WO2008138232A1 - Dérivés pyrrolo-azotés hétérocycliques, leur préparation et leur utilisation pharmaceutique - Google Patents

Dérivés pyrrolo-azotés hétérocycliques, leur préparation et leur utilisation pharmaceutique Download PDF

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WO2008138232A1
WO2008138232A1 PCT/CN2008/001352 CN2008001352W WO2008138232A1 WO 2008138232 A1 WO2008138232 A1 WO 2008138232A1 CN 2008001352 W CN2008001352 W CN 2008001352W WO 2008138232 A1 WO2008138232 A1 WO 2008138232A1
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group
methyl
aryl
oxo
ethyl
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PCT/CN2008/001352
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English (en)
Chinese (zh)
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Peng Cho Tang
Yidong Su
Yali Li
Lei Zhang
Fuqiang Zhao
Jialiang Yang
Ying Zhou
Pingyan Bie
Guangtao Qian
Minggang Ju
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Shanghai Hengrui Pharmaceutical Co., Ltd.
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Priority claimed from CN2008100875648A external-priority patent/CN101307052B/zh
Priority to JP2010507781A priority Critical patent/JP5342547B2/ja
Priority to CN2008800150088A priority patent/CN101675061B/zh
Priority to MX2009011964A priority patent/MX2009011964A/es
Priority to CA002685757A priority patent/CA2685757A1/fr
Priority to US12/451,466 priority patent/US8329682B2/en
Application filed by Shanghai Hengrui Pharmaceutical Co., Ltd. filed Critical Shanghai Hengrui Pharmaceutical Co., Ltd.
Priority to EP08783545A priority patent/EP2157093A4/fr
Priority to AU2008250895A priority patent/AU2008250895B2/en
Priority to BRPI0811865-5A2A priority patent/BRPI0811865A2/pt
Publication of WO2008138232A1 publication Critical patent/WO2008138232A1/fr
Priority to HK10104918.9A priority patent/HK1137027A1/xx
Priority to US13/628,446 priority patent/US20130303518A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a novel pyrrolo-N heterocyclic derivative, a process for producing the same, a pharmaceutical composition containing the same, and a pharmaceutical composition containing the same, and a pharmaceutical composition thereof They are useful as therapeutic agents, particularly as protein kinase inhibitors. Background technique
  • Cellular signaling is a fundamental mechanism of action. During signal transduction, extracellular stimuli are transmitted to the interior of the cell, which in turn regulates the progression of different cells. These signals regulate a variety of physiological responses, including cell proliferation, differentiation, apoptosis, and exercise, which exist as different types of lytic factors, including growth factors that are predominantly paracrine, autocrine, and endocrine. By binding to specific transmembrane receptors, growth factor ligands transmit extracellular signals to intracellular signaling pathways, causing individual cells to respond to extracellular signals. Many signaling processes are reversible processes that utilize protein phosphorylation involving specific protein kinases and phosphorylating enzymes.
  • Protein kinases are enzymes that catalyze the phosphorylation of hydroxyl groups on tyrosine, serine, and threonine residues of proteins.
  • the reverse mechanism of protein kinases and phosphorylases balances and regulates signal flow during signaling.
  • a protein phosphorylation state can affect its conformation, enzyme activity, cell localization, and the corresponding roles of protein kinases and phosphatases are modified.
  • Phosphorylation is an important regulatory mechanism in signal transduction, and abnormalities during signal transduction. Lead to abnormal differentiation, transformation and growth of cells.
  • a cell can become a cancer cell by converting a portion of its DNA into an oncogene, a growth factor receptor protein encoded by such an oncogene; a tyrosine kinase can also be mutated into an activated form resulting in a variety of Variations in human cells, it can be said that over-expressed normal tyrosine kinases can cause abnormal cell proliferation.
  • Tyrosine kinases can be conveniently divided into two classes: protein tyrosine kinases (PTKs) and serine-threonine kinases (STKs). PTKs phosphorylate tyrosine residues on proteins, and STKs phosphorylate serine and threonine residues on proteins. Tyrosine kinases can be not only receptor type (including extracellular domain, intracellular domain and transmembrane cell domain) but also non-receptor type (including all intracellular domains). A major aspect of PTK activity is that they are involved as cell surface protein growth factor receptors.
  • RTKs receptor tyrosine kinases
  • 90 tyrosine kinases are recognized in human genes, of which about 60 are receptor types and about 30 are non-receptive.
  • the growth factor receptor family can be further divided into 20 receptor tyrosine kinase subfamilies and 10 non-receptor tyrosine kinase subfamilies (Robinson et al, Oncogene, 2000, !£, 5548-5557) .
  • the RTKs subfamily includes the following: (1) EGF family, such as EGF, TGFa, Neu and erbB, etc.; (2) Insulin family, including insulin receptor, insulin-like growth factor I receptor (IGF1) and insulin receptor-related Sexual receptors (IRR); (3) family 111, such as platelet-derived growth factor receptors (PDGF, including PDGFa and PDGFP receptors), stem cell factor RTKs (SCF RTK, commonly referred to as c-Kit), fins- Related tyrosine Enzyme 3 (Flt3) receptor tyrosine kinase and colony stimulating factor 1 receptor (CSF-1R) tyrosine kinase and the like.
  • EGF family such as EGF, TGFa, Neu and erbB, etc.
  • Insulin family including insulin receptor, insulin-like growth factor I receptor (IGF1) and insulin receptor-related Sexual receptors (IRR)
  • family 111 such as platelet-derived growth factor receptors (PDGF, including PDGF
  • a portion of the non-limiting kinases include Abl, ARaf, ATK, ATM, bcr-abl, Blk, BRaf, Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CHK, AuroraA, AuroraB, AuroraC, cfms, c-fms, c-Kit, c-Met, cRafl, CSF1R, CSK, c-Src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Fps, Frk
  • PKs are thought to be associated with central nervous system diseases such as Alzheimer's disease (see Mandelkow, EM et al. FEBS Lett. 1992, 314, 315; Sengupta, A. et al. Mol. Cell. Biochem. 1997, 167, 99), pain (see Yashpal, KJ Neurosci. 1995, 15, 3263-72), inflammation such as arthritis (see Badger, J. Pharmn Exp. Ther. 1996, 279, 1453), psoriasis (see Dvir, et al, J. Cell Biol.
  • osteoporosis see Tanaka et al, Nature, 1996, 383, 528
  • cancer see Hunter and Pines, Cell 1994, 79, 573
  • atherosclerosis see Hajjar and Pomerantz, FASEB) J. 1992, 6, 2933
  • thrombosis see Salari, FEBS 1990, 263, 104
  • metabolic disorders such as diabetes (see Borthwick, AC et al. Biochem. Biophys. Res. Commun. 1995, 210, 738), vascular proliferative diseases such as Angiogenesis (see Stmwn et al. Cancer Res. 1996, 56, 3540; Jackson et al. J. Pharm. Exp. Ther.
  • PTKs signaling specific growth factors (ligands) interact extracellularly, followed by receptor dimerization, which activates the intrinsic activity of the protein kinase and phosphorylates.
  • the binding site of the internal signaling molecule is generated to form a complex with the cytoplasmic signaling molecule, promoting various cellular responses such as cell division (proliferation), expression of extracellular microenvironment metabolism, and the like.
  • the binding site for phosphorylation of the receptor tyrosine kinase is also a binding site with a high affinity for the SH2 (synchronous to src) domain of the signaling molecule.
  • SH2 synchronous to src domain of the signaling molecule.
  • Many intracellular substrate proteins associated with receptor tyrosine kinases have been identified and can be divided into two categories: (1) substrate with catalytic domain (2) substrate without catalytic region, but can be used as a combination, and Certain catalytically active molecules are related.
  • the specificity of the interaction of a receptor or protein with the substrate SH2 domain is determined by the amino acid sequence near the phosphorylated tyrosine residue, the amino acid sequence surrounding the SH2 domain and the phosphorylated tyrosine sequence and the specific receptor The difference in binding is consistent with the difference in substrate phosphorylation.
  • Protein tyrosine kinase function can be determined by expression pattern and ligand availability, as well as by downstream region signaling pathways activated by specific receptors. Therefore, phosphorylation provides an important adjustable step that can be determined A selective and differentiation factor receptor for signaling that is activated by a specific receptor. Abnormal expression or mutation of a receptor tyrosine kinase may result in uncontrolled cell proliferation (such as malignant tumor growth) or loss of key developmental processes. ,
  • Tyrosine kinases in most human tumors, such as leukemia, breast cancer, prostate cancer, non-small cell lung cancer (including adenocarcinoma, lung squamous cell carcinoma), gastrointestinal cancer (including colon cancer, rectal cancer, and gastric cancer) In cancers such as bladder cancer, esophageal cancer, ovarian cancer, and pancreatic cancer, mutations or overexpression may occur.
  • non-small cell lung cancer including adenocarcinoma, lung squamous cell carcinoma
  • gastrointestinal cancer including colon cancer, rectal cancer, and gastric cancer
  • mutations or overexpression may occur.
  • the broadness and relevance of tyrosine kinases have been further confirmed by detection of human tumor cells.
  • EGFR tyrosine kinase is mutated and overexpressed.
  • the "HER” or "Erb” receptor tyrosine kinase subfamily includes EGFR, HER2, HER3 and HER4. These subfamilies consist of an extracellular glycosylation ligand binding domain, a transmembrane domain, and an intracellular cytoplasmic catalytic domain that phosphorylates the tyrosine sequence on the protein.
  • the receptor tyrosine kinase catalytic activity can be activated by receptor overexpression or ligand-mediated dimerization.
  • the HER2 family of polymers has both homodimers and heterodimers.
  • homodimerization is the polymerization of HER1 (EGFR) with EGF family ligands (including EGF, transforming growth factor a, betacellulin, heparin-binding EGF, epiregulin), between four HER tyrosine kinases.
  • EGF EGF family ligands
  • the heterodimerization can be accelerated by binding to the heregulin (also known as neuregulin) family of ligands.
  • the receptors for HER3 has no enzymatic activity
  • heterodimerization of HER2 with HER3, or HER3 and HER4 also significantly stimulates tyrosine kinase receptor dimerization. In various cell types, receptor overexpression activates the activity of HER2 kinase.
  • MAP kinases microtubule-associated protein kinases
  • PI3 kinase phosphatidylcholines Alcohol
  • RTK insulin receptor
  • IGF-1R insulin-like growth factor-1 receptor
  • IRR insulin receptor-related receptor
  • IGF-1R interacts with insulin, IGF-I and IGF-II, resulting from two completely extracellular glycosylated ot subunits and two tyrosine kinase domain beta subunits that cross the cell membrane Heterotetramer.
  • the third subgroup of RTK refers to the platelet-derived growth factor receptor (PDGFR) family, including PDGFRci, PDGFRp, CSFIR, c-Kit and c-fms. These receptors are composed of a variety of immunoglobulin-like cyclic glycosylated extracellular domains and an extracellular domain in which the tyrosine kinase domain in the intracellular domain is blocked by an unrelated amino acid sequence.
  • PDGFRci platelet-derived growth factor receptor
  • Platelet-derived growth factor receptors such as PDGFRa and PDGFRp are also transmembrane tyrosine kinase receptors. When they bind to a ligand, either form a homodimer (PDGF-AA, PDGF-BB), or a heterodimer (PDGF-AB) o followed by receptor dimerization, the tyrosine kinase is activated, The downstream zone signals to promote tumor growth. Mutations in genes are responsible for receptors that are not dependent on binding to ligands and are a driving force for tumorigenesis.
  • c-Kit is a member of the PDGF receptor family and its activity is activated when it binds to the ligand SCF (stem cell factor).
  • SCF stem cell factor
  • GIST is a non-epithelial cell tumor, most of which is present in the stomach, a few in the small intestine, rarely in the esophagus, but also in the liver, peritoneal cavity and other parts.
  • GIST is derived from Cajal interstitial cells (ICC), which partially forms the intestinal autonomic nervous system and is involved in the control of gastric motility. Most (50 ⁇ 80%) GIST production is due to mutation of c-Kit gene. In the digestive tract, c-Kit/CD117 staining is generally GIST, and c-Kit mutation can make it independent of SCF activation.
  • c-Kit function resulting in increased cell division rate, leading to instability of the genome.
  • c-Kit expression can also be detected, and c-Kit expression is also found in acute AML and malignant lymphoma, in small cells.
  • Bronchial carcinoma, seminoma, dysgerminoma, testis, intraepithelial neoplasia, melanoma, breast cancer, neuroblastoma, Ewing's sarcoma have c-Kit expression (see ScMtte et al" innovartis 3/ 2001). It is well known that RET (rearranged during transfection).
  • Proto-oncogene point genetic mutation is tumorigenic, and patients with multiple endocrine neoplasia 2 (MEN 2) may cause pheochromocytoma and medullary thyroid Cancer and parathyroid adenomas and hyperplasia (see Huang et al., Cancer Res. 60, 6223-6 (2000)).
  • MEN 2 multiple endocrine neoplasia 2
  • Flk fetal liver kinase receptor subfamily
  • This subfamily consists of a kinase-containing insertion domain-receptor fetal liver kinase-1 (DR/FLK-1, VEGFR2), Flk-1R, Flk-4 and fms-like tyrosine kinase l (Flt-1).
  • FGF fibroblast growth factor
  • This subfamily consists of four receptors, FGFR1-4, seven ligands and FGF1-7. Although not yet determined, these receptors are composed of an extracellular domain comprising various immunoglobulin-like cycloglycosylation and an intracellular domain in which the tyrosine kinase sequence is blocked by an unrelated amino acid sequence.
  • VEGF vascular endothelial growth factor receptor subfamily
  • VEGFR is involved in angiogenesis, inhibits angiogenesis by inhibiting VEGFRs, and is being used in clinical treatment of tumors, and has achieved good results.
  • VEGF is strongly expressed in various malignant solid tumors such as lung cancer, breast cancer, non-Hodgkin's lymphoma, ovarian cancer, pancreatic cancer, malignant pleural mesothelioma, and melanoma, and is associated with the progression of cancer, in white blood cells.
  • VEGFR vascular endothelial growth factor
  • VEGF vascular endothelial growth factor
  • PDGF vascular endothelial growth factor
  • vascular endothelial cells activates angiogenesis and has been shown to stimulate the production of vascular endothelial cells in vivo.
  • Some peptides have been identified, including Acidic, basic fibroblast growth factor (aFGF and bFGF) and vascular endothelial growth factor.
  • VEGF Due to the restricted expression of the VEGF receptor, its growth factor activity is relatively specific to endothelial cells compared to aFGF and bFGF activity. Recent evidence suggests that VEGF is a very important stimulator during angiogenesis and vascular infiltration in both normal and pathological conditions. VEGF induces a vascular sprouting phenotype that induces endothelial cell proliferation, protease expression and migration to promote capillary formation, thereby forming a super-osmotic, immature vascular network, which is typical of typical pathological angiogenesis. It is expected that antagonizing VEGF activity can be of value in the treatment of diseases associated with angiogenesis or vascular permeability, such as tumors, particularly tumor growth inhibition.
  • FLT3 Fms-like tyrosine kinase
  • AML acute myeloid leukemia
  • AML acute myeloid leukemia
  • myelodysplastic syndrome In the case of the disease, the FLT3 gene is abnormally expressed.
  • FLT3 mutations are activated and the prognosis is poor. Most of the mutations have intrastructural replication in the proximal membrane domain, and 5-10% of patients have a point mutation in asparagine 835.
  • FLT3 The tyrosine kinase activity of FLT3 is activated, resulting in the presence of a signal and proliferation in the absence of a ligand. According to the study, the probability of cure in patients with mutant form of receptor expression is reduced. In conclusion, in human leukemia and myelodysplastic syndromes, FLT3 mutations are associated with tumorigenesis.
  • Hepatocyte growth factor (HGF) receptor (c-MET or HGFR) tyrosine kinases have been shown to be closely associated with tumorigenesis, cell motility, invasion and metastasis (see Ma, PC et al. (2003b). Cancer Metastasis i? Ev, 22, 309-25; Maulik, G. et al. & Q02b). Cytokine Growth Factor Rev, 13, 41-59). Overexpression or mutation in various tumors, including small cell lung cancer (SCLC), activates c-MET (HGFR) (see Ma, P.C. et al. (2003a). Cancer Res, 63, 6272-6281).
  • SCLC small cell lung cancer
  • the proto-oncogene c-Met encodes a hepatocyte growth factor receptor, which is a cell membrane glycoprotein with tyrosine kinase activity, which has important physiological regulation effects on various cell proliferation and differentiation.
  • the c-met gene has been used in many malignant tumors. Expression is an important factor in the carcinogenesis of thyroid follicular epithelial cells and is closely related to the pathological stage, invasion and metastasis of thyroid cancer.
  • CTK receptor tyrosine kinase inhibitors
  • STKs serine-threonine kinases or STKs are dominant in cells, although there are only a few STK-type receptor kinases.
  • STKs are the most common cytosolic kinase, ie it plays its part in the ministry In the cytoplasm, not in the cytoplasmic organelles.
  • the cytosol is a region within the cell where metabolic and biosynthetic activities occur in most cells; for example, proteins are synthesized on cytosol ribosomes.
  • the object of the present invention is to tyrosine kinase inhibitor SU-11248 and patent literature
  • X is selected from a carbon atom or a nitrogen atom
  • Rx and R 2 are each independently selected from a hydrogen atom or a fluorenyl group in each case;
  • R 5 is absent, and R 6 , R 7 and R 8 are each independently selected from a hydrogen atom or a halogen; when X is a carbon atom, R 5 , R 7 and R 8 are independently selected.
  • R 9 and R 1G together form a 4 to 8 membered heterocyclic group, wherein the 5 to 8 membered heterocyclic ring contains one to a plurality of N, 0, S heteroatoms, and the 4 to 8 membered heterocyclic ring is further Or a plurality of alkyl, halogen, aryl, heteroaryl, haloalkyl, hydroxy, cyano, alkoxy, aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxy Substituted by an acid ester or -NR 9 R 1Q ;
  • Ri selected from a hydrogen atom or an alkyl group
  • n 2 ⁇ 6
  • r 1 ⁇ 6
  • the compound of the formula (I) or a salt thereof of the present invention is a methyl group.
  • the present invention includes the following salts -
  • X is selected from a carbon atom or a nitrogen atom
  • Ri are respectively selected from a hydrogen atom or an alkyl group
  • R 3 is selected from the group consisting of alkyl, trifluoromethyl, aryl, aryl fluorenyl, wherein the alkyl, aryl or aralkyl group is further substituted with one or more halogens;
  • R 6 , R 7 , and R 8 are each independently selected from a hydrogen atom or a halogen; when X is a carbon atom, R 5 , R 6 , R 7 , and R 8 are each independently Selected from hydrogen atom, hydroxy, hydroxyalkyl, decyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, cyano, nitro, -OR 9 , -0[CH 2 CH 2 0] r Rn , -NR 9 Ri.
  • R 9 and R 1Q are each selected from a hydrogen atom, an alkyl group, a cycloalkyl group, an aryl group, a heterocyclic fluorenyl group, a heteroaryl group, wherein the above alkyl group, a cycloalkyl group, an aryl group, a heterocyclic fluorenyl group, a heteroaryl group Further further by one or more fluorenyl, aryl, haloaryl, hydroxy, amino, cyano, alkoxy, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or Replaced by NR 9 R 1Q ;
  • R 1D Simultaneously with R 1D to form a 4 to 8 membered heterocyclic group, wherein the 5 to 8 membered heterocyclic ring contains one to a plurality of N, 0, S heteroatoms, and the 4 to 8 membered heterocyclic ring is subjected to one or more Sulfhydryl, halogen, aryl, heteroaryl, haloalkyl, hydroxy, chloro, alkoxy, aryloxy, amidino, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or Replaced by NR 9 R 1Q ;
  • R u is selected from a hydrogen atom or an alkyl group;
  • n 2 to 6;
  • r 1 ⁇ 6 ;
  • the invention includes the following salts:
  • X is selected from a carbon atom or a nitrogen atom
  • Ri are respectively selected from a hydrogen atom or an alkyl group
  • R 3 is selected from the group consisting of alkyl, trifluoromethyl, aryl, aralkyl, wherein alkyl, aryl or aralkyl is further substituted by one or more halogens;
  • R4 is selected from the group consisting of alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -(CI ⁇ OCftCH ⁇ Rn, -[CH 2 CH(OH)] r CH 2 NR9R 10 or -(CH 2 n NR 9 R 10 , wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroaryl is further substituted by one or more aryl, hydroxy, amino, amide, aminocarbonyl, Alkoxy, aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or substituted with -NR 9 R 10 ;
  • R 5 is absent, and R 6 , R 7 and R 8 are each independently selected from a hydrogen atom or a halogen; when X is a carbon atom, R 5 , R 6 , R 7 and R 8 are each independently Selected from hydrogen atom, halogen, hydroxyalkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, cyano, nitro, -OR 9 , -0[CH 2 CH 2 0] r R n , -NR 9 R l0 , -(CH 2 ) n C0 2 R 9 > -(CH 2 ) n CONR 9 R 10 , -COR 9 , -NR 9 CORi 0 , -S0 2 R 9 or -NHCO 2 R 10 , wherein aryl, heteroaryl, cycloalkyl, heterocycloalkyl is further substituted by one or more substituents
  • R 9 and each independently selected from the group consisting of a hydrogen atom, an alkyl group, a cyclodecyl group, an aryl group, a heterocycloalkyl group, a heteroaryl group, wherein the above-mentioned indenyl group, cyclodecyl group, aryl group, heterocycloalkyl group, heteroaryl group Monoterpene by one or more fluorenyl, aryl, haloaryl, hydroxy, amino, cyano, decyloxy, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or -NR Substituted by 9 R 1G ;
  • R 9 and R 1Q together form a 4 to 8 membered heterocyclic group, wherein the 5 to 8 membered heterocyclic ring contains one to a plurality of N, 0, S hetero atoms, and the 4 to 8 membered heterocyclic ring is further subjected to a Or a plurality of alkyl, halogen, aryl, heteroaryl, haloalkyl, hydroxy, cyano, decyloxy, aryloxy, aminoalkyl, hydroxyalkyl, heterocyclic a mercapto group, a carboxylic acid, a carboxylic acid ester or a substituent of -NR 9 R 1Q ;
  • Rn is selected from a hydrogen atom or an alkyl group;
  • n 2 to 6;
  • r is 1-6;
  • Typical compounds of the invention include, but are not limited to:
  • a pharmaceutical composition comprising a compound of the formula (I) according to the invention, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.
  • a method of modulating protein kinase catalytic activity comprising contacting a protein kinase with a compound of formula (I) or a pharmaceutically acceptable salt of the invention.
  • This protein kinase is selected from the group consisting of a receptor tyrosine kinase, a non-receptor tyrosine kinase, and a serine-threonine kinase.
  • the pharmaceutically acceptable salt of the present invention is a salt of the compound of the present invention and a compound with an acid selected from the group consisting of malic acid, lactic acid, maleic acid, hydrochloric acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid , tartaric acid, acetic acid or trifluoroacetic acid.
  • the present invention includes a compound represented by the following formula (IC) or (ID) as an intermediate for the synthesis of the compound of the formula (I):
  • R 2 is each selected from a hydrogen atom or an alkyl group
  • 3 ⁇ 4 is selected from the group consisting of alkyl, trifluoromethyl, aryl, aryl fluorenyl, wherein the alkyl, aryl or aryl group is further substituted by one or more halogens;
  • 3 ⁇ 4 is selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -(CHb OCHsCH ⁇ Ru, -[CH 2 CH(OH)] r CH 2 NR 9 R 1Q or -(CH 2 n R 9 R l() wherein fluorenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heteroaryl is further substituted by one or more aryl, hydroxy, amino, amide, amino a carbonyl group, an alkoxy group, an aryloxy group, an aminoalkyl group, a hydroxyindenyl group, a heterocycloalkyl group, a carboxylic acid, a carboxylic acid ester or a -NR 9 R 10 ;
  • R 1Q are each selected from the group consisting of a hydrogen atom, a fluorenyl group, a cyclodecyl group, an aryl group, a heterocycloalkyl group, a heteroaryl group, wherein the above alkyl group, cyclodecyl group, aryl group, heterocycloalkyl group, heteroaryl group further By one or more fluorenyl, aryl, haloaryl, hydroxy, amino, cyano, alkoxy, aryloxy, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester or -NR 9 Replaced by R i() ;
  • R 9 and R 1Q together form a 4 to 8 membered heterocyclic group, wherein the 5 to 8 membered heterocyclic ring contains one to a plurality of N, 0, S hetero atoms, and the 4 to 8 membered heterocyclic ring is further subjected to a Or a plurality of alkyl, halogen, aryl, heteroaryl, haloalkyl, hydroxy, cyano, alkoxy, aryloxy, aminoalkyl, hydroxyalkyl, heterocycloalkyl, carboxylic acid, carboxylic acid ester Or replaced by -NR 9 R 1Q ;
  • R u is selected from a hydrogen atom or an alkyl group
  • n 2 to 6;
  • r is 1 to 6.
  • a method of treating or preventing a mammal associated with a protein kinase comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition of the invention, the composition comprising a compound of the invention or A pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the disease associated with protein kinases is selected from the group consisting of VEGFR-2, EGFR, HER-2, HER-3, HER-4, PDGFR, c-Kit, c-Met, FGFR, Flt3 related diseases.
  • Protein kinase-related diseases can also be leukemia, diabetes, autoimmune disease, hyperproliferative disease, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, cardiovascular disease, multiple hemangioblastoma (Von-Heppel) -Lindau), inflammation, fibrosis.
  • Protein kinase-related diseases can also be squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma (Kaposi), non-small cell lung cancer, small cell lung cancer, lymphoma, thyroid cancer, breast cancer, head and neck cancer, uterine cancer.
  • the mammal is a human.
  • the method of the above-mentioned mammal for treating or preventing a protein kinase-related disease comprises simultaneously administering a treatment to a mammal in need of treatment.
  • the mammal is preferably a human.
  • Another aspect of the invention relates to the use of a compound of the invention in the manufacture of a medicament for the treatment of a disease associated with a protein kinase.
  • the protein kinase-associated disease is selected from the group consisting of a disease associated with VEGFR-2, EGFR, HER-2, HER-3, HER-4, PDGFR, c-Kit, c-Met, FGFR or Flt3;
  • the protein kinase-related disease is selected from the group consisting of leukemia, diabetes, autoimmune disease, hyperproliferative disease, psoriasis, osteoarthritis, rheumatoid arthritis, angiogenesis, cardiovascular disease, multiple hemangioblastoma, inflammation or Fibrosis disease; or the protein kinase-related disease is cancer, selected from the group consisting of squamous cell carcinoma, renal cell carcinoma, Kaposi's sarcoma, non-small cell lung cancer, small cell lung cancer, lymphom
  • the pyrrole methyl carboxylic acid diester IC-1 is obtained by reacting the raw material pyrrole methyl carboxylic acid diester IC-1 at room temperature in tetrahydrofuran solution with acetic acid in the presence of acetic acid;
  • IC-1 IC-2 compound pyrrole formaldehyde carboxylic acid diester IC-2 in anhydrous tetrahydrofuran, (Wittig) reaction with (ethyl ester benzylidene) triphenylphosphorane to obtain compound pyrrole ethoxycarbonyl vinyl Dicarboxylate IC-3;
  • IC-4 Pyrrole ethoxycarbonylethyl dicarboxylate IC-4 is hydrolyzed in aqueous lithium hydroxide to obtain pyrrole carboxyethyl dicarboxylate IC-5; IC-4
  • pyrrole mesylate oxypropyl dicarboxylate IC-7 is reacted with a different amine to obtain pyrrolamidate IC-8;
  • pyrrole formaldehyde carboxylic acid diester IC-2 is reacted with Grignard reagent cyclopropylmagnesium bromide in anhydrous tetrahydrofuran to obtain pyrrolecyclopropyl hydroxycarboxylic acid diester ID-1;
  • Bromobutylpyrroledicarboxylate ID-3 is reacted with different amines in dichloromethane under reflux to give pyrrolidinamine dicarboxyl
  • R 2, R 3 and t are as defined above further, another aspect of the present invention is a method of preparing pyrrole and N heterocyclic derivative, in the presence of a base (such as triethylamine, piperidine), and The aldehyde and the fluorenone are reacted, and the reaction liquid is heated for 2 to 12 hours, wherein the above aldehyde is of the following formula
  • Anthrone is a compound of the formula
  • the present invention relates to a compound which discriminates the catalytic activity of a protein kinase, which contacts a cell expressing the protein kinase with a compound or salt of the present invention, and then detects the effect on the cell.
  • the present invention also relates to a compound which discriminates the catalytic activity of a protein kinase by contacting an artificially recombinant synthetic kinase protein with a compound or salt of the present invention, and then detecting the effect on the kinase activity by the Elisa method.
  • DETAILED DESCRIPTION OF THE INVENTION Unless otherwise stated, the following terms used in the specification and claims have the following meanings.
  • Alkyl means a saturated aliphatic hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to medium-sized alkyl groups having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like. More preferred are lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like.
  • Sulfhydryl may be substituted or unsubstituted Preferred groups, when substituted, are halogen, hydroxy, lower decyloxy, aryl, aryloxy, heteroaryl, heterocycloalkyl, -OR 9 , -NR 9 Rio ⁇ -COR 9 , -0[CH 2 C3 ⁇ 40] r R u , -NR 9 COR 10 , -S0 2 R 9 or -NHCO 2 R 10 .
  • Cyclopentyl means a 3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6 fused or polycyclic fused ring (“fused" ring means in the system Each ring shares an adjacent pair of carbon atoms) groups with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. Examples of the group are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentene, cyclohexyl, cyclohexadiene, adamantane, cycloheptane, cycloheptatriene, etc.
  • the cycloalkyl group may be substituted or not.
  • the substituent is preferably one or more substituents independently selected from the group consisting of lower fluorenyl, trihaloalkyl, halogen, hydroxy, lower alkoxy, aryl (optionally selected from one or Substituted by a plurality of groups, the substituents are independently of each other a halogen, a hydroxyl group, a lower alkyl group or a lower alkoxy group), an aryloxy group (which may be selected by one or more groups, and the substituents are independently of each other a halogen , hydroxy, lower alkyl or lower alkoxy), 6-membered heteroaryl (having from 1 to 3 nitrogen atoms in the ring, optionally in the ring Substituted by one or more groups, the substituents are, independently of each other, halogen, hydroxy, lower alkyl or lower decyloxy), 5-membered heteroaryl (having 1 to
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.
  • the alkenyl group may be optionally substituted by one or more substituents selected from the group consisting of: halogen, trihalomethyl, hydroxy, nitro, cyano, alkoxy, alkyl, carboxylic acid, carboxylic acid ester -OR 9 , -NR 9 R 1G , -COR 9 , -0[CH 2 CH 2 0] r R u , -NR 9 CORi. , -S0 2 R 9 or - NHCO 2 R 10 .
  • Alkynyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. Representative examples include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • the alkynyl group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, nitro, cyano, alkoxy, alkyl, carboxylic acid, carboxylic acid esters. , -OR 9 , -NR 9 R 10 . -COR 9 , -0[CH 2 CH 2 0] r R hinder, -NR 9 COR 10 , -S0 2 R 9 or - NHCO 2 R 10o
  • Aryl means a group having at least one aromatic ring structure, that is, an aromatic ring having a conjugated ⁇ -electron system, including a carbocyclic aryl group, a heteroaryl group, and a biaryl group.
  • the aryl group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, nitro, cyano, decyloxy, alkyl, carboxylic acid, carboxylic acid ester, -OR 9 , -NR 9 R 1() , -COR 9 , -0[CH 2 CH 2 0] r R u , -NR 9 CORi. , -S0 2 R 9 or -NHCO 2 Ri 0 .
  • Heteroaryl means an aryl group having from 1 to 3 heteroatoms as ring atoms, the remaining ring atoms being carbon, and heteroatoms including oxygen, sulfur and nitrogen.
  • the ring may be a 5- or 6-membered ring.
  • heterocyclic aryl groups include furan Base, thienyl, pyridyl, pyrrole, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl and the like.
  • the heteroaryl group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, nitro, cyano, decyloxy, decyl, carboxylic acid, carboxylic acid esters. , -0, -NR 9 R 1Q , -COR 9 ,
  • Heterocycloalkyl means a monocyclic or fused ring radical having from 5 to 9 ring atoms in the ring wherein one or two ring atoms are selected from nitrogen, oxygen or S(0)n (where n is an integer) From 0 to 2), the remaining ring atoms are carbon. These rings may also have one or more double bonds, however, these rings do not have a fully conjugated pi-electron system.
  • Unsubstituted heterocycloalkyl includes, but is not limited to, pyrrolidinyl, piperidino, piperidino, morpholinyl, thiomorpholinyl, homopiperazine, etc., heterocycloalkyl can be substituted or Unsubstituted.
  • the substituent is preferably optionally substituted with one or more substituents selected from the group consisting of: halogen, trihalomethyl, hydroxy, nitro, cyano, alkoxy, decyl, carboxylic, carboxylic acid Ester, -OR 9 , -NR 9 R 1Q , -COR 9 , -0[CH 2 CH 2 0] r R u , -NR 9 COR 10 , -S0 2 R 9 or -NHCO 2 R 10 .
  • substituents selected from the group consisting of: halogen, trihalomethyl, hydroxy, nitro, cyano, alkoxy, decyl, carboxylic, carboxylic acid Ester, -OR 9 , -NR 9 R 1Q , -COR 9 , -0[CH 2 CH 2 0] r R u , -NR 9 COR 10 , -S0 2 R 9 or -NHCO 2 R 10 .
  • Haldroxy means an -OH group.
  • Alkoxy means -O-(indenyl) and -O-(unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • the alkoxy group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, nitro, cyano, alkoxy, alkyl, carboxylic acid, carboxylic acid ester -OR 9 , -NR 9 R 1Q , -COR 9 , -0[CH 2 CH 2 0] r Rn . -NR 9 COR 10 , -S0 2 R 9 or -NHCO 2 R 10 .
  • Halodecyloxy means -O-(haloalkyl). Representative examples include, but are not limited to, trifluoromethoxy, tribromomethoxy, and the like.
  • Aryloxy means -O-aryl and -0-heteroaryl, and aryl and heteroaryl are as defined above. Representative examples include, but are not limited to, phenoxy, pyridyloxy, furanoxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and derivatives thereof.
  • the aryloxy group may be optionally substituted by one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, nitro, cyano, alkoxy, alkyl, carboxylic acid, carboxylic acid esters.
  • Haldroxycarbonyl means -(CH 2 ) n OH.
  • Halogen means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
  • Trihalomethyl means -CX 3 wherein X is a halogen as defined above.
  • Optional or “optional” means that the event or environment described subsequently may, but need not, occur, including where the event or environment occurs or does not occur.
  • optionally substituted with an alkyl group means that a fluorenyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted by a thiol group and the case where the heterocyclic group is not substituted by an alkyl group.
  • “Pharmaceutical composition” means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as a physiological/pharmaceutically acceptable carrier. And excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
  • the compounds of the invention can be synthesized by methods known in the art. Combinations of these compounds are provided in the examples
  • the pyrrole methyl carboxylic acid diester IC-1 is reacted with cerium nitrate in the presence of acetic acid at room temperature to obtain pyrrole formaldehyde carboxylic acid diester IC-2; the obtained compound pyrrole formaldehyde carboxylic acid diester IC-2
  • the reaction with (ethyl ester benzylidene) triphenylphosphorane to obtain the compound pyrrole ethoxycarbonyl vinyl dicarboxylate IC-3
  • Pyrodiethoxycarbonylethyldicarboxylate IC-4 is obtained by reduction of hydrogen carboxylic acid ester IC-3 in anhydrous ethanol at room temperature
  • pyrrole formaldehyde carboxylic acid diester IC-2 is reacted with Grignard reagent cyclopropyl magnesium bromide in anhydrous tetrahydrofuran to obtain pyrrolecyclopropyl hydroxycarboxylic acid diester ID-1; Hydroxycarboxylic acid diester ID-1 is reacted with hydrobromic acid in methanol solvent to obtain bromobutenylpyrrolediester ID-2 at room temperature; palladium/carbon catalyzed, butenylpyrroledicarboxylate ID- 2 in anhydrous ethanol, reduced by hydrogen at room temperature to obtain butyl hexyl pyrrole dicarboxylate ID-3; bromobutylpyrroledicarboxylate ID-3 in dichloromethane, heated reflux and reacted with different amines Pyrrolamide dicarboxylic acid diester ID-4; pyrrole amide dicarboxylic acid diester ID-4 in anhydr
  • the configuration of the double bond in the molecule of the general formula (I) is the z configuration (cis), which can be inferred by the nuclear magnetic data.
  • the chemical shift of NH on the pyrrole ring is about 9 ppm
  • the NH on the pyrrole ring in the obtained compound is about 14 ppm, mainly because the NH on the pyrrole ring has an intramolecular hydrogen bond with the oxygen of the adjacent fluorenone carbonyl. , causing the chemical shift of NH to shift to the lower field. This is also described in the patent WO0160814 (Su-11248).
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention or a salt thereof and a pharmaceutical carrier.
  • the present invention relates to the use of a compound of the formula (I) or a salt thereof for the preparation of a tyrosine kinase inhibitor drug.
  • the present invention also provides a composition comprising the above compound in an effective amount, and the use of the compound and/or a pharmaceutical composition containing the same in the preparation of a tyrosine kinase inhibitor.
  • the structure of the example compounds was determined by nuclear magnetic resonance (MR) or mass spectrometry (MS).
  • the NMR shift ( ⁇ ) is given in parts per million (ppm).
  • NMR was measured using a Bmker AVANCE-400 nuclear magnetic apparatus.
  • the solvent was deuterated chloroform (CDC1 3 ), deuterated dimethyl sulfoxide (DMSO-D 6 ), internal standard tetramethylsilane (TMS), chemical shift. is 10- 6 (ppm) given as a unit.
  • the MS was measured using a FINNIG AN LCQAd (ESI) mass spectrometer.
  • the average inhibition rate of the kinase VEGFR was measured using an HTScan microplate reader (Cell Signaling).
  • the average inhibition rate of the kinase EGFR/HER-2 was measured using a NovoStar plate reader (BMG, Germany).
  • Thin layer silica gel is used in Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • DMSO-D 6 deuterated dimethyl sulfoxide
  • the mixture was stirred at room temperature for about 0.5 hours, and the reaction mixture turned from orange to orange, and the spot was monitored to indicate that the reaction was complete and the reaction was stopped.
  • the reaction mixture was poured into ice-water (400 ml), EtOAc (EtOAc m. - 2-tert-butyl dihydroxy acid 4-ethyl ester lb (3 L 13 g, pale yellow solid), Yield: 98%.
  • the salt bath was used to control the temperature of the reaction system at -10 to -5 ° C, and a solution of borane in tetrahydrofuran (90 ml, 1 mol/L, 90 mmol) was slowly added dropwise to the reaction system. After the addition, the ice salt bath was removed, and the reaction solution was naturally warmed to room temperature, and stirring was continued for 2 to 3 hours. The plate indicated that the reaction of the starting material was complete and the reaction was stopped. The reaction mixture was evaporated to dryness under reduced pressure, and then evaporated and evaporated.
  • Triethylamine (7.0 ml, 50 mmol) was slowly added, and methanesulfonyl chloride (3.5 ml, 45 mmol) was added slowly. After stirring, the ice salt bath was removed, and the temperature of the reaction system was naturally raised to room temperature, and stirring was continued for 4 hours. The dot plate indicates that the starting material is completely reacted, and a small amount of ice is added to quench the reaction.
  • reaction mixture was washed with dilute hydrochloric acid (0.5 mol/L, 80 ml ⁇ 2) to remove triethylamine, and washed with saturated sodium carbonate (80 ml ⁇ 2) to remove excess hydrochloric acid, and then washed with saturated sodium chloride (80 ml ⁇ l), and the reaction mixture was evaporated under reduced pressure.
  • Triethyl orthoformate (0.34 ml, 1.7 mmol) was added and stirring was continued for 2 min.
  • the ice salt bath was removed, the temperature of the reaction solution was naturally raised to room temperature, and stirring was continued for about 2 hours.
  • the dot plate indicates that the starting material is completely reacted and the reaction is stopped.
  • 3 ml of ice water and 10 ml of dichloromethane were added to the reaction system, and the pH was adjusted to about 11 with a sodium hydroxide solution (2 mol/L), and the mixture was extracted with dichloromethane (10 ml x 3). The combined organic layers were dried with EtOAc EtOAc.
  • Example 1 of the present invention 2-(5-Chloro-2-oxo-1,2-dihydro-indol-3-methyl)-5-(2-diethylamino-ethyl)-3-methyl-5,6 ,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one
  • the tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used.
  • 2,4-Dinitro-5-fluoro-phenylacetic acid 3b (10 g, 38.7 mmol) was dissolved in 150 ml of methanol with stirring at room temperature, and palladium/carbon was added under a hydrogen atmosphere at a pressure of 0.3 MPa. Under hydrogenation. The plate is tracked until the material disappears and the reaction is stopped. The reaction solution was filtered twice, and the filtrate was evaporated evaporated evaporated.
  • 2,4-Diamino-5-fluoro-phenylacetic acid 3c (7.12 g, 38.7 mmol) was dissolved in 100 ml of hydrochloric acid (1 mol/L) with stirring at room temperature, and heated under reflux for 1 hour. Disappear, stop the reaction. The reaction solution was cooled to room temperature, and then cooled in an ice water bath, and 100 ml of sodium hydroxide (1 mol/L) was added dropwise to neutralize the reaction mixture.
  • the tenth step of the first embodiment of the present invention was repeated except that the compound obtained in the ninth example of Example 1 was used, 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1. ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde lj and 5-fluoro-6-(4-fluoro-amino group)-1,3 -Dihydro-indol-2-one 3e as a starting material to give the title product 5-(2-diethylamino-ethyl)-2-[5-fluoro-6-(4-fluoro-benzylamino)-2- Oxo-1,2-dihydro-indol-3-ylmethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine 4-ketone 3 (61 mg, reddish brown solid), Yield: 62.2%.
  • Example 1 of the present invention The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used.
  • ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-formaldehyde lj and 7-bromo-5-fluoro-1,3-dihydro-indole 2-ketone 4b was used as the starting material to give the title product 2-(7-bromo-5-fluoro-2-oxo-1,2-dihydroindole-3-methyl)-5-(2-di- Amino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 4 (55 mg, tarnish solid) Yield: 61.1%.
  • Example 1 of the present invention The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used.
  • the title product 2-(5-bromo-2-oxo-1,2-dihydro-indol-3-methyl)-5-(2-diethylamino-ethyl)-3- Methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 5 (59 mg, yellow solid), Yield: 67.8%.
  • reaction system was stirred overnight in an oil bath at 75 ° C, and the plate indicated that the reaction of the starting material was complete and the reaction was stopped.
  • the reaction solution was cooled to room temperature, then extracted with ethyl acetate (20 ml ⁇ 3).
  • the organic phase was combined, and the organic phase was washed with saturated sodium chloride (10 ml XI), dried over anhydrous sodium sulfate. Concentrated by pressure. The obtained solid was subjected to EtOAc EtOAcjjjjjjjjjj
  • Example 1 of the present invention The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used.
  • ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-formaldehyde lj and 4-(2,3-difluoro-phenyl)-1,3- Dihydro-indol-2-one 6d was used as a starting material to give the title product 5-(2-diethylamino-ethyl)-2-[4-(2,3-difluoro-phenyl)-2-oxo -1,2-dihydro-indol-3-ylmethyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4 - Ketone 6 (43 mg, yellow solid), Yield: 61.4%.
  • 5-Fluoro-6-amino-2-indanone 3d (2.028 g, 12.2 mmol) was dissolved in 30 ml of tetrahydrofuran with stirring at room temperature, and 1.3 ml of P-pyridinium was added to the solution, using a dry ice-ethanol bath.
  • the reaction system was cooled to about -50 °C.
  • the methoxyacetyl chloride (1.35 g, 12.5 mmol) was dissolved in 20 ml of tetrahydrofuran with stirring and added dropwise to the above reaction system. After the addition, the dry ice-ethanol bath was removed, and the temperature of the reaction system was naturally raised to room temperature, and stirred overnight.
  • the plate is tracked until the material disappears and the reaction is stopped.
  • the reaction mixture was filtered, EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Example 1 of the present invention The tenth reaction of Example 1 of the present invention was repeated except that the compound obtained in the ninth example of Example 1 was used, 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1. ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-formaldehyde lj and N-(5-fluoro-2-oxo-2,3-dihydrogen -1H- ⁇ _6-yl)-2-methoxy-acetamide 7a as a starting material to give the title product N- ⁇ 3-[5-(2-diethylamino-ethyl)-3-methyl- 4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-methylene]-5-fluoro-2-oxo-2 ,3-dihydro-1H-indol-6-yl ⁇ -2-methoxy-acetamide
  • 5-Fluoro-6-amino-2-indanone 3d (450 mg, 2.71 mmol) was dissolved in 10 ml of tetrahydrofuran with stirring at room temperature, cooled to -45 ° C with dry ice-acetone bath, 364 ⁇ Bismuth pyridine.
  • 2-Acetoxypropionyl chloride (423 mg, 2.71 mmol) was dissolved in 10 ml of tetrahydrofuran with stirring, and added dropwise to the above reaction solution. After the addition, the dry ice-acetone bath was removed, and the temperature of the reaction system was naturally raised to room temperature. overnight. The plate was monitored until the reaction of the starting material was complete and the reaction was stopped.
  • Example 1 of the present invention The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used.
  • 1-(5- Fluoro-2-oxo-2,3-dihydro-1H-indole-6-carbamoyl)-1-methyl-ethyl ester 9a (2.035 g, 6.9 mmol) was dissolved in 20 ml of methanol with stirring.
  • Add 20 ml of sodium hydroxide solution (0.7 mol L) stir for 4 hours, and monitor the reaction until the reaction of the starting material is complete, and stop the reaction.
  • Example 1 of the present invention The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used.
  • ,4,5,6,7,8-hexahydro-P is more than [3,2-c] azepine-2-carbaldehyde lj and N-(5-fluoro-2-oxo-2,3- Dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propanamide 9b was used as the starting material to give the title product N- ⁇ 3-[5-(2-diethylamino-ethyl)- 3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-methylene]-5-fluoro-2 -Oxo-2,3-dihydro-1H-indol-6-yl ⁇ -2-car
  • the compound obtained in the sixth step of the first embodiment of the present invention is 5-(3-methanesulfonyloxy-propyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-B.
  • ester lg (5.812 g, 15 mmol) and 2-morphinolin-4-yl-ethylamine (10.725 g, 82.5 mmol) were stirred in a 30 Torr water bath until dissolved, and the mixture was stirred at room temperature for 5.5 hours. , stop the reaction. 100 ml of ethyl acetate and 100 ml of saturated sodium chloride were added to the reaction mixture, and the mixture was stirred for 5 minutes and then extracted with a layer.
  • the dot plate indicates that the starting material is completely reacted, the oil bath is removed, and a small amount of water is added to the reaction solution to quench the reaction.
  • the reaction solution was adjusted to pH 8 to 10 with dilute sodium hydroxide (2 mol/L), 50 ml of saturated sodium chloride was added, and ethyl acetate (50 ml X 3 ) was applied.
  • the combined organic phases were filtered with EtOAc EtOAc (EtOAc)EtOAc. 6,7,8-Hexahydro-pyrrolo[3,2-(;] azetidine-2-carboxylic acid tert-butyl ester 10b (1.218 g, pale yellow solid), yield: 61%.
  • reaction solution naturally rises to room temperature, the reaction solution is brown, and stirring is continued for about 2 hours.
  • the plate indicates that the reaction of the starting material is complete, and a small amount of water is added to the reaction system to quench the reaction.
  • the reaction solution is diluted with sodium hydroxide (2 mol/L).
  • the pH was adjusted to about 8 and extracted with dichloromethane (50 ml ⁇ 3).
  • 4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro-P-pyrolo[3,2-c]azepine-2-carbaldehyde 10c (240 mg , pale yellow solid), Yield: 40%.
  • Example 10 of the present invention was repeated except that the compound obtained in the third step of Example 10 was used.
  • Example 10 of the present invention was repeated except that the compound obtained in the third step of Example 10 was used.
  • 4-(2,3-Difluoro-phenyl)-1,3-dihydro-indole-2-one 6d was used as the starting material to give the title product 2-[4-(2,3-difluoro-phenyl).
  • Example 1 of the present invention The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used. ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-formaldehyde lj and 4-bromo-1,3-dihydro-indole-2-one As a starting material, the title product 2-(4-bromo-2-oxo-1,2-dihydro-B-indole-3-methylol)-5-(2-diethylamino-ethyl)-3 was obtained. -methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 13 (30 mg, orange solid), Yield: 45.5%
  • Example 1 of the present invention The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used.
  • 4,5,6,7,8-hexahydro-P is more than [3,2-c] azepine-2-carbaldehyde lj and 5-bromo-1,3-dihydro-pyrrolo[2, 3-b]pyrimidin-2-one as starting material to give the title product 2-(5-bromo-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyrimidin-3-methylmethyl -5-(2-Diethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 14 (23 mg, orange solid), Yield: 33.8%.
  • Example 1 of the present invention The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used. ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-formaldehyde lj and 6-methoxy-1,3-dihydro-indole-2- The ketone was used as a starting material to give the title product 5-(2-diethyl-ethyl-ethyl)-2-(6-methoxy-2-oxo-1,2-dihydro-indole-3-methine )-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 15 (31 mg, red solid), Yield: 52.7%
  • Example 1 of the present invention The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used. ,4,5,6,7,8-hexahydro-P-pyrolo[3,2-c]azepine-2-formaldehyde lj and 4-methyl-1,3-dihydro-indole-2 - Ketone as starting material to give the title product 5-(2-diethylamino-ethyl)-3-methyl-2-(4-methyl-2-oxo-1,2-dihydro-H-indole- 3-methine)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 16 (25 mg, yellow solid), Yield: 44.1 % .
  • Example 1 of the present invention The tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used. ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-formaldehyde lj and 4-(2-hydroxy-ethyl)-1,3-dihydro- Indole-2-one was used as a starting material to give the title product 5-(2-diethylamino-ethyl)-2-[4-(2-hydroxy-ethyl)-2-oxo-1,2-dihydro ⁇ -3-Methyl-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one 17 (18 mg, Yellow solid), Yield: 29.5 %.
  • N- ⁇ 5-fluoro-3-[3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro -P is more than [3,2-c] azepine-2-methyl]-2-oxo-2, -acetamide
  • Example 10 of the present invention The fourth step reaction of Example 10 of the present invention was repeated except that the compound obtained in the third step of Example 10 was used.
  • Example 10 of the present invention The fourth hydrazine reaction of Example 10 of the present invention was repeated except that the compound obtained in the third step of Example 10 was used.
  • 5-Fluoro-2-indanone 4a (5.0 g, 33 mmol) was added to 17.6 ml of sulfuric acid (98%) at -5 ° C, the temperature was controlled to not exceed 0 ° C, and 2.1 ml of nitric acid was added with stirring ( 65% - 68%), after adding, stirring at room temperature for 1 hour, the point plate is tracked until the raw materials disappear.
  • the reaction solution was added to ice, and after the ice was melted, it was filtered, and the filter cake was washed three times with water, and the obtained solid was recrystallized. This solid was the title product 5-fluoro-7-nitro-2-indanone 20a (4.0 g, orange crystal), yield: 62.5 %.
  • 5-Fluoro-7-nitro-2-indanone 20a (4.0 g, 20 mmol) was dissolved in 200 ml of acetic acid at room temperature, and palladium/carbon (5 %, 1.0 g) was added to remove air and then stirred. Hydrogen gas was charged into the reaction system, and the spot was traced until the raw material disappeared, and the reaction was stopped. The reaction mixture was filtered, and the ⁇
  • N- ⁇ 5-fluoro-3-[3-methyl-5-(2-morphinolin-4-yl-ethyl)-4-oxo-1,4,5,6,7,8-hexahydro -P is more than [3,2-c] azepine-2-methyl]-2-oxo-2,3-dihydro-1H-indol-7-yl ⁇ -carboxamide
  • Example 10 of the present invention was repeated except that the compound obtained in the third step of Example 10 was used.
  • Example 10 of the present invention The fourth step reaction of Example 10 of the present invention was repeated except that the compound obtained in the third step of Example 10 was used.
  • Example 10 of the present invention was repeated except that the compound obtained in the third step of Example 10 was used.
  • Example 23 of the present invention The fourth step reaction of Example 23 of the present invention was repeated except that the compound 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo obtained in the third step of Example 23 was used. 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carboxaldehyde 23c and 5-bromo-1,3-dihydroindol-2-one As a starting material, the title product 2-(5-bromo-2-oxo-1,2-dihydro-indol-3-methyl)-5-(2-dimethylamino-ethyl)-3 was obtained. Methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 24 (71 mg, red solid), yield: 77%.
  • Example 23 of the present invention The fourth step of the reaction of Example 23 of the present invention was repeated except that the compound 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo obtained in the third hydrazine of Example 23 was used. 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-methylbenzoate 23c and 5-fluoro-1,3-dihydro-indole-2- The ketone was used as a starting material to give the title product 2-(5-fluoro-2-oxo-1,2- Dihydro-indole-3-hydroxymethyl)-5-(2-dimethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-IH-pyrrolo[3,2 -c] ⁇ gone ketone 25 (205 mg, red solid), Yield: 68%.
  • Example 23 of the present invention The fourth step of the reaction of Example 23 of the present invention was repeated except that the compound 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo obtained in the third step of Example 23 was used.
  • N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-acetamide, acetic acid (5-fluoro-2-oxo-) 2,3-Dihydro-1H-indole-6-carbamoyl)-methyl ester 27a (58 mg, 0.22 mmol) was dissolved in 1 ml of methanol with stirring, and 1 ml of water and sodium hydroxide (15 mg, 0.375 mmol), after the addition, continue to stir for 1 hour. The plate is tracked until the material disappears and the reaction is stopped.
  • Example 23 of the present invention was repeated except that the compound 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo obtained in the third step of Example 23 was used.
  • 1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c and N-(5-fluoro-2-oxo-2,3-di Hydrogen-1H-indol-6-yl)-2-hydroxy-acetamide 27b was used as the starting material to give the title product N- ⁇ 3-[5-(2-dimethylamino-ethyl)-3-methyl- 4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-methylene]-5-fluoro-2-oxo-2 , 3-dihydro-1H-indol-6-yl ⁇ -2-carbyl-acetamide 27 (80 mg, orange-yellow solid), Yi
  • 2-tert-Butyl ester 4-ethyl ester 28a (6.754 g, 16.6 mmol) was dissolved in 150 ml of toluene with stirring, and a toluene solution of trimethylaluminum (16.6 ml, 2 mol/L, 33.2 mmol) was slowly added.
  • the reaction system was stirred at room temperature for 20 minutes until no more white smoke was present in the bottle, and the mixture was refluxed for 3.5 hours in an oil bath. The dot plate indicates that the starting material is completely reacted, the oil bath is removed, and a small amount of 95% ethanol is added to the reaction solution to quench the reaction.
  • reaction system was cooled to -5 ° C in an ice salt bath, and triethyl formate (2.96 ml, 14.8 mmol) was added in one portion, and the mixture was stirred at -5 ° C for 5 minutes, and then stirred at room temperature for 1 hour. 25 ml of water was added to the reaction system.
  • Example 28 of the present invention The fourth step of the reaction of Example 28 of the present invention was repeated except that the compound obtained in the third example of Example 28 was used.
  • 5-Nitro-2-indanone 30b (3.56 g, 20 mmol) was dissolved in 200 ml of acetic acid with stirring at room temperature, palladium/carbon (5 %, 1.0 g) was added, and the air was removed and stirred. The reaction system was filled with hydrogen gas, and the spot plate was traced until the raw material disappeared, and the reaction was stopped. Filtration, and the filtrate was concentrated under reduced pressure to give the title product, 5-amino-2-indoleone 30c (2.04 g, white solid), yield: 68.9%.
  • N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide stirring 5-amino-2-indanone 30c (3.5 g, 23.6 mmol) at room temperature Dissolved in 20 ml of tetrahydrofuran, added triethylamine (3.6 ml, 26 mmol), and the reaction was cooled to -30 ° C in a dry ice-acetone bath. Acetyl chloride (1.8 ml, 24.8 mmol) was slowly added to the reaction system, and the temperature of the reaction system was controlled to be lower than -20 ° C.
  • Example 28 of the present invention was repeated except that the compound obtained in the third step of Example 28 was used.
  • 3-methyl-4-oxo-5-(2-pyrrole-1-yl-ethyl)-1 ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 28c and N-(2-oxo-2,3-dihydro-1H-indole ⁇ -5-yl)-acetamide 30d was used as the starting material to give the title product N- ⁇ 3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-1.
  • Example 28 of the present invention was repeated except that the compound obtained in the third step of Example 28 was used.
  • the reaction solution was adjusted to a pH of about 7 with a sodium hydroxide solution (10 mol/L), and the mixture was decompressed. Evaporate the ethanol, adjust the pH of the mixture to 10 with sodium hydroxide solution (10 mol/L), dichloromethane extract (20 ml X 3), combine the organic phases, and wash the organic phase with saturated sodium chloride solution ( 20 ml of XI), dried over anhydrous magnesium sulfate, and filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to give the title product 3-methyl-5-(2-piperidin-1-yl-ethyl) -5 , 6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 32c (395 mg, white solid), yield: 57%.
  • Example 32 of the present invention was repeated except that the compound obtained in the fourth step of Example 32 was used.
  • 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1 ,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d and 5-(4-methoxy-phenyl)-1,3-di Hydrogen-inden-2-one was used as a starting material to give the title product 2-[5-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indole-3-indol.
  • Example 32 of the present invention The fifth oxime reaction of Example 32 of the present invention was repeated except that the compound 3 _methyl- 4 oxo-5-(2-piperidin-1-yl-ethyl)-1 obtained in the fourth step of Example 32 was used.
  • the title product 2-(5-chloro-2-oxo-1,2-dihydro-indol-3-methyl)-3-methyl-5-(2-piperidin-1-yl) -ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c] azepine 4-ketone 35 (44 mg, yellow solid), Yield: 64.8%.
  • Example 32 of the present invention was repeated except that the compound obtained in the fourth step of Example 32 was used.
  • Example 32 of the present invention The fifth step reaction of Example 32 of the present invention was repeated except that the compound obtained in the fourth step of Example 32 was used.
  • Example 32 of the present invention The fifth step reaction of Example 32 of the present invention was repeated except that the compound obtained in the fourth step of Example 32 was used.
  • Example 23 of the present invention was repeated except that the compound obtained in the third step of Example 23 was used.
  • Example 23 of the present invention 2-[4-(2,6-Difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylmethyl]-5-(2-dimethylamino-ethyl -3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepine-4-one
  • the fourth step reaction of Example 23 of the present invention was repeated except that the compound obtained in the third step of Example 23 was used.
  • Example 23 of the present invention was repeated except that the compound obtained in the third step of Example 23 was used.
  • the indole-2-one was used as a starting material to give the title product 5-(2-dimethylamino-ethyl) _ 2 _[ 4 _ (3 _fluoro-phenyl>_ 2 _oxo-1,2-dihydro- Indole-3-methyl-methyl]-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 41 (37 mg, yellow Solid), Yield: 38.9%.
  • Example 23 of the present invention The fourth step reaction of Example 23 of the present invention was repeated except that the compound obtained in the third step of Example 23 was used.
  • Difluoro-phenyl)-1,3-dihydro-indol-2-one 6d was used as the starting material to give the title product 2-[4-(2,3-difluoro-phenyl)-2-oxo-1 ,2-dihydro-indol-3-methylol]-5-(2-dimethylamino-ethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[ 3,2-c] azepin-4-one 42 (25 mg
  • Example 23 of the present invention The fourth step of the reaction of Example 23 of the present invention was repeated, except that the compound obtained in the third step of Example 23 was used.
  • Example 28 of the present invention was repeated except that the compound obtained in the third step of Example 28 was used.
  • Example 28 of the present invention was repeated except that the compound obtained in the third step of Example 28 was used.
  • 4-ketone 46 61 mg, yellow solid
  • Example 28 of the present invention was repeated except that the compound obtained in the third step of Example 28 was used.
  • Example 28 of the present invention 3-methyl-2-(2-oxo-5-phenyl-1,2-dihydro-indol-3-methyl)-5-(2-pyrrole-1-yl-ethyl) -SA ⁇ -tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one
  • the fourth hydrazine reaction of Example 28 of the present invention was repeated except that the compound obtained in the third step of Example 28 was used.
  • Example 28 of the present invention was repeated except that the compound obtained in the third step of Example 28 was used.
  • the title product 2-(4-bromo-2-oxo-1,2-dihydro-indol-3-methylmethyl)-3-methyl-5-(2-pyrrole-1-yl- Ethyl) -5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 49 (40 mg, yellow solid), yield: 60.5 %.
  • Example 28 of the present invention The fourth step reaction of Example 28 of the present invention was repeated except that the compound obtained in the third step of Example 28 was used.
  • Example 1 of the present invention N- ⁇ 3-[5-(2-Diethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2 -c] azepine-2-methyl]-2-oxo-2,3-dihydro-1H-indol-5-yl ⁇ -acetamide
  • the tenth step reaction of Example 1 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-1 obtained in the ninth step of Example 1 was used.
  • Example 28 of the present invention The fourth step reaction of Example 28 of the present invention was repeated except that the compound obtained in Example 28, Step 3, 3-methyl-4-oxo-5-(2-pyrrole-1-yl-ethyl)-1 was used. , 4,5,6,7,8-hexahydro-P-pyrolo[3,2-c]azepine-2-carbaldehyde 28c and the compound obtained in the first step of Example 7 of the present invention 5-fluoro-6- Methoxyacetamido-2-indanone 7a was used as the starting material to give the title product N- ⁇ 5-fluoro-3-[3-methyl-4-oxo-5-(2-pyrrolidin-1-yl- Ethyl) -1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-methylene]-2-oxo-2,3-dihydro -1H-indol-6-yl ⁇ -2-methoxy-acetamide 52 (45 mg
  • the morpholine 53a (8.712 ml, 0.1 mol) was dissolved in 4.5 ml of tert-butanol with stirring at room temperature. After cooling to 0 ° C in an ice bath, (R)-(-)-epichlorohydrin (8.05 ml, 0.1 mol) was slowly added dropwise. After the addition, the ice bath was removed, the temperature of the reaction system was naturally raised to room temperature, and stirring was continued for 24 hours. . The plate was monitored for reaction until the starting material disappeared.
  • reaction solution Evaporate the solvent under reduced pressure, add 20 ⁇ 1 hydrochloric acid (6 111 0 1 /1, stir at room temperature for 20 minutes, then adjust the pH to about 12 with sodium hydroxide solution (12 mol / L) in an ice bath, with dichloro Methane extraction (50 ml of X 2 ), EtOAc (EtOAc) Methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 53e (300 mg, white solid), yield - 57.6 %.
  • chloromethylene dimethylamine chloride 130 mg, 0.977 mmol was dissolved in 3 ml of dichloromethane with stirring and cooled to 0 ° C in an ice bath.
  • Example 32 of the present invention The fifth step reaction of Example 32 of the present invention was repeated except that the compound obtained in the fourth step of Example 32 of the present invention was used.
  • the indole-2-one was used as the starting material to give the title product 3-methyl-2-(2-oxo-4-pyridin-4-yl-1,2-dihydro-indol-3-methylmethyl)-5 -(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 54 (40 mg, yellow Solid), Yield: 54%.
  • Example 32 of the present invention The fifth step reaction of Example 32 of the present invention was repeated except that the compound obtained in the fourth step of Example 32 of the present invention was used.
  • Example 32 of the present invention The fifth step reaction of Example 32 of the present invention was repeated except that the compound obtained in the fourth step of Example 32 of the present invention was used.
  • the title product 2-(4-bromo-2-oxo-1,2-dihydro-indol-3-methylmethyl)-3-methyl-5-(2-piperidin-1-yl) -ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 57 (68 mg, yellow solid), yield: 91.2%.
  • Example 32 of the present invention The fifth step reaction of Example 32 of the present invention was repeated except that the compound obtained in the fourth step of Example 32 of the present invention was used.
  • Example 53 of the present invention was repeated except that the compound obtained in the fifth step of Example 53 of the present invention was used, 5-(2-light-methyl-3-morpholine-4-yl-propyl)-3-methyl 4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 53f and 5-bromo-1,3-dihydro- Indole-2-one was used as a starting material to give the title product 2-(5-bromo-2-oxo-1,2-dihydro-indole-3-indolyl-3-methyl)-5-(2-hydroxy-3) -morpholine-4-yl-propyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 59 (30 mg , yellow solid), Yield: 63%.
  • reaction was monitored until the starting material disappeared, and the reaction was quenched with water. 1 ml of hydrochloric acid (2 mol/L) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was adjusted to pH 10 with sodium hydroxide solution (10%), extracted with ethyl acetate (25 ml X 3), and the organic phase was combined and washed with saturated sodium chloride (25 ml ⁇ l) The magnesium is dried, and the desiccant is removed by suction filtration.
  • Example 60 of the present invention was repeated except that the compound 5-(2-diethylamino-ethyl)-3-methyl-4-oxo obtained in the fifth step of Example 60 was used.
  • the indole-2-one was used as a starting material to give the title product 5-(2-diethylamino-ethyl)-2-(5-bromo-2-oxo-1,2-dihydro) hydrazine-3- Hypomethyl)-3-methyl-6,7,8,9-tetrahydro-1H,5H-1,5-diaza-cyclopentacyclotetradec-4-one 61 (16 mg, Yellow solid), Yield: 68%.
  • the compound obtained in the fourth step of the first embodiment of the present invention is 5-(2-carboxy-ethyl)-3-methyl-1H-pyrrole-2,4-dihydroxy acid 2-tert-butyl ester 4-ethyl ester obtained at room temperature.
  • Le (9.85 g, 30.3 mmol) was dissolved in 50 ml of acetonitrile with stirring, and 1-hydroxybenzotriazole (8.2 g, 60.6 mmol) and N-ethyl-N,-(dimethylaminopropyl)-carbon were added.
  • Diimine (11.6 g, 60.6 mmol) added, and stirred at room temperature overnight. The dot plate indicates that the starting material is completely reacted and the reaction is stopped.
  • reaction was monitored by spotting until the reaction was completed and quenched with hydrochloric acid.
  • the reaction solution was further stirred at room temperature for 30 minutes, and the pH was adjusted to about 12 with a sodium hydroxide solution (10%), and ethyl acetate (30 ml X 3 ).
  • the organic phase was combined, and the organic phase was washed with saturated aqueous sodium chloride (30 ml), dried over anhydrous magnesium sulfate.
  • Ethyl 2-ethylamino-ethylamino)-propyl]-4-methyl-1H-pyrrole-3-carboxylate 62c (170 mg, white solid).
  • the reaction was monitored by spotting until the reaction of the starting material was complete, and the reaction was stopped.
  • the reaction solution was evaporated under reduced pressure.
  • the pH was adjusted to about 3 with hydrochloric acid (6 mol/L), stirred for 30 minutes, and then adjusted to pH 14 with sodium hydroxide solution (12 mol/L), and extracted with dichloromethane (100 ml) X 4).
  • Example 1 of the present invention is 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indole-3-indolyl) at room temperature. 3-methyl-3a,5,6,7,8,8a-hexahydro-1H-pyrrole[3,2-c] azepin-4-one 1 (2.01 g, 4.75 mmol) with stirring Dissolve in 279 ml of methanol, add 2-hydroxy-succinic acid (0.953 g, 7.11 mmol) in one time to obtain a clear orange solution. Evaporate the solvent under reduced pressure, add 45 ml of acetonitrile, and heat in an oil bath.
  • 2-Methyl-3-nitroaniline 74a (21.28 g, 0.14 mol) was dissolved in 70 ml of concentrated hydrochloric acid under ice-cooling, stirred under 40 ⁇ water, and the mixture was stirred at 0 to 5 °C. a yellow-green solid appears in the reaction solution, 40 ml of sodium nitrite solution (3.6 M) was added dropwise to the reaction solution, stirring was continued for 15 minutes, the reaction solution was filtered, and the filtrate was added dropwise to 280 ml of potassium iodide solution (5.25 M) at 0 to 5 ° C, and the mixture was continuously stirred. After 1 hour, the plate indicated that the reaction of the starting material was complete and the reaction was stopped.
  • the reaction solution was filtered under reduced pressure.
  • the filter cake was dissolved in ethyl acetate and washed with 10% sodium hydroxide solution, water, 5% sodium thiosulfate solution, and saturated sodium chloride solution, and the organic phase was dried over anhydrous sodium sulfate. 34.4 g of brown oil.
  • the crude product was purified by EtOAcjjjjjj Second step
  • the ester was washed (50 ml X 1) to remove the unreacted starting material, the pH of the aqueous phase was adjusted to 3 with 1M hydrochloric acid, and extracted with ethyl acetate (30 ml ⁇ 3). The organic phase was combined and washed with saturated sodium chloride (30 1) Drying with anhydrous sodium sulfate and concentrating under reduced pressure to give the title product 3-(2-iodo-6-nitro-benzene)-2-oxo-propionic acid 74c (2.94 g, brown oil) Step reaction.
  • the morphine 78a (4.356 ml, 50 mmol) was dissolved in 2.5 ml of tert-butanol with stirring at room temperature, and after cooling to 0 ° C with an ice bath, (S)-(+)-epichlorohydrin was slowly added dropwise. (4.02 ml, 50 mmol), the reaction mixture was warmed to room temperature and stirred overnight. The plate was monitored for reaction until the starting material disappeared. While maintaining the temperature of the reaction system below 10 ° C with ice bath, a solution of potassium tert-butoxide in tetrahydrofuran (30 ml, 1.67 mol/L, 50 mmol) was added dropwise, and the reaction mixture gradually changed from pale yellow to white turbid.
  • the in vitro cell assay described below determines the anti-angiogenic activity and the proliferative activity of the test compound against VEGFR-expressing tumor cells, and its activity can be expressed by the IC 5Q value.
  • the general protocol for such an experiment is as follows: first select human tumor cells with high expression of VEGFR, at the appropriate cell concentration (exp 5000 Cells/ml medium) were seeded on 96-well culture plates, and then the cells were cultured in a carbon dioxide incubator. When they grew to 85% confluence, the medium was changed to a series of concentration (generally 6 to 7 concentrations). The culture medium of the test compound solution was returned to the incubator for 72 hours.
  • test compound was tested for its ability to inhibit cell proliferation using the sulforhodamine B (SRB) method.
  • SRB sulforhodamine B
  • DMEM/F12 cell culture medium (Gibco, catalog 12400-024)
  • the following protocol was used to test the inhibitory cell proliferation IC 5 o values of the test compounds of the present invention against HUVEC cells.
  • the HUVEC cells were cultured in a 100 mm Connaught plate and cultured in a growth medium (DMEM/F12 + 10% fetal bovine serum as a medium) (37 V, 5 % C0 2 ) until the cells were fully confluent;
  • a growth medium DMEM/F12 + 10% fetal bovine serum as a medium
  • the medium is changed to a new medium supplemented with DMEM/F12 +10% fetal bovine serum, and 180 ⁇ l of the culture medium and 20 ⁇ M are added to each well.
  • the test compound solution prepared in the fifth step.
  • 20 ⁇ L of culture medium containing 0.5% DMSO was added, so that the final concentration of HUVEC cells exposed to the test compound solution was 100 ⁇ , 10 ⁇ , 5 ⁇ , 1 ⁇ , 0.1 ⁇ , 0.01 ⁇ , and 0.001.
  • the mixed colorant is dissolved in a certain volume of sulforhodamine, the solubilizing solution (10 mM Tris) is the same as the original volume of the medium, and the plate is allowed to stand at room temperature for 5 minutes, and slowly stirred with a shaker to accelerate Mixing of dyes;
  • the absorbance values are the absorbance at 565 mil minus the background absorbance at 96 nm for 690 nm;
  • IR lOOx (absorbance value of the control group - absorbance value of the drug group) / % absorbance value of the control group.
  • the IC 50 value can be calculated from the ratio of compound inhibition rates at different concentrations.
  • the biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC50 values are shown in the following table. 2 0.288
  • wash buffer PBS-T buffer: lx PBS (137 mM NaCK 2.7 mM KC1, 4.3 mM Na 2 HP0 4 , 1.4 mM KH 2 P0 4 , adjusted to pH 7.2) and 0.05% Tween-20
  • bovine serum albumin (BSA, Calbioc em #136593) PBS-T buffer
  • Stop reaction buffer 50 mM EDTA, pH 8.0
  • DELFIA® Streptavidin 96-well yellow plate (PerkinElmer Life Sciences #AAAND-0005)
  • g. Recombinant human VEGF-R2 kinase 50 mM Tris-HCl (pH 8.0), 100 mM NaCl, 5 mM DTT, 15 mM glutathione glycine and 20% glycerol (.611 signaling technology #7787)
  • h. 10 mM ATP solution Cell signaling technology #9804
  • test compound Dilute the test compound to the desired final concentration in DMSO, adding 1 ⁇ M of test compound, one negative control, and a blank control in each test (all do not accept any test compound);
  • reaction stop buffer 50 mM EDTA, pH 8.0
  • 25 ⁇ M reaction solution to each well of a 96-well streptavidin-coated plate. 75 ⁇ dH 2 0, shake at room temperature for 60 minutes;
  • the IC 50 value is calculated from the IR values at a range of concentration concentrations of the test compound.
  • the biochemical activity of the compound of the present invention was measured by the above test, and the measured IC 5Q value is shown in the following table.
  • Example 63 Effect on human colon cancer HT-29 nude mouse xenografts.
  • Example 63 Continuous oral administration significantly inhibited the growth of human colon cancer HT-29 and caused tumor shrinkage, and the mice were well tolerated by this compound.
  • Example 63 is a yellow powder.
  • Example 63 was formulated to the corresponding concentration with distilled water.

Abstract

La présente invention concerne de nouveaux dérivés pyrrolo-azotés hétérocycliques représentés par la formule (I) ou leurs sels, leur préparation, des compositions pharmaceutiques contenant de tels dérivés et l'utilisation de ces dérivés en tant qu'agents thérapeutiques, spécialement en tant qu'inhibiteurs de protéine kinases, chaque substituant dans la formule (I) étant tel que défini dans la description.
PCT/CN2008/001352 2007-05-14 2008-05-14 Dérivés pyrrolo-azotés hétérocycliques, leur préparation et leur utilisation pharmaceutique WO2008138232A1 (fr)

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BRPI0811865-5A2A BRPI0811865A2 (pt) 2007-05-14 2008-05-14 Derivados heterocíclicos pirrolo-nitrogenados, a preparação e o uso farmacêutico dos mesmos
CN2008800150088A CN101675061B (zh) 2007-05-14 2008-05-14 吡咯并n杂环类衍生物及其在医药上的应用
MX2009011964A MX2009011964A (es) 2007-05-14 2008-05-14 Derivados heterociclicos pirrolo-nitrogenosos, su preparacion y uso farmaceutico.
CA002685757A CA2685757A1 (fr) 2007-05-14 2008-05-14 Derives pyrrolo-azotes heterocycliques, leur preparation et leur utilisation pharmaceutique
US12/451,466 US8329682B2 (en) 2007-05-14 2008-05-14 Pyrrolo-nitrogenous heterocyclic derivatives, the preparation and the pharmaceutical use thereof
JP2010507781A JP5342547B2 (ja) 2007-05-14 2008-05-14 ピロロ窒素複素環誘導体、その調製および薬学的使用
EP08783545A EP2157093A4 (fr) 2007-05-14 2008-05-14 Dérivés pyrrolo-azotés hétérocycliques, leur préparation et leur utilisation pharmaceutique
AU2008250895A AU2008250895B2 (en) 2007-05-14 2008-05-14 Pyrrolo-nitrogenous heterocyclic derivatives, the preparation and the pharmaceutical use thereof
HK10104918.9A HK1137027A1 (en) 2007-05-14 2010-05-19 Pyrrolo-nitrogenous heterocyclic derivatives and the pharmaceutical use thereof
US13/628,446 US20130303518A1 (en) 2007-05-14 2012-09-27 Methods of Inhibiting the Catalytic Activity of a Protein Kinase and of Treating a Protein Kinase Related Disorder

Applications Claiming Priority (4)

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CN200710107463.8 2007-05-14
CN200710107463 2007-05-14
CN2008100875648A CN101307052B (zh) 2007-05-14 2008-04-11 吡咯并n杂环类衍生物的制备方法及其在医药上的应用
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WO2011095068A1 (fr) 2010-02-04 2011-08-11 江苏恒瑞医药股份有限公司 Sels de qualité pharmaceutique de dérivés hétérocycliques pyrrolo-azotés, leur procédé de préparation et leur utilisation médicale
CN102429901A (zh) * 2011-11-03 2012-05-02 合肥博太医药生物技术发展有限公司 吲哚-3-甲醇、二吲哚甲烷及其衍生物在制备防治肾纤维化药物中的应用
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Publication number Priority date Publication date Assignee Title
WO2011095068A1 (fr) 2010-02-04 2011-08-11 江苏恒瑞医药股份有限公司 Sels de qualité pharmaceutique de dérivés hétérocycliques pyrrolo-azotés, leur procédé de préparation et leur utilisation médicale
CN102421781A (zh) * 2010-02-04 2012-04-18 江苏恒瑞医药股份有限公司 吡咯并n杂环类衍生物的可药用的盐、其制备方法及其在医药上的应用
CN102429901A (zh) * 2011-11-03 2012-05-02 合肥博太医药生物技术发展有限公司 吲哚-3-甲醇、二吲哚甲烷及其衍生物在制备防治肾纤维化药物中的应用
CN102429901B (zh) * 2011-11-03 2013-11-06 合肥博太医药生物技术发展有限公司 吲哚-3-甲醇、二吲哚甲烷及其衍生物在制备防治肾纤维化药物中的应用
US11504359B2 (en) 2012-01-26 2022-11-22 Angion Biomedica Corp. Antifibrotic compounds and uses thereof

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