-he (to 0.127 g, 0.84 mmol) was dissolved in 1.4 ml of anhydrous ethanol under stirring at room temperature, the resulting mixture was stirred for 10 minutes in the dark and was added piperidine (0.15 ml, 1,49 mmol). The mixture was heated under reflux at 70°C for about 1.5 hours in an oil bath in an argon atmosphere, and formed a lot of orange sludge. When thin layer chromatography showed the disappearance of starting substances, the ice-salt bath was removed, and the reaction mixture was naturally cooled to room temperature, filtered and dried to obtain the connection specified in the header, (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]azepin-4-it 1 (in 0.288 g, yield 80,76%) as an orange solid.

MS m/z (ESI): 425,3 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.336-3.364 (t, 2H, amide N semiline ring-external CH2), 2.907-2.944 (t, 2H, semiline ring-intra-CH2C=C), 2.529-2.581 (m, 6H, 3×-CH2N), 2.455 (s, 3H, pyrrole-CH3), 2.040-2.079 (m, 2H, semiline number is CH-intra-CH2), 0.956-0.992 (t, 6H, 2×-CH3).

Example 2

(Z)-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

The connection specified in the header received in the same conditions as described for stage 10 of Example 1, with (Z)-5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j obtained at stage 9 of Example 1, and 5-chloro-1,3-dihydroindol-2-one as starting substances, obtaining 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-it 2 (27 mg, yield 60,0%) as a red solid.

MC m/z (ESI): 441,1 [M+1]

1H NMR (400 MHz, DMCO-d6) 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, semiline ring-intra-CH2N), 3.336-3.364 (t, 2H, amide N semiline ring-external CH2), 2.907-2.944 (t, 2H, semiline ring-intra-CH2C=C), 2.529-2.581 (m, 6H, 3×-CH2N), 2.455 (s, 3H, pyrrole-CH3), 2.040-2.079 (m, 2H, semiline ring-intra-CH2), 0.956-0.992 (t. 6H, 2×-CH3).

Example 3

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

Stage 1

(5 is the top-2,4-dinitrophenyl)acetic acid

(3-Forfinal)-acetic acid 3a (31,5 g, 0,204 mol) was dissolved in sulfuric acid (64 ml, 98%) under stirring at room temperature was added dropwise a mixture (about:about=1:1, 100 ml) of 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 starting substances in the reaction mixture were added ice and filtered after melting ice with obtaining the connection specified in the header (5-fluoro-2,4-dinitrophenyl)acetic acid 3b (49 mg) as a pale yellow oil.

MS m/z (ESI): 243,5 [M-1]

Stage 2

(2,4-Diamino-5-forfinal)-acetic acid

(5-fluoro-2,4-dinitrophenyl)acetic acid 3b (10 g, of 38.7 mmol) was dissolved in 150 ml of methanol under stirring, and added to a solution of palladium on activated carbon (1.5 g, 5%) at room temperature. The reaction mixture was subjected to hydrogenation at a hydrogen pressure of 0.3 MPa. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was twice filtered and concentrated under reduced pressure to get the connection specified in the header (2,4-diamino-5-forfinal)-acetic acid 3c (7,12 g) as a brown solid for the next stage.

Stage 3

5-fluoro-6-aminoindole-2-he

(2,4-Diamine is-5-forfinal)-acetic acid 3c (7,12 g, of 38.7 mmol) was dissolved in hydrochloric acid (100 ml, 1 mol/l) under stirring at room temperature. This solution was heated up to the formation of phlegmy for 1 hour. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was cooled to room temperature, neutralized with sodium hydroxide solution (100 ml, 1 mol/l) in a bath of ice and water, was 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 the drying agent and concentrated under reduced pressure to get the connection specified in the header, 5-fluoro-6-aminoindole-2-it 3d (5.3g, the yield of 82.8%) as a yellow solid.

MC m/z(ESI): 165,3 [M-1]

Stage 4

5-fluoro-6-(4-forbindelsen)-1,3-dihydroindol-2-he

6-Amino-5-fluoro-1,3-dihydro-indol-2-it is 3d (and 2.26 g of 13.6 mmol) was dissolved in 40 ml of ethanol under stirring at room temperature, the resulting solution was cooled to 0°C in a bath of ice and water was added to a solution of 4-forbindelse (1.5 ml, to 13.6 mmol). After complete addition, the resulting solution was stirred for 1 hour at room temperature, was added sodium borohydride (1.08 g, 28.5 mmol) and was heated up to the formation of phlegmy for 18 hours. When tongolo the Naya chromatography showed the disappearance of starting compounds, the reaction mixture was naturally cooled to room temperature, added to ice water, and formed much of the precipitate, which was filtered and washed with water (50 ml×3). The residue was purified column chromatography on silica gel with getting the connection specified in the header, 5-fluoro-6-(4-forbindelsen)-1,3-dihydroindol-2-she 3e (1,67 g, yield 45%) as a white solid.

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

Stage 5

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

The connection specified in the header received in the same conditions as described for stage 10 of Example 1 from 5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j obtained at stage 9 of Example 1, and 5-fluoro-6-(4-forbindelsen)-1,3-dihydroindol-2-one 3e as a source of substances with obtaining (Z)-5-(2-diethylaminoethyl)-2-[5-fluoro-6-(4-forbindelsen)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 3 (61 mg, yield 62,2%) as a reddish brown solid.

MS m/z (ESI): 548,3 [M+1]

1H NMR (400 MHz, DMSO-d6) 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-CH2), 3.466-3.501 (t, 2H, semiline ring is-intra-CH 2M), 3.336-3.364 (t, 2H, amide N semiline ring-external CH2), 2.907-2.944 (t, 2H, semiline ring-intra-CH2C=C), 2.529-2.581 (m, 6N, 3×-CH2N), 2.388 (s, 3H, pyrrole-CH3), 2.011-2.039 (m, 2H, semiline ring-intra-CH2), 0.967-blade 1.063 (t, 6H, 2×-CH3).

Example 4

(Z)-2-(7-Bromo-5-fluoro-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

Stage 1

7-Bromo-5-fluoro-1,3-dihydroindol-2-he

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

MC m/z(ESI): 228,3 [M-1]

Stage 2

(Z)-2-(7-Bromo-5-fluoro-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

The connection specified in the header received in the same conditions as described for stage 10 of Example 1 from 5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde (j, received at stage 9 of Example 1, 7-bromo-5-fluoro-1,3-dihydro-indol-2-one 4b as a source of substances with obtaining (Z)-2-(7-bromo-5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-5-(2-diethylaminoethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 4 (55 mg, yield 61,1%) in the form yellow solid.

MC m/z (ESI): 503,6 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.338-3.366 (t, 2H, amide N semiline ring-external CH2), 2.932-2.969 (t, 2H, semiline ring-intra-CH2C=C), 2.527-2.582 (m, 6H, 3×-CH2N), 2.470 (s, 3H, pyrrole-CH3), 2.031-2.093 (m, 2H, semiline ring-intra-CH2), 0.954-0.990 (t, 6H, 2×-CH3).

Example 5

(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]azepin-4-one

The connection specified in the header received in the same conditions as described in stage 10 of Example 1 from 5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j obtained at stage 9 of Example 1, and 5-bromo-1,3-dihydroindol-2-one as starting compounds to obtain (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]azepin-4-5 (59 mg, yield 67,8%) as a yellow Targovishte.

MS m/z (ESI): 485,5 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.336-3.364 (t, 2H, amide N semiline ring-external CH2), 2.907-2.944 (t, 2H, semiline ring-intra-CH2C=C), 2.490-2.578 (m, 6H, 3×-CH2N), 2.464 (s, 3H, pyrrole-CH3), 2.039-2.067 (m, 2H, semiline ring-intra-CH2), 0.954-0.990 (t. 6H, 2×-CH3).

Example 6

(Z)-5-(2-Diethylaminoethyl)-2-[4-(2,3-differenl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-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 consistently added bis(pinacolato)LIBOR (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 argon atmosphere. After complete addition, the reaction mixture was stirred at 80°C in oil bath for 22 hours. When thin layer chromatography showed the disappearance of starting substances to the reaction mixture were added water (2 l) and extracted with ethyl acetate (2 l×3). The combined organic extracts were washed with saturated brine (2 l×5), dried the hell anhydrous sodium sulfate, was filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified column chromatography on silica gel and recrystallize with obtaining 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole 6b (20 g, yield 60%) as a white solid.

MS m/z (ESI): 243,9 [M+1]

Stage 2

4-(2,3-Differenl)-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 under stirring was added 1-bromo-2,3-differental (0.97 g, 5 mmol), tetrakis(triphenylphosphine)palladium (0.17 g, 0.15 mmol) and sodium hydroxide solution (7 ml, 2 mol/l) in an 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 starting compounds, the reaction mixture was naturally cooled to room temperature and was 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 the drying agent and concentrated under reduced pressure. The residue was purified column chromatography on silica gel to obtain 4-(2,3-differenl)-1H-indole 6 (800 mg, yield 70%) as a white solid.

MC m/z(ESI): 228,4 [M-1]

Stage 3

-(2,3-Differenl)-1,3-dihydroindol-2-he

4-(2,3-Differenl)-1H-indole 6s (744 mg, 3.25 mmol) was dissolved in 12 ml of ethanol under stirring and successively added tert-butanol (21 ml), glacial acetic acid (6.4 ml) and pyridinium tribromide (3.12 g, 9.7 mmol) at room temperature. After complete addition, the reaction mixture was stirred for 3 hours, was added glacial acetic acid (16 ml) and zinc dust (1.1 g, 16,25 mmol) and stirred for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure. To the residue was added ethyl acetate (30 ml), then washed 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 to obtain 4-(2,3-differenl)-1,3-dihydroindol-2-she 6d (780 mg, yield 97%) as a white solid.

MS m/z (ESI): 246,6 [M+1]

Stage 4

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

The connection specified in the header received in the same conditions as described in stage 10 of Example 1 from 5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j obtained at stage 9 of Example 1 and 4-(2,3-differenl)-1,3-dihydroindol-2-one 6d in which the quality of the original substances to obtain (Z)-5-(2-diethylaminoethyl)-2-[4-(2,3-differenl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 6 (43 mg, the output of 61.4%) as a yellow solid.

MS m/z (ESI): 519,6 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.313 (m, 2H, amide N semiline ring-external CH2), 2.868-3.904 (t, 2H, semiline ring-intra-CH2C=C), 2.465-2.542 (m, 6H, 3×-CH2N), 2.002-2.032 (m, 2H, semiline ring-intra-CH2), 1.794 (s, 3H, pyrrole-CH3), 0.930-0.965 (t, 6H, 2×-CH3).

Example 7

(Z)-N-{3-[5-(2-Diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxyacetate

Stage 1

N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxyacetate

6-Amino-5-fluoro-1,3-dihydroindol-2-it 3d (2,028 g, 12.2 mmol) was dissolved in 30 ml of tetrahydrofuran under stirring, and added to a solution of 1.3 ml of pyridine at room temperature. The reaction system was cooled to about -50°C in a bath of dry ice and ethanol. To the above reaction system was added dropwise a solution of methoxyacetanilide (1.35 g, 12.5 mmol) in tetrahydrofuran (20 ml). After complete addition, the ice bath with ethanol was removed and the reaction mixture was allowed to warm to room temperature the s and was stirred overnight. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was filtered. The resulting solid was washed with water (10 ml×3) and recrystallize with methanol to obtain N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxyacetate 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-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxyacetate

The connection specified in the header received in the same conditions as described in stage 10 of Example 1 from 5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j obtained at stage 9 of Example 1 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxyacetate 7a as a source of substances with obtaining (Z)-N-{3-[5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxyacetate 7 (37 mg, yield 53,6%) as a brown solid.

MC m/z (ESI): 512,5 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, -CH2O)3.483-3.517 (t, 2H, semiline ring-intra-CH2N), 3.336-3.362 (t, 2H, amide N semiline ring-external CH2), 3.314 (s, 3H, -With the 3O), 2.902-2.939 (t. 2H, semiline ring-intra-CH2C=C), 2.530-2.562 (m, 6N, 3×-CH2N)2.444 (s, 3H, pyrrole-CH3), 2.037-2.066 (m, 2H, semiline ring-intra-CH2), 0.958-0.993 (t, 6N, 2×-CH3).

Example 8

(S,Z)-N-{3-[5-(2-Diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxypropionic

Stage 1

Acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indole-6-ylcarbonyl)-ethyl ester

5-fluoro-6-amino-1,3-dihydroindol-2-it 3d (450 mg, a 2.71 mmol) was dissolved in 10 ml of tetrahydrofuran under stirring at room temperature. The mixture was cooled to -45°C in a bath of dry ice and acetone, and added 364 μl of piperidine. A solution of 1-chlorocarbonyl ether acetic acid (423 mg, a 2.71 mmol) in 10 ml of tetrahydrofuran was added dropwise to the above reaction system. After adding a 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 starting compounds, the reaction mixture was filtered. The filter cake was rinsed with water, and the resulting solid was dried to obtain the connection specified in the header, - 1-(5-fluoro-2-oxo-2,3-dig the DRO-1H-indole-6-ylcarbonyl)-ethyl ester acetic acid 8A (840 mg) as a white solid, which was used directly in the next stage.

MC m/z (ESI): 281,5 [M+1]

Stage 2

N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxypropionate

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

MC 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-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxypropionic

The connection specified in the header received in the same conditions as described in stage 10 of Example 1 from 5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j obtained at stage 9 of Example 1, and (S,Z)-N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxypropylamino 8b as a source of substances with p what torching N-{3-[5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxypropionic 8 (28 mg, the output of 40.8%) as a yellow solid.

MC m/z (ESI): 512,4 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.336-3.362 (t, 2H, amide N semiline ring-external CH2), 2.902-2.939 (t, 2H, semiline ring-intra-CH2C=C), 2.530-2.562 (m, 6N, 3×-CH2N), 2.443 (s, 3H, pyrrole-CH3), 2.037-2.066 (m, 2H, semiline ring-intra-CH2), 1.328-1.345 (d, 3H, -CH3), 0.958-0.993 (t, 6N, 2×-CH3).

Example 9

(Z)-N-{3-[5-(2-Diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-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-indole-6-ylcarbonyl)-1-metaliteracy ether acetic acid

5-fluoro-6-amino-1,3-dihydroindol-2-it 3d (410 mg, 2,47 mmol) was dissolved in 10 ml of tetrahydrofuran under stirring at room temperature. The mixture was cooled to -45°C in a bath of dry ice and acetone was added piperidine (322 μl). A solution of acetic acid 1-chlorocarbonyl-1-mutilative ester (423 mg, a 2.71 mmol) in tetrahydrofuran (10 ml) was added dropwise to the above reaction system. After adding a bath of dry ice-acetone was removed and the reaction is Messi was allowed to warm to room temperature and was stirred overnight. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was filtered. The filter cake was rinsed with water, and the resulting solid was dried to obtain acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indole-6-ylcarbonyl)-1-mutilative ester 9a (792 mg) as white solids for the next stage.

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-indole-6-ylcarbonyl)-ethyl ester 9a (2,035 g, 6,9 mmol) was dissolved in 20 ml of methanol under stirring, was added to a solution of the sodium hydroxide solution (20 ml, 0.7 mol/l) (20 ml) and was stirred for 4 hours at room temperature. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was neutralized with hydrochloric acid (1 mol/l) and concentrated under reduced pressure. The residue was purified column chromatography on silica gel 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-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-2-methylpropionate the

The connection specified in the header received in the same conditions as described for stage 10 of Example 1 from 5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j obtained at stage 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 substances to obtain N-{3-[5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[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 of 62.4%) as a yellow solid.

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

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N)3.334-3.361 (t, 2H, amide N semiline ring-external CH2), 2.902-2.939 (t, 2H, semiline ring-intra-CH2C=C), 2.530-2.562 (m, 6H, 3×-CH2N), 2.443 (s, 3H, pyrrole-CH3), 2.037-2.066 (m, 2H, semiline ring-intra-CH2), 1.377 (s, 6H, 2×-CH3), 0.958-0.993 (t, 6H, 2×-CH3).

Example 10

(Z)-2-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-morpholine-4-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

Stage 1

3-Methyl-5-[3-(2-morpholine-4-ylethylamine)-propyl]-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-e the silt ether

5-(3-Methanesulfonylaminoethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1g (5,812 g, 15 mmol)obtained in stage 6 of Example 1, and 2-morpholine-4-ylethylamine (10,725 g of 82.5 mmol) was dissolved in water bath at 30°C and was stirred for 5.5 hours at room temperature. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was added ethyl acetate (100 ml) and saturated brine (100 ml)was 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 the drying agent and concentrated under reduced pressure. The residue was purified column chromatography on silica gel with 3-methyl-5-[3-(2-morpholine-4-ylethylamine)-propyl]-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 10A (2,238 g, yield 87%) as a pale yellow oil.

MS m/z (ESI): 424,9 [M+1]

Stage 2

3-Methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carboxylic acid tert-butyl methyl ether

3-Methyl-5-[3-(2-morpholine-4-ylethylamine)-propyl]-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 10A (2,238 g of 5.29 mmol) was dissolved in 50 ml of toluene under stirring, and was slowly added a solution of trimethylaluminum in toluene is (3.9 ml, 2 mol/l, 7.9 mmol) in argon atmosphere. The reaction system was stirred for 30 minutes at room temperature before until white smoke did not cease to stand out, and boiled under reflux for 3 hours in an oil bath. When thin layer chromatography showed the disappearance of starting substances, the oil bath was removed and the reaction mixture is quickly cooled small amount of water, brought to pH 8-10 with diluted sodium hydroxide solution (2 mol/l)was added a saturated brine (50 ml) and was extracted with ethyl acetate (50 ml×3). The combined organic extracts were filtered through a layer of cellite, concentrated under reduced pressure to get the connection specified in the header, 3-methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carboxylic acid tert-butyl ester 10b (1,218 g, yield 61%) as a pale yellow solid.

MC m/z (ESI): 378,2 [M+1]

Stage 3

3-Methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde

3-Methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carboxylic acid tert-butyl ester 10b (725 mg, 1.92 mmol) was dissolved in triperoxonane acid (2.6 ml, 34.2 mmol) in a bath of ice-water with stirring. The reaction mixture was stirred at 40°C in a water bath for 5 minutes, was added treat ximeta (0,42 ml, 2.5 mmol) in one portion at

-5°C in a bath of ice and water and stirred for 2 minutes. Then bath salt and water were removed, and the reaction mixture was allowed to warm to room temperature, it was brown, and it was stirred for another 2 hours. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture is quickly cooled small amount of water, brought to pH 8 with dilute sodium hydroxide solution (2 mol/l) and was 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 column chromatography on silica gel with getting the connection specified in the header, 3-methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 10C (240 mg, yield 40%) 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-ylidenemethyl)-3-methyl-5-(2-morpholine-4-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

3-Methyl-5-(2-morpholine-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 10C (53 mg, 0,174 mmol) and 5-chloro-1,3-dihydroindol-2-he (29 mg, 0.84 mmol) was dissolved in 0.9 ml of ethanol under stirring, and to the solution was added piperidine (0.1 ml, 1.0 mmol) at room the Oh temperature. The mixture was heated to education phlegmy for 2 hours in an oil bath, and was formed a lot of sediment. Then the oil bath was removed and the reaction mixture was naturally cooled to room temperature and filtered to obtain the connection specified in the header, (Z)-2-(5-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-morpholine-4-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-10 (30 mg, yield 38%) as a red solid.

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

1H NMR (400 MHz, DMSO-d6) 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 semiline ring-CH2, 2×-CH2O)3.346-3.360 (t, 2H, amide N semiline ring-external CH2), 2.938-2.974 (t, 2H, -CH2C=C), 2.463 (s, 3H, pyrrole-CH3), 2.438-2.510 (m, 6H, 2×-CH2N), 2.054-2.083 (m, 2H, semiline ring-intra-CH2).

Example 11

(Z)-2-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-morpholine-4-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header received in the same conditions as described for stage 4 of Example 10, 3-methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 10C, obtained in stage 3 of Example 10, and 5-fluoro-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-2-(5-fluoro-2-oxo,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-morpholine-4-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 11 (29 mg, output 51,5%) as a yellow solid.

MS m/z (ESI): RUR 439,3 [M+1]

1H NMR (400 MHz, DMSO-d6) 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 semiline ring-CH2, 2×-CH2O), 3.344-3.371 (t, 2H, amide N semiline ring-external CH2), 2.934-2.971 (t, 2H, -CH2C=C), 2.454 (s, 3H, pyrrole-CH3), 2.438-2.510 (m, 6H, 2×-CH2N), 2.053-2.082 (m, 2H, semiline ring-intra-CH2).

Example 12

(Z)-2-[4-(2,3-Differenl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-5-(2-morpholine-4-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header received in the same conditions as described for stage 4 of Example 10, 3-methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 10C, obtained in stage 3 of Example 10 and 4-(2,3-differenl)-1,3-dihydroindol-2-one 6d, obtained in stage 3 of Example 6 as starting substances to obtain (Z)-2-[4-(2,3-differenl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-5-(2-morpholine-4-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 12 (20 mg, yield 29%) as a yellow solid.

MS m/z (ESI): 533,3 [M+1]

1H NMR (400 MHz, DMSO-d6) 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), 6.12 (s, 1H, -CH=C), 3.547-3.560 (m, 6H, N semiline ring-CH2, 2×-CH2O)3.295-3.310 (t, 2H, amide N semiline ring-external CH2), 2.897-2.933 (t, 2H, -CH2C=C), 2.410-2.510 (m, 6H, 2×-CH2N), 1.999-2.061 (m, 2H, semiline ring-intra-CH2), 1.794 (s, 3H, pyrrole-CH3).

Example 13

(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]azepin-4-one

The connection specified in the header received in the same conditions as described for stage 10 of Example 1 from 5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j obtained at stage 9 of Example 1 and 4-bromo-1,3-dihydroindol-2-one as starting compounds to obtain (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]azepin-4-it 13 (30 mg, yield of 45.5%) as an orange solid.

MC m/z(ESI): 585,1 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N)3.346-3.373 (t, 2H, amide N semiline ring-external CH2), 2.930-2.966 (t, 2H, semiline ring-intra-CH2C=C), 2.508-2.569 (m, 6H, 3×-CH2N)2.412 (s, 3H, pyrrole-CH3), 2.030-2.095 (m, 2H, semiline ring-intra-CH2), 0.959-0.994 (t, 6H, 2×-CH3).

Example 14

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

The connection specified in the header received in the same conditions as described for stage 10 of Example 1 from 5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j obtained at stage 9 of Example 1, and 5-bromo-1,3-dihydropyrrolo[2,3-b]pyridine-2-one as starting compounds to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydropyrrolo[2,3-b]pyridine-3-ylidenemethyl)-5-(2-diethylaminoethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-she 14 (23 mg, yield of 33.8%) as an orange solid.

MS m/z (ESI): 486,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.354 (t, 2H, amide N semiline ring-external CH2), 2.930-2.966 (t, 2H, semiline ring-intra-CH2C=C), 2.508-2.569 (m, 6H, 3×-CH2N)2.472 (s, 3H, pyrrole-CH3), 2.030-2.095 (m, 2H, semiline ring-intra-CH2), 0.959-0.994 (t, 6H, 2×-CH3).

Example 15

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

The connection specified in the header received in the same conditions, campisano for stage 10 of Example 1, 5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j obtained at stage 9 of Example 1 and 6-methoxy-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-5-(2-diethylaminoethyl)-2-(6-methoxy-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 15 (31 mg, yield 52,7%) as a red solid.

MS m/z (ESI): 437,4 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, -CH3), 3.477-3.510 (t, 2H, semiline ring-intra-CH2N), 3.316-3.347 (t, 2H, amide N semiline ring-external CH2), 2.888-2.924 (t, 2H, semiline ring-intra-CH2C=C), 2.489-2.573 (m, 6N, 3×-CH2N)2.416 (s, 3H, pyrrole-CH3), 2.030-2.095 (m, 2H, semiline ring-intra-CH2), 0.954-0.982 (t, 6N, 2×-CH3).

Example 16

(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]azepin-4-one

The connection specified in the header received in the same conditions as described for stage 10 of Example 1 from 5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j obtained at stage 9 of Example 1 and 4-methyl-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-5-(2-diethylaminoethyl)-3-methyl-2-(4-m is Tyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-she's 16 (25 mg, output to 44.1%) as a yellow solid.

MS m/z (ESI): 421,5 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.339-3.366 (t, 2H, amide N semiline ring-external CH2), 2.909-2.946 (t, 2H, semiline ring-intra-CH2C=C), 2.489-2,573 (m, 6N, 3×-CH2N)2.590 (s, 3H, benzene-CH3), 2.386 (s, 3H, pyrrole-CH3), 2.041-2.069 (m, 2H, semiline ring-intra-CH2), 0.956-0.991 (t, 6N, 2×-CH3).

Example 17

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

The connection specified in the header received in the same conditions as described for stage 10 of Example 1 from 5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j obtained at stage 9 of Example 1 and 4-(2-hydroxyethyl)-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-5-(2-diethylaminoethyl)-2-[4-(2-hydroxyethyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-she is 17 (18 mg, yield of 29.5%) as a yellow solid.

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

1H NMR (400 MHz, DMSO-d6) 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 is emilienne ring-external CH 2O), 3.486-3.502 (t, 2H, semiline ring-intra-CH2N), 3.342-3.556 (t, 2H, -CH2), 3.095 (t, 2H, benzene-CH2), 2.910-2.946 (t, 2H, semiline ring-intra-CH2C=C), 2.504-2.566 (m, 6N, 3×-CH2N)2.398 (s, 3H, pyrrole-CH3), 2.092 (m, 2H, semiline ring-intra-CH2), 0.957-0.993 (t, 6N, 2×-CH3).

Example 18

(Z)-N-{5-fluoro-3-[3-methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxyacetate

The connection specified in the header received in the same conditions as described for stage 4 of Example 10, 3-methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 10C, obtained in stage 3 of Example 10 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxyacetate 7a, obtained in stage 1 of Example 7, as a source of substances with obtaining (Z)-N-{5-fluoro-3-[3-methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxyacetate 18 (47 mg, yield 60%) as a yellow solid.

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

1H NMR (400 MHz, DMSO-d6) 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, -CH2O)3.561-3.571 (m, 6H, N semiline ring-CH2, 2×-CH2O)3.397 (s, 3H, -CH3O)3.331-3.345 (t, 2H, amide N semiline ring-external CH 2), 2.918-2.954 (t, 2H, -CH2C=C), 2.432 (s, 3H, pyrrole-CH3), 2.431-2.500 (m, 6H, 2×-CH2N), 2.040-2.067 (m, 2H, semiline ring-intra-CH2).

Example 19

(Z)-2-[5-fluoro-6-(4-forbindelsen)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-5-(2-morpholine-4-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header received in the same conditions as described in stage 4 of Example 10, 3-methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 10C, obtained in stage 3 of Example 10, and 5-fluoro-6-(4-forbindelsen)-1,3-dihydroindol-2-one 3e, obtained in stage 4 of Example 3 as starting compounds to obtain (Z)-2-[5-fluoro-6-(4-forbindelsen)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-5-(2-morpholine-4-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-she's 19 (57 mg, yield 69%) as a red solid.

MC m/z (ESI): 526,1 [M+1]

1H NMR (400 MHz, DMSO-d6) 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-CH2), 3.544-3.555 (m, 6H, N semiline ring-CH2, 2×-CH2O), 3.310-3.326 (t, 2H, amide N semiline ring-external CH2), 2.870-2.906 (t, 2H, -CH2C=C), 2.378 (s, 3H, pyrrole-CH3), 2.416-2.500 (m, 6H, 2×-CH2N), 2.014-2.041 (m, 2H, semiline ring-intra-CH2).

Example 20

(Z)-N-{5-fluoro-3-[3-methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-7-yl}-formamide

Stage 1

5-fluoro-7-nitroindole-2-he

5-fluoro-1,3-dihydroindol-2-he 4a (5.0 g, 33 mmol) was dissolved in sulfuric acid (17.6 ml, 98%) under stirring at -5°C, and to the solution was added nitric acid (2.1 ml, 65%-68%), maintaining a 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 compounds, the reaction mixture was poured into ice water and filtered after the ice melted. The filter cake was washed with water three times, and the resulting solid was recrystallize with getting the connection specified in the header, 5-fluoro-7-nitro-1,3-dihydroindol-2-she 20a (4.0 g, yield 62.5%) as orange solid.

MC m/z (ESI): 196,3 [M+1]

Stage 2

7-Amino-5-fluoro-1,3-dihydroindol-2-he

5-fluoro-7-nitro-1,3-dihydroindol-2-it, 20A (4.0 g, 20 mmol) was dissolved in 200 ml of acetic acid under stirring was added palladium on activated carbon (1.0 g, 5%) at room temperature. The reaction system was stirred in hydrogen atmosphere. When thin layer chromatography showed icesn is their starting compounds, the reaction mixture was filtered and concentrated under reduced pressure to get the connection specified in the header, 7-amino-5-fluoro-1,3-dihydroindol-2-it 20b (3.2 g, yield of 97.5%) as a white solid.

MC m/z (ESI): 167,4 [M+1]

Stage 3

5-fluoro-7-formimidoyl-2-he

A mixture of acetic anhydride (0.8 ml) and formic acid (0.6 ml) was stirred for 1 hour at room temperature, and the above mixture was added 7-amino-5-fluoro-1,3-dihydroindol-2-he 20b (2.0 g, 12 mmol) in 30 ml of tetrahydrofuran, followed by addition of piperidine (0,02 ml). The resulting mixture was stirred for 3 hours to precipitate formation was filtered to obtain crude product (1,95 g) and recrystallize from methanol to obtain the connection specified in the header, 5-fluoro-7-formimidoyl-2-she 20C (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-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-7-yl}-formamide

The connection specified in the header received in the same conditions as described in stage 4 of Example 10, 3-methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 10C, obtained in stage 3 of Example 10 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-formamide 20s as a source of vases is in obtaining (Z)-N-{5-fluoro-3-[3-methyl-5-(2-morpholine-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydrofuro[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.

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

1H NMR (400 MHz, DMSO-d6) 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 semiline ring-CH2, 2×-CH2O)3.331-3.345 (t, 2H, amide N semiline ring-external CH2), 2.935-2.971 (t, 2H, -CH2C=C), 2.451 (s, 3H, pyrrole-CH3), 2.431-2.500 (m, 6H, 2×-CH2N), 2.046-2.074 (m, 2H, semiline ring-intra-CH2).

Example 21

(S,Z)-N-{5-fluoro-3-[3-methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxypropionic

The connection specified in the header received in the same conditions as described for stage 4 of Example 10, 3-methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 10C, obtained in stage 3 of Example 10 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxypropylamino 8b, obtained in stage 2 of Example 8, as a source of substances with receipt (S,Z)-N-{5-fluoro-3-[3-methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxypropionic 21 (44 mg, yield 58%) as an orange solid.

MC m/z (ESI): 526,1 [M+1]

1H NMR (400 MHz, DMSO-d6) δ 13.599 (s, 1H, pyrrole-NH), 10.895 (s, 1H, indole-NH), 9.236 (s, 1H, -NHCO), 7.46-7.874 (d, 1H, -ArH), 7.718-7.734 (d, 1H, -ArH), 7.663 (s, 1H, -CH=C), 6.051-6.064 (d, 1H, HE), 4.199-4.229 (t, 1H, -CHO), 3.560-3.586 (m, 6H, N semiline ring-CH2, 2×-CH2O)3.331-3.345 (t, 2H, amide N semiline ring-external CH2), 2.918-2.954 (t, 2H, -CH2C=C), 2.456 (s, 3H, pyrrole-CH3), 2.431-2.500 (m, 6H, 2×-CH2N), 2.048-2.077 (m, 2H, semiline ring-intra-CH2), 1.321-1.338 (d, 2H, -CH3).

Example 22

(Z)-2-(5-Bromo-2-oxo-1,2-dihydropyrrolo[2,3-b]pyridine-3-ylidenemethyl)-3-methyl-5-(2-morpholine-4-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header received in the same conditions as described for stage 4 of Example 10, 3-methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 10C, obtained in stage 3 of Example 10, and 5-bromo-1,3-dihydropyrrolo[2,3-b]pyridine-2-one as starting compounds to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydropyrrolo[2,3-b]pyridine-3-ylidenemethyl)-3-methyl-5-(2-morpholine-4-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-she's 22 (59 mg, yield 60%) as an orange solid.

MC m/z (ESI): 500,0 [M+1]

1H NMR (400 MHz, DMSO-d6) 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 semiline ring-CH2, 2×-CH2O), 3.336-3.364 (t, 2H, amide N semiline ring-external CH2), 2.946-2.983 (t, 2H, -CH2C=C), 2.456 (s, 3H, pyrrole-CH3), 2.45-2.500 (m, 6H, 2×-CH2N), 2.048-2.077 (m, 2H, semiline ring-intra-CH2).

Example 23

(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

Stage 1

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

5-(3-Methanesulfonylaminoethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1g (11,964 g of 25.7 mmol)obtained in stage 6 of Example 1, was 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 starting compounds, the reaction mixture was added ethyl acetate (80 ml) and saturated brine (80 ml)was 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 the drying agent and concentrated under reduced pressure to obtain brown oil. This residue was purified column chromatography on silica gel with getting the connection specified in the header, 5-[3-(2-diethylaminoethylamine)-propyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 23a (5,85 g, output 45,9%) as a yellow oil.

MC m/z(ESI): 382,2 [M+1]

Stage 2

5-(2-Dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carboxylic acid tert-butyl methyl ether

5-[3-(2-Diethylaminoethylamine)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 23a (5,85 g of 13.8 mmol) was dissolved in 130 ml of toluene under stirring, and the solution was slowly added a solution of trimethylaluminum in toluene (12 ml, 2 mol/l, 24 mmol) in argon atmosphere. After complete addition, the reaction mixture was stirred for 10 minutes at room temperature before until white smoke did not cease to stand out, and they were heated to education phlegmy for 3 hours in an oil bath. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was quickly cooled with ice water. After cooling the reaction system to room temperature, to the mixture was added hydrochloric acid (50 ml, 2 mol/l) and was stirred for 10 minutes. The mixture was brought to pH 9 with an aqueous solution of sodium hydroxide (2 mol/l) and was extracted with dichloromethane (50 ml×4). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to obtain the compound indicated in the title the information, 5-(2-dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carboxylic acid tert-butyl ester 23b (3,3 g, 71.4%) 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-hexahydrofuro[3,2-C]azepin-2-carbaldehyde

5-(2-Dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carboxylic acid tert-butyl ester 23b (774 mg, 2.3 mmol) was dissolved in triperoxonane acid (3.1 ml, 20 mmol) under stirring, the resulting solution was heated at 40°C for 5 minutes in an oil bath in an argon atmosphere. The reaction mixture was cooled to -5°C in an ice-salt bath under stirring, was added triethoxysilane (0.5 ml, 3.0 mmol) and was stirred for 2 minutes. Then the ice-salt bath was removed, and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was added ice water (3 ml) and dichloromethane (10 ml), brought to pH 11 with aqueous solution of sodium hydroxide (2 mol/l) and was extracted with dichloromethane (10 ml×3). The combined organic extracts were dried over anhydrous sulfate machiya, was filtered to remove the drying agent and concentrated under reduced pressure with procediemineto-brown oil. This residue was purified column chromatography on silica gel with getting the connection specified in the header, 5-(2-dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 23C (223 mg, yield 37%) as a yellow oil.

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

Stage 4

(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

5-(2-Dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 23C (53 mg, 0.2 mmol) was dissolved in 1 ml of methanol under stirring, and to the solution was added 5-chloro-1,3-dihydroindol-2-he (34 mg, 0.2 mmol) and piperidine (0.1 ml). After complete addition, the mixture was stirred for good mixing in the dark, was heated to obrazovaniya phlegmy for 2 hours, whereby was formed a lot of sediment. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed with ethanol and dried to obtain the connection specified in the header, (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-it 23 (62 mg, 75%yield) as an orange powder.

MC m/z (ESI): 413,1 [M+1]

1H NMR (400 MHz, DMSO-d6) δ 13.667 (s, 1H, pyrrole-NH), 11.004 (s, 1H, ind the l-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 semiline ring-CH2), 3.336-3.364 (t, 2H, amide N semiline ring-external CH2), 2.909-2.945 (t, 2H, -CH2C=C), 2.463 (s, 3H, pyrrole-CH3), 2.401-2.434 (t, 2H, -CH2N), 2.204 (s, 6H, 2×-CH2N), 2.035-2.079 (m, 2H, semiline ring-intra-CH2).

Example 24

(Z)-2-(5-Bromo-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 connection specified in the header received in the same conditions as described for stage 4 of Example 23 5-(2-dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 23C, obtained in stage 3 of Example 23, and 5-bromo-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-5-(2-dimethylaminoethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-she's 24 (71 mg, yield 77%) as a red solid.

MS m/z (ESI): 457,0 [M+1]

1H NMR(400 MHz, DMSO-d6) 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 semiline ring-CH2), 3.336-3.364 (t, 2H, amide N semiline ring-external CH2), 2.909-2.945 (t, 2H, -CH2C=C), 2.465 (s, 3H, pyrrole-CH3), 2.401-2.434 (t, 2H, -CH2N), 2.204 (s, 6N, 2×-CH2N), 2.035-2.079 (m, 2H, semiline ring-intra-CH2 ).

Example 25

(Z)-5-(2-Dimethylaminoethyl)-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

The connection specified in the header received in the same conditions as described for stage 4 of Example 23 5-(2-dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 23C, obtained in stage 3 of Example 23, and 5-fluoro-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-5-(2-dimethylaminoethyl)-2-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-she is 25 (205 mg, yield 68%) as a red solid.

MC m/z (ESI): 397,0 [M+1]

1H NMR (400 MHz, DMSO-d6) 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 semiline ring-CH2), 3.336-3.364 (t, 2H, amide N semiline ring-external CH2), 2.909-2.945 (t, 2H, -CH2C=C), 2.457(s, 3H, pyrrole-CH3), 2.401-2.434 (t, 2H, -CH2N), 2.204 (s, 6H, 2×-CH3N), 2.035-2.079 (m, 2H, semiline ring-intra-CH2).

Example 26

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

The connection specified in the header received in the same conditions as described for stage 4 of Example 23 5-(2-dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 23C, obtained in stage 3 of Example 23 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-formamide 20s, obtained in stage 3 of Example 20 as starting compounds to obtain (Z)-N-{3-[5-(2-dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl}-formamide 26 (71 mg, yield 79%) as a red solid.

MC m/z (ESI): 440,1 [M+1]

1H NMR (400 MHz, DMSO-d6) 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 semiline ring-CH2), 3.336-3.364 (t, 2H, amide N semiline ring-external CH2), 2.919-2.955 (t, 2H, -CH2C=C), 2.463 (s, 3H, pyrrole-CH3), 2.403-2.436 (t, 2H, -CH2N), 2.204 (s, 6H, 2×-CH3N), 2.035-2.079 (m, 2H, semiline ring-intra-CH2).

Example 27

(Z)-N-{3-[5-(2-Dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxyacetamido

Stage 1

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

6-Amino-5-fluoro-1,3-dihydroindol-2-it 3d (500 mg, 3.0 mmol) was dissolved in 10 ml of tetrahydrofuran under stirring, and added to a solution of 0.4 ml of pyridine at room temperature. After mixing to achieve good mixing, the mixture was cooled to -4°C in a bath of dry ice-acetone. To the above reaction system was added dropwise acetic acid chlorocarbonylsulfenyl ester (420 mg, 3.0 mmol) in 10 ml of tetrahydrofuran. After adding a bath of dry ice-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 starting compounds, the reaction mixture was filtered. The resulting solid was washed with water three times and dried to obtain the connection specified in the header, acetic acid (5-fluoro-2-oxo-2,3-dihydro-1H-indole-6-ylcarbonyl)-methyl ester 27A (562 mg, yield of 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-hydroxyacetamido

Acetic acid (5-fluoro-2-oxo-2,3-dihydro-1H-indole-6-ylcarbonyl)-methyl ester 27A (58 mg, 0.22 mmol) was dissolved in 1 ml of methanol under stirring, and added to a solution of 1 ml of water and sodium hydroxide (15 mg, the 0.375 mmol) at room temperature. After complete addition, the reaction mixture was stirred for 1 hour. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was filtered. The resulting solid was washed with water three times and dried to obtain the connection specified in the header of N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxyacetamido 27b (46 mg, output 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-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxyacetamido

The connection specified in the header received in the same conditions as described for stage 4 of Example 23 5-(2-dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 23C, obtained in stage 3 of Example 23 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxyacetamido 27b as a source of substances with obtaining (Z)-N-{3-[5-(2-dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxyacetamido 27 (80 mg, yield of 83.4%) as an orange solid.

MS m/z (ESI): 470,1 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, -CH2O)3.544 (t, 2H, N semiline ring-CH2), 3.315-3.340 (t, 2H, amide N semiline ring-external CH2), 2.924 (t, 2H, -CH2C=C), 2.464 (t, 2H, -CH2N)2.442 (s, 3H, pyrrole-CH3), 2.199 (s, 6H, 2×-CH3N), 2.044 (m, 2H, semiline ring-intra-CH2).

Example 28

(Z)-2-[4-(2,3-Differenl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-5-(2-pyrrolidin-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

Stage 1

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

5-(3-Methanesulfonylaminoethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1g (8,462 g, a 21.75 mmol) was dissolved in 2-pyrrolidin-1-ylethylamine (6.3 ml, of 49.79 mmol) under stirring and the resulting solution was stirred at room temperature overnight. When thin layer chromatography of parassala the disappearance of the starting substances to the reaction mixture were added ethyl acetate (200 ml) and a small amount of methanol to obtain a clear solution. 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 column chromatography on silica gel with getting the connection specified in the header, 3-methyl-5-[3-(2-pyrrolidin-1 ylethylamine)-propyl]-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 28a (4,488 g, yield of 63.5%) as a yellow oil.

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

Stage 2

3-Methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carboxylic acid tert-butyl methyl ether

3-Methyl-5-[3-(2-pyrrolidin-1 ylethylamine)-propyl]-1H-pyrrole-2,4-dicarboxylic acid 2-tert-Putilov the th ester 4-ethyl ester 28a (6,754 g, of 16.6 mmol) was dissolved in 150 ml of toluene under stirring, and the solution was slowly added a solution of trimethylaluminum in toluene (16.6 ml, 2 mol/l, a 33.2 mmol) in argon atmosphere. The reaction mixture was stirred for 20 minutes at room temperature before until white smoke did not cease to stand out, and boiled under reflux for 3.5 hours in an oil bath. When thin layer chromatography showed the disappearance of starting substances, the oil bath was removed. The reaction mixture was rapidly cooled with a small amount of ethanol (95%), was added ethyl acetate (100 ml), filtered through a layer of cellite and concentrated under reduced pressure. The residue was purified column chromatography on silica gel with getting the connection specified in the header, 3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-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-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde

3-Methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carboxylic acid tert-butyl ether 28b (3,562 g, 9,87 mmol) was dissolved in 50 ml of dichloromethane under stirring, and added to a solution of triperoxonane acid (19.7 ml, 260 mmol) at room temperature. After the evershine add the mixture was heated to education phlegmy for 30 minutes in an oil bath. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was cooled to -5°C in an ice-salt bath, was added triethoxysilane (2,96 ml of 14.8 mmol) in one portion, stirred at

-5°C for 5 minutes and for 1 hour at room temperature. To the reaction was added water (25 ml), brought to about pH 11 with dilute sodium hydroxide solution (2 mol/l) and was 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 column chromatography on silica gel with getting the connection specified in the header, 3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 28C (1,116 g, yield 49%) as a yellow solid.

MC m/z(ESI): 290,2 [M+1]

Stage 4

(Z)-2-[4-(2,3-Differenl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-5-(2-pyrrolidin-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

3-Methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 28C (40 mg, 0,134 mmol) and 4-(2,3-differenl)-1,3-dihydroindol-2-6d he obtained in stage 3 of Example 6, was dissolved in 0.3 ml of methanol under stirring, and to the solution was added piperidine (of 0.03 ml, 0.3 mmol). After complete addition, the mixture was stirred at to matnog temperature during the night. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was concentrated under reduced pressure to get the connection specified in the header, (Z)-2-[4-(2,3-differenl)-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-it 28 (40 mg, yield 57%) as a yellow solid.

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

1H NMR (400 MHz, DMSO-d6) 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 semiline ring-external CH2), 3.273-3.302 (t, 2H, N semiline ring-CH2), 2.854-2.891 (t, 2H, -CH2C=C), 2.536-2.570 (t, 2H, -CH2N)2.498-2.515 (m, 4H, five-membered ring-CH2N), 1.982-2.012 (m, 2H, semiline ring-CH2), 1.777 (s, 3H, pyrrole-CH3), 1.657 (m, 4H, five-membered ring-CH2).

Example 29

(Z)-N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-7-yl}-formamide

The connection specified in the header received in the same conditions as described for stage 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 28C, obtained in stage 3 of Example 28, and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-7-yl)-FD is maledom 20C, obtained in stage 3 of Example 20 as starting compounds to obtain (Z)-N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-7-yl}-formamide 29 (59 mg, yield 95%) as a yellow solid.

MS m/z (ESI): 466,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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 semiline ring-external CH2), 3.330-3.357 (t, 2H, N semiline ring-CH2), 2.907-2.944 (t, 2H, -CH2C=C), 2.576-2.610 (t, 2H, -CH2N)2.498-2.515 (m, 4H, five-membered ring-CH2N), 2.449 (s, 3H, pyrrole-CH3), 2.026-2.055 (m, 2H, semiline ring-CH2), 1.679 (m, 4H, five-membered ring-CH2).

Example 30

(Z)-N-{3-[3-Methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-ndimethylacetamide

Stage 1

5-Nitroindole-2-he

1,3-Dihydroindol-2-he 30A (20,0 g, 150 mmol) was dissolved in sulfuric acid (100 ml, 98%) in a bath of ice and water with stirring was added dropwise nitric acid (10 ml, 65%-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 starting compounds, R is the promo mixture was added ice and filtered after the melting of ice. The filter cake was washed with water (20 ml×3), and the resulting solid was recrystallize with getting the connection specified in the header, 5-nitroindole-2-it 30b (25,3 g, yield 92,4%) as an orange solid.

MC m/z (ESI): 177,3 [M-1]

Stage 2

5-Amino-1,3-dihydroindol-2-he

5-Nitro-1,3-dihydroindol-2-he 30b (of 3.56 g, 20 mmol) was dissolved in 200 ml of acetic acid under stirring, and added to a solution of palladium on activated carbon (1.0 g, 5%) at room temperature. The reaction mixture was stirred in hydrogen atmosphere. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was filtered and concentrated under reduced pressure to get the connection specified in the header, 5-amino-1,3-dihydroindol-2-she 30C (2,04 g, yield 68,9%) as a white solid.

MC m/z (ESI): 149,4 [M+1]

Stage 3

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

5-Amino-1,3-dihydroindol-2-he 30c (3.5 g, 23.6 mmol) was dissolved in 20 ml of tetrahydrofuran under stirring, and added to a solution of triethylamine (3.6 ml, 26 mmol) at room temperature. After complete addition, the mixture was cooled to -30°C in a bath of dry ice and acetone and slowly added acetylchloride (1.8 ml, of 24.8 mmol), keeping the temperature below -20°C. After complete addition, bath with dry ice and acetone was removed is, 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 compounds, the reaction mixture was added ethyl acetate (20 ml)was founded gray solids, and the mixture was filtered. The filter cake was washed with water (70 ml×3) to obtain 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 with getting the connection specified in the header, N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-ndimethylacetamide 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-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-ndimethylacetamide

The connection specified in the header received in the same conditions as described for stage 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 28c, obtained in stage 3 of Example 28, and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-ndimethylacetamide 30d as a source of substances with obtaining (Z)-N-{3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-ndimethylacetamide 30 (50 mg, yield 80%) as yellow is th solids.

MS m/z (ESI): 462,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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 semiline ring-external CH2), 3.303-3.330 (t, 2H, N semiline ring-CH2), 2.866-2.903 (t, 2H, -CH2C=C), 2.540-2.574 (t, 2H, -CH2N), 2.461-2.513 (m, 4H, five-membered ring-CH2N), 2.388 (s, 3H, pyrrole-CH3), 2.002-2.024 (m, 2H, semiline ring-CH2), 2.024 (s, 3H, -CH3), 1.648 (m, 4H, five-membered ring-CH2).

Example 31

(Z)-N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxyacetamido

The connection specified in the header received in the same conditions as described in stage 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 28C, obtained in stage 3 of Example 28, and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxyacetamido 27b, obtained in stage 2 of Example 27, as initial substances to obtain (Z)-N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxyacetamido 31 (50 mg, yield 76%) as a yellow solid.

MS m/2 (ESI): 496,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, -CH2O)3.536-3.570 (t, 2H, N semiline ring-CH2), 3.339 (t, 2H, amide N semiline ring-external CH2), 2.889-2.926 (t, 2H, -CH2C=C), 2.562-2.596 (t, 2H, -CH2N)2.483-2.513 (m, 4H, five-membered ring-CH2N), 2.427 (s, 3H, pyrrole-CH3), 2.034 (m, 2H, semiline ring-CH2), 1.673 (m, 4H, five-membered ring-CH2).

Example 32

(Z)-2-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

Stage 1

3-Methyl-5-[3-(2-piperidine-1-ylethylamine)-propyl]-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester

5-(3-Methanesulfonylaminoethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1g (at 10.64 g and 27.3 mmol) was dissolved in 2-piperidine-1-ylethylamine (7 ml, and 49.2 mmol), the reaction solution was stirred at room temperature overnight. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was added ethyl acetate (200 ml) and a small amount of methanol to obtain a clear solution. 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 column is cromatografia on silica gel to obtain compound, specified in the header, 3-methyl-5-[3-(2-piperidine-1-ylethylamine)-propyl]-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 32A (5.35 g, yield 46.5%) as a yellow oil.

MC m/z (ESI): 422,3 [M+1]

Stage 2

3-Methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carboxylic acid tert-butyl methyl ether

3-Methyl-5-[3-(2-piperidine-1-ylethylamine)-propyl]-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 32A (225 mg, 0,534 mmol) was dissolved in 5 ml dry toluene under stirring, the reaction system was cooled in a bath of ice and water was added a solution of trimethylaluminum in toluene (0,534 ml, 2 mol/l, 1.07 mmol) in argon atmosphere. After complete addition, the reaction system was stirred for 20 minutes at room temperature before until white smoke did not cease to stand out, and boiled under reflux for 3 hours in an oil bath. When thin layer chromatography showed the disappearance of starting substances, the oil bath was removed, the reaction mixture was added saturated brine (10 ml) and ethyl acetate (20 ml)was stirred for 15 minutes at room temperature and was 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 Russolo is (10 ml×2), was dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to get the connection specified in the header, 3-methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carboxylic acid tert-butyl ester 32b (105 mg) as a colourless oil, which was directly used in the next stage.

MC m/z (ESI): 376,2 [M+1]

Stage 3

3-Methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

3-Methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carboxylic acid tert-butyl ether 32b (953 mg, 2.54 mmol) was dissolved in 3 ml of ethanol under stirring, and added dropwise hydrochloric acid (3.2 ml, 12 mol/l) in the bath with ice and water in the atmosphere of argon. When you are finished adding bath with ice and water was removed, and the reaction mixture was stirred at 60°C in oil bath for 1 hour. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture is brought to about pH 7 with an aqueous solution of sodium hydroxide (10 mol/l) and concentrated under reduced pressure to evaporate the ethanol. The residue is brought to about pH 10 with an aqueous solution of sodium hydroxide (10 mol/l) and was extracted with dichloromethane (20 ml×3). The combined organic extracts were washed nassen the m brine (20 ml), was dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified column chromatography on silica gel with getting the connection specified in the header, 3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 32 (395 mg, yield 57%) as a white solid.

MS m/z (ESI): 276,1 [M+1]

Stage 4

3-Methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde

Dichloromethane (36 ml, 559 mmol) and N,N-dimethylformamide (1,637 ml of 20.9 mmol) was stirred for 5 minutes at -15°C in an ice salt bath in an argon atmosphere. To the solution was added dropwise phosphorus oxychloride (1.07 ml, 11.5 mmol) and was stirred for 15 minutes, maintaining the temperature at -10°C. 3-Methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-he 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 starting compounds, the reaction mixture was quickly cooled with ice water, brought to about pH 10 with sodium hydroxide solution (10 mol/l) and stirred is within 30 minutes was 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 the drying agent and concentrated under reduced pressure. The residue was purified column chromatography on silica gel with getting the connection specified in the header, 3-methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 32d (993 mg, 71.4%) 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-ylidenemethyl)-3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

3-Methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 32d (50 mg, 0,165 mmol) and 5-fluoro-1,3-dihydroindol-2-he (of 22.4 mg, 0.15 mmol) was dissolved in 0.3 ml of ethanol under stirring, and to the solution was added piperidine (0.05 ml, 0.5 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 starting compounds, the reaction mixture was filtered to obtain yellow solid. This solid substance was dissolved in ethanol (2 ml)was heated to education phlegmy for 30 minutes, cooled to room temperature and filter the Lee connection, specified in the header, (Z)-2-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 32 (38 g, yield 58%) as a yellow solid.

MS m/z (ESI): 437,1 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.326-3.354 (t, 2H, amide N semiline ring-external CH2), 2.922-2.958 (t, 2H, semiline ring-intra-CH2C=C), 2.452 (s, 3H, pyrrole-CH3), 2.386-2.431 (m, 6H, 3×-CH2N), 2.027-2.091 (t, 2H, semiline ring-intra-CH2), Including 1,474-1.499 (m, 4H, six-membered ring-2×-CH2), 1.379-1.391 (m, 2H, semiline ring-CH2).

Example 33

(Z)-2-[4-(2,3-Differenl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header received in the same conditions as described for stage 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 32d obtained in stage 4 of Example 32, and 4-(2,3-differenl)-1,3-dihydro-indol-2-one 6d, obtained in stage 3 of Example 6 as starting substances to obtain (Z)-2-[4-(2,3-differenl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-Pirro is about[3,2-C]azepin-4-it 33 (51 mg, the output of 80.9%) as a yellow solid.

MS m/z (ESI): 531,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.289-3.312 (t, 2H, amide N semiline ring-external CH2), 2.887-2.923 (t, 2H, semiline ring-intra-CH2C=C), 2.365-2.417 (m, 6H, 3×-CH2N), 2.009-2.038 (t, 2H, -CH2), 1.792 (s, 3H, pyrrole-CH3), 1.456-1.468 (m, 4H, semiline ring-2×-CH2), 1.368-1.377 (m, 2H, semiline ring-CH2).

Example 34

(Z)-2-[5-(4-Methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header received in the same conditions as described for stage 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 32d obtained in stage 4 of Example 32, and 5-(4-methoxyphenyl)-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-2-[5-(4-methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 34 (68 mg, 68.7%) as a yellow solid.

MS m/z (ESI): 525,2 [M+1]

1H NMR (400 MHz, DMSO-d6) δ 13.653 (s, 1H, pyrrole-NH), 11.003 (s, 1H, ind the l-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, -CH3O), 3.541-3.574 (t, 2H, semiline ring-intra-CH2N), 3.343 (t, 2H, amide N semiline ring-external CH2), 2.926-2.962 (t, 2H, semiline ring-intra-CH2C=C), 2.386-2.449 (m, 9H, pyrrole-CH3, 3×-CH2N), 2.062 (m, 2H, semiline ring-intra-CH2), 1.475-1.487 (m, 4H, six-membered ring-2×-CH2), 1.379-1.391 (m, 2H, six-membered ring-CH2).

Example 35

(Z)-2-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header, was obtained in the same conditions as described for stage 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 32d obtained in stage 4 of Example 32, and 5-chloro-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-2-(5-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 35 (44 mg, yield 64,8%) as a yellow solid.

MC m/z (ESI): 453,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.313-3.342 (t, 2H, amide N semiline ring-external CH2), 2.925-2.962(t, 2H, semiline ring-intra-CH2C=C), 2.399-2.459 (m, 9H, pyrrole-CH3, 3×-CH2N), 2.047-2.074 (t, 2H, semiline ring-intra-CH2), 1.490(m, 4H, six-membered ring-2×-CH2), 1.385(m, 2H, six-membered ring-CH2).

Example 36

(Z)-2-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header received in the same conditions as described for stage 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 32d obtained in stage 4 of Example 32, and 5-bromo-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 36 (43 mg, yield of 57.6%) as a yellow solid.

MS m/z (ESI): 497,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.315-3.339 (t, 2H, amide N semiline ring-external CH2), 2.924-2.960 (t, 2H, semiline ring-intra-CH2C=C), 2.389-2.460 (m, 9H, pyrrole-CH3, 3×-CH2N), 2.045-2.074 (t, 2H, semiline ring-intra-CH2), 1.476-1.489 (m, 4H, six-membered ring-2×-CH2), 1.381 (m, 2H, six-membered ring is H 2).

Example 37

(Z)-N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxyacetate

The connection specified in the header received in the same conditions as described for stage 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 32d obtained in stage 4 of Example 32, and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxyacetate 7a, obtained in stage 1 of Example 7, in as initial substances to obtain (Z)-N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxyacetate 37 (59 mg, 75%yield) as a yellow solid.

MC m/z (ESI): 524,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, -CH2O), 3.540-3.572 (t, 2H, semiline ring-intra-CH2N)3.406 (s, 3H, CH3O), 3.315-3.340 (t, 2H, amide N semiline ring-external CH2), 2.918-2.954 (t, 2H, semiline ring-intra-CH2C=C), 2.390-2.467 (m, 9H, pyrrole-CH3, 3×-CH2N), 2.043-2.072 (t, 2H, semiline ring-intra-CH2), 1.478-1.490 (m, 4H, six-membered ring-2×-CH2), 1.382-1.393 (m, 2H, six-membered ring-CH2).

Example 38

(S,Z)-N-{5-fluoro-3-[3-methyl--oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxypropionic

The connection specified in the header received in the same conditions as described for stage 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 32d obtained in stage 4 of Example 32, and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxypropylamino 8b, obtained in stage 2 of Example 8, as a source of substances with receipt (S,Z)-N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxypropionic 38 (49 mg, yield 62.5%) as a yellow solid.

MC m/z (ESI): 524,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.326-3.354 (t, 2H, amide N semiline ring-external CH2), 2.917-2.954 (t, 2H, semiline ring-intra-CH2C=C), 2.392-2.440 (m, 9H, pyrrole-CH3, 3×-CH2N), 2.025-2.089 (t, 2H, semiline ring-intra-CH2), 1.478-1.490 (m, 4H, six-membered ring-2×-CH2), 1.383 (m, 2H, six-membered ring-CH2), 1.330-1.347(d, 3H, CH3O).

Example 39

(Z)-N-{3-[5-(2-Dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxyacetate

The connection specified in the header received in the same conditions as described in stage 4 of Example 23 5-(2-dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 23C, obtained in stage 3 of Example 23 and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxyacetate 7a, obtained in stage 1 of Example 7 as starting substances to obtain (Z)-N-{3-[5-(2-dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1 H-indol-6-yl}-2-methoxyacetate 39 (75 mg, yield of 76.5%) as a brown solid.

MC m/z (ESI): Ozenmunaygas given KZT 484.1 ecological [M+1]

1H NMR (400 MHz, DMSO-d6) 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, -CH2O)3.531-3.564 (t, 2H, N semiline ring-CH2), 3.406 (s, 3H, -CH3O), 3.333-3.359 (t, 2H, amide N semiline ring-external CH2), 2.904-2.941 (t, 2H, -CH2C=C), 2.445 (s, 3H, pyrrole-CH3), 2.404-2.420 (t, 2H, -CH2N), 2.206 (s, 6H, 2×-CH3N), 2.029-2.057 (m, 2H, semiline ring-intra-CH2).

Example 40

(Z)-2-[4-(2,6-Differenl)-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 connection specified in the header received in the same conditions as described for stage 4 of Example 23 5-(2-dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexage romeralo[3,2-C]azepin-2-carbaldehyde 23C, obtained in stage 3 of Example 23, and 4-(2,6-differenl)-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-2-[4-(2,6-differenl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-5-(2-dimethylaminoethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 40 (36 mg, yield of 36.4%) as an orange solid.

MC m/z (ESI): 491,1 [M+1]

1H NMR (400 MHz, DMSO-d6) 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 semiline ring-CH2), 3.280-3.316 (t, 2H, amide N semiline ring-external CH2), 2.868-2.904 (t, 2H, -CH2C=C), 2.355-2.388 (t, 2H, -CH2N), 2.171 (s, 6H, 2×-CH3N), 1.992-2.021 (m, 2H, semiline ring-intra-CH2), 1.764 (s, 3H, pyrrole-CH3).

Example 41

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

The connection specified in the header received in the same conditions as described for stage 4 of Example 23 5-(2-dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 23C, obtained in stage 3 of Example 23, and 4-(3-forfinal)-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-5-(2-dimethylaminoethyl)-2-[4-(3-forfinal)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]asapi the-4-it 41 (37 mg, output 38,9%) as a yellow solid.

MC m/z (ESI): 473,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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 semiline ring-CH2), 3.277-3.315 (t, 2H, amide N semiline ring-external CH2), 2.859-2.896 (t, 2H, -CH2C=C), 2.361-2.394 (t, 2H, -CH2N), 2.176 (s, 6H, 2×-CH3N), 1.989-2.018 (m, 2H, semiline ring-intra-CH2), 1.774 (s, 3H, pyrrole-CH3).

Example 42

(Z)-2-[4-(2,3-Differenl)-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 connection specified in the header received in the same conditions as described for stage 4 of Example 23 5-(2-dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 23C, obtained in stage 3 of Example 23, 4-(2,3-differenl)-1,3-dihydroindol-2-6d he obtained in stage 3 of Example 6, was used as starting substances, to obtain (Z)-2-[4-(2,3-differenl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-5-(2-dimethylaminoethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 42 (25 mg, yield of 25.2%) as a yellow solid.

MC m/z (ESI): 491,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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 semiline ring-CH2), 3.292-3.315 (t, 2H, amide N semiline ring-external CH2), 2.869-2.905 (t, 2H, -CH2C=C), 2.362-2.395 (t, 2H, -CH2N), 2.176 (s, 6H, 2×-CH3N), 1.993-2.018 (m, 2H, semiline ring-intra-CH2), 1.795 (s, 3H, pyrrole-CH3).

Example 43

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

The connection specified in the header received in the same conditions as described for stage 4 of Example 23 5-(2-dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 23C, obtained in stage 3 of Example 23, and 5-fluoro-6-(4-forbindelsen)-1,3-dihydroindol-2-3e he obtained in stage 4 of Example 3, was used as starting substances, to obtain (Z)-5-(2-dimethylaminoethyl)-2-[5-fluoro-6-(4-forbindelsen)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 43 (50 mg, yield 43,7%) as a red solid.

MS m/z (ESI): 520,1 [M+1]

1H NMR (400 MHz, DMSO-d6) 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-CH2), 3.982-3.996 (d, 2H, -CH2O)3.531-3.564 (t, 2H, N semiline ring-CH2, 3.316-3.344 (t, 2H, amide N semiline ring-external CH2), 2.856-2.893 (t, 2H, -CH2C=C), 2.398-2.415 (t, 2H, -CH2N), 2.390 (s, 3H, pyrrole-CH3), 2.192 (s, 6H, 2×-CH3N), 2.002-2.030 (m, 2H, semiline ring-intra-CH2).

Example 44

(Z)-N-{3-[5-(2-Dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-2-hydroxyacetamido

Stage 1

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

5-Amino-1,3-dihydroindol-2-he 30C (500 mg, to 3.38 mmol) was dissolved in 10 ml of dichloromethane under stirring at room temperature, and to the solution was added pyridine (470 μl, 5 mmol) at -40°C in a bath of dry ice and acetone. Acetic acid chlorocarbonylsulfenyl ether (473 mg, of 3.48 mmol) was dissolved in 10 ml of dichloromethane, the resulting solution was added dropwise to the above solution. When you are finished adding 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 starting compounds, the reaction mixture was filtered. The filter cake was washed with water (10 ml×3) and recrystallize with getting the connection specified in the header, acetic acid (2-oxo-2,3-dihydro-1H-indol-5-carbamoyl)-methyl ester 44a (510 mg, the output of 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)-ndimethylacetamide

Acetic acid (2-oxo-2,3-dihydro-1H-indol-5-ylcarbonyl)methyl ether 44a (2,43 g, 10 mmol) was dissolved in 60 ml of methanol under stirring, and to the solution was added a solution of sodium hydroxide (20 ml, 2 mol/l) and stirred at room temperature overnight. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was neutralized with hydrochloric acid (6 mol/l) in a bath of ice and water and then concentrated under reduced pressure. The resulting solid was purified column chromatography on silica gel with getting the connection specified in the header, 2-hydroxy-N-(2-oxo-2,3-dihydro-1 H-indol-5-yl)-ndimethylacetamide 44b (402 mg, yield of 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-methylaminomethyl)-4-oxo-1,4,5,6,7,8-hexahydropyrazino,2]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-ndimethylacetamide

The connection specified in the header received in the same conditions as described for stage 4 of Example 23 5-(2-dimethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepine-2-carbaldehyde 23C obtained from stage 3 of Example 23, and 2-hydroxy-N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-ndimethylacetamide 44b in to the important source of substances with obtaining (Z)-2-hydroxy-N-{3-[3-methyl-5-(2-methylaminomethyl)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-ndimethylacetamide 44 (52 mg, the output of 50.5%) as an orange solid.

MS m/z (ESI): 452,1 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, -CH2O)3.531-3.564 (t, 2H, N semiline ring-CH2), 3.337-3.365 (t, 2H, amide N semiline ring-external CH2), 2.908-2.944 (t, 2H, -CH2C=C), 2.433 (s, 3H, pyrrole-CH3), 2.394-2.411 (t, 2H, -CH2N), 2.199 (s, 6H, 2×-CH3N), 2.031-2.059 (m, 2H, semiline ring-intra-CH2).

Example 45

(Z)-2-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header, was obtained in the same conditions as described for stage 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 28C, obtained in stage 3 of Example 28, and 5-fluoro-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-2-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 45 (61 mg, yield 80,8%) as an orange solid.

MS m/z (ESI): 423,1 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring and the tra-CH 2N), 3.337-3.365 (t, 2H, amide N semiline ring-external CH2), 3.314 (m, 4H, five-membered ring-2×-CH2N), 2.990-3.027 (t, 2H, semiline ring-intra-CH2C=C), 2.573-2.607 (t, 2H, -CH2N), 2.473 (s, 3H, pyrrole-CH3), 2.101-2.129 (m, 2H, semiline ring-intra-CH2), 1.751 (m, 4H, five-membered ring-CH2).

Example 46

(Z)-2-(5-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header received in the same conditions as described for stage 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 28C, obtained in stage 3 of Example 28, and 5-bromo-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-2-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 46 (61 mg, yield of 70.4%) as a yellow solid.

MS m/z (ESI): 485,1 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.337-3.364 (t, 2H, amide N semiline ring-external CH2), 3.312 (m, 4H, five-membered ring-2×-CH2N), 2.905-2.942 (t, 2H, semiline ring-intra-CH2C=C), 2.573-2.606 (t, 2H,

-CH2N), 2.462 (s, 3H, Pyrrhus the l-CH 3), 2.028-2.057 (m, 2H, semiline ring-intra-CH2), 1.751 (m, 4H, five-membered ring-CH2).

Example 47

(Z)-2-(5-Chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header received in the same conditions as described for stage 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 28C, obtained in stage 3 of Example 28, and 5-chloro-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-2-(5-chloro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 47 (61 MS, the output 77,7%) as a yellow solid.

MS m/z (ESI): 439,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.384-3.412 (t, 2H, amide N semiline ring-external CH2), 3.337-3.384 (m, 4H, five-membered ring-2×-CH2N), 2.990-3.027 (t, 2H, semiline ring-intra-CH2C=C), 2.650-2.684 (t, 2H,

-CH2N), 2.473 (s, 3H, pyrrole-CH3), 2.101-2.129 (m, 2H, semiline ring-intra-CH2), 1.751 (m, 4H, five-membered ring-CH2).

Example 48

(Z)-3-Methyl-2-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-5-(2-pyrrolidin-1 ileti is)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header received in the same conditions as described for stage 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 28C, obtained in stage 3 of Example 28, and 5-phenyl-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-3-methyl-2-(2-oxo-5-phenyl-1,2-dihydroindol-3-ylidenemethyl)-5-(2-pyrrolidin-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 48 (41 mg, yield of 62.3%) as a yellow solid.

MC m/z (ESI): 481,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.362-3.376 (t, 2H, amide N semiline ring-external CH2), 3.289-3.347 (m, 4H, five-membered ring-2×-CH2N), 2.990-3.027 (t, 2H, semiline ring-intra-CH2C=C), 2.650-2.684 (t, 2H, -CH2N), 2.473 (s, 3H, pyrrole-CH3), 2.101-2.129 (m, 2H, semiline ring-intra-CH2), 1.751 (m, 4H, five-membered ring-2×-CH2).

Example 49

(Z)-2-(4-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header received in the same conditions as described for stage 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrole the Jn-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 28C, obtained in stage 3 of Example 28, and 4-bromo-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-2-(4-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 49 (40 mg, yield of 60.5%) as a yellow solid.

MS m/z (ESI): 483,2 [M-1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.410-3.438 (t, 2H, amide N semiline ring-external CH2), 3.356-3.378 (m, 4H, five-membered ring-2×-CH2N), 2.990-3.027 (t, 2H, semiline ring-intra-CH2C=C), 2.650-2.684 (t, 2H,

-CH2N), 2.473 (s, 3H, pyrrole-CH3), 2.101-2.129 (m, 2H, semiline ring-intra-CH2), 1.751 (m, 4H, five-membered ring-CH2).

Example 50

(Z)-2-(7-Bromo-5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header received in the same conditions as described for stage 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[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 substances to obtain (Z)-2-(7-bromo-5-fluoro-2-oxo-1,2-digitron the ol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-she's 50 (51 mg, output 73,2%) as an orange solid.

MC m/z (ESI): 501,1 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.317-3.359 (t, 2H, amide N semiline ring-external CH2), 3.294-3.359 (m, 4H, five-membered ring-2×-CH2N), 2.935-2.971 (t, 2H, semiline ring-intra-CH2C=C), 2.587-2.620 (t, 2H, -CH2N), 2.473 (s, 3H, pyrrole-CH3), 2.059 (m, 2H, semiline ring-intra-CH2), 1.751 (m, 4H, five-membered ring-CH2).

Example 51

(Z)-N-{3-[5-(2-Diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-ndimethylacetamide

The connection specified in the header received in the same conditions as described for stage 10 of Example 1 from 5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j obtained at stage 9 of Example 1 and N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-ndimethylacetamide 30d, obtained in stage 3 of Example 30 as a source of substances with obtaining (Z)-N-{3-[5-(2-diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-5-yl}-ndimethylacetamide 51 (12 mg, yield of 18.9%) as an orange solid.

MC m/z (ESI): 464,2 [M+1]

1H NMR (400 MHz, HMCO-d6) 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, semiline ring-intra-CH2N), 3.322-3.347 (t, 2H, amide N semiline ring-external CH2), 2.902-2.939 (t, 2H, semiline ring-intra-CH2C=C), 2.530-2.562 (m, 6N, 3×-CH2N)2.423 (s, 3H, pyrrole-CH3), 2.029-2.051 (m, 2H, semiline ring-intra-CH2), 2.029 (s, 3H, -CH3WITH), 0.958-0.993 (t, 6N, 2×-CH3).

Example 52

(Z)-N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxyacetate

The connection specified in the header received in the same conditions as described for stage 4 of Example 28 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 28C, obtained in stage 3 of Example 28, and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxyacetate 7a, obtained in stage 1 of Example 7, in as initial substances to obtain (Z)-N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-methoxyacetate 52 (45 mg, yield of 63.7%) as a yellow solid.

MC m/z (ESI): 510,1 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, -CH2O)3.597-3.631 (t, 2H, semiline ring-II andstc is-CH 2N)3.447 (s, 3H, -CH3O), 3.381-3.408 (t, 2H, amide N semiline ring-external CH2), 3.331-3.355 (m, 4H, five-membered ring-2×-CH2N), 2.945-2.981 (t, 2H, semiline ring-intra-CH2C=C), 2.660 (m, 2H, -CH2N), 2.489 (s, 3H, pyrrole-CH3), 2.069-2.099 (m, 2H, semiline ring-intra-CH2), 1.731 (m, 4H, five-membered ring-CH2).

Example 53

(R,Z)-2-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholine-4-yl-propyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

Stage 1

4-Oxiranylmethyl

Morpholine 53A (8,712 ml, 0.1 mol) was dissolved in tert-butanol (4.5 ml) under stirring at room temperature, and the solution was slowly added (R)-(-)-1-chloro-2,3-epoxypropane (8,05 ml, 0.1 mol) at 0°C in a bath of ice and water. When you are finished adding bath with ice and water 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 starting compounds, the reaction mixture was added dropwise a solution of tert-butoxide potassium in tetrahydrofuran (60 ml, 1,67 mol/l, 100 mmol), keeping the temperature below 10°C in a bath of ice and water, the solution gradually turned from light yellow white turbid, and it was stirred for 30 minutes. When thin-layer chromatogr the FFL showed disappearance of the starting compounds, the reaction mixture was concentrated under reduced pressure, was added water (50 ml), was 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 the drying agent and concentrated under reduced pressure to get the connection specified in the header, 4-oxiranylmethyl 53b (12.7 g, yield and 88.8%) as a yellow oil.

MC m/z (ESI): 144,4 [M+1]

Stage 2

1-Amino-3-morpholine-4-improper-2-ol

To 4-oxiranylmethyl 53b (6.3 g, 44 mmol) was slowly added ammonia (450 ml, 25%, 6.6 mol), keeping the temperature below 0°C in a bath of ice-water. 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 starting compounds, the reaction mixture was concentrated under reduced pressure to get the connection specified in the header, 1-amino-3-morpholine-4-improper-2-ol s (7 g, yield 99%) as a white solid.

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

Stage 3

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

5-(3-Methanesulfonylaminoethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-these are the new ether 1g (1.13 g, 2.9 mmol) was dissolved in 5.6 ml of dichloromethane under stirring, and to the solution was added 1-amino-3-morpholine-4-improper-2-ol s (0,93 g, 5.8 mmol) 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 compounds, the reaction mixture was added saturated brine (15 ml) and was extracted with dichloromethane (20 ml×3). The combined organic extracts were concentrated under reduced pressure, was purified column chromatographia on silica gel with getting the connection specified in the header, 5-[3-(2-hydroxy-3-morpholine-4-ylpropionic)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 53d (600 mg, yield of 72.5%) as a colourless oil.

MS m/z (ESI): 454,2 [M+1]

Stage 4

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

5-[3-(2-Hydroxy-3-morpholine-4-ylpropionic)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 53d (580 mg, 1.28 mmol) was dissolved in 6 ml of toluene under stirring, and added dropwise trimethylaluminum in toluene (1.9 ml, 2 mol/l of 3.84 mmol) in a bath of ice-water in the atmosphere of argon. When you are finished adding bath with ice and water to remove the, and the reaction mixture was heated up to the formation of phlegmy within 24 hours. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was concentrated under reduced pressure, the solution was added hydrochloric acid (20 ml, 6 mol/l) and was stirred for 20 minutes at room temperature. The mixture is brought to about pH 12 aqueous sodium hydroxide solution (12 mol/l) in a bath of ice and water and was extracted with dichloromethane (50 ml×2). The combined organic extracts were concentrated under reduced pressure, was purified column chromatography on silica gel with getting the connection specified in the header, 5-(2-hydroxy-3-morpholine-4-ylpropyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it e (300 mg, yield of 57.6%) as a white solid.

MS m/z (ESI): 308,2 [M+1]

Stage 5

5-(2-Hydroxy-3-morpholine-4-ylpropyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde

(Chlormethine)dimethylammonio chloride (130 mg, 0,977 mmol) was dissolved in 3 ml of dichloromethane under stirring, the resulting solution was cooled to 0°C in a bath of ice and water in the atmosphere of argon. 5-(2-Hydroxy-3-morpholine-4-ylpropyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one e (300 mg, 0,977 mmol) was dissolved in 2 ml of dichloromethane, the resulting solution was added dropwise to the above reaction the th system, maintaining the temperature below 0°C, and was stirred for 20 minutes. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture is quickly cooled aqueous sodium hydroxide solution (12 mol/l)was added saturated brine (10 ml) and was extracted with a mixture of solvents (about:about=10:1, 100 ml×3) dichloromethane and methanol. The combined organic extracts were washed with saturated brine (100 ml), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified column chromatography on silica gel with getting the connection specified in the header, 5-(2-hydroxy-3-morpholine-4-ylpropyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 53f (200 mg, yield 61%) 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-ylidenemethyl)-5-(2-hydroxy-3-morpholine-4-ylpropyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

5-(2-Hydroxy-3-morpholine-4-ylpropyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 53f (50 mg, 0,149 mmol) was dissolved in 261 μl of ethanol under stirring, and to the solution was added 5-fluoro-1,3-dihydroindol-2-he (to 20.28 mg, 0,134 mmol) and piperidine (7,3 μl, 0,074 mmol) at room temperature. After complete addition, the reaction mixture is PE is amasyali for 2 hours in the dark at 80°C in oil bath. When thin layer chromatography showed the disappearance of starting substances, the oil bath was removed and the reaction mixture was naturally cooled to room temperature, filtered and dried to obtain the connection specified in the header, (R,Z)-2-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholine-4-ylpropyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 53 (40 g, yield 57%) as a yellow solid.

MS m/z (ESI): 469,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, HE), 3.897 (m, 1H, -CHO), 3.749-3.792 (dd, 1H, amide N semiline ring-external CH2), 3.570-3.592 (t, 4H, morpholine-2×-CH2O), 3.384-3.351 (t, 2H, N semiline ring-CH2), 3.138-3.191 (dd, 1H, amide N semiline ring-external CH2), 2.917-2.953 (t, 2H, -CH2C=C), 2.457 (s, 3H, pyrrole-CH3), 2.418-2.507 (m, 4H, -CH2N, morpholine-CH2N), 2.289-2.313 (t, 2H, morpholine-CH2M), 2.076 (m, 2H, semiline ring-CH2).

Example 54

(Z)-3-Methyl-2-(2-oxo-4-pyridin-4-yl-1,2-dihydroindol-3-ylidenemethyl)-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header received in the same conditions as described for stage 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-a]AZE is in-2-carbaldehyde 32d, obtained in stage 4 of Example 32, and 4-pyridine-4-yl-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-3-methyl-2-(2-oxo-4-pyridin-4-yl-1,2-dihydroindol-3-ylidenemethyl)-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 54 (40 mg, yield 54%) as yellow solid.

MS m/z (ESI): 496,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.270-3.298 (t, 2H, amide N semiline ring-external CH2), 2.879-2.916 (t, 2H, semiline ring-intra-CH2C=C), 2.361-2.413 (m, 6H, 3×-CH2N), 2.055-2.084 (t, 2H, semiline ring-intra-CH2), 1.732 (s, 3H, pyrrole-CH3), 1.453-1.478 (m, 4H, six-membered ring-2×-CH2), 1.365-1.377 (m, 2H, six-membered ring-CH2).

Example 55

(Z)-2-[5-fluoro-6-(4-forbindelsen)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header received in the same conditions as described for stage 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 32d obtained in stage 4 of Example 32, and 5-fluoro-6-(4-forbindelsen)-1,3-dihydroindol-2-one 3e, obtained in stage 4 of Example 3, in which the quality of the original substances to obtain (Z)-2-[5-fluoro-6-(4-forbindelsen)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 55 (77 mg, output 90,8%) as a yellow solid.

MS m/z (ESI): 560,1 [M+1]

1H NMR (400 MHz, DMSO-d6) 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-CH2), 3.524-3.557 (t, 2H, semiline ring-intra-CH2N), 3.314-3.337 (t, 2H, amide N semiline ring-external CH2), 2.869-2.906 (t, 2H, semiline ring-intra-CH2C=C), 2.390-2.467 (m, 9H, pyrrole-CH3, 3×-CH2N), 1.999-2.063 (t, 2H, semiline ring-intra-CH2), 1.476-1.489 (m, 4H, six-membered ring-2×-CH2), 1.383-1.393 (m, 2H, six-membered ring-CH2).

Example 56

(Z)-2-(7-Bromo-5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header received in the same conditions as described for stage 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 32d obtained in stage 4 of Example 32, 7-bromo-5-fluoro-1,3-dihydroindol-2-one 4b, obtained in stage 1 of Example 4 as starting substances to obtain (Z)-2-(7-bromo-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 56 (63 mg, yield 76,44%) as a yellow solid.

MC m/z (ESI): 515,1 [M+1]

1H NMR (400 MHz, DM what About the-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 semiline ring-intra-CH2), 3.331-3.358 (t, 2H, amide N semiline ring-external CH2), 2.950-2.986 (t, 2H, semiline ring-intra-CH2C=C), 2.390-2.467 (m, 9H, pyrrole-CH3, 3×-CH2N), 2.055-2.084 (t, 2H, semiline ring-intra-CH2), 1.476-1.489 (m, 4H, six-membered ring-2×-CH2), 1.383-1.393 (m, 2H, six-membered ring-CH2).

Example 57

(Z)-2-(4-Bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header received in the same conditions as described for stage 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 32d obtained from stage 4 of Example 32, and 4-bromo-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-2-(4-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 57 (68 mg, yield and 91.2%) as a yellow solid.

MS m/z (ESI): 499,1 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N)3.402 (t, 2H, amide N semiline ring-external CH2), 2.9913.028 (t, 2H, semiline ring-intra-CH2C=C), 2.454-2.556 (m, 9H, pyrrole-CH3, 3×-CH2N), 2.102-2.131 (t, 2H, semiline ring-intra-CH2), Of 1.523-1.550 (m, 4H, six-membered ring-2×-CH2), 1.429-1.441 (m, 2H, six-membered ring-CH2).

Example 58

(Z)-3-Methyl-2-(4-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

The connection specified in the header received in the same conditions as described in stage 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 32d obtained from stage 4 of Example 32, and 4-methyl-1,3-dihydroindol-2-one as starting compounds to obtain (Z)-3-methyl-2-(4-methyl-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-5-(2-piperidine-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one 58 (46 mg, yield to 70.9%) as a yellow solid.

MS m/z (ESI): 433,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.331-3.359 (t, 2H, amide N semiline ring-external CH2), 2.926-2.962 (t, 2H, semiline ring-intra-CH2C=C), 2.591 (s, 3H, benzene-CH3), 2.383-2.437 (m, 9H, -CH3, pyrrol-3×-CH2N), 2.030-2.092 (t, 2H, semiline ring-intra-CH2), 1.479-1.491 (m, 4H, six-membered ring-2×-CH2), 1.383-1.394 (m, 2H, sixth is ichinoe ring-CH 2).

Example 59

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

The connection specified in the header received in the same conditions as described for stage 6 of Example 53 5-(2-hydroxy-3-morpholine-4-ylpropyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 53f, obtained in stage 5 of Example 53, and 5-bromo-1,3-dihydroindol-2-one as starting compounds to obtain (R,Z)-2-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholine-4-ylpropyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 59 (30 mg, yield 63%) as a yellow solid.

MS m/z (ESI): 529,1 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, HE), 3.897 (m, 1H, -CHO), 3.748-3.758 (dd, 1H, amide N semiline ring-external CH2), 3.570-3.593 (t, 4H, morpholine-2×-CH2O)3.433 (t, 2H, N semiline ring-CH2), 3.159 (dd, 1H, amide N semiline ring-external CH2), 2.917-2.954 (t, 2H, -CH2C=C), 2.465 (s, 3H, pyrrole-CH3), 2.418-2.465 (m, 4H, -CH2N, morpholine-CH2N), 2.290-2.314 (t, 2H, morpholine-CH2N), 2.061-2.092 (m, 2H, semiline ring-CH2).

Example 60

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

Stage 1

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

Cyclopropylamine 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 ester 4-ethyl ester 1b (1.26 g, 4.5 mmol) was dissolved in 10 ml of tetrahydrofuran under stirring, the resulting 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 starting compounds, the reaction mixture was rapidly cooled with water, was added a solution of sulfuric acid (20 ml, 10%), was 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 the drying agent and concentrated under reduced pressure. The residue was purified column chromatography on silica gel with getting the connection specified in the header, 5-(cyclopropylmethoxy)-3-methyl-1H-pyrrole-2,4-dicarbon the second acid 2-tert-butyl ester 4-ethyl ester 60A (576 mg, output 39,6%) as a white solid.

MS m/z (ESI): 322,2 [M-1]

Stage 2

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

5-(Cyclopropylmethoxy)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 60A (323 mg, 1 mmol) was dissolved in 4 ml of ethanol under stirring, and to the solution was added Hydrobromic acid (2.8 ml, 40%) and was stirred for 30 minutes at room temperature. When thin layer chromatography showed the disappearance of starting compounds, 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 the drying agent and concentrated under reduced pressure. The residue was purified column chromatography on silica gel with getting the connection specified in the header, 5-(4-brombach-1-enyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 60b (345 mg, yield to 89.5%) 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 ester 4-ethyl ester

5-(4-Brombach-1-enyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 60b (30 mg, 0.08 to IMO is b) was dissolved in 3 ml of ethanol under stirring, to the solution was added palladium on activated carbon (6 mg, 5%) at room temperature. The reaction mixture was stirred for 45 minutes in a hydrogen atmosphere. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was filtered and concentrated under reduced pressure to get the connection specified in the header, 5-(4-bromobutyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 60C (21 mg, yield 70%) as a colourless oil.

MS m/z (ESI): 388,0 [M+1]

Stage 4

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

5-(4-Bromobutyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 60C (220 mg, or 0.57 mmol) was dissolved in 5 ml of dichloromethane under stirring, and to the solution was added N,N-diethylethylenediamine (164 μl, 1.13 mmol) and boiled under reflux for 30 minutes in an oil bath. The reaction mixture was concentrated to evaporate the solvent and boiled under reflux for one hour. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was concentrated under reduced pressure, was purified column chromatography on silica gel with getting the connection specified in the header, 5-(4-dieti aminobutyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 60d (187 mg, yield 78%) 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-diazacyclooctadecane-2-carbaldehyde

Trimethylaluminum (489 μl, 2 mol/l) was dissolved in 3 ml of toluene under stirring, to the above solution was added a solution of 5-(4-diethylaminomethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 60d (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, was heated to education phlegmy for 2 hours in an oil bath, was added an additional amount of trimethylaluminum (900 ml, 2 mol/l) and boiled under reflux for 7 hours. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was rapidly cooled with water, the solution was added hydrochloric acid (1 ml, 2 mol/l) and was stirred for 30 minutes at room temperature. The mixture is brought to about 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 the drying agent and concentrated under reduced pressure the AI. The residue was purified column chromatography on silica gel with getting the connection specified in the header, 5-(2-diethylaminoethyl)-3-methyl-4-oxo-4,5,6,7,8,9-hexahydro-1H-1,5-diazacyclooctadecane-2-carbaldehyde 60s (60 mg, yield 26,7%) 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-ylidenemethyl)-3-methyl-6,7,8,9-tetrahydro-1H,5H-1,5-diazacyclooctadecane-4-one

5-(2-Diethylaminoethyl)-3-methyl-4-oxo-4,5,6,7,8,9-hexahydro-1H-1,5-diazacyclooctadecane-2-carbaldehyde 60s (20 mg, of 0.066 mmol) was dissolved in 1 ml of ethanol under stirring, and to the solution was added 5-fluoro-1,3-dihydroindol-2-he (9,9 mg, of 0.066 mmol) at room temperature. The reaction mixture was stirred in the dark before the dissolution, was added 0.1 ml of piperidine and heated to form phlegmy within 2 hours. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was naturally cooled to room temperature and filtered to obtain the connection specified in the header, (Z)-5-(2-diethylaminoethyl)-2-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-6,7,8,9-tetrahydro-1H,5H-1,5-diazacyclooctadecane-4-one 60 (14 mg, output 48.8%) as a yellow solid.

MS m/z (ESI): 439,2 [M+1]

1H NMR (400 MHz, DMSO-d6) δ 13.462 (s, 1H, pyrrole-NH), 10.874 (s, 1H, indole-NH), 7.739-7.78 (d, 1H, -ArH), 7.715 (s, 1H, -CH=C), 6.832-6.933 (m, 2H, -ArH), 3.406 (m, 4H, 2×-CH2NCO), 2.874 (t, 2H, -CH2C=C), 2.597-2.630 (t, 2H, -CH2N)2.486-2.538 (q, 4H, ethyl 2×-CH2N), 2.322 (s, 3H, pyrrole-CH3), 1.733 (m, 4H, eight-membered ring intra-2×-CH2), 0.963-0.968 (t, 6H, 2×-CH3).

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-diazacyclooctadecane-4-one

The connection specified in the header received in the same conditions as described for stage 6 of Example 60 5-(2-diethylaminoethyl)-3-methyl-4-oxo-4,5,6,7,8,9-hexahydro-1H-1,5-diazacyclooctadecane-2-carbaldehyde 60s, obtained in stage 5 of Example 60, and 5-bromo-1,3-dihydroindol-2-one as starting compounds to obtain (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-diazocyclopentadiene-4-it 61 (16 mg, yield 68%) as a yellow solid.

MS m/z (ESI): 499,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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×-CH2NCO), 2.874 (t, 2H, -CH2C=C), 2.597-2.630 (t, 2H, -CH2N)2.486-2.538 (q, 4H, ethyl 2×-CH2N), 2.322 (s, 3H, pyrrole-CH3), 1.733 (m, 4H, eight-membered ring intra-2×-CH2), 0.963-0.968 (t, 6H, 2×-CH3).

Example 62

(Z)-5-(2-Ethylaminomethyl)-2-(5-fluoro-2-oxo-1,2-dihydroindol-3-and identity)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

Stage 1

5-[2-(2-Acetylaminophenol)-ethyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butovogo ester 4-ethyl ester

5-(2-Carboxyethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1E (9,85 g, 30.3 mmol), obtained from stage 4 of Example 1, was dissolved in acetonitrile (50 ml) under stirring, and added to a solution of 1-hydroxy-1H-benzotriazole (8,2 g, to 60.6 mmol) and N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide (11.6 g, to 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 starting compounds, the reaction mixture was concentrated under reduced pressure, was added water (200 ml) and was 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 the drying agent and concentrated under reduced pressure. The residue was purified column chromatography on silica gel with getting the connection specified in the header, 5-[2-(2-acetylaminophenol)-ethyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester a (8 g, yield 65%) as white is on solid.

MC m/z (ESI): 410,1 [M+1]

Stage 2

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

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

MC m/z (ESI): 310,1 [M+1]

Stage 3

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

2-[2-(2-Acetylaminophenol)-ethyl]-4-methyl-1H-pyrrol-3-carbon is Oh acid ethyl ester 62b (600 mg, 1.94 mmol) was dissolved in 4 ml of tetrahydrofuran under stirring, and added to a solution of solution of borane in tetrahydrofuran (7,79 ml, 1 mol/l, 7,79 mmol) in a bath of ice-water in the atmosphere of argon. After complete addition, the reaction mixture was heated up to the formation of phlegmy within 2 hours. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture is quickly cooled hydrochloric acid, stirred for 30 minutes at room temperature, brought about pH 12 with an aqueous solution of sodium hydroxide (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 the drying agent and concentrated under reduced pressure. The residue was purified column chromatography on silica gel with getting the connection specified in the header, 2-[3-(2-ethylenediamino)-propyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester s (170 mg, yield 31%) as a white solid.

MS m/z (ESI): 282,2 [M+1]

Stage 4

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

2-[3-(2-Ethylenediamino)-propyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester s (350 mg, 1,245 mmol) and trimethylaluminum (1.25 ml, 2.49 mmol) was dissolved in 75 ml of toluene at paramasivan the and and the resulting mixture was heated to education phlegmy at 140°C in an oil bath for 24 hours. When thin-layer chromatographia showed disappearance of the starting compounds, the reaction mixture was concentrated under reduced pressure, brought to approximately pH 3 with hydrochloric acid (6 mol/l) and was stirred for 30 minutes. The mixture was brought to pH 14 with aqueous solution of sodium hydroxide (12 mol/l) and was 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 the drying agent and concentrated under reduced pressure to get the connection specified in the header, 5-(2-ethylaminomethyl)-3-methyl-5,b,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 62d (450 mg) as a yellow oil which was used directly in the next stage.

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]-carbamino acid tert-butyl methyl ether

5-(2-Ethylaminomethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one 62d (450 mg, at 1.91 mmol) was dissolved in 20 ml of dichloromethane under stirring, and added to a solution of di-tert-BUTYLCARBAMATE (834 mg, a 3.83 mmol), potassium carbonate (528 mg, a 3.83 mmol) and tetrahydrofuran (30 ml). After complete addition, the reaction mixture was stirred at room temperature overnight. When thin layer chromatography showed the disappearance of the Exodus is the breaking substances, to the reaction mixture were added water (50 ml) and was 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 the drying agent and concentrated under reduced pressure. The residue was purified column chromatography on silica gel with getting the connection specified in the header, ethyl-[2-(3-methyl-4-oxo-4,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-5-yl)-ethyl]-carbamino acid tert-butyl ester e (40 mg, yield 6%) 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]-carbamino acid tert-butyl methyl ether

Ethyl-[2-(3-methyl-4-oxo-4,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-5-yl)-ethyl]-carbamino acid tert-butyl ether e (40 mg, 0,119 mmol) was dissolved in 25 ml of dichloromethane under stirring, and added to a solution of (chlormethine)dimethylammonio chloride (15,92 mg, 0.12 mmol). After complete addition, the reaction mixture was stirred at room temperature for 10 minutes. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture is quickly cooled aqueous sodium hydroxide solution (12 mol/l), stirred for 15 minutes at room temperature and extragere the Ali dichloromethane (20 ml×3). The combined organic extracts were washed with saturated brine (20 ml), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to get the connection specified in the header, ethyl-[2-(2-formyl-3-methyl-4-oxo-4,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-5-yl)-ethyl]-carbamino acid tert-butyl ether 62f (54 mg) as a yellow solid, which was used directly in the next stage.

MC m/z (ESI): 364,1 [M+1]

Stage 7

5-(2-Ethylaminomethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde

Ethyl-[2-(2-formyl-3-methyl-4-oxo-4,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-5-yl)-ethyl]-carbamino acid tert-butyl ether 62f (43 mg, the amount of 0.118 mmol) was dissolved in 10 ml of dichloromethane under stirring, and to the solution was added triperoxonane acid (272 μl, 3,55 mmol) and was stirred for 15 minutes in a bath of ice and water. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was concentrated under reduced pressure to get the connection specified in the header, 5-(2-ethylaminomethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 62j, which was used directly in the next stage.

MC m/z (ESI): 264,1 [M+1]

Stage 8

(Z)-5-(2-Ethylaminomethyl)-2-(5-fluoro-2-oxo-1,2-di is Idro-indol-3-ylidenemethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

5-(2-Ethylaminomethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 62j (45 mg, the amount of 0.118 mmol) was dissolved in 5 ml of ethanol under stirring, and to the solution was added 5-fluoro-1,3-dihydroindol-2-he (16 mg, 0,106 mmol) and piperidine (0.15 ml, 1,49 mmol). After complete addition, the reaction mixture is boiled under reflux at 90°C in oil bath for 1 hour. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was concentrated under reduced pressure, was added a small amount of ethanol and filtered to obtain the connection specified in the header, (Z)-5-(2-ethylaminomethyl)-2-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it 62 (34 mg, yield 76%) as a yellow solid.

MS m/z (ESI): 397,1 [M+1]

1H NMR (400 MHz, DMSO-d6) 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 semiline ring-CH2), 3.371-3.398 (t, 2H, amide N semiline ring-external CH2), 2.959-3.026 (m, 4H, -CH2C=C, -CH2N), 2.864-2.918 (q, 2H, ethyl-CH2), 2.488 (s, 3H, pyrrole-CH3), 2.056-2.083 (m, 2H, semiline ring-CH2), 1.136-1.172 (t, 3H, ethyl-CH3).

Example 63

(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]azepin-4-it is Alat

(Z)-5-(2-Diethylaminoethyl)-2-(5-fluoro-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-3-methyl-3a,5,6,7,8,8A-hexahydro-1H-pyrrolo[3,2-C]azepin-4-one 1 (2,01 g of 4.75 mmol), obtained according to Example 1, was dissolved in 279 ml of methanol under stirring, and to the solution was added 2-hydroxyestrone acid (0,953 g, 7,11 mmol) in one portion. The orange solution was concentrated under reduced pressure, was added 45 ml of acetonitrile was heated to education phlegmy 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 obtain the connection specified in the header, (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]azepin-4-it malate 63 (2,02 g, yield 76,2%) as an orange solid.

MC m/z (ESI): 425,1 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, semiline ring-intra-CH2N), 3.374-3.401 (t, 2H, amide N semiline ring-external CH2), 2.911-2.958 (t, 2H, semiline ring-intra-CH2C=C), 2.536-2.575 (m, 6H, 3×-CH2N), 2.471 (s, 3H, pyrrole-CH3), 2.053-2.079 (m, 2H, semiline ring-intra-CH2), 1.137 (t, 6H, 2×-CH3).

Example 64

(Z)-2-((5-(2,6-Dichlorobenzyl sulfonyl)-2-oxindole-3-ilidene)methyl)-3-methyl-5-(2-morpholinoethyl)-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

Stage 1

5-Chlorosulfonyl-2-he

To 1,3-dihydroindol-2-ONU 64A (13.3 g, 100 mmol) was slowly added chlorosulfonic acid (to 26.6 ml, 400 mmol) in a bath of ice and water. After complete addition, the reaction mixture was stirred for 1 hour in a bath of ice-water, for 1 hour at room temperature and was heated to 68°C for 1 hour. The reaction mixture was cooled to room temperature, was slowly added water (400 ml), mixed, and formed a yellow precipitation. After standing for 1 hour at room temperature, the filter cake washed with water (20 ml×4) and dried to obtain the connection specified in the header, 5-chlorosulfonyl-2-he 64b (15.0 g, yield 65%) as a yellow solid.

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

Stage 2

5-(2,6-Dichlorobenzenesulfonyl)-1,3-dihydroindol-2-he

Monohydrogenphosphate sodium dodecahydrate (142 g, 1.0 mol) and sodium sulfite (252 g, 2.0 mol) was dissolved in 2 l of water at room temperature, was heated to 30°C and was added 2-oxo-2,3-dihydro-1H-indol-5-sulphonylchloride 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-dichlorobenzamide (240 g, 1.0 mol) in acetone (1.8 l)was stirred at 60°C during the 1 hour, added an additional amount of acetone (200 ml) and stirred for 2 hours. The reaction mixture was rapidly cooled with water (5 l)was stirred at room temperature for 1 hour and filtered. The filter cake was washed with water (1 l) and acetone (1 l) and dried under vacuum to obtain the connection specified in the header, 5-(2,6-dichlorobenzenesulfonyl)-1,3-dihydroindol-2-it s (314 g, yield 88%) as a white solid.

MS m/z (ESI): 357,3 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, -ArCH2).

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

Stage 3

(Z)-2-((5-(2,6-Dichlorobenzenesulfonyl)-2-oxindole-3-ilidene)methyl)-3-methyl-5-(2-morpholinoethyl)-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

3-Methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 10C (100 mg, 0,325 mmol) and 5-(2,6-dichlorobenzenesulfonyl)-1,3-dihydroindol-2-he 64 (104 mg, 0,293 mmol) was dissolved in 3 ml of ethanol and added to a solution of 52 μl of piperidine at room temperature. After complete addition, the reaction mixture was heated up to the formation of phlegmy within 2 hours. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was naturally cooled to room temperature and filtered. Filter ke is washed with anhydrous ethanol (3 ml×2) and dried to obtain compound, specified in the header, (Z)-2-((5-(2,6-dichlorobenzenesulfonyl)-2-oxindole-3-ilidene)methyl)-3-methyl-5-(2-morpholinoethyl)-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he 64 (166 mg, yield 88%) as an orange solid.

MS m/z (ESI): 643,3 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, -ArCH2), 3.58-2.08 (m, 18H, aliphatic H), 2.44 (s, 3H, pyrrole-CH3).

Example 65

(Z)-2-[5-(4-PerformanceCounter)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-5-(2-pyrrolidin-1-retil)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-one

about

Stage 1

5-(4-PerformanceCounter)-1,3-dihydroindol-2-he

Monohydrogenphosphate sodium dodecahydrate (3.58 g, 10 mmol) and sodium sulfite (2,52 g, 20 mmol) was dissolved in 20 ml of water, was heated to 30°C and was added 2-oxo-2,3-dihydro-1H-indol-5-sulphonylchloride 64b (2,32 g, 10 mmol). After complete addition, the reaction mixture was stirred at 60°C for 16 hours. To the above solution was slowly added a solution of 5-ftorangidridy (1.9 g, 10 mmol) in acetone (18 ml) and stirred at 60°C for 2 hours. The reaction mixture was rapidly cooled with water (50 ml), and formed a lot of sediment. The mixture was stirred at room temperature for one hour, filtered washed with a mixture of solvents (20 ml, about:about=1:1) of water and acetone and dried in vacuum to obtain the connection specified in the header, 5-(4-PerformanceCounter)-1,3-dihydroindol-2-it 65A (1.8 g, yield 59%) as a pale yellow solid.

MC m/z (ESI): 304,1 [M-1]

1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H, indole-NH), 7.42 (m, 2H, -AGN), 7.21 (m, 3H, -ArH), 6.95 (d, 1H, -ArH), 4.59 (s, 2H, -ArCH2).

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

Stage 2

2-[5-(4-PerformanceCounter)-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

3-Methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 28C (a 60.2 mg, 0.21 mmol) and 5-(4-PerformanceCounter)-1,3-dihydroindol-2-he 65A (57.6 mg, 0,19 mmol) was dissolved in 2 ml ethanol and added to a solution of 50 μl of piperidine at room temperature. After complete addition, the reaction mixture was heated up to the formation of phlegmy for 3 hours. When thin layer chromatography showed the disappearance of starting compounds, 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 connection specified in the header, (Z)-2-[5-(4-PerformanceCounter)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-3-methyl-5-(2-pyrrolidin-1-retil)-5,6,7,8-tetrahydro-1H-Pirro is about[3,2-C]azepin-4-it 65 (90 mg, output 81,8%) as an orange solid.

MS m/z (ESI): 577,3 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, -ArCH2), 4.33 (m, 2H, -NCH2), 4.11-3.25 (m, 12H, aliphatic H), 3.70 (m, 2H,

-NCH2), 2.81 (m, 2H, -NCH2), 2.46 (s, 3H, pyrrole-CH3).

Example 66

(Z)-2-((5-(2,6-Dichlorobenzenesulfonyl)-2-oxindole-3-ilidene)methyl)-3-methyl-5-(2-(pyrrolidin-1-yl)ethyl)-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

3-Methyl-4-oxo-5-(2-pyrrolidin-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 28C (75 mg, 0,262 mmol) and 5-(2,6-dichlorobenzenesulfonyl)-1,3-dihydroindol-2-he s (84 mg, 0,236 mmol) was 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 up to the formation of phlegmy for 3 hours. When thin layer chromatography showed the disappearance of starting compounds, 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 connection specified in the header, (Z)-2-((5-(2,6-dichlorobenzenesulfonyl)-2-oxindole-3-ilidene) methyl)-3-methyl-5-(2-(pyrrolidin-1-yl)ethyl)-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-it 66 (117 mg, yield of 79.6%) in the IDA orange solid.

MS m/z (ESI): 627,3 [M+1]

1H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H, indole-NH), 9.04 (s, 1H, -ArH), 8.66 (s, 1H, -ArH), 8.25 (s, 1H, -CH=C), 8.23-8.16 (m, 3H, -ArH), 7.99 (d, 1H, -ArH), 5.64 (s, 2H, -ArCH2), 4.34 (m, 2H, -NCH2), 4.12-3.26 (m, 12H, aliphatic H), 3.70 (m, 2H,

-NCH2), 2.81 (m, 2H, -NCH2), 2.46 (s, 3H, pyrrole-CH3).

Example 67

(Z)-2-((5-(4-Perpenicular)-2-oxindole-3-ilidene)methyl)-3-methyl-5-(2-(piperidine-1-yl)ethyl)-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

3-Methyl-4-oxo-5-(2-piperidine-1-retil)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 32d (57.6 mg, 0.21 mmol) and 5-(4-PerformanceCounter)-1,3-dihydroindol-2-he 65A (57.6 mg, 0,19 mmol) was dissolved in 2 ml ethanol and added to a solution of 42 μl of piperidine at room temperature. After complete addition, the reaction mixture was heated up to the formation of phlegmy for 3 hours. When thin layer chromatography showed the disappearance of starting compounds, 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 connection specified in the header, (Z)-2-((5-(4-perpenicular)-2-oxindole-3-ilidene)methyl)-3-methyl-5-(2-(piperidine-1-yl)ethyl)-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-it 67 (84 mg, yield 76%) as an orange solid.

MC m/z (ESI): 591,3 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, -ArCH2), 3.58 (m, 2H, -NCH2), 3.29-2.40 (m, 11H, aliphatic H), 2.97 (m, 2H, -NCH2), 2.08 (m, 2H, -NCH2), 1.49 (s, 3H, pyrrole-CH3).

Example 68

(Z)-2-((5-(2,6-Dichlorobenzenesulfonyl)-2-oxindole-3-ilidene)methyl)-3-methyl-5-(2-(piperidine-1-yl)ethyl)-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

3-Methyl-4-oxo-5-(2-piperidine-1-yl-ethyl)-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 32d (57.6 mg, 0.21 mmol) and 5-(2,6-dichlorobenzenesulfonyl)-1,3-dihydroindol-2-he s (67.2 per mg, 0,19 mmol) was 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 up to the formation of phlegmy for 3 hours. When thin layer chromatography showed the disappearance of starting compounds, 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 connection specified in the header, (Z)-2-((5-(2,6-dichlorobenzenesulfonyl)-2-oxindole-3-ilidene)methyl)-3-methyl-5-(2-(piperidine-1-yl)ethyl)-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-it 68 (93 mg, yield of 77.5%) as an orange solid.

MC m/z (ESI): 641,2 [M+1]

1H NMR (400 MHz, LCA is-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, -ArCH2), 3.57 (m, 2H, -NCH2), 3.35 (m, 2H,

-NCH2), 2.97 (m, 2H, -NCH2), 3.31-2.39 (m, 15H, aliphatic H), 2.07 (m, 2H, -NCH2).

Example 69

(Z)-2-((5-(4-Perpenicular)-2-oxindole-3-ilidene)methyl)-3-methyl-5-(2-morpholinoethyl)-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

3-Methyl-5-(2-morpholine-4-retil)-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 10C (80 mg, 0.26 mmol) and 5-(4-PerformanceCounter)-1,3-dihydroindol-2-he 65A (72 mg, 0.24 mmol) was 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 up to the formation of phlegmy for 3 hours. When thin layer chromatography showed the disappearance of starting compounds, 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 connection specified in the header, (Z)-2-((5-(4-perpenicular)-2-oxindole-3-ilidene)methyl)-3-methyl-5-(2-morpholinoethyl)-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-it 69 (120 mg, yield of 85.7%) as an orange solid.

MS m/z (ESI): 593,5 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, 1, -ArH), 7.24 (m, 3H, 3×-ArH), 7.21 (s, 1H,

-CH=C), 7.01 (d, 1H, -ArH), 4.64 (s, 2H, -ArCH2), 3.58-2.07 (m, 18H, aliphatic H), 2.44 (s, 3H, pyrrole-CH3).

Example 70

(Z)-2-((5-(2,6-Dichlorobenzenesulfonyl)-2-oxindole-3-ilidene)methyl)-5-(2-(diethylamino)ethyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

5-(2-Diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j (60 mg, 0.21 mmol) and 5-(2,6-dichlorobenzenesulfonyl)-1,3-dihydroindol-2-he s (67 mg, 0,19 mmol) was dissolved in 3 ml of ethanol and added to a solution of 52 μl of piperidine at room temperature. After complete addition, the reaction mixture was heated up to the formation of phlegmy within 2 hours. When thin layer chromatography showed the disappearance of starting compounds, 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 connection specified in the header, (Z)-2-((5-(2,6-dichlorobenzenesulfonyl)-2-oxindole-3-ilidene)methyl)-5-(2-(diethylamino)ethyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-it 70 (95 mg, yield 79%) as an orange solid.

MS m/z (ESI): 629,3 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, -NCH2), 7.06 (s, 1H, -ArH), 4.89 (s, 2H, -ArCH2), 352-2 .07 (m, 14H, aliphatic H), 2.50 (s, 3H, pyrrole-CH3), 1.00 (m, 6H, 2×-CH3).

Example 71

(Z)-2-((5-(4-Perpenicular)-2-oxindole-3-ilidene)methyl)-5-(2-(diethylamino)ethyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

5-(2-Diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j (60 mg, 0.21 mmol) and 5-(4-PerformanceCounter)-1,3-dihydroindol-2-he 65A (58 mg, 0,19 mmol) was dissolved in 2 ml ethanol and added to a solution of 34 μl of piperidine at room temperature. After complete addition, the reaction mixture was heated up to the formation of phlegmy for 3 hours. When thin layer chromatography showed the disappearance of starting compounds, 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 connection specified in the header, (Z)-2-((5-(4-perpenicular)-2-oxindole-3-ilidene)methyl)-5-(2-(diethylamino)ethyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-71 (73 mg, yield 66%) as an orange solid.

MS m/z (ESI): 579,3 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, -ArCH2), 3.52-2.06 (m, 14H, aliphatic H), 2.50 (s, 3H, pyrrole-CH3), 1.00 (m, 6H, 2×-CH 3).

Example 72

(R,Z)-2-((5-(2,6-Dichlorobenzenesulfonyl)-2-oxindole-3-ilidene)methyl)-5-(2-hydroxy-3-morpholinopropan)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

5-(2-Hydroxy-3-morpholine-4-ylpropyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 53f (80 mg, 0.24 mmol) and 5-(2,6-dichlorobenzenesulfonyl)-1,3-dihydroindol-2-he s (75 mg, 0.21 mmol) was dissolved in 3 ml of ethanol and added to a solution of 30 μl of piperidine at room temperature. When you are finished adding, after stirring for 4 minutes, the reaction mixture was left to interact at 120°C for 4 minutes under microwave irradiation, and formed orange turbid solution. When thin layer chromatography showed the disappearance of starting compounds, 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 connection specified in the header, (R,Z)-2-((5-(2,6-dichlorobenzenesulfonyl)-2-oxindole-3-ilidene)methyl)-5-(2-hydroxy-3-morpholinopropan)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-it 72 (120 mg, yield 85%) as a yellow solid.

MS m/z (ESI): 673,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, -is N=C), 7.06 (d, 1H, -ArH), 4.89 (s, 2H, -ArCH2), 4.74 (m, 1H, -Cho), 3.92-2.33 (m, 18H, aliphatic H), 2.44 (s, 3H, pyrrole-CH3).

Example 73

(R,Z)-2-((5-(4-Perpenicular)-2-oxindole-3-ilidene)methyl)-5-(2-hydroxy-3-morpholinopropan)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

5-(2-Hydroxy-3-morpholine-4-ylpropyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 53f (80 mg, 0.24 mmol) and 5-(4-PerformanceCounter)-1,3-dihydroindol-2-he 65A (64 mg, 0.21 mmol) was dissolved in 3 ml of ethanol and added to a solution of 30 μl of piperidine at room temperature. When you are finished adding, after stirring for 4 minutes, the reaction mixture was left to interact at 120°C for 4 minutes under microwave irradiation, and formed orange turbid solution. When thin layer chromatography showed the disappearance of starting compounds, 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 connection specified in the header, (R,Z)-2-((5-(4-perpenicular)-2-oxindole-3-ilidene)methyl)-5-(2-hydroxy-3-morpholinopropan)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-it 73 (100 mg, yield 76%) as a yellow solid.

MC m/z (ESI): 621,3 [M-1]

1H NMR (400 MHz, DMSO-d62), 3.92-2.32 (m, 18H, aliphatic H), 2.44 (s, 3H, pyrrole-CH3).

Example 74

(Z)-5-(2-(Diethylamino)ethyl)-2((4-(2,3-differenl)-5-fluoro-2-oxindole-3-ilidene)methyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

Stage 1

1-Iodine-2-methyl-3-nitrobenzene

2-Methyl-3-nitrophenylamino a (21,28 g, 0.14 mol) was dissolved in 70 ml of concentrated hydrochloric acid in a bath of ice and water was added water (40 ml), was stirred at 0-5°C, and formed a yellow-green precipitate. To the reaction mixture was added dropwise a solution of nitric acid (40 ml, 3.6 M), was 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 starting compounds, 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 obtain a brown oil (34.4 g). This crude product was purified colonoscopy because it allows the Noah chromatography on silica gel to obtain compound, specified in the header, 1-iodine-2-methyl-3-nitrobenzene 74b (30.1 g, yield of 81.7%) as a white solid.

Stage 2

3-(2-Iodine-6-nitrophenyl)-2-oxopropionate acid

To a solution of ethoxide sodium (35 ml, 44 mmol) in a bath of ice-water was added dropwise a solution of 1-iodine-2-methyl-3-nitrobenzene 74b in ethanol (35 ml, 40 mmol) in argon atmosphere. After complete addition, the reaction mixture was stirred until the formation of large amount of brown precipitation was added diethyloxalate (6 ml, 44 mmol) in one portion. The reaction mixture is boiled under reflux at 100°C in oil bath for half an hour, was added water (70 ml) and boiled under reflux for one hour. The reaction mixture was concentrated under reduced pressure to evaporate the ethanol, washed with ethyl acetate (50 ml) in basic conditions, brought to pH 3 with hydrochloric acid (1 M) and was 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 get the connection specified in the header, 3-(2-iodine-6-nitrophenyl)-2-oxopropanoic acid 74 (2,94 g) as a brown oil which was used directly in the next stage.

MS: 334,2 [M-1].

Stage 3

(2-Iodine-6-nitrophenyl)-acetic to the slot

3-(2-Iodine-6-nitrophenyl)-2-oxopropionate acid s (2,086 g, 6.2 mmol) was dissolved in 6 ml of methanol under stirring, and to the solution was added 20 ml of water and 7 ml of hydrogen peroxide 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 compounds, 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-described filter cecom and dried to obtain the connection specified in the header (2-iodine-6-nitrophenyl)-acetic acid 74d (1.77 g, yield 70%) as a brown solid.

Stage 4

1-Hydroxy-4-iodine-1,3-dihydroindol-2-he

(2-Iodine-6-nitrophenyl)-acetic acid 74d (0,91 g, 3 mmol) was dissolved in ethanol (30 ml, 95%) was added to a solution of palladium on activated carbon (30 mg, 3%). After complete addition, the reaction mixture was stirred for 2 hours in hydrogen atmosphere. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified column chromatography on silica gel with getting the connection specified in the header, 1-hydroxy-4-iodine-1,dihydroindol-2-it 74A (516 mg, output 63,4%) as a white solid.

MS: 274,1 [M-1]

Stage 5

5-fluoro-4-iodine-1,3-dihydroindol-2-he

1-Hydroxy-4-iodine-1,3-dihydroindol-2-it 74A (326 mg, 1,19 mmol) was dissolved in 24 ml of dichloromethane in a bath of dry ice and acetone and slowly added TRIFLUORIDE (diethylamino)sulfur (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 compounds, the reaction mixture is quickly cooled saturated sodium bicarbonate solution was added saturated brine (30 ml) and was extracted with dichloromethane (30 ml×3). The combined organic extracts were washed with saturated brine (30 ml) and dried over anhydrous sodium sulfate to obtain yellow solid (284 mg). This crude product was purified column chromatography on silica gel with getting the connection specified in the header, 5-fluoro-4-iodine-1,3-dihydroindol-2-it 74f (114 mg, yield 34,7%) as a white solid.

MS: 276,6 [M-1]

Stage 6

4-(2,3-Differenl)-5-fluoro-1,3-dihydroindol-2-he

5-fluoro-4-iodine-1,3-dihydroindol-2-he 74f (277 mg, 1 mmol) was dissolved in 10 ml of N,N-dimethylformamide and added to a solution of 2,3-ftorhinolony acid (158 mg, 1 mmol), sodium bicarbonate (168 mg, 2 mmol) and water (10 is l) in argon atmosphere. After complete addition, the mixture was stirred to achieve good mixing, was added tetrakis(triphenylphosphine)palladium (109 mg, 0.15 mmol) and was heated up to the formation of phlegmy during the night. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was concentrated under reduced pressure, the solution was added hydrochloric acid (10 ml, 1 M)and was 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 column chromatography on silica gel with getting the connection specified in the header, 4-(2,3-differenl)-5-fluoro-1,3-dihydroindol-2-it 74g (42 mg, yield 16%) as a gray solid.

MS: 262.0 [M+1]

Stage 7

(Z)-5-(2-(Diethylamino)ethyl)-2-((4-(2,3-differenl)-5-fluoro-2-oxindole-3-ilidene)methyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

5-(2-Diethylaminoethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 1j (73 mg, 0.25 mmol) and 4-(2,3-differenl)-5-fluoro-1,3-dihydro-indol-2-he 74g (60 mg, 0.23 mmol) was dissolved in 2 ml of ethanol and to the solution was added 35 μl of piperidine at room temperature. After complete addition, the mixture was heated to education phlegmy within 2 hours. When thin layer chromatography showed the disappearance is of the original substances, 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 connection specified in the header, (Z)-5-(2-(diethylamino)ethyl)-2-((4-(2,3-differenl)-5-fluoro-2-oxindole-3-ilidene)methyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-74 (23 mg, yield 19%) as an orange solid.

MS m/z (ESI): 537,2 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, -NCH2), 2.91 (m, 2H, -NCH2), 2.54 (s, 3H, pyrrole-CH3), 1.2-3.4 (m, 14N, aliphatic H), 2.20 (m, 2H, -NCH3).

Example 75

2-((Z)-(4-(2,3-Differenl)-5-fluoro-2-oxindole-3-ilidene)methyl)-5-((R)-2-hydroxy-3-morpholinopropan)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

5-(2-Hydroxy-3-morpholine-4-ylpropyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 53f (84 mg, 0.25 mmol) and 4-(2,3-differenl)-5-fluoro-1,3-dihydroindol-2-he 74g (60 mg, 0.23 mmol) was dissolved in 2 ml of ethanol and to the solution was added 35 μl of piperidine at room temperature. After complete addition, the mixture was heated to education phlegmy within two hours. When thin layer chromatography showed the disappearance of starting compounds, the reaction mixture was naturally cooled to whom atoi temperature and filtered. The filter cake was washed with anhydrous ethanol (3 ml×2) and dried to obtain the connection specified in the header, 2-((Z)-(4-(2,3-differenl)-5-fluoro-2-oxindole-3-ilidene)methyl)-5-((R)-2-hydroxy-3-morpholinopropan)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he 75 (100 mg, yield 78%) as an orange solid.

MC m/z (ESI): 581,3 [M+1]

1H NMR (400 MHz, DMSO-d6) 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, -SEN), 3.86 (m, 2H, -NCH2), 2.89 (m, 2H, -NCH2), 2.33 (m, 2H, -NCH2), 3.86-2.28 (m, 12H, aliphatic H).

Example 76

(R,Z)-5-(2-Hydroxy-3-morpholinopropan)-3-methyl-2-((4-methyl-2-oxindole-3-ilidene)methyl)-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

5-(2-Hydroxy-3-morpholine-4-ylpropyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 53f (30 mg, 0.09 mmol) and 4-methyl-1,3-dihydroindol-2-he (12 mg, 0.08 mmol) was dissolved in 156 μl of ethanol, and added to a solution of 4.4 μl of 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 compounds, 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 compound, pointed to by the th header, (R,Z)-5-(2-hydroxy-3-morpholinopropan)-3-methyl-2-((4-methyl-2-oxindole-3-ilidene)methyl)-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-it 76 (12 mg, 30%yield) as an orange solid.

MC m/z (ESI), 465,2 (M+1)

1H NMR (400 MHz, DMSO-d6) 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, -SEN), 3.78 (dd, 1H, semiline ring outer amide-NCH2), 3.58 (t, 4H, morpholine-intra-2×-CH2O), 3.40 (m, 2H, semiline ring-NCH2), 3.17 (dd, 1H, semiline ring outer amide-NCH2), 2.94 (t, 2H, pyrrole-CH2), 2.59 (s, 3H, benzylmethyl), 2.44 (m, 4H, morpholine-intra-2×CH2N), 2.39 (s, 3H, pyrrole-CH3), 2.29 (m, 2H, morpholine-external NCH2), 2.08 (m, 2H, semiline ring-CH2-CH2-CH2).

Example 77

(R,Z)-5-(2-Hydroxy-3-morpholinopropan)-2-((6-methoxy-2-oxindole-3-ilidene)methyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

5-(2-Hydroxy-3-morpholine-4-ylpropyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 53f (30 mg, 0.09 mmol) and 6-methoxy-1,3-dihydroindol-2-he (13 mg, 0.08 mmol) was dissolved in 156 μl of ethanol was added to a solution of 4.4 μl of 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 compounds, the reaction mixture EU is the natural enemy was cooled to room temperature and filtered. The filter cake was washed with anhydrous ethanol (1 ml×2) and dried to obtain the connection specified in the header, (R,Z)-5-(2-hydroxy-3-morpholinopropan)-2-((6-methoxy-2-oxindole-3-ilidene)methyl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-it 77 (22 mg, 51%yield) as a yellow solid.

MC m/z (ESI), 481,2 (M+1)

1H NMR (400 MHz, DMSO-d6) 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,

-HE), 3.89 (m, 1H, -SEN), 3.77 (dd, 1H, semiline ring outer amide-NCH2), 3.58 (t, 4H, morpholine-intra-2×-CH2O), 3.41 (m, 2H, semiline ring-NCH2), 3.17 (dd, 1H, semiline ring outer amide-NCH2), 2.93 (t, 2H, pyrrole-CH2), 2.41 (s, 3H, pyrrole-CH3), 2.34 (m, 4H, morpholine-intra-2×-CH2N), 2.29 (m, 2H, morpholine external NCH2), 2.07 (m, 2H, semiline ring-CH2-CH2-CH2).

Example 78

(S,Z)-2-((5-fluoro-2-oxindole-3-ilidene)methyl)-5-(2-hydroxy-3-morpholinopropan)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

Stage 1

(S)-4-Oxiranylmethyl

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 to the solution was slowly added (S)-(+)-2-chloromethyloxirane (4.02 ml, 50 mmol). After complete addition, the reaction system of the EU is the natural enemy was heated to room temperature and was stirred overnight. When thin layer chromatography showed the disappearance of starting compounds, the reaction system was cooled to 10°C in a bath of ice-water, was added a solution of tert-butoxide potassium in tetrahydrofuran (30 ml, 1,67 mol/l, 50 mmol), 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 starting compounds, the reaction was stopped. The reaction mixture was concentrated under reduced pressure, was added 20 ml of water, was 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 the drying agent, the filtrate was concentrated to obtain the connection specified in the header (S)-4-oxiranylmethyl 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-morpholine-4-improper-2-ol

To (S)-4-oxiranylmethyl 78b (5,52 g, and 38.6 mmol) was slowly added 395 ml of aqueous ammonia (25%, 5.8 mol) in a bath of ice and water, keeping the temperature below 0°C. After complete addition, the reaction mixture was naturally warmed up to room temperature and stirred for 18 hours. When thin layer chromatography pokazyvaetsia initial substances, the reaction was stopped. The reaction solution was concentrated under reduced pressure to remove the solvent of the reaction and got the connection specified in the header, (R)-1-amino-3-morpholine-4-improper-2-ol s (6,1 g, yield 99%) as a pale yellow oil.

MC m/z (ESI): 161,3 (M+1)

Stage 3

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

5-(3-Methanesulfonylaminoethyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1D (1.13 g, 2.9 mmol) was dissolved in 5.6 ml of dichloromethane under stirring, and to the solution were added (R)-1-amino-3-morpholine-4-improper-2-ol s (0,93 g, 5.8 mmol) 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 starting compounds, the reaction was stopped. To the reaction solution was added 15 ml of saturated brine was extracted with dichloromethane (20 ml×3), combined organic phase was concentrated under reduced pressure, and the residue was purified column chromatography on silica gel with getting the connection specified in the header (S)-5-[3-(2-hydroxy-3-morpholine-4-ylpropionic)-propyl]-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 78d (600 m is, the yield of 72.5%) as a yellow oil.

MC m/z (ESI): 454,2 (M+1)

Stage 4

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

(S)-5-[3-(2-Hydroxy-3-morpholine-4-ylpropionic)-propyl]-3-methyl-1H-pyrrol-2 and 4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 78d (580 mg, 1.28 mmol) was dissolved in 6 ml of toluene in an argon atmosphere, the reaction mixture was cooled in a bath of ice-water, at this time, to the solution was added a solution of trimethylaluminum in toluene (1.9 ml, 2 mol/l of 3.84 mmol). After adding a bath of ice and water was removed, and the reaction solution was heated up to the formation of phlegmy within 24 hours. When thin layer chromatography showed the disappearance of starting compounds, the reaction was stopped. The reaction solution was concentrated under reduced pressure to remove the reaction solvent, was added 20 ml of hydrochloric acid (6 mol/l) and was stirred for 20 minutes, brought to about pH 12 with sodium hydroxide solution (12 mol/l) in a bath of ice 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 column chromatography on silica gel with getting the connection specified in the header (S)-5-(2-hydroxy-3-morpholine-4-ylpropyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-C]azepin-4-it e 300 mg, output 57,6%) as a white solid.

MC m/z (ESI): 308,2 (M+1)

Stage 5

(S)-5-(2-Hydroxy-3-morpholine-4-ylpropyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde

(Chlormethine)dimethylammonio chloride (130 mg, 0,977 mmol) was dissolved in 3 ml of dichloromethane under stirring in argon atmosphere, the solution was cooled to 0°C in a bath of ice and water. (S)-5-(2-Hydroxy-3-morpholine-4-ylpropyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one e (300 mg, 0,977 mmol) was dissolved in 2 ml of dichloromethane under 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 compounds, the reaction solution was added sodium hydroxide solution (12 mol/l) for rapid cooling of the reaction mixture. To the reaction solution was added 10 ml of saturated brine, were extracted with a mixture solvent of dichloromethane and methanol (about:about=10:1) (100 ml×3), combined organic phase was washed with saturated brine (100 ml×1), dried over anhydrous magnesium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, the residue was purified column chromatography on silica compound the gel with a connection, specified in the header, (S)-5-(2-hydroxy-3-morpholine-4-ylpropyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 78f (200 mg, yield 61%) as a white solid.

MC m/z (ESI): 336,2 (M+1)

Stage 6

(S,Z)-2-((5-fluoro-2-oxindole-3-ilidene)methyl)-5-(2-hydroxy-3-morpholinopropan)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

(S)-5-(2-Hydroxy-3-morpholine-4-ylpropyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 78f (50 mg, 0,149 mmol) was dissolved in 261 μl of ethanol under stirring, and to the solution was added 5-fluoro-1,3-dihydroindol-2-he (to 20.28 mg, 0,134 mmol) and piperidine (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 oil bath. When thin layer chromatography showed the disappearance of starting compounds, 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 compound indicated in heading (S,Z)-2-((5-fluoro-2-oxindole-3-ilidene)methyl)-5-(2-hydroxy-3-morpholinopropan)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-it 78 (40 mg, yield 57%) as a yellow solid.

MC m/z (ESI): 469,2 (M+1)

1H NMR (400 MHz, DMSO-d6) 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, -SEN), 3.76 (dd, 1H, semiline ring outer amide-NCH2), 3.58 (t, 4H, morpholine-2×-CH2O), 3.42 (m, 2H, semiline ring-NCH2), 3.15 (dd, 1H, semiline ring outer amide-NCH2), 2.94 (t, 2H, -CH2C=C), 2.457 (s, 3H, pyrrole-CH3), 2.413 (m, 4H, morpholine-intra-2×-CH2N), 2.306 (m, 2H, morpholine external NCH2), 2.08 (m, 2H, semiline ring-CH2-CH2-CH2).

Example 79

(S,Z)-2-((5-Chloro-2-oxindole-3-ilidene)methyl)-5-(2-hydroxy-3-morpholinopropan)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

(S)-5-(2-Hydroxy-3-morpholine-4-ylpropyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 78f (40 mg, 0.12 mmol/l) and 5-chloro-1,3-dihydroindol-2-he (20 mg, 0.12 mmol) was dissolved in 1.5 ml of ethanol and to the solution was added 6 μl of 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 compounds, 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 compound indicated in heading (S,Z)-2-((5-chloro-2-oxindole-3-ilidene)methyl)-5-(2-hydroxy-3-morpholinopropan)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-it 79 (46 mg, output is 79%) as a yellow solid.

MC m/z (ESI): 485,2 (M+1)

1H NMR (400 MHz, DMSO-d6) 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, -SEN), 3.76 (dd, 1H, semiline ring outer amide-NCH2), 3.58 (t, 4H, morpholine-2×-CH2O)3.418 (m, 2H, semiline ring-NCH2), 3.15 (m, 1H, semiline ring outer amide-NCH2), 2.937 (t, 2H, -CH2C=C), 2.464 (s, 3H, pyrrole-CH3), 2.428 (m, 4H, morpholine-intra-2×-CH2N)2.299 (m, 2H, morpholine outer-NCH2), 2.076 (m, 2H, semiline ring-CH2-CH2-CH2).

Example 80

(S,Z)-2-((5-bromo-2-oxindole-3-ilidene)methyl)-5-(2-hydroxy-3-morpholinopropan)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

(S)-5-(2-Hydroxy-3-morpholine-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 78f (40 mg, 0.12 mmol) and 5-bromo-1.3-dihydroindol-2-he (25 mg, 0.12 mmol) was dissolved in 1.5 ml of ethanol, and added to a solution of 6 μl of 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 compounds, 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 compound indicated in heading (S,Z)-2-((5-b is ω-2-oxindole-3-ilidene)methyl)-5-(2-hydroxy-3-morpholinopropan)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-it 80 (51 mg, yield 81%) as a yellow solid.

MC m/z (ESI): 529,1 (M+1)

1H NMR (400 MHz, DMSO-d6) 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, -SEN), 3.792-3.748 (dd, 1H, semiline ring outer amide-NCH2), 3.58 (t, 4H, morpholine-2×-CH2O), 3.437-3.398 (m, 2H, semiline ring-NCH2), 3.193-3.140 (m, 1H, semiline ring outer amide-NCH2), 2.936 (t, 2H, -CH2C=C), 2.465 (s, 3H, pyrrole-CH3), 2.431-2.420 (m, 4H, morpholine-intra-2×-CH2N), 2.315 (m, 2H, morpholine-external NCH2), 2.09 (m, 2H, semiline ring-CH2-CH2-CH2).

Example 81

(S,Z)-2-((4-Bromo-2-oxindole-3-ilidene)methyl)-5-(2-hydroxy-3-morpholinopropan)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

(S)-5-(2-Hydroxy-3-morpholine-4-ylpropyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 78f (40 mg, 0.12 mmol) and 4-bromo-1,3-dihydroindol-2-he (25 mg, 0.12 mmol) was dissolved in 1.5 ml of ethanol and to the solution was added 6 μl of 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 compounds, the reaction mixture was naturally cooled to room temperature and filtered. The filter cake was washed anhydrous this is Nole (1 ml×2) and dried to obtain compound, specified in the header, (S,Z)-2-((4-bromo-2-oxindole-3-ilidene)methyl)-5-(2-hydroxy-3-morpholinopropan)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-it 81 (34 mg, yield 54%) as a yellow solid.

MS m/z (ESI): 529,3 (M+1)

1H NMR (400 MHz, DMSO-d6) 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, -SEN), 3.800-3.757 (dd, 1H, semiline ring outer amide-NCH2), 3.593-3.570 (t, 4H, morpholine-2×-CH2O)3.446 (m, 2H, semiline ring-NCH2), 3.192 (dd, 1H, semiline ring outer amide-NCH2), 2.956 (t, 2H, -CH2C=C), 2.447-2.428 (m, 4H, morpholine-intra-2×-CH2N), 2.411 (s, 3H, pyrrole-CH3), 2.301 (m, 2H, morpholine-external NCH2), 2.08 (m, 2H, semiline ring-CH2-CH2-CH2).

Example 82

(S,Z)-2-((7-Bromo-5-fluoro-2-oxindole-3-ilidene)methyl)-5-(2-hydroxy-3-morpholinopropan)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-he

(S)-5-(2-Hydroxy-3-morpholine-4-ylpropyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 78f (40 mg, 0.12 mmol) and 7-bromo-5-fluoro-1,3-dihydroindol-2-he 4b (27 mg, 0.12 mmol) was dissolved in 1.5 ml of ethanol and to the solution was added 6 μl of piperidine at room temperature. After complete addition, the reaction mixture was subjected to interaction at 45°C for 16 hours. When thin layer chromatography showing the shaft disappearance of the starting compounds, 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 compound indicated in heading (S,Z)-2-((7-bromo-5-fluoro-2-oxindole-3-ilidene)methyl)-5-(2-hydroxy-3-morpholinopropan)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-she is 82 (48 mg, yield of 73.8%) as a yellow solid.

MC m/z (ESI): 547,5 (M+1)

1H NMR (400 MHz, DMSO-d6) 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, -SEN), 3.75 (dd, 1H, semiline ring outer amide-NCH2), 3.583 (t, 4H, morpholine-2×-CH2O), 3.480-3.415 (m, 2H, semiline ring-NCH2), 3.15 (dd, 1H, semiline ring outer amide-NCH2), 2.471 (s, 3H, pyrrole-CH3), 2.430 (m, 4H, morpholine-intra-2×-CH2N), 2.310 (t, 2H, morpholine-external NCH2), 2.086 (m, 2H, semiline ring-CH2-CH2-CH2).

Example 83

(S,Z)-5-(2-Hydroxy-3-morpholinopropan)-3-methyl-2-((4-methyl-2-oxindole-3-ilidene)methyl)-5,6,7,8-tetrahydropyrrolo[3,2-C]aselin-4(1H)-he

(S)-5-(2-Hydroxy-3-morpholine-4-ylpropyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydrofuro[3,2-C]azepin-2-carbaldehyde 78f (40 mg, 0.12 mmol/l) and 4-methyl-1.3-dihydroindol-2-he (18 mg, 0.12 mmol) was dissolved in 1.5 ml of ethanol and to the solution was added 6 μl of piperidine at room temperature. P the following complete addition, the reaction mixture was stirred at 45°C for 16 hours. When thin layer chromatography showed the disappearance of starting compounds, 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 compound indicated in heading (S,Z)-5-(2-hydroxy-3-morpholinopropan)-3-methyl-2-((4-methyl-2-oxindole-3-ilidene)methyl)-5,6,7,8-tetrahydropyrrolo[3,2-C]azepin-4(1H)-she's 83 (35 mg, yield of 63.6%) as a yellow solid.

MC m/z (ESI): 465,2 (M+1)

1H NMR (400 MHz, DMSO-d6) 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, -SEN), 3.75 (dd, 1H, semiline ring-intra-amide-NCH2), 3.58 (t, 4H, morpholine-2×-CH2O)3.441 (m, 2H, semiline ring-NCH2), 3.15 (m, 1H, semiline ring outer amide-NCH2), 2.939 (t, 2H, -CH2CH=C), 2.594 (s, 3H, pyrrole-CH3), 2.426 (m, 4H, morpholine-intra-2×-CH2N), 2.388 (s, 3H, pyrrole-CH3), 2.309-2.293 (m, 2H, morpholine-external NCH2), 2.078 (m, 2H, semiline ring-CH2-CH2-CH2).

BIOLOGICAL SYSTEMS ANALYSIS

EXAMPLE 1: System ELISA inhibition of cell proliferation

To determine the level of activity and effect of various compounds of the present invention on the inhibition of proliferation (cell toxicity) cancerous human cells with high expre is the Sion receptor endothelial growth factor (VEGFR) - cells HUVEC (human umbilicial vein endothelium cells are human cells, umbilical vein endothelium) you can use the following system analysis in vitro.

Cellular analysis described here is intended for testing mediated VEGFR activity of compounds against angiogenesis and the effect of inhibiting the proliferation of cancer cells in vitro. The effect and the activity expressed by the value of the IC50that destroys the cancer cell. General methods of analysis are described below: human Cells with high expression of VEGFR selected and seeded in 96-well plate for cell culture at a suitable concentration (exponential 5000 cells/ml of medium). The cells are then cultivated in an incubator with carbon dioxide (CO2) to their confluences approximately 85%. Then the environment for culturing cells replaced with fresh medium, adding the test compounds in a series of concentrations (typically from 6 to 7 concentrations). The cells are then again placed in the incubator and cultured continuously for 72 hours. After 72 hours cells exposed to compounds, and control cells analyzed for their proliferation using the method of sulforhodamine In (SRB). IC50compounds against the tested cell is calculated on the basis of these indicators inhibition of serial concentrations of the test compounds.

Material and methods:

(a) D is methylsulfoxide (firm reagents Sinophma, catalog No. T20050806)

(b) HUVEC Cells (purchased at the Institute of biochemistry and cell biology)

(in) Tablets for cell cultures Falcon 100 mm (Baton Dickison Labware, Baton Dickison and company, catalog No. 18677)

(g) 96-well culture kit Corning (Corning Incorporated, catalog No. 3599)

(d) pipette Fisher (Fisher scientific, catalog No. 03-692-164)

(e) Cell DMEM/F12 (Gibco, catalog No. 12400-024)

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

(C) Phosphate-saline buffer solution (Gibco, catalog No. 10010-072)

(and) 0.25% Trypsin-EDTA (Gibco, catalog No. 25200-056)

(K) Sulforhodamine (Sigma, catalog No. 3520-42-1)

(l) Acetic acid (firm reagents Sinophma, catalog No. T)

(m) Trichloroacetic acid (firm reagents Sinophma, catalog No. T)

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

(a) Biological laminar Boxing class II A/B3 (ThermoForma, catalog No. NV-03)

(n) CO2incubator with a water jacket series II (ThermoForma, Model: 3111)

(R) Centrifuge (Fisher Scientific Marathon 8K, No. 0027-02)

(C) a card Reader for tablets Novastar (BMG Labtech, catalog No. 700-0081)

(t) Orbital shaker (Qilinbeier, catalog No. TS-1)

Protocol:

The following Protocol is used to analyze the activity of cellular toxicity values IC50test compounds invented by the th cells HUVEC:

1. The HUVEC cells were grown in growth medium (DMEM/F12, with the addition of 10% Fetal bovine serum - FBS) in 100 mm culture tablets Corning to confluently at 37°C, 5% CO2.

2. The HUVEC cells were washed in 100 mm tablets PBS, then cells were collected by trypsinization and were sown in 96-well plates to cell cultures Corning at a concentration of 50,000 cells/ml, leaving 6 holes on each plate empty in the background.

3. Cells were grown in 96-well tablets at 37°C, 5% CO2up to 85% of confluently.

4. Prepared the original mortar joints using DMSO for dissolving candidate compounds to a concentration of 20 mm. Then for dilution of the initial solution to a series of concentrations of the test compounds used DMSO (namely 2 mm, 1 mm, 0.2 mm, 20 μm, 2 μm, 0.2 μm).

5. Cell culture medium (in this case, DMEM/F12, with the addition of 10% FBS) was used for cultivation of a solution of the compound prepared above. Each standard solution concentration of the compounds in DMSO were diluted 20 times with culture medium by adding 5 μl of a solution of the compound in DMSO to 95 μl of culture medium, Hatem well mixed on the vortex. This ensured that the concentration of DMSO, the impact of which is subjected to the HUVEC cells, would not exceed 0.5%.

6. After attachment of HUVEC cells to the bottom of the Cup and reaching conflu is nutnosti approximately 85% of the culture medium was replaced with fresh DMEM/F12, with the addition of 10% FBS. To each well was added 180 μl of medium, and then to each well was added 20 μl of a solution of test compounds in the environment, prepared in stage 5. For holes, group negative control was added 20 μl of culture medium containing 0.5% pure DMSO. Thus, cells HUVEC were exposed to the effect of each test compound in serial final concentration of 100 μm, 10 μm, 5 μm, 1 μm, from 0.1 μm to 0.01 μm and 0.001 μm.

7. Cultural tablets were placed back in the incubator and cultured for 72 hours at 37°C, 5% CO2.

8. After 72 hours of culture was removed from the incubator in a sterile working area.

9. The latch (50% trichloroacetic acid - THU) were prepared by adding water, pure for analysis, THU, fixation of the cells by gently layering of 50 μl of cold trichloroacetic acid on the surface of the growth environment.

10. The plates were incubated for 1 hour at 4°C, and then washed with water several times to remove THU, whey protein, etc. of the Tablets were dried in air and kept until use. The optical density of the net control's background was measured in the wells, inkubiruemykh with growth medium without cells.

11. 0.4% Solution of sulforhodamine was prepared using a 10% solution of acetic acid. In each well of 96-well plates was added 50 μl of a solution of sulforhodamine Century

12. The cells were allowed to appear within 30 minutes.

13. Preparing a wash solution 10% acetic acid. At the end of the dyeing, the dye was removed, and cells were quickly rinsed with 1% acetic acid. Repeated to remove the incorporated dye. The time of washing maintained at a minimum to reduce the desorption of the dye associated with the protein. After rinsing the culture was dried in the air.

14. Then enabled the dye was dissolved in the volume of sulforhodamine Century Solution to solubilize (10 mm Tris) was equal to the original volume of culture medium. Then the crop was allowed to stand for 5 minutes at room temperature, and the mixing of the dye was increased by mild agitation in a rotary shaker.

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

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

IR = 100×(absorption control cells - absorption cells exposed to the test compounds at various concentrations)/absorption control cells %.

The value of the IC50can be inferred from the IR compounds with different concentration gradients.

The active compounds according to the invention

Biologicheskie the activity of the compounds according to the invention test, using the above analysis system. The values of the IC50measured and shown in the table below:

Example No.IC50(VEGFR/HUVEC) (μm)
10,09
2in 0.288
30,1
40,404
50,1
60,28
80,308
90,068
100,123
110,207
120,3
130,804
140,457
151.2
160,21
170,129
190,46

EXAMPLE 2: System analysis kinases VEGF-R2

This system of analysis used to measure in vitro kinase activity of recombinant human VEGF R2 ELISA analysis.

Materials and reagents:

A. A wash buffer (buffer FSB-T): 1× FSB (137 mm NaCl, 2.7 mm KCl, 4.3 mm Na2HPO4, 1.4 mm KH2PO4pH brought to 7.2) and 0.05% tween-20.

B. 1% Bovine serum albumin (BSA, Calbiochem #136593) in the buffer FSB-So

century of Stop buffer: 50 mm EDTA, pH 8.0.

, kits are used®labeled with europium IgG against mouse (PerkinElmer Life Sciences #AD0124).

D. kits are used®Amplifying solution (PerkinElmer Life Sciences #1244-105).

e. Kits are used®Streptavidin coated 96-well yellow tablet (PerkinElmer Life Sciences #AAAND-0005).

W. Recombinant human VEGF-R2 kinase (supplied in 50 mm Tris-HCl (pH 8.0), 100 mm NaCl, 5 mm DTG, 15 mm restored glutathione and 20% glycerol) (Cell signaling technology #7787).

C. 10 mm solution of ATP (Cell signaling technology #9804).

I. the Peptide is a precursor of Biotin-gastrin (Tyr87) (Cell signaling technology #1310).

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

L. the Buffer for tyrosine kinase HTScan™ (4×)

1x kinase buffer:

60 mm HEPES

5 mm MgCl2

5 mm MnCl2

3 μm Na3VO4

(Cell signaling technology #9805).

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

Technique:

Used the following Protocol:

1. The test compound was diluted with DMSO to wish the end of the analytical concentration. 1 μl of the test compounds, the negative control (a sample that is not added no test compound), in each analysis system was added 1 μl of DMSO.

2. 6 μm substrate peptide (Tyr87) bred dH2O (1:1), and each analysis was added to 15 μl.

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

4. In a test tube for the enzyme were collected to 2.2 µg enzyme VEGF-R2.

5. 10 μl of DTT (1.25 M) was added 2.5 ml tyrosinekinase buffer 4

HTScan™ (240 mm HEPES pH 7.5, 20 mm MgCl2, 20 mm MnCl2, 12 μm Na3VO4for preparation of DTT/kinase buffer.

6. 0.75 ml of DTT/kinase buffer was transferred into each tube for enzyme for the preparation of 4× reaction mixture, and 7.5 ál of 4x the reaction mixture was added to each analysis system.

7. 2 μl ATP (10 mm) was added to 498 μl dH2Oh and 7.5 μl was added to each analysis system.

Final analytical concentrations for 30 µl of the reaction mixture

60 mm HEPES pH 7.5

5 mm MgCl2

5 mm MnCl2

3 μm Na3VO4

1.25 mm DTT

10 μm ATP

a 1.5 ám substrate peptide

22 ng VEGF-R2 kinase

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

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

10. 25 μl of each reaction mixture and 75 ál dH2

11. Each well was washed three times with 200 ál buffer FSB So the Tablet was tapped on a paper towel to remove excess liquid.

12. The first antibody, phosphotyrosine mAb (P-Tyr-100) diluted 1:1000 in buffer FSB-T 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. Was carried out by washing, as described above for stage 11.

15. Labeled with europium IgG against mouse diluted 1:500 in buffer FSB-T with 1% BSA to each well was added 100 μl of diluted antibody.

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

17. Each well was washed five times with 200 ál buffer FSB So the Tablet was tapped on a paper towel to remove excess liquid.

18. Added 100 μl/well of strengthening solution kits are used®.

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

20. The emitted fluorescence was measured at 615 nm using a suitable reader for tablets with a temporal resolution.

The calculation of the index of inhibition: IR (%)=100-100*(X-B)/(N-B)

X = value of fluorescence in wells containing TEC is dummy connection

N = negative control

In = net control

The value of the IC50can be deduced from the IR compounds with different concentration gradients.

The active compounds according to the invention

The biochemical activity of the compounds according to the invention are tested using the above analysis system. The values of the IC50measured and shown in the table below:

Example NoIC50(VEGFR/bio) (μm)
10,014
20,021
30,28
40,041
50,0085
60,023
70,69
80,115
90,49
100,014
110,001
120,001
13 0,003
140,004
150,002
160,0013
170,001
180,01
190,012
200,072
210,16

PHARMACODYNAMIC SYSTEMS ANALYSIS IN VIVO

therapeutic effect of the compound from Example 63 against xenografts of cancer of the colon of human HT-29 in mice deprived of hairline

1. Summary:

Evaluated therapeutic effects of the compound from Example 63 against xenografts of cancer of the colon of human HT-29 in mice devoid of hair. Prolonged oral administration of the compound of Example 63 markedly inhibited growth of colon cancer human HT-29 and reduced tumor volume, the mouse may well endure this connection.

2. Purpose:

Evaluated therapeutic effects of the compound of Example 63 against xenografts of cancer of the colon of human HT-29 in mice devoid of hair.

3. The tested drugs is a war tool:

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

The method of obtaining the compound of Example 63 was diluted to the appropriate concentration with distilled water.

4. The animals in the study:

Female mice BALB/cA-nude at the age of six to seven weeks bought in Slaccas Experimental Animal. No. of certificate: SCXK(Shanghai) 2003-0003. Conditions of cultivation: the SPF level.

5. Testing Protocol:

Mice deprived of hair, were infected subcutaneously with cells colon cancer human HT-29. After tumors grew to 100-300 mm3mice are randomly divided into groups (d0). Doses and dose regimens are shown in table 1. The volume of tumors and weight of mice was measured 2-3 times per week. The formula tumor volume (V) represents the formula: V=1/2×a×b2and: length of the tumor, b: width of the tumor.

Table 1
therapeutic effect of the compound of Example 63 against xenografts of cancer of the colon of human HT-29 in mice deprived of hairline
GroupDose (mg/kg)IntroductionThe number of animals d0/dn/td> TV (X±SD, mm3)RTVT/C (%)
d0dnX±SD
Controlp,o9/9291±66729±2982,54±1,01
Connection40d0-125/5364±46300±1540,80±0,4231,5*
Example 63
d0: the first dosage; dn: the 13th day after the first dose; TV (tumor volume): tumor volume; RTV (relative tumor volume): relative tumor volume; *P<0,01 vs. control.

6. Conclusion:

Example 63 obviously inhibited growth of colon cancer human HT-29 and reduced tumor volume; mouse may well re ositi this connection without obvious toxicity.

The test compound was a compound obtained according to example 53.

Additional example 1: test for inhibition of proliferation of cancer cells

Cellular analysis described in this paper aims to test the potency of the compound from example 53 in relation to inhibition of proliferation of cancer cells in vitro using the method sulforhodamine In (SRV). Cancer cells include HUVEC (human cells of the umbilical vein endothelium), HT-29 (cells of human colorectal cancer), MoE (human cell line megakaryoblastic leukemia), A431 (human cells carcinoma of the epidermis), NCI-H526 (cell small-cell lung cancer) and SK-BR-3 (breast cancer cells). Activity is given in table 1.1.

Table 1.1
The activity of inhibiting the proliferation of cancer cells in vitro for connection example 53
# exampleIC50 (µM, mean±SD)
HUVECHT-29MoEA431NCI-H526 SK-BR-3
531,12,4±1,60,8±0,22,0±0,58,3±0,37,8±1,5

The results show that the compound according to example 53 unexpectedly inhibited the proliferation of HUVEC, MoE expressing a high degree of receptor tyrosinekinase VEGFR and c-kit. The values of the IC50equal to 1.1 µm and 0.8 µM, respectively. Additionally, the compound from example 53 inhibits the proliferation of A431, SK-BR-3 expressing a high degree of EGFR, HER2 and inhibits cell proliferation of NCI-H526, expressing a high degree of c-kit.

The specified analysis proves that the claimed compounds according to the invention can inhibit protein kinases VEGFR, c-kit, EGFR, HER2. Moreover, the claimed compounds according to the invention obviously inhibit the proliferation of cancer cells of the colon, rectum, leukemia cell, cell squamous cell carcinoma, small-cell lung cancer cells, breast cancer cells.

Additional example 2: Anticancer pharmacodynamic analysis of in vivo

The methodology of the test and the stage are the same as described in "PHARMACODYNAMIC SYSTEMS ANALYSIS IN VIVO of the present invention. therapeutic effects of the compound from example 53 in relation to xenotransplant is anatov of cancer of the colon and rectum, non-small cell lung cancer, liver cancer, melanoma, kidney cancer was evaluated in mice devoid of hair. The test results are shown in table 2.1.

Example 53
Table 2.1
Anticancer activity of the compounds according to example 53 in vivo
Cancer cellsMedicationDose (mg/kg)IntroductionThe initial tumor volume (mm3)T/C (%)Note
HT-29 (colon cancer and rectum)Controlsolventp/o D0-20146±8
Example 5315p/o D0-20147±749,4
Example 5330p/o D0-20151±448,5the
Example 5360p/o D0-20156±1831,6
Calu-3 (nemelka cell lung cancer)Controlsolventp/o D0-20227±27
Example 5315p/o D0-20223±2926,3
Example 5330p/o D0-20252±4414,73/6(PR)
Example 5360p/o D0-20200±3716,13/6(PR)
NCI-N (nemelka cell lung cancer)Controlsolventp/o D0-13184±37
Example 5315p/o D0-13185±2741,1*
Example 5330p/o D0-13181±2146.3*
Example 5360p/o D0-13176±2858,4*
Bel-7402 (liver cancer)Controlsolventp/o D0-17119±20
Example 5315p/o D0-17114±1539,8
Example 5330p/o D0-17120±2129,2
Example 53 60p/o D0-17119±1213,3
And 375 (drives of the working systems mA)Controlsolventp/o D0-16160±10
Example 5315p/o D0-16147±2582,5
Example 5330p/o D0-16146±758,5
Example 5360p/o D0-16155±646,4
Caki-1 (kidney cancer)Controlsolventp/o D0-22242±68
15p/o D0-22292±7873,0
Example 5330p/o D0-22303±5845,5
Example 5360p/o D0-22212±6236,8
*P<0,01 vs. control; control: n=12; group processing: n=6; PR: partial regression; p/o: oral; D0-17: from 0 days to 17 days; T/C (%): relative tumor volume (%).

The results show anticancer activity of the compounds according to example 53 against xenotransplantation colon cancer (HT-29), lung cancer (NCI-H460, Calu-3), liver cancer (Bel-7402), melanoma (A), kidney cancer (Caki-1) in mice, deprived of hair, in vivo. Connection example 53 holds pronounced anticancer activity against xenotransplantation listed above, reduces tumor volume and has a wide range of applications in anti-cancer medicine.

The connection is in accordance with the present invention as inhibitors of VEGFR are suitable for the treatment of non-small cell lung cancer, liver cancer, melanoma, kidney cancer, and not just colon cancer.

1. The compound having the formula (I)or its pharmaceutically acceptable salt:

where X represents carbon or nitrogen;
R1and R2each independently represents hydrogen;
R3represents a C1-10alkyl;
R4represents- (CH2CH(OH)]rCH2NR9R10or -(CH2)nNR9R10;
when X represents a nitrogen, R5no, R6, R7, R8each independently selected from the group consisting of hydrogen atom and halogen atom;
when X represents a carbon, R5, R6, R7, R8each independently selected from the group consisting of hydrogen atom, halogen atom, hydroxys1-10of alkyl, C1-10of alkyl, phenyl, a six-membered rings of heteroaryl with one nitrogen atom, hydroxyl, -OR9, -NR9R10, -(CH2)nCONR9R10, -NR9COR10, -SO2R9and-NHCO2R10where specified phenyl is unsubstituted or optionally substituted one or more than one group selected from the group consisting of C1-10of alkyl, C1-10alkoxyl and halogen atom;
R9and R10each independently selected from the group consisting of a hydrogen atom, a C110 of alkyl, where specified With1-10alkyl is unsubstituted or optionally substituted one or more than one group selected from the group consisting of C1-10of alkyl, phenyl, halogenfree, hydroxyl, C1-10alkoxyl, hydroxys1-10of alkyl;
R9and R10together with the attached atom to form a 5-6-membered heterokonta, where the specified 5-6-membered heterokonta may contain one heteroatom About;
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 Union, representing pyrrole-nitrogen-containing heterocyclic derivative or its pharmaceutically acceptable salt according to claim 1, where R3represents methyl.

3. The Union, representing pyrrole-nitrogen-containing heterocyclic derivative or its pharmaceutically acceptable salt according to claim 1, where R1and R2represent a hydrogen atom.

4. The Union, representing pyrrole-nitrogen-containing heterocyclic derivative or its pharmaceutically acceptable salt according to claim 1, including compounds having the following formula (IA), or pharmaceutically acceptable salt:

where X represents carbon or nitrogen;
R1and R2each independently represents waters of the rod;
R3represents a C1-10alkyl;
R4represents- (CH2CH(OH)]rCH2NR9R10or -(CH2)nNR9R10;
when X represents a nitrogen, R5no, R6, R7, R8each independently selected from the group consisting of hydrogen atom and halogen atom;
when X represents a carbon, R5, R6, R7, R8each independently selected from the group consisting of hydrogen atom, halogen atom, hydroxys1-10of alkyl, C1-10of alkyl, phenyl, a six-membered rings of heteroaryl with one nitrogen atom, hydroxyl, -OR9, -NR9R10, -(CH2)nCONR9R10, -NR9COR10, -SO2R9and-NHCO2R10where specified phenyl is unsubstituted or optionally substituted one or more than one group selected from the group consisting of C1-10of alkyl, C1-10alkoxyl of the halogen atom;
R9and R10each independently selected from the group consisting of a hydrogen atom, a C1-10of alkyl, where specified With1-10alkyl is unsubstituted or optionally substituted one or more than one group selected from the group consisting of C1-10of alkyl, phenyl, halogenfree, hydroxyl, C1-10alkoxyl, hydroxys1-10of alkyl;
R9and R10together the ones with the attached atom to form a 5-6-membered heterokonta, where the specified 5-6-membered heterokonta may contain one heteroatom About;
n is an integer from 2 to 6; and
r is an integer from 1 to 2.

5. The compound or its pharmaceutically acceptable salt according to claim 1, including compounds having the following formula (IB), or their pharmaceutically acceptable salts:

where X represents carbon or nitrogen;
R1and R2each independently represents hydrogen;
R3represents a C1-10alkyl;
R4represents- (CH2CH(OH)]rCH2NR9R10or -(CH2)nNR9R10;
when X represents a nitrogen, R5no, R6, R7, R8each independently selected from the group consisting of hydrogen atom and halogen atom;
when X represents a carbon, R5, R6, R7, R8each independently selected from the group consisting of hydrogen atom, halogen atom, hydroxys1-10of alkyl, C1-10of alkyl, phenyl, a six-membered rings of heteroaryl with one nitrogen atom, hydroxyl, -OR9, -NR9R10, -(CH2)nCONR9R10, -COR9, -NR9COR10, -SO2R9and-NHCO2R10where specified phenyl is unsubstituted or optionally substituted one or more than one g is POI, selected from the group consisting of C1-10of alkyl, C1-10alkoxyl and halogen atom;
R9and R10each independently selected from the group consisting of a hydrogen atom, a C1-10of alkyl, where specified With1-10alkyl is unsubstituted or optionally substituted one or more than one group selected from the group consisting of C1-10of alkyl, phenyl, halogenfree, hydroxyl, C1-10alkoxyl, hydroxys1-10of alkyl;
R9and R10together with the attached atom to form a 5-6-membered heterokonta, where the specified 5-6-membered heterokonta may contain one heteroatom About;
n is an integer from 2 to 6; and
r is an integer from 1 to 2.

6. The Union, representing pyrrole-nitrogen-containing heterocyclic derivative, or its pharmaceutically acceptable salt according to claim 1 or 2, including:


































7. The Union, representing pyrrole-nitrogen-containing heterocyclic derivative or its pharmaceutically acceptable salt according to claim 1, where these pharmaceutically acceptable salts are salts formed with acids selected from the group comprising malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonate acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid and triperoxonane acid.

8. The pharmaceutical composition inhibiting the protein kinase containing compound, representing pyrrole-nitrogen-containing heterocyclic derivative or its pharmaceutically acceptable salt according to any one of claims 1 to 6 the effective therapeutic dose, as well as pharmaceutically acceptable carrier.

9. The compound having the following formula (IC) or (ID), which is an intermediate compound in the synthesis of the compounds of formula (I):

where R2represents hydrogen;
R3represents a C1-10alkyl;
R4represents- (CH2CH(OH)]rCH2NR9R10or -(CH2)nNR9R10;
R9and R10each independently represents hydrogen, C1-10alkyl, where specified With1-10alkyl is unsubstituted or optionally substituted one or more than one group selected from the group consisting of C1-10of alkyl, phenyl, halogenfree, hydroxyl, C1-10alkoxyl, hydroxys1-10of alkyl;
R9and R10together with the attached atom to form a 5-6-membered heterokonta, where the specified 5-6-membered heterokonta may contain one heteroatom About;
n is an integer from 2 to 6;
r is an integer from 1 to 6.

10. The way to obtain the intermediate compounds of formula (IC) according to claim 9, comprising the following stages:
the reaction educt - diapir pyrrolidinylcarbonyl acid IC-1 in tetrahydrofuran in the presence of acetic acid with cerium ammonium nitrate n and room temperature to obtain diapir personaldevelopment acid IC-2; and

reaction diapir personaldevelopment acid IC-2 in anhydrous tetrahydrofuran (carletonville)triphenylphosphorane by Wittig reaction with obtaining ether pyrrolidinedithiocarbamate acid IC-3;

recovery of ether pyrrolidinedithiocarbamate acid IC-3 in anhydrous ethanol hydrogen, catalyzed by palladium on carbon at room temperature to obtain ether pyrrolidinedithiocarbamate acid IC-4;

hydrolysis of the ester pyrrolidinedithiocarbamate acid IC-4 in aqueous solution of lithium hydroxide with obtaining ether errorcorrection acid IC-5;

recovery of ether errorcorrection acid IC-5 in anhydrous tetrahydrofuran solution of borane-tetrahydrofuran at (-20) - (-5)°C with obtaining ether pyrrolidinylcarbonyl acid IC-6;

metilirovaniya ether pyrrolidinylcarbonyl acid IC-6 in anhydrous dichloromethane in the presence of triethylamine at (-20) - (-5)°C with obtaining ether pyrrolidinylthiosemicarbazone acid IC-7;

the reaction of the ether pyrrolidinecarboxamido the new acid IC-7 with various amines of the formula R 4NH2obtaining amide ether pyrrolocarbazols acid IC-8;

reaction of amide ether pyrrolocarbazols acid IC-8 with trimethylaluminum in anhydrous toluene boiling under reflux with getting pyrroloquinoline semichasnoho Aza-heterocyclic ester IC-9;

the reaction pyrroloquinoline semichasnoho Aza-heterocyclic ester IC-9 triperoxonane acid at 30-50°C in argon atmosphere to obtain pyrroloquinoline semichasnoho Aza-heterocyclic formaldehyde IC;

11. The method of obtaining compounds of intermediate of formula (ID) according to claim 9, comprising the following stages:
reaction diapir of aljadida terracarbon acid IC-2 with a Grignard reagent - bromide cyclopropylamine in anhydrous tetrahydrofuran at room temperature in an argon atmosphere to obtain diapir parallelprogramming acid ID-1;

reaction diapir parallelprogramming acid ID-1 with Hydrobromic acid in methanol to obtain diapir of bromoaniline ID-2;

recovery diapir of bromoaniline ID-2 in anhydrous ethanol by hydrogen catalyzed by palladium on what parade at room temperature with obtaining diapir of bambuterol ID-3;

reaction diapir of bambuterol ID-3 with various amines of the formula R4NH2in dichloromethane by boiling under reflux with obtaining diapir pyrrolidinecarbonyl acid ID-4;

reaction diapir pyrrolidinecarbonyl acid ID-4 with trimethylaluminum in toluene at boiling under reflux with getting pyrroloquinoline eight-membered Aza-heterocyclic aldehyde ID;

12. The method of obtaining pyrrole-nitrogen-containing heterocyclic derivative according to claims 1 to 6, comprising the stage of interaction of oxindole with aldehyde in the presence of triethylamine or piperidine and heated the reaction mixture to form compounds of formula (I) for 2-12 h, where specified aldehyde has the formula below:

and the specified oxindol has the following formula:

where R1-R8are the same as defined in claim 1.

13. A method of inhibiting the catalytic activity of protein kinases, which lead to the contact specified protein kinase with these pyrrole-nitrogen-containing heterocyclic derivatives or their pharmaceutically acceptable salts according to any one of claims 1 to 6

14. The method according to item 13, where the said protein kinase is selected from the group consisting of receptor tyrosinekinase.

15. The use of compounds according to claim 1 for the manufacture of drugs that inhibits protein kinase.

16. The application of clause 15, where specified disorders associated with protein kinases, selected from the group consisting of disorders associated with VEGFR-2, EGFR, HER-2 and c-Kit.

17. The application of clause 15, where specified disorders associated with protein kinases, selected from the group consisting of leukemia.

18. The application of clause 15, where specified disorders associated with protein kinases represent a cancer selected from squamous cell carcinoma, renal cell cancer, Kaposi's sarcoma, non-small cell lung cancer, small-cell lung cancer, lymphoma, adenocarcinoma of the thyroid gland, cancer of the breast, head and neck cancer, uterine cancer, esophageal cancer, melanoma, bladder cancer, carcinosarcoma in the urinary and reproductive system, gastrointestinal carcinoma, glioma, colon cancer, rectum and cancer of the ovary.

19. A method of inhibiting the catalytic activity of protein kinases, which lead to the contact specified protein kinase with a specified composition of claim 8.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new antibacterial compounds of formula I

wherein R1 represents halogen or alkoxy group; each U and W represents N; V represents CH, and R2 represents H or F, or each U and V represents CH; W represents N, and R2 represents H or F, or U represents N; V represents CH; W represents CH or CRa, and R2 represents H, or also when W represents CH, may represent F; Ra represents CH2OH or alkoxycarbonyl; A represents group CH=CH-B, a binuclear heterocyclic system D, phenyl group which is mono-substituted in the position 4 by C1-4 alkyl group, or phenyl group which is di-substituted in positions 3 and 4 wherein each of two substitutes is optionally specified in a group consisting of C1-4 alkyl and halogen; B represents mono- or di-substituted phenyl group wherein each substitute is a halogen atom; D represents group

wherein Z represents CH or N, and Q represents O or S; or to salts of such compounds.

EFFECT: compounds are used for treating bacterial infections.

13 cl, 2 tbl, 25 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to derivatives of antibiotics, which represent compounds of formula (I) and their pharmaceutically acceptable salts, where U, V, W, X, R1, R2, R3, R4, R5, R6, A, B, D, E, G, m and n are determined in description. Invention also relates to pharmaceutical composition, containing said compounds and their application for obtaining medication for prevention or treatment of bacterial infections.

EFFECT: obtaining useful antimicrobial agents, efficient against various pathogens of people and animals.

23 cl, 1 tbl, 186 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to anhydrous crystalline vinflunine salts of general formula (I) prepared with 1 or 2 equivalents of a pharmaceutically acceptable inorganic or organic acid. . In formula (I) [The acid] represents hydrobromic, lactic or fumaric acid for a group of water-soluble crystalline salts, as well as para-toluenesulphonic, benzoic, mandelic and para-hydroxybenzoic acid for a group of relatively water-insoluble crystalline salts.

EFFECT: preparing the anhydrous crystalline vinflunine salts.

8 cl, 8 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel azaindole derivatives, having JAK-2 and JAK-3 kinase inhibiting activity, or pharmaceutically acceptable salts thereof. In formula (I): R3 denotes H; X1 denotes N or CR4; R2 denotes H, COOH, COOR' or CONHR'; R4 denotes H, F, R, OH, OR', COR', COOH, COOR', CONH2 or CN; or R2 and R4, taken together, form a benzene ring optionally substituted with 1-2 R10; R' denotes C1-3-alkyl or C1-3-alkenyl, each optionally substituted 1-2 R5; each R5 is independently selected from CN, unsubstituted C1-2alkyl, or two groups R5 together with a carbon atom with which they are bonded form a cyclopropyl ring; each R10 is independently selected from halogen, OCH3 or OH; R1 denotes or , R is H or denotes C1-2alkyl, optionally substituted with 1-3 R11; R6 denotes C1-4alkyl, optionally substituted with 1-5 R12; values of radicals R7 -R9, ring A, R11 -R14. The invention also relates to a pharmaceutical composition containing said compounds and a method of treating or reducing severity of a pathological condition such as allergy, asthma, amyotrophic lateral sclerosis, multiocular sclerosis, graft rejection, rheumatoid arthritis, solid malignant tumour, haematologic malignant disease, leukaemia, lymphoma and myeloproliferative disorders.

EFFECT: high efficiency of using the compounds.

41 cl, 6 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to substituted imidazopyridine derivatives of general formula (I) or enantiomers, diastereomers and tautomers and pharmaceutically acceptable salts thereof, in which A denotes -NH-, -CH2-, -CH2-CH2- or a bond; X denotes phenyl, phenyl condensed with a saturated heterocyclic 5- or 6-member ring, where the heterocyclic ring can contain one or two heteroatoms selected from O and N, and where the heterocyclic ring can further be substituted with an oxo group, a 6-member saturated heterocyclyl containing O as a heteroatom, a 5-6-member heteroaryl containing 1 or 2 heteroatoms selected from N, O and S, and where each phenyl and heteroaryl is possibly substituted with 1 to 2 R14 and/or 1 substitute R4b and/or 1 substitute R5; R1 and R2 are independently selected from the following groups: C1-6-alkyl and C1-6-alkylene-C3-7-cycloalkyl, and where each alkyl is possibly substituted with a OH group, or R1 and R2 together with the nitrogen atom with which they are bonded form a 5-6-member ring which is possibly substituted with one substitute selected from C1-6-alkyl and O-C1-6-alkyl; R4b denotes C(O)NH2, C(O)OH, C(O)NH-C1-6-alkyl, C(O)N-(C1.6-alkyl)2, SO2-C1-6-alkyl, oxo group, and where the ring is at least partially saturated, NH2, NH-C1-6-alkyl, N-(C1-6-alkyl)2; R5 denotes a 6-member heteroaryl containing N as a heteroatom; R3 denotes -(CR8R9)n-T; R8 and R9 are independently selected from the following groups: H and C1-6-alkyl; n equals 1, 2, 3, 4, 5 or 6; T denotes or NR12R13; R10 denotes H, NH2, OH, C1-6-alkyl, possibly substituted with one OH, a halogen atom, NH(C1-6-alkyl) or N(C1-6-alkyl)2; q equals 1 or 2; Y denotes CH2, NR11 or O; R11 denotes H, or C1-6-alkyl; R12 and R13 are independently selected from the following groups: H, C1-6-alkyl, C1-6-alkynyl, (CH2)0-2-C3-7-cycloalkyl, and C1-6-alkylene-O- C1-6-alkyl, where C1-6-alkyl is possibly substituted with one halogen; R14 denotes a halogen atom, CN, C1-6-alkyl, possibly substituted with 1-3 substitutes selected from halogen atom, OH, O- C1-6-alkyl, O-C(O)C1-6-alkyl, O- C1-6-alkyl, possibly substituted with one substitute selected from OH, O- C1-6-alkyl, and O-C(O) C1-6-alkyl, or OH. The invention also relates to a pharmaceutical composition based on the compound of formula (I).

EFFECT: novel imidazopyridine derivatives are obtained, which can be used as melanocortin-4 receptor modulators.

17 cl, 8 tbl, 22 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new compounds of formula , wherein A represents residues of formulae

, , , X represents O; X1-X4 represents N, CH, CR1 or C-, X9-X12 represents N, CH, CR4 or C-, X13-X16 represents N, CH, CR or C-, wherein C represents an attachment point of the group A to a residue of the structure of formula (I); R' represents H or alkyl; R represents alkoxy, or Het; R1 represents F, CI, Br, I, OH, CN, carboxy, CONR6R7, NR2COR8, NR2COOR8, alkoxy, fluorinated alkoxy, Ar, Het or OHet; or R1 represents one of the following formulas: wherein n is equal to 2 and m is equal to 3; R2 represents H, alkyl, fluorinated alkyl, cycloalkyl, Het or Het-NH-CO-; R4 represents F, Cl, Br, I, OH, alkoxy, cycloalkoxy, Het or OHet; or R4 represents one of the following formulae: , wherein n is equal to 2 and t is equal to 3; each R6 and R7 independently represents alkyl, or cycloalkyl, or R6 and R7 together represent alkylene group containing 5-6 carbon atoms which forms a cycle with N atoms; R8 represent alkyl, or cycloalkylalkyl; R9 represents alkyl; Ar represents aryl group; Het represents heterocyclic group which is completely saturated, particularly saturated or completely unsaturated containing 5 to 10 ring atoms in which at least 1 ring atom represents N, O or S atom which is unsubstituted or substituted once or several times by the substituted specified in cl. 1; and their pharmaceutically acceptable salts or solvates or N-oxides, or solvates of their pharmaceutically acceptable salts, or solvates of N-oxides of their pharmaceutically acceptable salts wherein said compound can be presented in the form of a polymorph, wherein if said compound shows chirality, it can be presented in the form of a mixture of enanthiomers or a mixture of diastereoisomers, or can be presented in the form of single enanthiomer or single diastereoisomer; and wherein at least one of the groups R, R1 or R4 represents Het or OHet, wherein the group Het is specified in each case in substituted or unsubstituted azabicyclooctyl, oxaazabicycloheptyl, diazabicycloheptyl, diazabicyclononyl, diazabicyclooctyl, pyrazolyl, dihydroimidazolyl, 1,4-diazepanyl, hezahydropyrrolopyrazinyl and octahydropyrrolopyridinyl. Also the invention refers to other compounds of formula (I), to specific compounds, to a pharmaceutical composition based on the compound of formula (I), to a method of selective activation/stimulation of α-7 nicotinic receptors, to application of the compound of formula (I) for making the drug.

EFFECT: there are produced new compounds showing effective biological properties.

53 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present application describes substituted bicyclic beta-lactams of formula I: which are class A and class C β-lactamase inhibitors wherein X, R1 and R2 are specified in the application, as well as a method for producing them. The compounds of formula I and their pharmaceutically acceptable salts are applicable for preparing a pharmaceutical composition and for producing a drug. The declared compounds are applicable for treating bacterial infections, optionally in a combination with a β-lactam antibiotic. Particularly, the compounds may be used with such β-lactam antibiotics, as e.g. imipenem, piperacillin or ceftazidime to control microorganisms resistant to β -lactam antibiotics due to the presence of β-lactamases.

EFFECT: preparing the composition for treating bacterial infections.

28 cl, 117 ex, 3 tbl, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae

and ,

which can be used to inhibit lipid kinase, including PI3K, and treat lipid kinase-mediated disorders. Values of radicals are given in claim 1.

EFFECT: improved properties of the compound.

11 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae and including their stereoisomers, as well as pharmaceutically acceptable salt, where X denotes O or S; R1 is selected from H, F, CI, Br, I, CN, -CR14R15-NR16R17, -CR14R15-NHR10, -(CR14R15)NR10R11, -(CR14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -(CR14R15)mOR10, -(CR14R15)nS(O)2R10, -C(OR10)R11R14, -C(R14)=CR18R19, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NR12OR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NHR12, -NR12C(=Y)R10, -S(O)2R10, -S(O)2NR10R11, C2-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C4 carbocyclyl, piperidinyl, thiopyranyl, phenyl or C5-C6 heteroaryl; R2 is selected from H, C2-C12 alkyl and thiazolyl; R3 denotes a condensed bicyclic heteroaryl selected from indazole, indole, benzoimidazole, pyrrolopyridine, imidazopyridine and quinoline; R10, R11 and R12 independently denote H, C2-C12 alkyl, C3 carbocyclyl, heterocyclyl selected from pyrrolidine, morpholine and piperazine, phenyl or heteroaryl selected from pyrazole, pyridine, benzothiophene; or R10 and R11 together with a nitrogen atom with which they are bonded possibly form a saturated C3-C6 heterocyclic ring, possibly containing one additional ring atom selected from N or O, where said heterocyclic ring is possibly substituted with one or more groups independently selected from oxo, (CH2)mOR10, NR10R11, SO2R10, C(=O)R10, NR12S(O)R11, C(=Y)NR10R11, C1-C12 alkyl and heterocyclyl selected from pyrrolidine; R14 and R15 are independently selected from H or C1-C12 alkyl; R16 and R17 independently denote H or phenyl; R18 and R19 together with a carbon atom with which they are bonded form a C3-C20 heterocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, phenyl, heteroaryl, piperidinyl and condensed bicyclic heteroaryl possibly substituted with one or more groups independently selected from F, CI, Br, I, CF3, -C(=Y)R10, -C(=Y)OR10, oxo, R10, -C(=Y)NR10R11, -(CR14R15)nNR10R11, -NR10R11, -NR12C(=Y)R10, -NR12C(=Y)NR10R11, -NR12SO2R10, OR10, SR10, -S(O)2R10, -S(O)2NR10R11, possibly substituted with carbocyclyl, selected from cyclopropyl, possibly substituted heterocyclyl selected from piperazine, possibly substituted with alkyl and alkylsulphonyl, pyrrolidine, morpholine, piperdine, possibly substituted CH3, phenyl and possibly substituted heteroaryl selected from imidazole and triazole; Y denotes O; m equals 0, 1 or 2; n equals 1 and t equals 2. The invention also relates to a pharmaceutical composition which modulates lipid kinase activity, based on said compounds.

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used to treat lipid kinase-mediated diseases, for example, cancer.

48 cl, 2 tbl, 372 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula where R1 is selected from H, F, CI, Br, CF3, C1-C6 alkoxy and OH; R2 is selected from H and C1-C6 alkyl; n equals 1-5; m equals 0 or 1; and Y is selected from CH2, NR3, (NR3R4)+X-, O and S; R3 and R4 are independently selected from H and C1-C4 alkyl; and X- is selected from pharmaceutically acceptable anions. The invention also relates to a method of producing said compound and to an antiviral pharmaceutical composition based on said compound of formula (I).

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used in medicine to treat a viral diseases such as herpes.

19 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrolopyrimidines of formula (I) and pharmaceutically acceptable salts and solvates thereof, having IGF-IR and IR inhibiting properties, which can be used to treat proliferative cancerous diseases such as breast cancer, sarcoma, lung cancer and prostate cancer. In the compound of formula (I): R1 is selected from H and C1-C3alkyl; R2 is selected from H, C1-C3alkyl and halogen; R3 is selected from H, OH, C1-C6alkyl, groups -C1-C6alkylene-OH, -C1-C6alkylene-phenyl (optionally substituted with a halogen) and -C1-C6alkylene-C(O)NH2; R4 is selected from H, halogen, C1-C6alkyl and -O-C1-C6alkyl; or R3 and R4, together with atoms with which they are bonded, form a 5- or 6-member lactam; each of R5 and R6 is independently selected from H, halogen, C1-C6alkyl and -O-C1-C6alkyl, or R5 and R6 together with an aryl with which they are bonded form naphthalene; R7 is selected from C1-C6alkyl, -O-C1-C6alkyl, halogen, -N-R19R19 and -O-C1-C6alkylene-halogen; R8 is selected from H, halogen and C1-C6alkyl; one of R9 and R10 is selected from -C1-C6alkylene-SO2-C1-C6alkyl, -NR19-C(O)-C0-C6alkylene-NR22R23, -O- C0-C6alkylene(optionally substituted with -OH)-NR22R23, and etc, given in the claim and the other of R9 and R10 is selected from H, C1-C6alkyl, -O- C1-C6alkyl and halogen.

EFFECT: improved method.

41 cl, 12 dwg, 263 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a folate receptor ligand which is folate-polyethylene glycol-dihexadecyl-L-glutamate of formula and a method for production thereof. This compound exhibits the capacity to direct a nanosystem to target cells and increases the efficiency of transportation systems of antitumour agents since folate receptors are present in large amounts on the surface of tumour cells; also they become more at the later stages of development of the disease.

EFFECT: use of an approach based on click-chemistry principles for synthesis of a folate-targeted derivative provides a unique opportunity for fast and efficient modification of nanosystems.

2 cl

FIELD: chemistry.

SUBSTANCE: invention relates to biologically active compounds, specifically to a group of 2-substituted 1,2,4,5-tetrahydro-3H-pyrrolo[1,2-a][1,4]diazepin-3-ones of general formula where R denotes hydrogen, a straight or branched (C1-C4)-alkyl; a hydroxyalkyl having an alkyl chain with 2-3 C atoms; a phenylalkyl having an alkyl chain with 1-2 C atoms, wherein the phenyl ring can have one or two methoxy groups. The invention also relates to a method of producing said compounds.

EFFECT: novel compounds can be used in medicine as antidepressant and antianxiety agents.

6 cl, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: compound is a pyrrolidine derivative having a fragment of a sterically hindered phenol, having general formula: where R1 denotes H, Me, Et; R2 denotes Me, Et, i-Pr, i-Bu; Ar denotes Ph, 2-HalPh, 3-HalPh, 4-HalPh, (where Hal denotes F, Cl, Br, I), 2,6-diMePh, 2,3,5,6-tetraFPh, 2-MeOPh, 3-MeOPh, 4-MeOPh, (naphthalen-1-yl), (naphthalen-2-yl), 2-NO2PH, 3-NO2Ph, 4-NO2Ph. The compounds are obtained by mixing a solution of azomethine of formula: where values of R1, R2 are given above, with N-substituted malemide in air and reaction thereof is induced by catalytic amounts of N-tert-butoxycarbonyl derivatives of alpha-amino acids (glycine, alanine, phenylalanine), followed by concentration of the organic phase at low pressure, and cleaning the residue by chromatography on silica gel using CHCl3/MeOH as the eluent.

EFFECT: prolonged antioxidant activity.

2 cl, 2 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (IX) wherein radicals and symbols have values given in the claim, and pharmaceutically acceptable salts or tautomers thereof. Said compounds are inhibitors of poly(ADP-ribose)polymerase (PARP) and can be used to treat cancer, inflammatory diseases, reperfusion injuries, ischaemic conditions, stroke, renal failure, cardiovascular diseases, vascular diseases other than cardiovascular diseases, diabetes mellitus, neurodegenerative diseases, retroviral infections, retinal damage, skin senescence and UV-induced skin damage, and as chemo- or radiosensitisers for cancer treatment. The invention also relates to a pharmaceutical composition containing said compounds, use of said compounds and a method of treating said diseases.

EFFECT: high efficiency of using the compounds.

10 cl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 3-aroyl-2-arylhydrazonopyrrolo[1,2-a]quinozaline-1,4(2H,5H)-diones of formula:

Ar=Ph, R=Me, R1=H (a); Ar=4-MeC6H4 R=Me, R1=H (b); Ar=Ph, R=H, R1=COOH (c).

EFFECT: there are produced new compounds possessing analgesic activity that makes them being suggested to be used in medicine as drugs with the analgesic properties.

1 cl, 3 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel, highly crystalline mono(benzenesulphonic acid)besylate salts and polymorphs of the compound of formula (I): , a pharmaceutical composition containing said compounds, methods of producing the salts and use thereof as medicinal agents, particularly for sedative or hypnotic, anxiolytic, muscle relaxation or anticonvulsant purposes.

EFFECT: improved method.

32 cl, 36 dwg, 22 tbl, 10 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a novel tricyclic derivative of chemical formula 1 or pharmaceutically acceptable salts thereof: formula 1, where Y1, Y2 and Y3 independently denote H, C1-C10 alkyl with a straight or branched chain, hydroxy, C1-C10 alkoxy, -CCOR1, -NR2R3 or -A-B; A denotes -O-, -CH2-, -CH(CH3)-, -CH-N- or -CONH-; B denotes -(CH2)n1-Z, -(CH2)n2-NR2R3 or -(CH2)n3-OR1; Z denotes C5-C20 aryl, unsubstituted or substituted with R5 and selectively R6, C3-C10 cycloalkyl, unsubstituted or substituted with R5 and selectively R6, C1-C20 heterocyclic compound, unsubstituted or substituted with R5 and selectively R6; R1 denotes H or C1-C10 alkyl with a straight or branched chain; R2 and R3 independently denote H, C1-C10 alkyl with a straight or branched chain or -(CH2)n4R7; R5 denotes H, C1-C10 alkyl with a straight or branched chain, C5-C20 aryl or C1-C20 heterocyclic compound; R6 denotes H or C1-C10 alkyl with a straight or branched chain; R7 denotes -NR8R9, -COOR1, -OR1, -CF3, -CN, halogen or Z; R8 and R9 independently denote H or C1-C10 alkyl with a straight or branched chain; n1-n4 respectively denote an integer from 0 to 15; Y denotes H or C1-C10 alkyl with a straight or branched chain. The invention also relates to methods of producing a compound of formula 1, compositions containing the described compound and with effective inhibiting activity on poly(ADP-ribose)polymerase (PARP).

EFFECT: obtaining and describing novel compounds which can be suitable for preventing or treating diseases caused by excess PARP activity, especially neuropathic pain, neurodegenerative diseases, cardiovascular diseases, diabetic neuropathy, inflammatory diseases, osteoporosis and cancer.

23 cl, 123 ex, 7 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula possessing action on a BH4 sensitive condition.

EFFECT: invention refers to a pharmaceutical composition containing said compound to applying the compound for preparing a drug for treating the BH4 sensitive condition, such as a vascular disease, a psychoneurological disease, hyperphenylalaninemia.

12 cl, 31 dwg, 20 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel derivatives of hexahydro pyrazino [2,1-c][1,2,4]triazine of general formula (III) (values of radicals are given in invention formula), their pharmaceutically acceptable salts and application of said compounds for obtaining medication for treatment and prevention of acute myeloid leukemia.

EFFECT: obtaining medication for treatment and prevention of acute myeloid leukemia

3 cl, 3 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of 2-heteroaryl-substituted benzothiophene and benzofuran, precursors thereof and therapeutic use of said compounds, having structural formula (1a) where R1, R2, X9 and Q assume values given in the description, and pharmaceutically acceptable salts thereof, which are suitable for imaging amyloid deposits in living patients. The invention also relates to pharmaceutical compositions based on compounds of formula 1a, use and methods of producing said compounds. More specifically, the present invention relates to a method of imaging brain amyloid deposits in vivo for intravital diagnosis of Alzheimer's disease, and measuring clinical efficiency of therapeutic agents against Alzheimer's disease.

EFFECT: high efficiency of using said compounds.

15 cl, 1 tbl, 14 ex

Up!