WO2009103218A1 - Ethylidene hydrazine carboxamide derivatives, preparation process and pharmaceutical use thereof - Google Patents

Ethylidene hydrazine carboxamide derivatives, preparation process and pharmaceutical use thereof Download PDF

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WO2009103218A1
WO2009103218A1 PCT/CN2009/000136 CN2009000136W WO2009103218A1 WO 2009103218 A1 WO2009103218 A1 WO 2009103218A1 CN 2009000136 W CN2009000136 W CN 2009000136W WO 2009103218 A1 WO2009103218 A1 WO 2009103218A1
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compound
ethyl
formula
mmol
group
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PCT/CN2009/000136
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WO2009103218A8 (en
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邓炳初
吕贺军
陈一千
宋鹏
王胜蓝
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上海恒瑞医药有限公司
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Publication of WO2009103218A1 publication Critical patent/WO2009103218A1/en
Publication of WO2009103218A8 publication Critical patent/WO2009103218A8/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/40—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of thiourea or isothiourea groups further bound to other hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel ethylene amide amide derivative of the formula (I), a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly as thrombopoietin (TPO) Mimetics and use as a thrombopoietin receptor agonist.
  • TPO thrombopoietin
  • TPO Thrombopoietin
  • MDF megakaryocyte growth and development factor
  • TEF thrombocytopoiesis stimulating factor
  • c-Mpl ⁇ ⁇ c -myeloproliferative leukemia ligand, c-Mpl
  • mpl ligand megapoietin
  • the activity of TPO is derived from the binding of TPO to the TPO receptor (also known as MPL).
  • TPO receptor also known as MPL.
  • the TPO receptor has been successfully cloned and the amino acid sequence has also been sequenced (Vigon et al., Proc. Nat. Acad. Sci., 89: 5640-5644 (1992)).
  • TPO is a 332-amino acid glycosylated polypeptide that plays a key role in regulating megakaryocyte production and platelet production by bone marrow megakaryocytes (Kuter et al., Proc. Nat. Acad. Sci. USA 91 : 11104 -11108 (1994); Barley et al., Cell 77: 1117-1124 (1994); Kaushansky et al., Nature 369: 568-571 (1994); Wendling et al” Nature 369: 571-574 (1994); And Sauvage et al., Nature 369: 533-538 (1994)).
  • TPO is produced in the liver but mainly acts on the bone marrow, stimulating the differentiation of stem cells into megakaryocytes and the proliferation of megakaryocytes, polyploidization, and most importantly, into platelets.
  • the body circulates and divides.
  • TPO is a major regulator of thrombocytopenia and a large number of platelet studies on increasing platelet count, size, and increased isotope in experimental animals (Metcalf, Nfltwre 369:519-520 (1994)).
  • megakaryocyte production is mainly affected by several ways: (1) causing an increase in the size and number of megakaryocytes; (2) increasing DNA inclusions, polyploid forms, megakaryocytes; (3) increasing the nuclear content of megakaryocytes Wired (4) Increase the number of mature megakaryocytes; (5) Increase the percentage of precursor cells, small acetylcholine enzyme-yang-sexual form of cells, bone marrow cells.
  • TPO has been used to diagnose and treat a variety of blood diseases, such as those caused primarily by platelet defects.
  • TP0 can be used to treat thrombocytopenia, especially chemotherapy, radiation and bone marrow transplantation for the treatment of cancer and lymphoma.
  • the thrombopoietin analog eltrombopag is reported by GSK in the patent (WO-00189457 / WO-01089457 / WO-2006064957) and exhibits considerable activity.
  • the present invention discloses a series of compounds that are more effective as TPO receptor agonists and are potent TPO mimetics. Summary of the invention
  • an object of the present invention to provide an ethylene amide amide derivative represented by the general formula (I), and their tautomers, enantiomers, and non-pairs.
  • R, R 2 or R 3 are each independently selected from a hydrogen atom or a fluorenyl group, or
  • R 2 with or R 3 and the atoms to which they are attached form a 4 to 6 membered ring;
  • R 5 is selected from a hydrogen atom or a fluorenyl group
  • X is selected from an oxygen atom or a sulfur atom
  • Y is 1 to 4 atomic spaces of one or more groups selected from a mercapto group or an aryl group, wherein the aryl group or alkyl group is optionally further further selected from one or more selected from halogen, decyl or aryl Substituted by a substituent.
  • Y is selected from
  • R 6 is selected from a hydrogen atom, a halogen, a fluorenyl group or an aryl group;
  • R 7 is selected from a hydrogen atom or a fluorenyl group.
  • the present invention provides a compound represented by the formula ( ⁇ ) or a pharmaceutically acceptable salt, hydrate or solvent compound thereof:
  • R. , R 2 or each independently selected from a hydrogen atom or a fluorenyl group
  • R 2 and R 3 and the atoms to which they are attached form a 4 to 6 membered ring;
  • R 5 is selected from a hydrogen atom or an alkyl group
  • R 6 is selected from a hydrogen atom, a halogen, a fluorenyl group or an aryl group;
  • X is selected from an oxygen atom or a sulfur atom.
  • the present invention provides a compound of the formula (III) or a pharmaceutically acceptable salt, hydrate or solvent compound thereof,
  • R, R 2 or R 3 are each independently selected from a hydrogen atom or an alkyl group, or are bonded to 1 or R 3 and a bonded atom to form a halogen, alkyl, tetrazolyl, carboxyl or carboxylate;
  • R 5 is selected from a hydrogen atom or a fluorenyl group;
  • R 7 is selected from a hydrogen atom or a fluorenyl group
  • X is selected from an oxygen atom or a sulfur atom.
  • Preferred compounds of the invention include, but are not limited to:
  • R4 is selected from the group consisting of halogen, decyl, tetrazolyl, carboxy or carboxylic acid ester;
  • R 5 is selected from a hydrogen atom or an alkyl group
  • X is selected from an oxygen atom or a sulfur atom.
  • the present invention provides a compound represented by the formula (IB) which is synthesized as a compound of the formula (I)
  • R 2 are independently selected from a hydrogen atom or an alkyl group, or
  • R 2 and R, or R 3 and the atoms to which they are attached form a 4 to 6 membered ring;
  • Y is 1 to 4 atomic spaces of one or more groups selected from a fluorenyl or aryl group, wherein the aryl or fluorenyl group is optionally further further selected from one or more selected from halogen, alkyl or aryl Substituted by a substituent.
  • Y is selected from
  • R 6 is selected from a hydrogen atom, a halogen, a fluorenyl group or an aryl group;
  • R 7 is selected from a hydrogen atom or an alkyl group.
  • a process for the preparation of a compound of the formula (; IA) which comprises the steps of: The substituted aniline is reacted with hydrazine, ⁇ '-deuterated carbonyl diimidazole, and the obtained compound is reacted with a hydrazine hydrate solution at room temperature to obtain a compound of the formula (I ⁇ ) wherein R 5 and X are as in the above formula (IA) Defined.
  • a process for the preparation of a compound of formula (IB) the process comprising the steps of:
  • the general formula (IB) and a compound X-substituted phenyl isocyanate under acidic conditions was heated to give compound of general formula (the I), wherein Ri, R2, R 3,, R 5, X and Y It is as defined in the above formula (I).
  • the invention relates to the use of a compound of formula (I) for the preparation of a TPO receptor agonist.
  • the invention relates to the use of a compound of formula (I) for the manufacture of a medicament for the treatment of thrombocytopenia. Further comprising a therapeutically effective amount of colony stimulating factor, a cytokine, a chemokine, an interleukin or a cytokine receptor agonist or antagonist, a soluble receptor, a receptor agonist, an antagonist antibody or with A combination of peptides or small molecules of the same mechanism.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), and a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.
  • the composition may further comprise a therapeutically effective amount of colony stimulating factor, cytokine, chemokine, leukocyte in combination Interleukin or cytokine receptor agonist.
  • Use of the composition in the manufacture of a medicament for treating thrombocytopenia.
  • the combined use includes the simultaneous or sequential use of the compounds described herein.
  • the present invention relates to a process for the preparation of a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of formula (I) and a pharmaceutically acceptable salt, hydrate or solvate thereof, which process comprises a formula (I)
  • the compound is combined with a pharmaceutically acceptable carrier and a diluent.
  • Alkyl means a saturated aliphatic hydrocarbon group comprising straight and branched chain groups of 1 to 20 carbon atoms.
  • fluorenyl 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 fluorenyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, a tetrazolyl group, an aryl group, a carboxylic acid or a carboxylic acid ester.
  • 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 substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from an alkyl group, a halogen, a hydroxyl group, a tetrazolyl group, an aryl group, a heteroaryl group, a carboxylic acid or Carboxylic acid ester.
  • Halogen means fluoro, chloro, bromo or iodo.
  • tetrazolyl refers to a five-membered heteroaryl group containing four nitrogen atoms.
  • “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 preparation method of the compound of the formula (I) or a salt thereof of the present invention comprises the following steps:
  • the substituted aniline is reacted with N,N'-X carbonyldiimidazole, and the obtained compound is reacted with a hydrazine hydrate solution at room temperature to obtain a compound of the formula ( ⁇ ⁇ ), or a substituted phenyl isocyanate and a hydrazine hydrate solution are reacted at room temperature.
  • a compound of the formula (I ⁇ ) is obtained by heating and condensing a compound of the formula dimethylaminoethylene and a compound of the formula (I ⁇ ) under acidic conditions.
  • the dimethylaminoethylidene derivative of the formula is reacted with a hydrazine hydrate solution at room temperature to obtain a compound of the formula (I ⁇ ); the compound of the formula (I ⁇ ) and the X-substituted phenylisocyanate are heated under acidic conditions. Condensation gives the compound of formula 1.
  • a compound of the formula (I ⁇ ) is reacted with a hydrazine hydrate solution at room temperature to obtain a compound of the formula (I ⁇ ); the compound of the formula (I ⁇ ) and the X-substituted phenylisocyanate are heated under acidic conditions. Condensation gives the compound of formula 1.
  • the structure of the compound is determined by nuclear magnetic resonance ('HNMR) or mass spectrometry (MS).
  • the 1H NMR shift ( ⁇ ) is given in parts per million (ppm).
  • the 1H NMR measurement was carried out using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated chloroform (CDC1 3 ), deuterated methanol (CD 3 OD), hexamethylene dimethyl sulfoxide (DMSO-
  • the internal standard is tetramethylsilane (TMS) and the chemical shift is given in units of l (T 6 (ppm);
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume;
  • the solution in the reaction means an aqueous solution
  • 1,3-dihydroindol-2-one lc (20 g, 150 mmol), m-bromo Toluene (30.78 g, 180 mmol), cuprous iodide (5.7 g, 30 mmol) and potassium carbonate (46 g, 330 mmol) were dissolved in 300 mL of acetonitrile, and ⁇ , ⁇ '-dimethyl-1 was added with stirring.
  • 2-Ethylenediamine (4 g, 45 mmol), heated to reflux for 2 h.
  • 1,3-Dihydroindole-2-one 2a (8.0 g, 60.1 mmol), 4-bromo-1,2-dimethylbenzene (13.4 g, 72.2 mmol), cuprous iodide (2.29 g, 12.0 mmol) And potassium carbonate (20.7 g, 150 mmol) was dissolved in 250 mL of acetonitrile, and hydrazine, ⁇ '-dimethyl-1,2-ethanediamine (1.59 g, 18 mmol) was added under stirring, and the mixture was refluxed for 2 hr.
  • Ethyl 4-isothiocyanate benzoate 2d (1.0 g, 4.83 mmol) was dissolved in 15 mL of absolute ethanol, and 50% hydrazine hydrate solution (2.4 mL, 24.13 mmol) and 20 mL absolute ethanol were added with stirring. Heat to reflux for 0.5 hours. The spot plate was traced until the starting material disappeared, cooled to room temperature, filtered, and the filter cake was dried under vacuum to give ethyl 4-(indolesulfonyl)benzoate 2e (1.l g, white solid). Yield: 95.7%.
  • the residue was purified by silica gel column chromatography eluting eluting eluting Yield: 13.7%.
  • Methyl 4-methylaminobenzoate 10c (100 mg, 0.605 mmol) and hydrazine, hydrazine, -thiocarbonyldiimidazole (162 Mg, 0.908 mmol) was dissolved in 15 mL of dichloromethane and allowed to react at room temperature for 4 days. The reaction was quenched by TLC to dryness eluting with silica gel elution elution elution elution elution elution elution elution Yield: 77.8%.
  • 2,3-Dihydro-1H-indole-5-amine 13a (11.73 g, 88.2 mmol) was dissolved in 50 mL of acetonitrile with stirring Hydrochloric acid (2N, 100 mL) was added. After cooling in ice-water bath, sodium nitrite (6.87 g, 99.6 mmol) was added. After 20 minutes, potassium iodide (31.3 g, 188.6 mmol) was added, and the mixture was cooled in an ice water bath, and the reaction was stirred overnight. TLC followed the reaction to the disappearance of the starting material, and the reaction mixture was extracted with n-hexane (150 mL ⁇ 2).
  • Methyl 4-isothiocyanate benzoate 20d (4 g, 19.3 mmol) was dissolved in 50 mL of ethanol, and a 50% hydrazine hydrate solution (3.86 mL, 38.6 mmol) was added and reacted at 80 ° C for 30 minutes. The reaction was quenched by TLC until the title material disappeared. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethanol (5 mL) and dried under vacuum to give methyl 4-(sulfonylamino)benzoate 20e (4.0 g, white solid ). Yield: 86.9%.
  • 5-Aminoindan 21a (6 g, 45 mmol) was dissolved in hydrochloric acid (2N, 50 mL) under ice-water bath, and 15 mL of sodium nitrite solution (3.4 g, 50 mmol) was added dropwise with stirring, and stirred for 30 minutes.
  • stannous chloride dihydrate (30.6 g, 135 mmol) was dissolved in 20 mL of concentrated hydrochloric acid, and added to the above solution, and reacted at room temperature for 1 hour.
  • the pH was adjusted to 10 with sodium hydroxide solution (3N, 30 mL), EtOAc (EtOAc)EtOAc.
  • the solution was concentrated to 400 mL under reduced pressure.
  • Example 7 The TPO series of compounds (Example 7) was observed for activation of STAT3 in 32D-Mpl mouse prolymphocytes B cells transfected with TPO receptor Mpl in vitro. After treatment of the cells with different concentrations of the compound of Example 7 and TPO-EoA, the effect was evaluated by Western blot. It was found by experiment that the activity of Example 7 is comparable to that of TPO-EoA.
  • RPMI-1640 was purchased from Gibco BRL; fetal bovine serum was purchased from Hyclone; anti-STAT3 phosphorylated antibody was purchased from Cell signaling; anti-rabbit lgG secondary antibody, nitrocellulose membrane, and ECL detection kit were purchased from Amershan; Reagents were purchased from Sigma
  • the 32D-Mpl cells were treated with the compound of Example 7, and then, the cells were collected and lysed, and the proteins were fixed to the same amount. After denaturation of the protein, SDS-PAGE was performed, transferred to a nitrocellulose membrane, and hybridized with an anti-STAT3 phosphorylated antibody (an anti-rabbit IgG antibody (secondary antibody), and finally detected by an ECL kit, and the X-ray film was exposed. The size and density of the protein bands were evaluated for the degree of activation of STAT3 by the compound of Example 7.
  • mouse 1L-3 ( chemicon Catalog no.ILOl 5 )
  • TPO Huma Thrombopoietin R Mab
  • Plasmid construction According to the TPOR gene sequence ⁇ ij provided by Entrez Gene ID: 4325, Refseq: NM-005373, the purchased EX-B0010-M02 plasmid (FulenGen) utilizes QuikChange® Multi Site Directed
  • the Mutagenesis Kit (Stratagene) kit performs a 2-point mutation.
  • the multi-point mutation primer sequences are: g49 la: 5'-gggaacttcagatcagctgggaggagccg-3 ', g491 a anti sense:
  • BAF3-TPOR cell line A BaF3 cell line stably expressing a highly functional TPO receptor was constructed. The by expressing human after the 2-point mutant TPO receptor and screening gene neomycin the EX-B0010-M02 plasmid 25 ⁇ ⁇ transfected with wild-type BaF3 cells (1X10 7), transfection instruments as Electro Square Porator ECM830 (BTX Division of Genetronic, Inc. US), transfection conditions: 250V, 18ms. The BAF3-TPOR stable cell line was obtained by G418 (Gibco, US) screening. BAF3-TPOR in RPMI1640
  • Centrifuge the cells by centrifugation Take appropriate amount of cell suspension at 1000 rpm, centrifuge for 5 minutes, discard the supernatant, resuspend the cells with 10 mL of cell culture medium without IL3, centrifuge at lOOOOrpm for 5 minutes, discard the supernatant. ;
  • test compound powder into 10 mM stock solution in DMSO, and dilute it with RPM11640. Same concentration: 30 ⁇ , 10 ⁇ , 3 ⁇ , ⁇ ⁇ , 0.3 ⁇ , 0.1 ⁇ , 0.03 ⁇ , 0.01 ⁇ , 0.003 ⁇ , 0.001 ⁇ ;

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Abstract

Ethylidene hydrazidecarboxamide derivatives of formula (I) or pharmaceutically acceptable salts, hydrate or solvation thereof, methods for their preparation, pharmaceutical compositions containing the same and their use as a therapeutic agent, especially as thrombopoietin (TPO) mimetics and their use as agonists of thrombopoietin receptor. The definitions of substituents in formula (I) are the same as the description.

Description

亚乙基肼酰胺类衍生物、 其制备方法及其在医药上的应用  Ethylene oxime amide derivative, preparation method thereof and application thereof in medicine
技术领域 Technical field
本发明涉及一种通式 (I)所示新的亚乙基肼酰胺类衍生物，其制备方法以及含有 该衍生物的药物组合物， 以及其作为治疗剂特别是作为血小板生成素 (TPO)模拟物 和作为血小板生成素受体激动剂的用途。 背景技术  The present invention relates to a novel ethylene amide amide derivative of the formula (I), a process for the preparation thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly as thrombopoietin (TPO) Mimetics and use as a thrombopoietin receptor agonist. Background technique
血小板生成素（Thrombopoietin , TPO), 又称为巨核细胞生长发育因子 (megakaryocyte growth and development factor, MGDF) , 血小板生成朿 !j激因子 (thrombocytopoiesis stimulating factor, TSF)， c-Mpl 酉己体 (c-myeloproliferative leukemia ligand, c-Mpl) , mpl 配体， megapoietin, 是一种与产生血小板有关的糖蛋 白 (Wendling, F.， et. al., Biotherapy 10(4):269-77 (1998); Kuter D.l. et al., The Oncologist; 1 :98-106(1996); Metcalf, Nature 369: 519-520 (1994))。  Thrombopoietin (TPO), also known as megakaryocyte growth and development factor (MGDF), thrombocytopoiesis stimulating factor (TSF), c-Mpl 酉 体 (c -myeloproliferative leukemia ligand, c-Mpl), mpl ligand, megapoietin, is a glycoprotein associated with platelet production (Wendling, F., et. al., Biotherapy 10(4): 269-77 (1998); Kuter Dl et al., The Oncologist; 1: 98-106 (1996); Metcalf, Nature 369: 519-520 (1994)).
在某些情况下， TPO的活性源自 TPO与 TPO受体 (也称 MPL)的结合。 TPO受体己 经被成功克隆， 也进行了氨基酸序列的测序 (Vigon et al., Proc. Nat. Acad. Sci., 89:5640-5644(1992))。  In some cases, the activity of TPO is derived from the binding of TPO to the TPO receptor (also known as MPL). The TPO receptor has been successfully cloned and the amino acid sequence has also been sequenced (Vigon et al., Proc. Nat. Acad. Sci., 89: 5640-5644 (1992)).
TPO是一种 332-氨基酸糖基化多肽，在调节巨核细胞生成和由骨髓巨核细胞产 生血小板的过程中起着关键的作用 (Kuter et al., Proc. Nat. Acad. Sci. USA 91 : 11104-11108 (1994); Barley et al., Cell 77: 1117-1124 (1994); Kaushansky et al., Nature 369:568-571 (1994); Wendling et al" Nature 369: 571-574 (1994); and Sauvage et al., Nature 369: 533-538 (1994)). TPO产生于肝脏但主要作用于骨髓， 刺激干细胞分化 成为巨核细胞以及巨核细胞的增殖， 多倍体化， 最重要的是进入血小板身体循环 分裂。 TPO在血小板减少症和大量关于增加血小板数量、大小、增加实验动物同位 素参入的血小板研究中是一种主要的调节剂 (Metcalf， Nfltwre 369:519-520 (1994))。 TPO被认为主要通过几个途径影响巨核细胞生成： （1)引起巨核细胞大小和数量的 增加； （2)增加 DNA内含物， 多倍体的形式， 巨核细胞； （3)增加巨核细胞的核内有 丝分裂； （4)增加成熟的巨核细胞； （5)增加前体细胞的百分比， 小乙酰胆碱酶一阳' 性形式的细胞， 骨髓细胞。  TPO is a 332-amino acid glycosylated polypeptide that plays a key role in regulating megakaryocyte production and platelet production by bone marrow megakaryocytes (Kuter et al., Proc. Nat. Acad. Sci. USA 91 : 11104 -11108 (1994); Barley et al., Cell 77: 1117-1124 (1994); Kaushansky et al., Nature 369: 568-571 (1994); Wendling et al" Nature 369: 571-574 (1994); And Sauvage et al., Nature 369: 533-538 (1994)). TPO is produced in the liver but mainly acts on the bone marrow, stimulating the differentiation of stem cells into megakaryocytes and the proliferation of megakaryocytes, polyploidization, and most importantly, into platelets. The body circulates and divides. TPO is a major regulator of thrombocytopenia and a large number of platelet studies on increasing platelet count, size, and increased isotope in experimental animals (Metcalf, Nfltwre 369:519-520 (1994)). It is believed that megakaryocyte production is mainly affected by several ways: (1) causing an increase in the size and number of megakaryocytes; (2) increasing DNA inclusions, polyploid forms, megakaryocytes; (3) increasing the nuclear content of megakaryocytes Wired (4) Increase the number of mature megakaryocytes; (5) Increase the percentage of precursor cells, small acetylcholine enzyme-yang-sexual form of cells, bone marrow cells.
血小板是血液凝固必需的， 当它的数量非常低时， 病人就有出血死亡的危险。 因此， TPO己经被用于诊断和治疗多种血液疾病，如主要由血小板缺陷引起的疾病。 同时， TP0可以用于治疗血小板减少症，尤其是为治疗癌症和淋巴瘤而进行的化疗、 放疗和骨髓移植。  Platelets are essential for blood clotting, and when it is very low, the patient is at risk of bleeding. Therefore, TPO has been used to diagnose and treat a variety of blood diseases, such as those caused primarily by platelet defects. At the same time, TP0 can be used to treat thrombocytopenia, especially chemotherapy, radiation and bone marrow transplantation for the treatment of cancer and lymphoma.
患者因血小板减少症而导致血小板水平恢复过慢是一个严重的问题， 因此希 望可以找到一种治疗血小板减少症的活性 TPO类似物。几年前， 多肽类 ΤΡ0类似物 的发展被报导。 （WO96/40189, WO96/40750, W098/25965) 这些多肽被设计结合并 活化 ΤΡΟ受体， 但是不具备天然 ΤΡ0的序列同源性。 最近几年， 一些小分子的活性 ΤΡ0类似物被报导。 包括 1,4-苯并二氮杂卓 -2-酮类 (JP11001477), 由希夫碱配体得 到的金属络合物 (WO 99/11262)，环多胺衍生物 (WO00/28987),噻唑 -2-基-苯酰胺类 (WO01/07423, WOOl/53267), 偶氮 -芳基衍生物 (WOOO/35446, WOl/17349), 2-芳基- 萘唑类 (WO01/39773, WOOl/53267)和缩氨基脲衍生物 (WO01/34585)。 在基于细胞 的体系内，所有这些分子都能活化细胞膜上的 TPO受体的信号转导途径，一些类型 能直接作用于 TPO受体本身。 据介绍， 取代缩氨硫脲居然是非常有效的 TPO受体 激动剂。 这一系列中一些最优先的化合物被发现可以刺激 TPO- responsive人类细胞 系和低于 ΙΟΟηΜ的人类骨髓培养液中的 TPO的增殖和分化。 It is a serious problem that patients with thrombocytopenia cause platelet levels to recover too slowly. It is hoped that an active TPO analog for treating thrombocytopenia can be found. A few years ago, the development of peptide ΤΡ0 analogs was reported. (WO 96/40189, WO 96/40750, W098/25965) These polypeptides are designed to bind to and activate purinoceptors, but do not possess the sequence homology of native ΤΡ0. In recent years, some small molecule active ΤΡ0 analogs have been reported. Including 1,4-benzodiazepine-2-ones (JP11001477), metal complexes obtained from Schiff base ligands (WO 99/11262), cyclic polyamine derivatives (WO 00/28987), thiazole -2-yl-benzamides (WO 01/07423, WOOl/53267), azo-aryl derivatives (WOOO/35446, WOl/17349), 2-aryl-naphthazoles (WO 01/39773, WOOl/ 53267) and a semicarbazone derivative (WO 01/34585). Within a cell-based system, all of these molecules activate the signal transduction pathway of the TPO receptor on the cell membrane, and some types act directly on the TPO receptor itself. According to reports, the replacement of thiourea is actually a very effective TPO receptor agonist. Some of the most preferential compounds in this series have been found to stimulate the proliferation and differentiation of TPO-responsive human cell lines and TPO in human bone marrow broth below ΙΟΟηΜ.
GSK公司在专利 (WO-00189457/ WO-01089457/WO-2006064957)中报道血小板 生成素类似物 eltrombopag, 并表现出了相当的活性。  The thrombopoietin analog eltrombopag is reported by GSK in the patent (WO-00189457 / WO-01089457 / WO-2006064957) and exhibits considerable activity.
本发明公开了一系列化合物且更有效地用作 TPO受体激动剂， 是有效的 TPO 模拟物。 发明内容  The present invention discloses a series of compounds that are more effective as TPO receptor agonists and are potent TPO mimetics. Summary of the invention
为了克服现有技术的不足之处， 本发明的目的在于提供一种通式（ I )所示的亚 乙基肼酰胺类衍生物， 以及它们的互变异构体、 对映体、 非对映体、 消旋体和药 学上可接受的盐、 水合物或溶剂化合物， 以及代谢产物和代谢前体或前药。  In order to overcome the deficiencies of the prior art, it is an object of the present invention to provide an ethylene amide amide derivative represented by the general formula (I), and their tautomers, enantiomers, and non-pairs. Enantiomers, racemates and pharmaceutically acceptable salts, hydrates or solvent compounds, as well as metabolites and metabolic precursors or prodrugs.
Figure imgf000004_0001
射:
Figure imgf000004_0001
Shoot :
R, , R2或 R3各自独立地选自氢原子或垸基， 或者 R, R 2 or R 3 are each independently selected from a hydrogen atom or a fluorenyl group, or
R2、 与 或 R3和其相连接的原子形成一个 4〜6元环； R 2 , with or R 3 and the atoms to which they are attached form a 4 to 6 membered ring;
选自卤素、 垸基、 四唑基、 羧基或羧酸酯；  Selected from halogen, decyl, tetrazolyl, carboxyl or carboxylic acid esters;
R5选自氢原子或垸基； R 5 is selected from a hydrogen atom or a fluorenyl group;
X选自氧原子或硫原子； 且  X is selected from an oxygen atom or a sulfur atom;
Y是一个或多个基团的 1〜4个原子空间， 选自垸基或芳基， 其中所述芳基或 烷基任选地进一步被一个或多个选自卤素、 垸基或芳基的取代基所取代。  Y is 1 to 4 atomic spaces of one or more groups selected from a mercapto group or an aryl group, wherein the aryl group or alkyl group is optionally further further selected from one or more selected from halogen, decyl or aryl Substituted by a substituent.
优选地， Y选自
Figure imgf000005_0001
Preferably, Y is selected from
Figure imgf000005_0001
R6选自氢原子、 卤素、 垸基或芳基； R 6 is selected from a hydrogen atom, a halogen, a fluorenyl group or an aryl group;
R7选自氢原子或垸基。 具体地， 本发明提供了通式 (Π )所示的化合物或其药学上可接受的盐、 水合物 或溶剂化合物： R 7 is selected from a hydrogen atom or a fluorenyl group. Specifically, the present invention provides a compound represented by the formula (Π) or a pharmaceutically acceptable salt, hydrate or solvent compound thereof:
Figure imgf000005_0002
Figure imgf000005_0002
(Π)  (Π)
其中：  among them:
R. 、 R2或 各自独立地选自氢原子或垸基， R. , R 2 or each independently selected from a hydrogen atom or a fluorenyl group,
或者 R2与 或 R3和其相连接的原子形成一个 4〜6元环； Or R 2 and R 3 and the atoms to which they are attached form a 4 to 6 membered ring;
选自卤素、 烷基、 四唑基、 羧基或羧酸酯；  Selected from halogen, alkyl, tetrazolyl, carboxyl or carboxylic acid esters;
R5选自氢原子或烷基； R 5 is selected from a hydrogen atom or an alkyl group;
R6选自氢原子、 卤素、 垸基或芳基； 且 R 6 is selected from a hydrogen atom, a halogen, a fluorenyl group or an aryl group;
X选自氧原子或硫原子。 进一步， 本发明提供了通式 (III)所示的化合物或其药学上可接受的盐、 水合物 或溶剂化合物，  X is selected from an oxygen atom or a sulfur atom. Further, the present invention provides a compound of the formula (III) or a pharmaceutically acceptable salt, hydrate or solvent compound thereof,
Figure imgf000005_0003
中-
Figure imgf000005_0003
in-
R, R2或 R3各自独立地选自氢原子或烷基， 或者 与1^ 或 R3和相连接的原子并成一个 选自卤素、 烷基、 四唑基、 羧基或羧酸酯; R5选自氢原子或垸基； R, R 2 or R 3 are each independently selected from a hydrogen atom or an alkyl group, or are bonded to 1 or R 3 and a bonded atom to form a halogen, alkyl, tetrazolyl, carboxyl or carboxylate; R 5 is selected from a hydrogen atom or a fluorenyl group;
R7选自氢原子或垸基； 且 R 7 is selected from a hydrogen atom or a fluorenyl group;
X选自氧原子或硫原子。 本发明通式（ 所示的优选化合物包括， 但不限于:  X is selected from an oxygen atom or a sulfur atom. Preferred compounds of the invention (including preferred compounds include, but are not limited to:
Figure imgf000006_0001
Figure imgf000007_0001
(Z)- 4-(2-( l-(2,3-二氢 -1H-茚 -5-
Figure imgf000006_0001
Figure imgf000007_0001
(Z)- 4-(2-( l-(2,3-Dihydro-1H-茚-5-)
18 基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙
Figure imgf000008_0001
基) -N-甲基肼硫酰氨基)苯甲酸 18 yl)-2-oxo-1,3-dihydroindole-3-ylidene)
Figure imgf000008_0001
-N-methylsulfonylamino)benzoic acid
F  F
(Z)-4-(2-( 1 -( 1 -(2,3-二氢- 1 H-茚 -5- (Z)-4-(2-( 1 -( 1 -(2,3-dihydro-1 H-茚 -5-)
19 基) -5-氟 -2-氧代 -1,3-二氢吲哚 -3-亚基） 乙基) 甲基肼硫酰氨基)苯甲酸19 base) -5-fluoro-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)methylsulfonylamino)benzoic acid
H 1 H 1
(Ζ)-4-(Ν'- {1-[1-(3,4--甲苯基 )-3-甲基 (Ζ)-4-(Ν'- {1-[1-(3,4--tolyl)-3-methyl
20 -5-氧代 -1,5-二氢吡唑 -4-亚基] -乙基 } - 肼硫酰氨基) -苯甲酸 20 -5-oxo-1,5-dihydropyrazole-4-ylidene]-ethyl}-decylsulfonylamino)-benzoic acid
(Ζ)-4-{Ν'-[1-(1-茚满 -5-基 -3-甲基 -5-氧 (Ζ)-4-{Ν'-[1-(1-indan-5-yl-3-methyl-5-oxo
21 代 -1 ,5-二氢吡唑 -4-亚基)-乙基] -肼硫
Figure imgf000008_0002
酰氨基 }-苯甲酸 21 generation-1,5-dihydropyrazol-4-ylidene)-ethyl]-sulfonium sulphide
Figure imgf000008_0002
Amido}-benzoic acid
(Ζ)-4-(Ν'-{1-[1-(3,4-二甲苯基)- 3-甲基( Ζ )-4-(Ν'-{1-[1-(3,4-Dimethylphenyl)-3-methyl
22 -5-氧代 -1,5-二氢吡唑 -4-亚基] -乙基 } -22 -5-oxo-1,5-dihydropyrazole-4-ylidene]-ethyl } -
1 H 1 肼硫酰甲氨基) -苯甲酸 1 H 1 sulfonylmethylamino)-benzoic acid
(Z)-4- {N'-[l -( 1 -茚满 -3 -甲基 -5-氧代 (Z)-4- {N'-[l -( 1 - indane -3 -methyl -5-oxo
23 ca¾： -1 ,5-二氢吡唑 -4-亚基)-乙 23 ca3⁄4: -1 ,5-dihydropyrazole -4-subunit)-B
H人 。  H people.
1 H 基] -肼硫酰 甲氨基 }-苯甲酸 进一步， 本发明提供了通式（Ι Α)所示的化合物，其作为通式（ I：)化合物合成的 中间体：
Figure imgf000008_0003
1 H-yl] - hydrazine thionyl methylamino} - benzoic Further, the present invention provides general formula (Ι Α) shown compound represented by formula (I :) synthetic intermediates compounds:
Figure imgf000008_0003
( I A )  ( I A )
中 ··  Medium ··
R4选自卤素、 垸基、 四唑基、 羧基或羧酸酯；  R4 is selected from the group consisting of halogen, decyl, tetrazolyl, carboxy or carboxylic acid ester;
R5选自氢原子或烷基； 且 R 5 is selected from a hydrogen atom or an alkyl group;
X选自氧原子或硫原子。 进一歩， 本发明提供了通式（I B)所示的化合物， 其作为通式（ I )化合物合成的
Figure imgf000009_0001
X is selected from an oxygen atom or a sulfur atom. Further, the present invention provides a compound represented by the formula (IB) which is synthesized as a compound of the formula (I)
Figure imgf000009_0001
( I B)  ( I B)
中- 、 R2或 各自分别选自氢原子或烷基， 或者 Wherein -, R 2 or each are independently selected from a hydrogen atom or an alkyl group, or
R2与 R, 或 R3和其相连接的原子形成一个 4〜6元环； 且 R 2 and R, or R 3 and the atoms to which they are attached form a 4 to 6 membered ring;
Y是一个或多个基团的 1〜4个原子空间， 选自垸基或芳基， 其中所述芳基或 垸基任选地进一步被一个或多个选自卤素、 烷基或芳基的取代基所取代。  Y is 1 to 4 atomic spaces of one or more groups selected from a fluorenyl or aryl group, wherein the aryl or fluorenyl group is optionally further further selected from one or more selected from halogen, alkyl or aryl Substituted by a substituent.
优选地， Y选自
Figure imgf000009_0002
Preferably, Y is selected from
Figure imgf000009_0002
R6选自氢原子、 卤素、 垸基或芳基； 且 R 6 is selected from a hydrogen atom, a halogen, a fluorenyl group or an aryl group;
R7选自氢原子或烷基。 在本发明的另一个方面提供了制备通式 (； I A)化合物的方法， 该方法包括以下 步骤：
Figure imgf000009_0003
取代苯胺与 Ν,Ν'-Χ代羰基二咪唑反应， 得到的化合物与水合肼溶液在室温下 反应， 得到通式（ I Α)化合物， 其中 、 R5和 X如上述通式（ I A)中所定义。 在本发明的另一个方面提供了制备通式（ I B)化合物的方法， 该方法包括以下 步骤： R 7 is selected from a hydrogen atom or an alkyl group. In another aspect of the invention there is provided a process for the preparation of a compound of the formula (; IA) which comprises the steps of:
Figure imgf000009_0003
The substituted aniline is reacted with hydrazine, Ν'-deuterated carbonyl diimidazole, and the obtained compound is reacted with a hydrazine hydrate solution at room temperature to obtain a compound of the formula (I Α) wherein R 5 and X are as in the above formula (IA) Defined. In another aspect of the invention there is provided a process for the preparation of a compound of formula (IB), the process comprising the steps of:
Figure imgf000009_0004
Figure imgf000009_0004
( I B) 将二甲氨基亚乙基衍生物与水合肼溶液在室温下反应， 得到通式（ I B)化合物， 其中 R卜 R2、 R3和 Y如上述通式（ I B)中所定义。 进一步， 本发明的另一方面提供了一种通式化合物（I )的制备方法， 该方法包 括以下步骤： ( IB) The dimethylaminoethylidene derivative is reacted with a hydrazine hydrate solution at room temperature to obtain a compound of the formula (IB) wherein R, R 2 , R 3 and Y are as defined in the above formula (IB). Further, another aspect of the present invention provides a process for producing a compound of the formula (I), which comprises the steps of:
Figure imgf000010_0001
Figure imgf000010_0001
将二甲氨基亚乙基衍生物和通式（ I A)化合物在酸性条件下 (如甲酸、乙酸)加热 缩合得到通式（ I )化合物， 其中 、 R2、 R3、 、 R5、 X和 Y如上述通式（ I )中所 定义。 本发明的另一方面提供了一种通式化合物 (： 1 )的制备方法， 该方法包括以下步 骤： The compound of the formula (I) wherein R 2 , R 3 , R 5 , X and Y is as defined in the above formula (I). Another aspect of the present invention provides a process for the preparation of a compound of the formula (: 1 ), which comprises the steps of:
Figure imgf000010_0002
Figure imgf000010_0002
( I B )  ( I B )
将通式（I B)化合物和 X取代异氰酸苯酯在酸性条件下 (如甲酸、 乙酸)加热缩 合得到通式（ I )化合物， 其中 Ri、 R2、 R3、 、 R5、 X和 Y如上述通式（I )中所定 义。 本发明涉及通式（ I )化合物在制备 TPO受体激动剂中的用途。 The general formula (IB) and a compound X-substituted phenyl isocyanate under acidic conditions (e.g. formic acid, acetic acid) was heated to give compound of general formula (the I), wherein Ri, R2, R 3,, R 5, X and Y It is as defined in the above formula (I). The invention relates to the use of a compound of formula (I) for the preparation of a TPO receptor agonist.
本发明涉及通式（ I )化合物在制备治疗血小板减少症中的用途。 进一歩包括与 治疗有效量集落刺激因子、 细胞因子、 趋化因子、 白细胞介素或细胞因子受体激 动剂或拮抗剂、 可溶的受体、 受体激动剂、 拮抗剂抗体或与它们具有相同的机理 的肽或小分子类物质的联合使用。  The invention relates to the use of a compound of formula (I) for the manufacture of a medicament for the treatment of thrombocytopenia. Further comprising a therapeutically effective amount of colony stimulating factor, a cytokine, a chemokine, an interleukin or a cytokine receptor agonist or antagonist, a soluble receptor, a receptor agonist, an antagonist antibody or with A combination of peptides or small molecules of the same mechanism.
本发明涉及一种药用组合物， 其含有治疗有效剂量的通式（ I )化合物及其药学 上可以接受的盐、 水合物或溶剂化合物及药学上可接受的载体。 该组合物可以进 一步含有联合使用的治疗有效量的集落刺激因子、 细胞因子、 趋化因子、 白细胞 介素或细胞因子受体激动剂。 该组合物在制备治疗血小板减少症中的用途。 The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), and a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier. The composition may further comprise a therapeutically effective amount of colony stimulating factor, cytokine, chemokine, leukocyte in combination Interleukin or cytokine receptor agonist. Use of the composition in the manufacture of a medicament for treating thrombocytopenia.
所述的联合使用包括同时使用或先后依次使用本发明所述的化合物。  The combined use includes the simultaneous or sequential use of the compounds described herein.
本发明涉及一种制备含有药用载体或稀释剂和有效量的通式（ I )化合物及其药 学上可以接受的盐、 水合物或溶剂化合物的药物组合物的方法， 该方法包括将通 式（ I )化合物与药用载体和稀释剂相结合。 发明的详细说明  The present invention relates to a process for the preparation of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an effective amount of a compound of formula (I) and a pharmaceutically acceptable salt, hydrate or solvate thereof, which process comprises a formula (I) The compound is combined with a pharmaceutically acceptable carrier and a diluent. Detailed description of the invention
除非有相反陈述， 下列用在说明书和权利要求书中的术语具有下述含义。 "烷基 "指饱和的脂族烃基团， 包括 1至 20个碳原子的直链和支链基团。 优选 含有 1至 10个碳原子的垸基， 例如甲基、 乙基、 丙基、 2-丙基、 正丁基、 异丁基、 叔丁基、 戊基等。 更优选的是含有 1至 4个碳原子的低级垸基， 例如甲基、 乙基、 丙基、 2-丙基、 正丁基、 异丁基或叔丁基等。 烷基可以是取代的或未取代的， 当被 取代时， 取代基优选为一个或多个， 独立地选自烷基、 卤素、 羟基、 四唑基、 芳 基、 羧酸或羧酸酯。  Unless otherwise stated, the following terms used in the specification and claims have the following meanings. "Alkyl" means a saturated aliphatic hydrocarbon group comprising straight and branched chain groups of 1 to 20 carbon atoms. Preferred are fluorenyl 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 fluorenyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, a tetrazolyl group, an aryl group, a carboxylic acid or a carboxylic acid ester.
"芳基"指具有至少一个芳环结构的基团， 即具有共轭的 π电子体系的芳环， 包 括碳环芳基、 杂芳基和联芳基。 芳基可以是取代的或未取代的， 当被取代时， 取 代基优选为一个或多个， 独立地选自烷基、 卤素、 羟基、 四唑基、 芳基、 杂芳基、 羧酸或羧酸酯。  "Aryl" means a group having at least one aromatic ring structure, that is, an aromatic ring having a conjugated π-electron system, including a carbocyclic aryl group, a heteroaryl group, and a biaryl group. The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from an alkyl group, a halogen, a hydroxyl group, a tetrazolyl group, an aryl group, a heteroaryl group, a carboxylic acid or Carboxylic acid ester.
"卤素"指氟、 氯、 溴或碘。  "Halogen" means fluoro, chloro, bromo or iodo.
"羧酸 "指 ('烷基) C(=0)OH。  "Carboxylic acid" means ('alkyl) C(=0)OH.
"羧酸酯"指 (垸基) C(=0)0(垸基)。  "Carboxylic ester" means (indenyl) C(=0)0(indenyl).
"四唑基"基指含四个氮原子的五元杂芳基。  The "tetrazolyl" group refers to a five-membered heteroaryl group containing four nitrogen atoms.
"药物组合物 "表示一种或多种本文所述化合物或其生理学上 /药学上可接受的 盐或前体药物与其他化学组分的混合物， 其他组分例如生理学 /药学上可接受的载 体和赋形剂。 药物组合物的目的是促进化合物对生物体的给药。 本发明化合物的合成方法  "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, such as a physiological/pharmaceutically acceptable carrier. And excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism. Method for synthesizing the compound of the present invention
为了完成本发明的目的， 本发明采用如下技术方案：  In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:
本发明通式（ I )所述的化合物或其盐的制备方法， 包括以下步骤: The preparation method of the compound of the formula (I) or a salt thereof of the present invention comprises the following steps:
Figure imgf000012_0001
Figure imgf000012_0001
( I B)  ( I B)
取代苯胺与 N,N'-X代羰基二咪唑反应， 得到的化合物与水合肼溶液在室温下 反应， 得到通式（Ι Α)化合物， 或者取代苯基异氰酸酯与水合肼溶液在室温下反应 得到通式（ I Α)化合物。将通式二甲氨基亚乙基衍生物和通式（ I Α)化合物在酸性条 件下加热缩合得到通式（ I )化合物。  The substituted aniline is reacted with N,N'-X carbonyldiimidazole, and the obtained compound is reacted with a hydrazine hydrate solution at room temperature to obtain a compound of the formula (Ι Α), or a substituted phenyl isocyanate and a hydrazine hydrate solution are reacted at room temperature. a compound of the formula (I Α). The compound of the formula (I) is obtained by heating and condensing a compound of the formula dimethylaminoethylene and a compound of the formula (I Α) under acidic conditions.
或者， 通式二甲氨基亚乙基衍生物与水合肼溶液在室温下反应得到通式（ I Β) 化合物； 将通式（ I Β)化合物和 X取代异氰酸苯酯在酸性条件下加热缩合得到通式 ①化合物。 具体实施方式  Alternatively, the dimethylaminoethylidene derivative of the formula is reacted with a hydrazine hydrate solution at room temperature to obtain a compound of the formula (I Β); the compound of the formula (I Β) and the X-substituted phenylisocyanate are heated under acidic conditions. Condensation gives the compound of formula 1. Detailed ways
以下结合实施例用于进一步描述本发明， 但这些实施例并非限制着本发明的 范围。  The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.
实施例  Example
化合物的结构是通过核磁共振 ('HNMR)或质谱 (MS)来确定的。 1HNMR位移 (δ) 以百万分之一 (ppm)的单位给出。 1HNMR的测定是用 Bruker AVANCE-400核磁仪 , 测定溶剂为氘代氯仿 (CDC13), 氘代甲醇 (CD3OD), 六氘代二甲基亚砜 (DMSO- 内标为四甲基硅烷 (TMS), 化学位移是以 l(T6(ppm)作为单位给出；The structure of the compound is determined by nuclear magnetic resonance ('HNMR) or mass spectrometry (MS). The 1H NMR shift (δ) is given in parts per million (ppm). The 1H NMR measurement was carried out using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated chloroform (CDC1 3 ), deuterated methanol (CD 3 OD), hexamethylene dimethyl sulfoxide (DMSO- The internal standard is tetramethylsilane (TMS) and the chemical shift is given in units of l (T 6 (ppm);
MS的测定用 FINNIGAN LCQAd (ESI)质谱仪 (生产商： Therm, 型号： Finnigan LCQ advantage MAX); The measurement of MS was performed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Therm, model: Finnigan LCQ advantage MAX);
薄层硅胶使用烟台黄海 HSGF254或青岛 GF254硅胶板；  Thin layer of silica gel using Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate;
柱层析一般使用烟台黄海硅胶 200〜300目硅胶为载体；  Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as carrier;
实施例中无特殊说明， 反应均在进行；  There is no special description in the examples, and the reaction is all carried out;
氮气氛是指反应瓶连接一个约 1L容积的氮气气球；  The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume;
实施例中无特殊说明， 反应中的溶液是指水溶液；  Unless otherwise specified in the examples, the solution in the reaction means an aqueous solution;
TLC是指薄层色谱。 实施例 1  TLC refers to thin layer chromatography. Example 1
(Z)-3-(2-(l-(2-氧代 -1-间甲苯基 -U-二氢吲哚 -3-亚基)乙基)肼硫酖氨基)苯甲酸  (Z)-3-(2-(l-(2-oxo-1-m-tolyl-U-indoline-3-ylidene)ethyl)phosphonium sulfonylamino)benzoic acid
Figure imgf000013_0001
Figure imgf000013_0001
1f  1f
第一步  First step
3- (肼硫酰氨基)苯甲酸甲酯  3-(anthracenesulfonylamino)benzoate
将 3-异硫氰酸酯基苯甲酸甲酯 la (3.0 g, 15.5 mmd)溶解于 30 mL无水乙醇中, 搅拌下加入 50%水合肼溶液 (3 mL , 30 mmol)和 20 mL无水乙醇，加热回流 1小时。 TLC 跟踪反应至原料消失， 冷却反应液至室温， 过滤， 滤饼在真空下干燥， 得到 3- (肼硫酰氨基)苯甲酸甲酯 lb(3.1 g, 白色固体)。 产率： 88.8%。  Methyl 3-isothiocyanate benzoate la (3.0 g, 15.5 mmd) was dissolved in 30 mL of absolute ethanol, and 50% hydrazine hydrate solution (3 mL, 30 mmol) and 20 mL of anhydrous were added with stirring. Ethanol was heated to reflux for 1 hour. The reaction was quenched by TLC until the material disappeared. The reaction mixture was cooled to room temperature, filtered, and then filtered and dried under vacuo to give <RTI ID=0.0>> Yield: 88.8%.
MS m/z (ESI): 226[M+1]  MS m/z (ESI): 226 [M+1]
Ή N R(400M Hz, CD3OD-c¾: 59.25(s,lH), 8.35(s,lH), 7.88(d,lH, J=6.4 Ή NR (400M Hz, CD 3 OD-c3⁄4: 59.25(s,lH), 8.35(s,lH), 7.88(d,lH, J=6.4
Hz),7.69(d,l H, J-7.2 Hz),7.44(t,l H, J=8.4 Hz),4.76(br,2H),3.86(s,3H) 第二歩 - 1 间甲苯基 -1,3-二氢吲哚 -2-酮 Hz), 7.69 (d, l H, J-7.2 Hz), 7.44 (t, l H, J = 8.4 Hz), 4.76 (br, 2H), 3.86 (s, 3H) Second 歩 - 1 m-tolyl-1,3-dihydroindol-2-one
采用公知的方法 [Bulletin de la Societe Chimique de France (1968), (3), 1090-1.], 将 1,3-二氢吲哚 -2-酮 lc(20 g, 150 mmol), 间溴甲苯 (30.78 g, 180 mmol), 碘化亚铜 (5.7 g, 30 mmol)和碳酸钾 (46 g, 330 mmol)溶解于 300 mL乙腈中，搅拌下加入 Ν,Ν'- 二甲基 -1,2-乙二胺 (4 g, 45 mmol), 加热回流 2小时。 TLC跟踪反应至原料消失， 加入 500 mL水， 用 1N盐酸调节 pH=5， 用乙酸乙酯萃取 (150 mL><3)， 合并的有机 相依次用无水硫酸锾干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得残余 物， 则得到 1-间甲苯基 -1,3-二氢吲哚 -2-酮 ld(32 g， 黄色固体)。 产率： 91.4%。 MS m/z (ESI): 224.2[M+1] 第三步  Using a known method [Bulletin de la Societe Chimique de France (1968), (3), 1090-1.], 1,3-dihydroindol-2-one lc (20 g, 150 mmol), m-bromo Toluene (30.78 g, 180 mmol), cuprous iodide (5.7 g, 30 mmol) and potassium carbonate (46 g, 330 mmol) were dissolved in 300 mL of acetonitrile, and Ν, Ν'-dimethyl-1 was added with stirring. 2-Ethylenediamine (4 g, 45 mmol), heated to reflux for 2 h. TLC followed the reaction until the disappearance of the starting material, adding 500 mL of water, adjusting pH=5 with 1N hydrochloric acid, and extracting with ethyl acetate (150 mL><3). The combined organic phases were dried over anhydrous sulphate, filtered, and the filtrate was evaporated. The residue was purified by silica gel column chromatography eluting elut elut elut elut Yield: 91.4%. MS m/z (ESI): 224.2 [M+1] Step 3
(Z)-3-(l- (二甲氨基)亚乙基) - 1 -间甲苯基 - 1 ,3-二氢吲哚 -2-酮  (Z)-3-(l-(dimethylamino)ethylidene)-1 -m-tolyl-1,3-dihydroanthracene-2-one
将 1-间甲苯基吲哚 -2-酮 Id (5 g, 33 mmol)溶解于 120 mL氯仿中， 搅拌下加入 (1,1-二甲氧基乙基)-二甲胺 (8.8 g, 66 mmol), 缓慢升温至 80°C回流 2小时。 TLC跟 踪反应至原料消失， 减压下浓缩反应液， 用硅胶柱色谱法纯化所得残余物， 得到 (Z)-3-(l- (二甲氨基)亚乙基 )-1-间甲苯基 -1,3-二氢吲哚 -2-酮 le (6.1 g， 棕色油状液 体)。 产率： 63.5 %。  1-Inter-tolylin-2-one Id (5 g, 33 mmol) was dissolved in 120 mL of chloroform, and (1,1-dimethoxyethyl)-dimethylamine (8.8 g, 66 mmol), slowly warmed to 80 ° C and refluxed for 2 hours. The reaction was traced to the disappearance of the starting material by TLC, and the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give (Z)-3-(l-(dimethylamino)ethylidene)-1-m-tolyl- 1,3-Dihydroindol-2-one le (6.1 g, brown oily liquid). Yield: 63.5 %.
第四步  the fourth step
(Z)-3- (2-(1-(2-氧代 -1-间甲苯基 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯  (Z)-3-(2-(1-(2-oxo-1-inter-tolyl-1,3-dihydroindol-3-ylidene)ethyl)sulfonylamino)benzene
甲酸甲酯  Methyl formate
将 (Z)- 3-(1- (二甲氨基)亚乙基 )-1-间甲苯基 -1,3-二氢吲哚 -2-酮 le (250 mg, 0.86 mmol)溶解于 20 mL无水乙醇中， 搅拌下加入 3- (肼硫酰氨基)苯甲酸甲酯 lb (192 mg, 0.86 mmol)和 1 mL乙酸， 加热回流 1小时。 TLC跟踪反应至原料消失， 减压 下浓缩反应液，得到 (Z)-3-(2-(l-(2-氧代 -1-间甲苯基 -1,3-二氢吲哚 -3-亚基)乙基)肼硫 酰氨基)苯甲酸甲酯 If (240 mg, 黄色固体)。 产率： 59.1%。  Dissolve (Z)-3-(1-(dimethylamino)ethylidene)-1-m-tolyl-1,3-dihydroindol-2-one le (250 mg, 0.86 mmol) in 20 mL In anhydrous ethanol, methyl 3-(decylsulfonyl)benzoate lb (192 mg, 0.86 mmol) and 1 mL of acetic acid were added under stirring, and the mixture was heated to reflux for 1 hour. The reaction was traced by TLC until the starting material disappeared, and the reaction mixture was concentrated under reduced pressure to give (Z)-3-(2-(l-(2-oxo-1-m-tolyl-1,3-dihydroindole-3-) Subunit)ethyl) sulfonylamino)benzoic acid methyl ester If (240 mg, yellow solid). Yield: 59.1%.
MS m/z (ESI): 473 [M+1] MS m/z (ESI): 473 [M+1]
Ή NMR(400M Hz, CDC13): Ή NMR (400M Hz, CDC1 3 ):
511.39(br, 1 H), 10.35(br, 1 H ), 10.6(br, 1 H),8.16(s, 1 H),7.82(d, 1 H, J=8.4 Hz), 7.75(d,lH, J=7.6 Hz), 7.63(m,2H),7.57(m,2H),7.53(d,lH, J=7.6 Hz),7.13(m,3H),6.68(t,lH, J=4.8 Hz),3.42(s,3H),2.38(s,6H)  511.39(br, 1 H), 10.35(br, 1 H ), 10.6(br, 1 H), 8.16(s, 1 H), 7.82(d, 1 H, J=8.4 Hz), 7.75(d,lH , J=7.6 Hz), 7.63 (m, 2H), 7.57 (m, 2H), 7.53 (d, lH, J = 7.6 Hz), 7.13 (m, 3H), 6.68 (t, lH, J = 4.8 Hz) ), 3.42 (s, 3H), 2.38 (s, 6H)
第五步  the fifth step
(Z)-3-(2-(l-(2-氧代 -1-间甲苯基 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸 将 (Z)-3-(2-(l-(2-氧代 -1-间甲苯基 -1,2-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲 酸甲酯 If (240 mg, 0.51 mmol)溶解于 10 mL无水乙醇中， 搅拌下加入氢氧化钠溶 液 (lN ,1.53 mL)， 加热回流反应 2小时。 TLC跟踪反应至原料消失， 将反应液冷却 至室温， 冰浴下用浓盐酸调节 pH=2〜3， 过滤， 滤饼在真空下干燥， 得到标题产 物 (Z)-3-(2-(l-(2-氧代 -1 -间甲苯基 -1 ,3-二氢吲哚 -3-亚基）乙基)肼硫酰氨基)苯甲酸(Z)-3-(2-(l-(2-oxo-1-m-tolyl-1,3-dihydroindol-3-ylidene)ethyl)sulfonylamino)benzoic acid ( Z)-3-(2-(l-(2-oxo-1-m-tolyl-1,2-dihydroindol-3-ylidene)ethyl) sulfonylamino)benzoic acid methyl ester If (240 mg, 0.51 mmol) was dissolved in 10 mL of absolute ethanol, and sodium hydroxide solution (1N, 1.53 mL) was added with stirring, and the mixture was heated and refluxed for 2 hours. TLC followed the reaction until the disappearance of the starting material, the reaction solution was cooled to room temperature, adjusted to pH = 2 to 3 with concentrated hydrochloric acid in an ice bath, filtered, and the filter cake was dried under vacuum to give the title product. (Z)-3-(2-(l-(2-oxo-1-m-tolyl-1,3-dihydroindol-3-ylidene)ethyl)phosphonylamino)benzoic acid
1(78 mg, 淡黄色固体)。 产率： 33.6%。 1 (78 mg, light yellow solid). Yield: 33.6%.
MS m/z (ESI): 459[M+1]  MS m/z (ESI): 459 [M+1]
Ή NMR(400M Hz, DMSO- 6): Ή NMR (400 M Hz, DMSO- 6 ):
613.01(br,lH),11.33(br,lH),10.27(br,lH),10.19(br,lH), 8.08(s,lH),7.81(d,lH, J=8.4 Hz),7.74(d,l H, J=7.6 Hz),7.54(d,lH, J=4.8 Hz), 7.45(m,2H), 7.23(m,3H), 7.06(t,2H, J=4.0 Hz), 6.81(t,lH, J=4.8 Hz),3.30(s,3H), 2.39(s,3H) 实施例 2  613.01(br,lH),11.33(br,lH),10.27(br,lH),10.19(br,lH), 8.08(s,lH),7.81(d,lH, J=8.4 Hz), 7.74(d , l H, J = 7.6 Hz), 7.54 (d, lH, J = 4.8 Hz), 7.45 (m, 2H), 7.23 (m, 3H), 7.06 (t, 2H, J = 4.0 Hz), 6.81 ( t, lH, J = 4.8 Hz), 3.30 (s, 3H), 2.39 (s, 3H) Example 2
(Z)-4-(2— Π -( 1— (3，4—二甲苯基)— 2—氧代— 二氢吲哚— 3—亚基)乙基)肼硫酰氨基)苯甲 (Z) - 4 - (2 - Π - ( 1 - (3 , 4 - xylyl) - 2 - oxo - indoline - 3 - ylidene) ethyl) sulfonylamino) benzoate
酸  Acid
Figure imgf000015_0001
第一步
Figure imgf000015_0001
first step
1-(3,4-二甲苯基) -1，3-二氢吲哚 -2-酮  1-(3,4-dimethylphenyl)-1,3-dihydroanthracene-2-one
将 1,3-二氢吲哚- 2-酮 2a(8.0 g, 60.1 mmol)，4-溴 - 1,2-二甲苯 (13.4 g, 72.2 mmol), 碘化亚铜 (2.29 g, 12.0 mmol)和碳酸钾 (20.7 g， 150 mmol)溶解于 250 mL 乙腈中， 搅 拌下加入 Ν,Ν'-二甲基 -1 ,2-乙二胺 (1.59 g, 18 mmol), 加热回流 2小时。 TLC跟踪反 应至原料消失，加入 500 mL水，用 1N盐酸调节 pH=5，用乙酸乙酯萃取 (100 mL><3)， 无水硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得残余物， 则得 到 1-(3,4-二甲苯基) -1,3-二氢吲哚 -2-酮 2b(8.0 g， 黄色固体)。 产率： 57.1 %。  1,3-Dihydroindole-2-one 2a (8.0 g, 60.1 mmol), 4-bromo-1,2-dimethylbenzene (13.4 g, 72.2 mmol), cuprous iodide (2.29 g, 12.0 mmol) And potassium carbonate (20.7 g, 150 mmol) was dissolved in 250 mL of acetonitrile, and hydrazine, Ν'-dimethyl-1,2-ethanediamine (1.59 g, 18 mmol) was added under stirring, and the mixture was refluxed for 2 hr. TLC followed the reaction to the disappearance of the starting material, added 500 mL of water, adjusted to pH = 5 with 1N hydrochloric acid, extracted with ethyl acetate (100 mL > < 3), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified to give 1-(3,4-dimethylphenyl)-1,3-dihydroindol-2-one 2b (8.0 g,yel. Yield: 57.1%.
MS m/z (ESI): 238[M+1] MS m/z (ESI): 238 [M+1]
第二歩  Second
(Z)-3-(l-二甲氨基亚乙基) -1-(3,4-二甲苯基) -1,3-二氢吲哚 -2-酮 将 l-(3,4-二甲苯基) -1，3-二氢吲哚 -2-酮 2b (2.4 g, 10 mmol)溶解于 50 mL氯仿 中， 搅拌下加入 (U-二甲氧基乙基)-二甲胺 (2.45 g, 15 mmol), 缓慢升温至 80 °C回 流 2小时。 TLC跟踪反应至原料消失， 用硅胶柱色谱法纯化所得残余物， 则得到 (Z)- 3-(1-二甲氨基亚乙基 )-1-(3,4-二甲苯基) -U-二氢吲哚 -2-酮 2c (2.4 g， 黄色油状 液体)。 产率： 78.4 %。 (Z)-3-(l-dimethylaminoethylidene)-1-(3,4-dimethylphenyl)-1,3-dihydroindol-2-one Dissolve l-(3,4-dimethylphenyl)-1,3-dihydroindol-2-one 2b (2.4 g, 10 mmol) in 50 mL of chloroform and add (U-dimethoxy) with stirring Ethyl)-dimethylamine (2.45 g, 15 mmol) was slowly warmed to 80 ° C for 2 hours. The reaction was traced to the disappearance of the starting material by TLC, and the obtained residue was purified by silica gel column chromatography to give (Z) 3-(1-dimethylaminoethylidene)-1-(3,4-dimethylphenyl)-U- Indoline-2-one 2c (2.4 g, yellow oily liquid). Yield: 78.4%.
MS m/z (ESI): 307[ +1] MS m/z (ESI): 307[ +1]
'HNMR(400M HZ, CDC13): 57.36(m,2H),7.28(d,lH, J=8.0 Hz),7.16(m,2H), 7.01(d,lH, J=7.6 Hz), 6.95(d,lH, J-7.2 Hz), 3.4(s,3H), 3.02(s,6H),2.35(s,6H) 'HNMR (400M HZ, CDC1 3 ): 57.36 (m, 2H), 7.28 (d, lH, J = 8.0 Hz), 7.16 (m, 2H), 7.01 (d, lH, J = 7.6 Hz), 6.95 ( d,lH, J-7.2 Hz), 3.4(s,3H), 3.02(s,6H),2.35(s,6H)
第三步  third step
4- (肼硫酰氨基)苯甲酸乙酯  4-(anthracenesulfonylamino)benzoic acid ethyl ester
将 4-异硫氰酸酯基苯甲酸乙酯 2d (1.0 g， 4.83 mmol)溶解于 15mL无水乙醇中， 搅拌下加入 50%水合肼溶液 (2.4 mL, 24.13 mmol)和 20mL无水乙醇， 加热回流 0.5 小时。 点板跟踪至原料消失， 冷却至室温， 过滤， 滤饼在真空下干燥， 得到 4- (肼 硫酰氨基)苯甲酸乙酯 2e(l.l g, 白色固体)。 产率： 95.7%。  Ethyl 4-isothiocyanate benzoate 2d (1.0 g, 4.83 mmol) was dissolved in 15 mL of absolute ethanol, and 50% hydrazine hydrate solution (2.4 mL, 24.13 mmol) and 20 mL absolute ethanol were added with stirring. Heat to reflux for 0.5 hours. The spot plate was traced until the starting material disappeared, cooled to room temperature, filtered, and the filter cake was dried under vacuum to give ethyl 4-(indolesulfonyl)benzoate 2e (1.l g, white solid). Yield: 95.7%.
MS m/z (ESI): 240[M+1] MS m/z (ESI): 240 [M+1]
Ή NMR(400M Hz, CDC13): δ 9.49(br,lH), 8.08(m,2H), 7.82(d,2H, J=7.6 Hz), NMR NMR (400 M Hz, CDC1 3 ): δ 9.49 (br, lH), 8.08 (m, 2H), 7.82 (d, 2H, J = 7.6 Hz),
4.42(t,2H, J=7.2 Hz), 1.30(t, 3H, J= 6.8 Hz) 4.42 (t, 2H, J = 7.2 Hz), 1.30 (t, 3H, J = 6.8 Hz)
第四步  the fourth step
(Z)-4-(2-G-(l-(3,4-二甲苯基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲 酸乙酯  (Z)-4-(2-G-(l-(3,4-dimethylphenyl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)phosphonylamino Ethyl benzoate
将 (Z)-3-(l-二甲氨基亚乙基 )小(3,4-二甲苯基) -1,3-二氢吲哚 -2-酮 2c (250 mg, 0.82 mmol)溶解于 20 mL无水乙醇中， 搅拌下加入 4- (肼硫酰氨基)苯甲酸乙酯 2e (147 mg, 0.65 mmol)和 1 mL乙酸， 加热回流 1小时。 TLC跟踪反应至原料消失， 减压下浓缩反应液，用硅胶色谱法纯化所得残余物，得到 (Z)-4-(2-(l-(l-(3,4-二甲苯 基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基）肼硫酰氨基)苯甲酸乙酯 2f (128 mg, 黄褐色 油状液体)。 产率： 32.1%。  (Z)-3-(l-Dimethylaminoethylidene) small (3,4-dimethylphenyl)-1,3-dihydroindol-2-one 2c (250 mg, 0.82 mmol) was dissolved in To 20 mL of absolute ethanol, ethyl 4-(decylsulfonyl)benzoate 2e (147 mg, 0.65 mmol) and 1 mL of acetic acid were added with stirring, and the mixture was refluxed for 1 hour. The reaction was quenched by TLC until the material disappeared, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford (Z)-4-(2-(l-(l-(3,4-dimethylphenyl)) -Oxo-1,3-dihydroindole-3-ylidene)ethyl) sulfonylamino)benzoic acid ethyl ester 2f (128 mg, a tan oily liquid). Yield: 32.1%.
MS m/z (ESI): 487[M+1] MS m/z (ESI): 487 [M+1]
Ή NMR(400M Hz, DMSO-c 6): 11.40(br,lH), 10.48(br,2H), 8.16(s,lH), 7.91(d,lH, J=8.0 Hz), 7.76(t,2H, J=7.6 Hz), 7.50(t,lH, J=5.2 Hz), 7.48(d,lH, J=7.8 Hz), 7.21(t,lH, J=5.6 Hz), 7.13(d,lH, J=4.8 Hz), 7.08(t,lH, J=8.4 Hz), 7.01(t,2H, J=6.4 Hz), 4.04(q,2H: J=7.2 Hz), 3.50(s,3H), 2.30(s,6H), 1.67(t, 3H,J=6.8 Hz) NMR (400 M Hz, DMSO-c 6 ): 11.40 (br, lH), 10.48 (br, 2H), 8.16 (s, lH), 7.91 (d, lH, J = 8.0 Hz), 7.76 (t, 2H) , J=7.6 Hz), 7.50(t,lH, J=5.2 Hz), 7.48(d,lH, J=7.8 Hz), 7.21(t,lH, J=5.6 Hz), 7.13(d,lH, J =4.8 Hz), 7.08 (t, lH, J = 8.4 Hz), 7.01 (t, 2H, J = 6.4 Hz), 4.04 (q, 2H : J = 7.2 Hz), 3.50 (s, 3H), 2.30 ( s,6H), 1.67(t, 3H, J=6.8 Hz)
第五歩  Fifth
(Z)-4-(2-(l-(l-(3,4-二甲苯基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲 酸  (Z)-4-(2-(l-(l-(3,4-dimethylphenyl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)phosphonyl Amino)benzoic acid
将 (Z)-4-(2-(l-(l-(3,4-二甲苯基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基) 苯甲酸乙酯 2f (128 mg, 0.26 mmol)溶解于 10 mL无水甲醇中， 搅拌下加入氢氧化 钠溶液 (lN,0.79 mL)， 加热回流反应 2小吋。 TLC跟踪反应至原料消失， 将反应液 冷却至室温， 冰浴下用浓盐酸调节 pH=2〜3， 过滤, 滤饼在真空下干燥， 得到标 题产物 (Z)-4-(2-(l- (1-(3,4-二甲苯基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基) 苯甲酸 2(38 mg, 淡黄色固体)。 产率： 31.1%。 (Z)-4-(2-(l-(l-(3,4-Dimethylphenyl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)sulfonium sulphide The acylamino) benzoic acid ethyl ester 2f (128 mg, 0.26 mmol) was dissolved in 10 mL of anhydrous methanol, and sodium hydroxide solution (1N, 0.79 mL) was added with stirring, and the mixture was heated to reflux for 2 hours. TLC tracks the reaction until the starting material disappears, and the reaction solution After cooling to room temperature, the pH was adjusted to 2 to 3 with concentrated hydrochloric acid in an ice bath, filtered, and the filter cake was dried under vacuum to give the title product (Z)-4-(2-(l-(1-(3,4-) Tolyl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)sulfonylamino)benzoic acid 2 (38 mg, pale yellow solid). Yield: 31.1%.
MS nVz (ESI): 473[M+1] MS nVz (ESI): 473[M+1]
'HNMR(400M HZ, DMSO-^): 512.78(br,lH),l 1.42(br,lH),10.50(br,2H),7.91 (d,2H, J=8.8 Hz),7.76(d,2H, J=8.4 Hz),7.52(t,l H, J=5.2 Hz),7.32(d,l H, J=8.0 Hz)，7.19(s,lH), 7.13(d,lH, J=5.0 Hz),7.07~7.01(m,2H),6.77(t,lH, J=8.0 Hz), 3.51(s,3H), 2.33(s,6H) 实施例 3  'HNMR (400M HZ, DMSO-^): 512.78 (br, lH), l 1.42 (br, lH), 10.50 (br, 2H), 7.91 (d, 2H, J = 8.8 Hz), 7.76 (d, 2H) , J=8.4 Hz), 7.52 (t, l H, J=5.2 Hz), 7.32 (d, l H, J=8.0 Hz), 7.19 (s, lH), 7.13 (d, lH, J=5.0 Hz) ), 7.07~7.01(m, 2H), 6.77(t, lH, J=8.0 Hz), 3.51(s, 3H), 2.33(s, 6H) Example 3
(Z)-3-(2-(l - (2-氧代 -1 -对-甲苯基 -1 ,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸  (Z)-3-(2-(l-(2-oxo-1-p-tolyl-1,3-dihydroindole-3-ylidene)ethyl)sulfonylamino)benzoic acid
Figure imgf000017_0001
Figure imgf000017_0001
第一步  First step
1 -(4-甲苯基 )- 1 ,3-二氢吲哚 -2-酮  1-(4-methylphenyl)- 1 ,3-dihydroanthracene-2-one
采用公知的方法 [Bulletin de la Societe Chimique de France (1968),(3)，1090-1.]， 将 1 ,3-二氢吲哚 -2-酮 lc(13.3 g, 100 mmol), 对溴甲苯 (20.5 g, 120 mmol), 碘化亚铜 (3.8 g, 20 mmol)和碳酸钾 (30.36 g， 220 mmol)溶解于 150 mL 乙腈中， 搅拌下加入 Ν,Ν'-二甲基 -1,2-乙二胺 (2.67 g， 30 mmol), 加热回流 2小时。 TLC跟踪反应至原料 消失， 加入 500 mL水， 用 1N盐酸调节 pH=5， 用乙酸乙酯萃取 (150 mL><3)， 无水 硫酸镁干燥， 过滤， 滤液减压浓缩， 用硅胶柱色谱法纯化所得残余物， 得到标题 产物 1 -(4-甲苯基 )-1,3-二氢吲哚 -2-酮 3a(16.0 g， 淡黄色固体)。 产率： 71.7%。  Using a known method [Bulletin de la Societe Chimique de France (1968), (3), 1090-1.], 1, 3-dihydroindol-2-one lc (13.3 g, 100 mmol), bromine Toluene (20.5 g, 120 mmol), cuprous iodide (3.8 g, 20 mmol) and potassium carbonate (30.36 g, 220 mmol) were dissolved in 150 mL of acetonitrile, and Ν, Ν'-dimethyl-1 was added with stirring. 2-Ethylenediamine (2.67 g, 30 mmol), heated to reflux for 2 h. TLC was used to trace the reaction to the disappearance of the starting material. Add 500 mL of water, adjust the pH to 5 with 1N hydrochloric acid, and extract with ethyl acetate (150 mL > < 3), dry over anhydrous magnesium sulfate, and filtered. The residue was purified to give the title compound-1-(4-methylphenyl)-1,3-dihydroindol-2-one 3a (16.0 g, pale yellow solid). Yield: 71.7%.
MS m/z (ESI): 224[M+1] MS m/z (ESI): 224 [M+1]
第二歩  Second
(Z)-3-( 1 -二甲氨基亚乙基) -1 -(4-甲苯基 )- 1 ,3-二氢吲哚 -2-酮 将 1-(4-甲苯基 )-1,3-二氢吲哚 -2-酮 3a (2.23 mg, 10 mmol)溶解于 40 mL氯仿 中， 搅拌下加入 (U-二甲氧基乙基) -二甲胺 (2.0 mg, 15 mmol), 缓慢升温至 80°C回 流 2小时。 TLC跟踪反应至原料消失， 减压下浓缩反应液， 用硅胶柱色谱法纯化 所得残余物，得到 (Z)-3- (1-二甲氨基亚乙基) -1 -(4-甲苯基 )-1，3-二氢吲哚 -2-酮 3b (2.1 g， 淡黄色固体)。 产率： 72.4 %。 (Z)-3-(1-dimethylaminoethylidene)-1-(4-methylphenyl)-1,3-dihydroindol-2-one 1-(4-methylphenyl)-1, 3-Dihydroindol-2-one 3a (2.23 mg, 10 mmol) was dissolved in 40 mL chloroform and (U-dimethoxyethyl)-dimethylamine (2.0 mg, 15 mmol). The temperature was slowly raised to 80 ° C and refluxed for 2 hours. TLC followed the reaction until the disappearance of the starting material, and the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography. The residue obtained gave (Z)-3-(1-dimethylaminoethylidene)-1 -(4-methylphenyl)-1,3-dihydroindol-2-one 3b (2.1 g, pale yellow solid). Yield: 72.4%.
MS m/z (ESl): 293 [M+1] MS m/z (ESl): 293 [M+1]
Ή NM (400M Hz, OMSO-d6): 57.40-7.30(m,5H),7.04-6.99(m,2H), 6.92(d,lH, J=7 Hz),3.37-3.24(m,6H),2.67(s,3H),2.48-2.45(m,3H) Ή NM (400M Hz, OMSO-d 6 ): 57.40-7.30 (m, 5H), 7.04-6.99 (m, 2H), 6.92 (d, lH, J = 7 Hz), 3.37-3.24 (m, 6H) , 2.67(s,3H), 2.48-2.45(m,3H)
第三步  third step
( -3-(2-( (2-氧代 -1 -对甲苯基 -U-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸甲酯 将 (Z)-3- ( 二甲氨基亚乙基)小 (4-甲苯基 )-1,3-二氢吲哚- 2-酮 3b(200 mg, 0.68 mmol)溶解于 25 mL无水乙醇中，加入 3- (肼硫酰氨基)苯甲酸甲酯 lb (123 mg, 0.55 mmol)和 1 mL乙酸， 加热回流 1.5小时。 TLC跟踪反应至原料消失， 减压浓缩， 用硅胶色谱法纯化， 得到标题产物 (Z)-3- (2-(1 -(2-氧代 -1-对甲苯基 -1,3-二氢吲哚 -3- 亚基)乙基)肼硫酰氨基)苯甲酸甲酯 3C(128 mg, 黄色固体)。 产率： 87.2%。 (-3-(2-((2-oxo-1-p-tolyl-U-indoline-3-ylidene)ethyl) sulfonylamino)benzoic acid methyl ester (Z)-3 - (Dimethylaminoethylidene) small (4-methylphenyl)-1,3-dihydroindole-2-one 3b (200 mg, 0.68 mmol) dissolved in 25 mL of absolute ethanol, added 3- ( Methyl sulfonylamino) benzoate lb (123 mg, 0.55 mmol) and 1 mL of EtOAc (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH -3-(2-(1 -(2-oxo-1-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl)sulfonylamino)benzoic acid methyl ester 3 C ( 128 mg, yellow solid) Yield: 87.2%.
MS m/z (ESI): 473 [M+1 ] MS m/z (ESI): 473 [M+1]
第四步  the fourth step
(Z)-3-(2-(l-(2-氧代小对甲苯基吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸 将 (Z)-3-(2- ( (2-氧代 -1 -对甲苯基 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲 酸甲酯 3c (250 mg, 0.53 mmol)溶解于 12 mL无水甲醇中， 搅拌下加入氢氧化钠溶 液 (IN, 1.59 mL)， 加热回流反应 2.5小时。 TLC跟踪反应至原料消失， 将反应液冷 却至室温， 冰浴下用浓盐酸调节 pH=2〜3， 过滤， 滤饼在真空下干燥， 得到标题 产物 (Z)- 3-(2-(1-(2-氧代 -1-对-甲苯基吲哚- 3-亚基）乙基)肼硫酰氨基)苯甲酸 3(118 mg, 淡黄色固体)。 产率： 48.6%。  (Z)-3-(2-(l-(2-oxo-p-tolylin-3-yl)ethyl)sulfonylamino)benzoic acid (Z)-3-(2-( (2-oxo-1 -p-tolyl-1,3-dihydroindole-3-ylidene)ethyl)phosphonamido)methyl benzoate 3c (250 mg, 0.53 mmol) dissolved in 12 mL In anhydrous methanol, a sodium hydroxide solution (IN, 1.59 mL) was added with stirring, and the mixture was heated under reflux for 2.5 hours. The reaction was stopped until the disappearance of the starting material by TLC. The reaction mixture was cooled to room temperature, adjusted to pH = 2 to 3 with concentrated hydrochloric acid in an ice bath, filtered, and the filter cake was dried under vacuum to give the title product (Z)- 3-(2-(1) -(2-oxo-1-p-tolyl-3-phenyl)ethyl)sulfonylamino)benzoic acid 3 (118 mg, pale yellow solid). Yield: 48.6%.
MS m/z (ESI): 459[M+1] MS m/z (ESI): 459 [M+1]
1 H NMR(400M Hz, DMSO-i¾): 813.11 (br, 1H),11.34(br, 1 H), 10.28(br,2H), 8.01 (s, 1 H), 7.84(m,3H), 7.45(d,lH, J=8.6 Hz), 6.90(d,lH, J= 7.2 Hz), 6.80(m,2H), 6.68(m,3H), 6.54(d,lH, J=7.0 Hz), 3.40(s,3H), 2.39(s,3H) 实施例 4 1 H NMR (400M Hz, DMSO -i¾): 813.11 (br, 1H), 11.34 (br, 1 H), 10.28 (br, 2H), 8.01 (s, 1 H), 7.84 (m, 3H), 7.45 (d, lH, J = 8.6 Hz), 6.90 (d, lH, J = 7.2 Hz), 6.80 (m, 2H), 6.68 (m, 3H), 6.54 (d, lH, J = 7.0 Hz), 3.40 (s, 3H), 2.39 (s, 3H) Example 4
(Z 4-(2-( 1— (2—氧代 _1-对甲苯基 -U-二氢吲哚—3-亚基)乙基)肼硫酰氨基)苯甲酸 (Z 4 - (2 - ( 1 - (2 - oxo- 1 - p-tolyl- U -dihydroindole-3-ylidene)ethyl) sulfonylamino)benzoic acid
Figure imgf000018_0001
Figure imgf000018_0001
Figure imgf000019_0001
第一步
Figure imgf000019_0001
first step
(Z)-4-(2-(l-(2-氧代 -1-对甲苯基 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸乙酯 将 (Z)-3-(l-二甲氨基亚乙基)小(4-甲苯基 )-1,3-二氢吲哚- 2-酮 3b (320 mg, 1.1 mmol)溶解于 25mL无水乙醇中， 加入 4- (；肼硫酰氨基)苯甲酸乙酯 2e (287 mg, 1.2 mmol)和 1 mL乙酸， 加热回流 1.5小时。 TLC跟踪反应至原料消失， 减压浓缩， 用硅胶色谱法纯化，得到 (Z)-4-(2-(l-(2-氧代 -1-对-甲苯基- 1,3-二氢吲哚 -3-亚基)乙基) 肼硫酰氨基)苯甲酸乙酯 4a(444mg, 黄色油状液体)。 产率： 82.8%。  (Z) 4-(2-(1-oxo-1-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl)phosphonylamino)benzoic acid ethyl ester (Z)-3-(l-Dimethylaminoethylidene) small (4-tolyl)-1,3-dihydroindole-2-one 3b (320 mg, 1.1 mmol) was dissolved in 25 mL of anhydrous To the ethanol, ethyl 4-(;sulfonylamino)benzoate 2e (287 mg, 1.2 mmol) and 1 mL of acetic acid were added, and the mixture was refluxed for 1.5 hr. The reaction was quenched by TLC until the title material disappeared, concentrated under reduced pressure and purified by silica gel chromatography to afford (Z)-4-(2-(2-oxo-1-p-tolyl-1,3-dihydroindole). Indole-3-yl)ethyl) sulfonylamino)benzoate ethyl ester 4a (444 mg, yellow oily liquid). Yield: 82.8%.
MSm/z(ESI): 487[M+1] MSm/z (ESI): 487 [M+1]
第二步  Second step
(Z)-4-(2-(l-(2-氧代 -1-对甲苯基- 1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸 将 (Z)-4-(2-(l-(2-氧代 -1-对甲苯基 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲 酸乙酯 4a (400 mg, 0.82 mmol)溶解于 20 mL无水甲醇中， 加入氢氧化钠溶液 (IN, 0.82 mL), 加热回流反应 3.5小时。 TLC跟踪反应至原料消失， 将反应液冷却至室 温， 冰浴下用浓盐酸调节 pH=2〜3， 过滤， 收集固体， 得到 (Z)-4-(2-(l-(2-氧代 -1- 对甲苯基 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸 4(72 mg, 淡黄色固体)。产 率： 19.1%。  (Z)-4-(2-(l-(2-oxo-1-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl)sulfonylamino)benzoic acid ( Z) 4-(2-(1-oxo-1-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl)phosphonylamino)benzoate ethyl ester 4a (400 mg, 0.82 mmol) was dissolved in 20 mL of anhydrous methanol, and sodium hydroxide solution (IN, 0.82 mL) was added and the mixture was refluxed for 3.5 hours. TLC followed the reaction until the disappearance of the starting material, the reaction solution was cooled to room temperature, adjusted to pH = 2 to 3 with concentrated hydrochloric acid in an ice bath, filtered, and solid was collected to give (Z)-4-(2-(l-(2-oxo) -1- p-Tolyl-1,3-dihydroindol-3-ylidene)ethyl) sulfonylamino)benzoic acid 4 (72 mg, pale yellow solid). Yield: 19.1%.
MSm/z(ESI): 457[M-1]  MSm/z (ESI): 457 [M-1]
'HNMR(400M HZ, OMSO-d6): 613.21(br,lH),11.30(br,lH),10.27(br,2H),8.10(s,lH), 7.81(d,lH, J=8.4 Hz), 7.74(m,5H), 7.50(d,2H, J=8.0 Hz), 6.81(d,lH, J=7.2 Hz), 6.50(dd, 2H, J=8.4 Hz, J2=4.0 Hz), 3.40(s,3H), 2.38(s,3H) 实施例 5 'HNMR (400M HZ, OMSO-d 6 ): 613.21 (br, lH), 11.30 (br, lH), 10.27 (br, 2H), 8.10 (s, lH), 7.81 (d, lH, J = 8.4 Hz ), 7.74 (m, 5H), 7.50 (d, 2H, J = 8.0 Hz), 6.81 (d, lH, J = 7.2 Hz), 6.50 (dd, 2H, J = 8.4 Hz, J 2 = 4.0 Hz) , 3.40(s,3H), 2.38(s,3H) Example 5
(2)-3-(2-( 0-(3，4-二甲苯基)-2-氧代-1,3-二氢吲哚-3-亚基)乙基)肼硫酰氨基)苯甲  (2)-3-(2-( 0-(3,4-Dimethylphenyl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)phosphonamido)benzene A
Figure imgf000019_0002
Figure imgf000019_0002
Figure imgf000020_0001
Figure imgf000020_0001
第一步  First step
(Z)-3-(l-肼基亚乙基 )小(3,4-二甲苯基) -1,3-二氢吲哚 -2-酮 将 (Z)-3-(l -二甲氨基亚乙基) -1-(3,4-二甲苯基) -1,3-二氢吲哚 -2-酮 2c(l .12 g, 3.66 mmol)溶解于 50 mL乙醇中， 加入 50%—水合肼溶液 (7.3 mL, 7.32 mmol), 室温反 应 1.5小时。 TLC跟踪反应至原料消失， 冷却至室温， 加入 100 mL水和 100 mL 二氯甲垸萃取， 有机相用饱和食盐水洗涤 (5 mLx2), 减压下浓缩， 干燥， 得到 (Z)-3-(l-肼基亚乙基) -1-(3,4-二甲苯基) -1,3-二氢吲哚 -2-酮 5a(751 mg, 棕黄色固 体)。 产率： 70.1%。  (Z)-3-(l-decylethylene) small (3,4-dimethylphenyl)-1,3-dihydroindol-2-one (Z)-3-(l-dimethyl Aminoethylidene)-1-(3,4-dimethylphenyl)-1,3-dihydroindol-2-one 2c (1.12 g, 3.66 mmol) was dissolved in 50 mL of ethanol and added to 50% - Hydrazine hydrate solution (7.3 mL, 7.32 mmol), reacted at room temperature for 1.5 hours. TLC followed the reaction to the disappearance of the starting material, cooled to room temperature, extracted with 100 mL of water and 100 mL of dichloromethane. The organic phase was washed with brine (5 mL×2), concentrated under reduced pressure and dried to give (Z)-3- (l-decylethylene)-1-(3,4-dimethylphenyl)-1,3-dihydroindol-2-one 5a (751 mg, brownish yellow solid). Yield: 70.1%.
MSm/z(ESI): 294[M+1] MSm/z (ESI): 294 [M+1]
'HNMR(400M HZ, DMSO-i/6): δ 11.31(br,lH), 7.42(d,lH, J= 7.6 Hz),7.28(d,lH, J=8.0 Hz),7.16(s, 1 H),7.09(t, 1 H, J=6.8 Hz),6.97(t,lH, J=7.6 Hz),6.90(t,lH, J=7.6 Hz), 6.76(d,lH, J = 7.6 Hz), 3.42 (s,3H),2.29(s,6H) 'HNMR (400M HZ, DMSO-i/ 6 ): δ 11.31 (br, lH), 7.42 (d, lH, J = 7.6 Hz), 7.28 (d, lH, J = 8.0 Hz), 7.16 (s, 1 H), 7.09 (t, 1 H, J = 6.8 Hz), 6.97 (t, lH, J = 7.6 Hz), 6.90 (t, lH, J = 7.6 Hz), 6.76 (d, lH, J = 7.6 Hz) ), 3.42 (s, 3H), 2.29 (s, 6H)
第二步  Second step
(Z)-3- (2-(l-(l-(3,4-二甲苯基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲 酸甲酯  (Z)-3-(2-(l-(l-(3,4-Dimethylphenyl)-2-oxo-1,3-dihydroindol-3-ylidene)ethyl)phosphonyl Amino)methyl benzoate
将 (Z)-3-0肼基亚乙基)小(3,4-二甲苯基) -U-二氢吲哚 -2-酮 5a(670 mg, 2.3 mmol)溶解于 100 mL 四氢呋喃中， 加入 3-异氰酸酯基苯甲酸甲酯 （451 mg, 2.5 mmol), 室温反应 0.5小时。 TLC跟踪反应至原料消失， 用硅胶柱色谱法纯化所得 残余物， 得到 (Z)-3-(2-(l-G-(3,4-二甲苯基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫 酰氨基)苯甲酸甲酯 5b(370mg, 黄色固体)。 产率： 34.2%。  (Z)-3-0-Methylidene) small (3,4-dimethylphenyl)-U-indan-2-one 5a (670 mg, 2.3 mmol) was dissolved in 100 mL of tetrahydrofuran. Methyl 3-isocyanate benzoate (451 mg, 2.5 mmol) was added and allowed to react at room temperature for 0.5 h. The reaction was traced to the disappearance of the starting material by TLC, and the obtained residue was purified by silica gel column chromatography to give (Z)-3-(2-(l-(3,4-dimethylphenyl)-2-oxo-1,3-di Hydroquinone-3-ylidene)ethyl)sulfonylamino)benzoic acid methyl ester 5b (370 mg, yellow solid). Yield: 34.2%.
MSm/z(ESI): 471[M+1] MSm/z (ESI): 471[M+1]
第三歩  Third
(Z)-3-(2- ( (1-(3,4-二甲苯基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲 酸  (Z)-3-(2-((1-(3,4-Dimethylphenyl)-2-oxo-1,3-dihydroindol-3-ylidene)ethyl)sulfonylamino) Benzoic acid
将 (Ζ)-3-(2-(μ(1-(3,4-二甲苯基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基) 苯甲酸甲酯 5b (190 mg, 0.4 mmol)溶解于 10 mL无水甲醇中， 加入氢氧化钠溶液 (1N,1 mL), 加热回流反应 2小时。 TLC跟踪反应至原料消失， 将反应液冷却至室 温， 冰浴下用浓盐酸调节 pH=2〜3， 过滤， 滤饼在真空下干燥， 得到标题产物 (Z)-3-(2-(l-(l-(3,4-二甲苯基) -2-氧代吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸 5(70 nig, 白色固体)。 产率： 38.5%。 (Ζ)-3-(2-(μ(1-(3,4-Dimethylphenyl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)phosphonyl Amino) Methyl benzoate 5b (190 mg, 0.4 mmol) was dissolved in 10 mL of anhydrous methanol, and then sodium hydroxide solution (1 N, 1 mL) was added and the mixture was refluxed for 2 hours. TLC followed the reaction until the disappearance of the starting material, the reaction solution was cooled to room temperature, adjusted to pH = 2 to 3 with concentrated hydrochloric acid in an ice bath, filtered, and the filter cake was dried under vacuum to give the title product. (Z)-3-(2-(l-(l-(3,4-dimethylphenyl)-2-oxoindole-3-ylidene)ethyl)sulfonylamino)benzoic acid 5 (70) Nig, white solid). Yield: 38.5%.
MS m/z (ESI): 455[M-1] MS m/z (ESI): 455 [M-1]
'HNMR(400M HZ, OMSO-d6): 88.22(s,lH),7.93-7.76(m,lH),7.75-7.70(m,lH), 7.54-7.50(m,lH),7.25-7.14(m,3H),6.95-6.79(m,2H),6.73-6.71(m,2H),2.08-2.15(m,9H) 实施例 6 'HNMR (400M HZ, OMSO-d 6 ): 88.22 (s, lH), 7.93-7.76 (m, lH), 7.75-7.70 (m, lH), 7.54-7.50 (m, lH), 7.25-7.14 ( m, 3H), 6.95-6.79 (m, 2H), 6.73-6.71 (m, 2H), 2.08-2.15 (m, 9H) Example 6
(Z)- 4-(2-(l-(5-氟 -2-氧代- 对甲苯基 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲 酸乙酯  (Z)- 4-(2-(l-(5-fluoro-2-oxo-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl)sulfonylamino)benzoic acid Ethyl ester
Figure imgf000021_0001
第一步
Figure imgf000021_0001
first step
5-氟 -1-对甲苯基 -1,3-二氢吲哚 -2-酮  5-fluoro-1-p-tolyl-1,3-dihydroindol-2-one
将5-氟-1，3-二氢吲哚-2-酮6$1(5.0§,33011110】)， 对溴甲苯 (6.79 g, 40 mmol)， 碘 化亚铜（1.26 g, 6.6 mmol)和碳酸钾（10.06 g, 73 mmol)溶解于 220 mL 乙腈中， 搅拌 下加入 Ν,Ν'-二甲基 -1,2-乙二胺 (0.87 g, 9.9 mmol), 加热回流 5小时。 TLC跟踪反 应至原料消失，过滤，用 1N盐酸调节 pH=7，加入 150 mL水，用乙酸乙酯萃取 (100 mLx2), 合并的有机相用无水硫酸镁干燥， 过滤， 滤液在减压下浓缩， 用硅胶柱色 谱法纯化所得残余物， 得到 5-氟 -1-对甲苯基 -1,3-二氢吲哚 -2-酮 6b(l.11 g, 棕色固 体)。 产率： 13.7%。 5-Fluoro-1,3-dihydroindol-2-one 6$ 1 (5.0 § , 33011 1 10 )), p-bromotoluene (6.79 g, 40 mmol), cuprous iodide (1.26 g, 6.6 Methyl acetate and potassium carbonate (10.06 g, 73 mmol) were dissolved in 220 mL of acetonitrile, and hydrazine, Ν'-dimethyl-1,2-ethanediamine (0.87 g, 9.9 mmol) was added with stirring, and heated under reflux for 5 hours. . The reaction was carried out with TLC, and the mixture was filtered, and then filtered, and the mixture was adjusted to pH=7 with 1N hydrochloric acid, 150 mL of water, and ethyl acetate (100 mL×2), and the combined organic phases were dried over anhydrous magnesium sulfate and filtered. The residue was purified by silica gel column chromatography eluting eluting eluting Yield: 13.7%.
MSm/z(ESI): 242[M+1]  MSm/z (ESI): 242 [M+1]
第二歩  Second
(Z)-3-(l-二甲氨基亚乙基) -5-氟小对甲苯基 -1,3-二氢吲哚 -2-酮 将 5-氟小对甲苯基 -1,3-二氢吲哚 -2-酮 6b (909 mg, 3.77 mmol)溶解于 25mL氯 仿中， 搅拌下加入 (1,1-二甲氧基-乙基)-二甲胺 (1.1 mL, 7.54 mmol), 室温反应 2小 时。 TLC 跟踪反应至原料消失， 用硅胶柱色谱法纯化所得残余物， 得到 (Z)-3-(l- 二甲氨基亚乙基) -5-氟 -1-对甲苯基 -1 ,3-二氢吲哚 -2-酮 6c(744 mg,棕色固体)。产率： 63.6%。 (Z)-3-(l-dimethylaminoethylidene)-5-fluorop-p-tolyl-1,3-dihydroindol-2-one 5-penta-p-tolyl-1,3- Dihydroindol-2-one 6b (909 mg, 3.77 mmol) was dissolved in 25 mL of chloroform and (1,1-dimethoxy-ethyl)-dimethylamine (1.1 mL, 7.54 mmol). Room temperature reaction 2 small Time. The reaction was traced to disappearance of the material by TLC, and the obtained residue was purified by silica gel column chromatography to give (Z)-3-(l-dimethylaminoethylidene)-5-fluoro-1-p-tolyl-1, 3- Hydroquinone-2-one 6c (744 mg, brown solid). Yield: 63.6%.
MS m/z (ESI): 311 [M+l]  MS m/z (ESI): 311 [M+l]
Ή NMR(400M Hz, CDC13): δ 7.34-7.37(4H, m),7.03(d,lH, J=9 Hz),6.78(s, NMR NMR (400 M Hz, CDC1 3 ): δ 7.34-7.37 (4H, m), 7.03 (d, lH, J = 9 Hz), 6.78 (s,
lH),6.69(dd,lH, J,=9 Hz,J2=2.4 Hz),3.42(s, 6H),2.60(s,3H),2.44(s,3H) lH), 6.69 (dd, lH, J, = 9 Hz, J 2 = 2.4 Hz), 3.42 (s, 6H), 2.60 (s, 3H), 2.44 (s, 3H)
第三步  third step
(Z)-5-氟 -3-(l-肼基亚乙基) - 1-对甲苯基 -1 ,3-二氢吲哚 -2-酮  (Z)-5-fluoro-3-(l-fluorenylethylene)-1- 1-p-tolyl-1,3-dihydroanthracene-2-one
将 (Z)-3-(l -二甲氨基亚乙基) -5-氟 -1-对甲苯基 -1,3-二氢吲哚- 2-酮 6c (456 mg, 1.47 mmol)溶解于 25mL二氯甲烷中， 搅拌下加入 50%水合肼溶液 (0.588 mL, 5.88 mmol), 加热回流 0.5小时。 TLC跟踪反应至原料消失， 冷却至室温， 减压下浓缩 反应液， 用硅胶柱色谱法纯化所得残余物， 得到 (Z)- 5-氟 -3-(1-肼基亚乙基) -1-对甲 苯基 -1 ,3-二氢吲哚 -2-酮 6d(333 mg, 灰色固体)。 产率： 76.2%。  (Z)-3-(l-Dimethylaminoethylidene)-5-fluoro-1-p-tolyl-1,3-dihydroindole-2-one 6c (456 mg, 1.47 mmol) was dissolved in In 25 mL of dichloromethane, a 50% hydrazine hydrate solution (0.588 mL, 5.88 mmol) was added with stirring, and the mixture was heated under reflux for 0.5 hr. The reaction was traced to the disappearance of the material by TLC, and the mixture was cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford (Z) 5- 5-fluoro-3-(1-indenylethylidene)-1 - p-Tolyl-1,3-dihydroindol-2-one 6d (333 mg, grey solid). Yield: 76.2%.
MS m/z (ESI): 298 [M+l]  MS m/z (ESI): 298 [M+l]
第四步  the fourth step
(Z)- 4-(2-(1- (5-氟 -2-氧代 - 对甲苯基 -1，3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲 酸乙酯  (Z)- 4-(2-(1-(5-fluoro-2-oxo-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl)sulfonylamino)benzoic acid Ethyl ester
将 (Z)-5-氟 -3-(1-肼基亚乙基) -1-对甲苯基- 1 ,3-二氢吲哚 -2-酮 6d (330 mg, 1.1 mmol)溶解于 10 mL四氢呋喃中， 搅拌下加入 4-异硫氰酸酯基苯甲酸乙酯 2d(274 mg, 1.32 mmol), 室温反应 4小时。 TLC跟踪反应至原料消失， 用硅胶柱色谱法纯 化所得残余物， 得到标题产物 (Z)-4-(2-(l-(5-氟 -2-氧代 -1-对甲苯基 -1,3-二氢吲哚 -3- 亚基)乙基)肼硫酰氨基)苯甲酸乙酯 6(430 mg, 黄色固体)。 产率： 76.9%。  (Z)-5-Fluoro-3-(1-mercaptoethylidene)-1-p-tolyl-1,3-dihydroindol-2-one 6d (330 mg, 1.1 mmol) was dissolved in 10 To the tetrahydrofuran, ethyl 2-isothiocyanate benzoate 2d (274 mg, 1.32 mmol) was added with stirring, and the mixture was reacted at room temperature for 4 hours. The reaction was quenched by TLC to elution of material, and the obtained residue was purified to silica gel column chromatography to afford the title product (Z)-4-(2-(5-fluoro-2-oxo-1-p-tolyl-1, Ethyl 3-dihydroindole-3-ylidene)ethyl)sulfonylamino)benzoate 6 (430 mg, yellow solid). Yield: 76.9%.
MS m/z (ESI): 505 [M+l]  MS m/z (ESI): 505 [M+l]
lH NMR(400M Hz, DMSO-^): δ 11.29(br, 1 H), 10.27(br,2H),8.21 (s, 1 H),7.82(dd,2H, Ji=8.4 Hz, J2=6.0 Hz),7.51(d,2H, J=7.6 Hz),7.53(d,lH, J=7.2 lH NMR (400M Hz, DMSO-^): δ 11.29 (br, 1 H), 10.27 (br, 2H), 8.21 (s, 1 H), 7.82 (dd, 2H, Ji = 8.4 Hz, J 2 = 6.0 Hz), 7.51 (d, 2H, J = 7.6 Hz), 7.53 (d, lH, J = 7.2
Hz),7.19(m,3H),6.85(d,2H, J=8.0 Hz),3.42(s,3H),3.28(m,2H),2.36(m,6H) 实施例 7  Hz), 7.19 (m, 3H), 6.85 (d, 2H, J = 8.0 Hz), 3.42 (s, 3H), 3.28 (m, 2H), 2.36 (m, 6H) Example 7
(Ζ)-4-(2-Π -(5-氟 -2-氧代 - 对甲苯基 -1.3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸 (Ζ) -4-(2-Π-(5-fluoro-2-oxo-p-tolyl-1.3-dihydroindole-3-ylidene)ethyl)sulfonylamino)benzoic acid
Figure imgf000022_0001
Figure imgf000023_0001
将 (Z)-4-(2-(l-(5-氟 -2-氧代 -1-对甲苯基 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基) 苯甲酸乙酯 6 (300 mg, 0.60 mmol)溶解于 15mL无水甲醇中， 搅拌下加入氢氧化钠 溶液 (lN, 2.4 mL)， 加热回流反应 4小时。 TLC跟踪反应至原料消失， 将反应液冷 却至室温， 冰浴下用 1N盐酸调节 pH=2〜3， 过滤， 滤饼在真空下干燥， 得到标题 产物 (Z)-4-(2-(l-(5-氟 -2-氧代 -1-对甲苯基 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯 甲酸 7(180 mg, 淡黄色固体)， 产率： 63.2%。
Figure imgf000022_0001
Figure imgf000023_0001
(Z)-4-(2-(l-(5-fluoro-2-oxo-1-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl)phosphonylamino Ethyl benzoate 6 (300 mg, 0.60 mmol) was dissolved in 15 mL of anhydrous methanol, and sodium hydroxide solution (1N, 2.4 mL) was added with stirring, and the mixture was heated and refluxed for 4 hours. TLC followed the reaction until the disappearance of the starting material, the reaction mixture was cooled to room temperature, adjusted to pH = 2 to 3 with 1 N hydrochloric acid in an ice bath, filtered, and the filter cake was dried under vacuum to give the title product (Z)-4-(2-(l) -(5-fluoro-2-oxo-1-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl)sulfonylamino)benzoic acid 7 (180 mg, pale yellow solid) , Yield: 63.2%.
Figure imgf000023_0002
Figure imgf000023_0002
1 H NMR(400M Hz,DMSO-^):613.31 (br, 1 H), 11.32(br, 1 H), 10.36(br, 1 H), 10.286(br, 1 H), 8.20(s,lH),7.88(d, 2H,J=8.4 Hz),7.55(d,2H, J=4.8 Hz),7.14(m,3H),6.94(d, 1H, J=8.4 Hz),6.56(dd,lH, J=8.0 Hz, J2=4.8 Hz),6.40(s,lH),3.40(s,3H),2.38(s,3H) 实施例 8 1 H NMR (400 M Hz, DMSO-^): 613.31 (br, 1 H), 11.32 (br, 1 H), 10.36 (br, 1 H), 10.286 (br, 1 H), 8.20 (s, lH) , 7.88 (d, 2H, J = 8.4 Hz), 7.55 (d, 2H, J = 4.8 Hz), 7.14 (m, 3H), 6.94 (d, 1H, J = 8.4 Hz), 6.56 (dd, lH, J = 8.0 Hz, J 2 = 4.8 Hz), 6.40 (s, lH), 3.40 (s, 3H), 2.38 (s, 3H) Example 8
(Ζ)-4-(2-Π-Π-(3,4-二甲苯基) -2-氧代 -1,3-二氢吲哚- 3-亚基)乙基)肼硫酰氨基)苯甲  (Ζ)-4-(2-Π-Π-(3,4-dimethylphenyl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)sulfonylamino) Benzyl
Figure imgf000023_0003
第一步
Figure imgf000023_0003
first step
(Z)-4-(2-(l-(l-(3,4-二甲苯基)- 2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲 酸甲酯  (Z)-4-(2-(l-(l-(3,4-dimethylphenyl)-2-oxo-1,3-dihydroindol-3-ylidene)ethyl)phosphonyl Amino)methyl benzoate
将 (Ζ)-5-氟 -3- (1-肼基亚乙基 )小对甲苯基 -1,3-二氢吲哚 -2-酮 5a(260 mg, 0.88 mmol)溶解于 70 mL四氢呋喃中， 搅拌下加入 4-异氰酸酯基苯甲酸甲酯 （186 mg, 0.97 mmol), 室温反应 10分钟。 TLC跟踪反应至原料消失， 用硅胶柱色谱法纯化 所得残余物， 得到 (Z)-4-(2-(l-(l-(3,4-二甲苯基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基) 肼硫酰氨基)苯甲酸甲酯 8a(250 mg,黄色固体)。 产率： 58.6%。 Dissolve (Ζ)-5-fluoro-3-(1-mercaptoethylidene)p-p-tolyl-1,3-dihydroindol-2-one 5a (260 mg, 0.88 mmol) in 70 mL of tetrahydrofuran The 4-isocyanate benzoic acid methyl ester (186 mg, 0.97 mmol) was added with stirring, and the mixture was reacted at room temperature for 10 minutes. The reaction was traced to the disappearance of the material by TLC, and the obtained residue was purified by silica gel column chromatography to afford (Z)-4-(2-(l-(3,4-dimethylphenyl)-2-oxo-1, Methyl 3-indoline-3-ylidene)ethyl)sulfonylamino)benzoate 8a (250 mg , yellow solid). Yield: 58.6%.
MS m/z (ESI): 485[M+1] 第二步 MS m/z (ESI): 485 [M+1] Second step
(Z)-4-(2-(l- (l-(3,4-二甲苯基)- 2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲 酸  (Z)-4-(2-(l-(l-(3,4-dimethylphenyl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)phosphonyl Amino)benzoic acid
将 (Z)-4- (2-(1- (1-(3,4-二甲苯基) -2-氧代 -1，3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基) 苯甲酸甲酯 8a (250 mg, 0.5 mmol)溶解于 10 mL无水甲醇中，搅拌下加入氢氧化钠 溶液 (1N,0.8 mL)， 加热回流反应 40分钟。 TLC跟踪反应至原料消失， 将反应液冷 却至室温， 冰浴下用浓盐酸调节 pH=2〜3， 过滤， 滤饼在真空下千燥， 得到标题 产物 (Z)- 4-(2-(1-(1-(3,4-二甲苯基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基) 苯甲酸 8(200 mg,黄色固体)。 产率： 85.1%。  (Z)-4-(2-(1-(1-(3,4-Dimethylphenyl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)sulfonium sulphide Amido)methyl benzoate 8a (250 mg, 0.5 mmol) was dissolved in 10 mL of dry methanol, and then sodium hydroxide solution (1 N, 0.8 mL) was added with stirring, and the mixture was heated and refluxed for 40 minutes. TLC followed the reaction until the starting material disappeared. The reaction solution was cooled to room temperature, adjusted to pH = 2 to 3 with concentrated hydrochloric acid in an ice bath, filtered, and the filter cake was dried under vacuum to give the title product (Z)- 4-(2-( 1-(1-(3,4-Dimethylphenyl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)sulfonylamino)benzoic acid 8 (200 mg, yellow solid). Yield: 85.1%.
Ή NMR(400M Hz, DMSO- ί/6):δ11.76(br,lH),8.00(d,2H, .1=9 Hz),7.73(d,2H, J=9 Hz), 7.24-7.18(m,3H),6.96-6.88(m,2H),6.88-6.72(m,2H),3.86(br,3H),2.15(s,3H),2.13(s,3H), 2.12(s,3H) 实施例 9 NMR NMR (400 M Hz, DMSO- ί/ 6 ): δ 11.76 (br, lH), 8.00 (d, 2H, .1 = 9 Hz), 7.73 (d, 2H, J = 9 Hz), 7.24-7.18 (m, 3H), 6.96-6.88 (m, 2H), 6.88-6.72 (m, 2H), 3.86 (br, 3H), 2.15 (s, 3H), 2.13 (s, 3H), 2.12 (s, 3H) Example 9
(Z)-3-(2-(l-(2-氧代 -1-对-甲苯基 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸  (Z)-3-(2-(l-(2-oxo-1-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl)phosphonylamino)benzoic acid
Figure imgf000024_0001
第一步
Figure imgf000024_0001
first step
(Z)-3-(l-肼基亚乙基)小对甲苯基 -1,3-二氢吲哚 -2-酮 将 (Z)-3-(l-二甲氨基亚乙基)小 (4-甲苯基 )-1,3-二氢吲哚 -2-酮 3b(1.4 g, 3.4 mmol) 溶解于 50 mL乙腈中， 搅拌下加入 50%水合肼溶液 (1.1 mL, 11 mmol), 室温反应 0.5小时。 TLC跟踪反应至原料消失， 冷却至室温， 加入 100 mL水和 100 mL二氯 甲垸萃取， 合并的有机相用饱和食盐水洗涤， 减压下浓缩， 干燥， 得到 (Z)-3-(l- 肼基亚乙基) -1-对甲苯基 -1,3-二氢吲哚 -2-酮 9a(1.27 g, 白色固体)。 产率： 94.9%。 MS m/z (ESI): 280[M+1]  (Z)-3-(l-decylethylene)p-p-tolyl-1,3-dihydroindol-2-one (Z)-3-(l-dimethylaminoethylidene) (4-Tolyl)-1,3-dihydroindol-2-one 3b (1.4 g, 3.4 mmol) was dissolved in 50 mL of acetonitrile, and 50% hydrazine hydrate solution (1.1 mL, 11 mmol) was added with stirring. The reaction was carried out for 0.5 hour at room temperature. TLC followed the reaction to the disappearance of the starting material, cooled to room temperature, extracted with 100 mL of water and 100 mL of dichloromethane. The combined organic phases were washed with brine, concentrated under reduced pressure and dried to give (Z) - mercaptoethylidene)-1-p-tolyl-1,3-dihydroindol-2-one 9a (1.27 g, white solid). Yield: 94.9%. MS m/z (ESI): 280 [M+1]
Ή NMR(400M Hz, CDC13): δ 7.52-7.50(m,lH),7.32-7.25(m, 4H), 7.10-7.01 (m,2H), 6.88-6.86(m,lH),2.10(s,3H), 2.03(s,3H) 第二步 NMR NMR (400 M Hz, CDC1 3 ): δ 7.52-7.50 (m, lH), 7.32-7.25 (m, 4H), 7.10-7.01 (m, 2H), 6.88-6.86 (m, lH), 2.10 (s) , 3H), 2.03(s, 3H) Second step
(Z)-3- (2-( 2-氧代- 1-对甲苯基 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸甲酯 将 (Z)-3-(l-肼基亚乙基) -1-对甲苯基 -1 ,3-二氢吲哚 -2-酮 9a (367 mg, 1.3 mmo】)溶 解于 40 mL四氢呋喃中，搅拌下加入 3-异氰酸酯基苯甲酸甲酯 (233 mg, 1.3 mmol), 室温反应 20分钟。 TLC跟踪反应至原料消失， 用硅胶柱色谱法纯化所得残余物， 得到 (Z)-3-(2-(l-(2-氧代 -1-对甲苯基 - -二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸 甲酯 9b(593 mg, 白色固体)。 产率： 100%。  (Z)-3-(2-(2-oxo-1-phenyl-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl)sulfonylamino)benzoic acid methyl ester (Z )-3-(l-decylethylene)-1-p-tolyl-1 ,3-dihydroindol-2-one 9a (367 mg, 1.3 mmo)) was dissolved in 40 mL of tetrahydrofuran with stirring Methyl 3-isocyanate benzoate (233 mg, 1.3 mmol) was added and allowed to react at room temperature for 20 min. The reaction was traced to the disappearance of the material by TLC, and the obtained residue was purified by silica gel column chromatography to give (Z)-3-(2-(2- oxo-1-p-tolyl-indanindole-3- Methylidene)ethyl)sulfonylamino)benzoic acid methyl ester 9b (593 mg, white solid). Yield: 100%.
MS m/z (ESI): 457[M+1] MS m/z (ESI): 457 [M+1]
Ή NMR(400M Hz, DMSO-i¾: δ 11.23(br,lH), 9.44(br,lH), 8.81(br,l H),8.20(s,lH), 7.76(d,lH, J=8 Hz),7.59(d,lH, J=8 Hz),7.52(d,l H, J=7 Hz),7.49-7.37(m,3H),  NMR NMR (400 M Hz, DMSO-i3⁄4: δ 11.23 (br, lH), 9.44 (br, lH), 8.81 (br, l H), 8.20 (s, lH), 7.76 (d, lH, J = 8 Hz ), 7.59 (d, lH, J = 8 Hz), 7.52 (d, l H, J = 7 Hz), 7.49-7.37 (m, 3H),
7.31 (d,2H, J=8 Hz),7.05-7.02(m,2H),6.81 -6.79(m, 1 H),3.85(s,3H),2.40(s,6H) 7.31 (d, 2H, J=8 Hz), 7.05-7.02 (m, 2H), 6.81 - 6.79 (m, 1 H), 3.85 (s, 3H), 2.40 (s, 6H)
第三步  third step
(Z)-3- (2- ( (2-氧代 -1-对甲苯基 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸 将 (Ζ)-3-(2-(μ(2-氧代- 1-对甲苯基 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲 酸甲酯 9b(295 mg, 0.6 mmol)溶解于 15 mL无水甲醇中， 搅拌下加入氢氧化钠溶液 (IN, 1 mL), 加热回流反应 40分钟。 TLC跟踪反应至原料消失， 将反应液冷却至 室温， 冰浴下用浓盐酸调节 pH=2〜3， 过滤， 滤饼在真空下干燥， 得到标题产物 (Z)-3-(2-(l-(2-氧代 - 对甲苯基 - -二氢吲哚_3-亚基）乙基)肼硫酰氨基)苯甲酸 9(156 mg, 白色固体)。 产率： 58.9%。  (Z)-3-(2-((2-oxo-1-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl)sulfonylamino)benzoic acid (Ζ) 3-(2-(μ(2-oxo-1- 1-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl)sulfonylamino)benzoic acid methyl ester 9b (295 mg , 0.6 mmol) was dissolved in 15 mL of anhydrous methanol, and a sodium hydroxide solution (IN, 1 mL) was added thereto with stirring, and the mixture was heated under reflux for 40 minutes. TLC followed the reaction until the disappearance of the starting material, the reaction mixture was cooled to room temperature, adjusted to pH = 2 to 3 with concentrated hydrochloric acid in an ice bath, filtered, and the filter cake was dried under vacuum to give the title product (Z)-3-(2-(l) -(2-oxo-p-tolyl-indanyl-3-(3-ylidene)ethyl)sulfonylamino)benzoic acid 9 (156 mg, white solid). Yield: 58.9%.
MS m/z (ESI): 441 [M-l] MS m/z (ESI): 441 [M-l]
!H NMR(400M Hz, DMSO-t 6): δ 13.09 (br, 1 H), 11.64(br, 1 H),8.23(s, 1 H), 7.87-7.74(m, 2H),7.57(d,2H, J=8 Hz),7.42-7.22(m,2H),7.10-6.93(m,2H),6.75(d,2H,J=2 Hz), ! H NMR (400M Hz, DMSO -t 6): δ 13.09 (br, 1 H), 11.64 (br, 1 H), 8.23 (s, 1 H), 7.87-7.74 (m, 2H), 7.57 (d , 2H, J=8 Hz), 7.42-7.22 (m, 2H), 7.10-6.93 (m, 2H), 6.75 (d, 2H, J = 2 Hz),
4.08-3.71(br,3H),2.04-1.89(m,6H) 实施例 10 4.08-3.71 (br, 3H), 2.04-1.89 (m, 6H) Example 10
(Z)- 4-(2-α-Π-(3,4-二甲苯基)- 5-氟 -2-氧代 _1,3-二氢吲哚 -3-亚基)乙基) -N-甲基肼硫 酰氨基)苯甲酸  (Z)- 4-(2-α-Π-(3,4-Dimethylphenyl)-5-fluoro-2-oxo-1,3-1,3-dihydroindole-3-ylidene)ethyl) N-methylsulfonylamino)benzoic acid
Figure imgf000025_0001
Figure imgf000025_0001
Figure imgf000026_0001
第一步
Figure imgf000026_0001
first step
1— (3,4-二甲苯基) -5-氟 -1 ,3-二氢吲哚 -2-酮  1-(3,4-Dimethylphenyl)-5-fluoro-1,3-dihydroanthracene-2-one
将 5-氟 -1,3-二氢吲哚- 2-酮 6a(27.2 g, 180 mmol), 3,4-二甲基溴苯 (40 g, 216 mmol), 碘化亚铜 (6.9 g, 36 mmol), 碳酸钾 (54.6 g, 396 mmol)和 Ν,Ν'-二甲基 -1,2-乙 二胺 (4.8 g, 54 mmol)搅拌下溶解于 600 mL 乙腈中， 加热回流过夜。 TLC跟踪反应 至原料消失， 将反应液冷却至室温， 倒入 500 mL乙酸乙酯和盐酸 (IN, 400 mL)的 混和溶剂中， 减压下浓缩， 残余物用乙酸乙酯重结晶， 过滤， 滤饼在真空下干燥， 得到 1-(3,4-二甲苯基) -5-氟 -1 ,3-二氢吲哚 -2-酮 10a(10 g， 黄色固体)。产率： 21.8 %。 MS m/z (ESI):256[M+1]  5-Fluoro-1,3-dihydroindole-2-one 6a (27.2 g, 180 mmol), 3,4-dimethylbromobenzene (40 g, 216 mmol), cuprous iodide (6.9 g , 36 mmol), potassium carbonate (54.6 g, 396 mmol) and hydrazine, Ν'-dimethyl-1,2-ethanediamine (4.8 g, 54 mmol) were dissolved in 600 mL of acetonitrile with stirring and heated to reflux overnight. . The reaction was quenched with EtOAc (EtOAc) (EtOAc)EtOAc. The filter cake was dried under vacuum to give 1-(3,4-dimethylphenyl)-5-fluoro-1,3-dihydroindol-2-one 10a (10 g, yellow solid). Yield: 21.8 %. MS m/z (ESI): 256 [M+1]
第二步  Second step
(Z)-3-(l-二甲氨基亚乙基)小(3,4-二甲苯基) -5-氟 -1 ,3-二氢吲哚 -2-酮 将 (3,4-二甲苯基) -5-氟- 1，3-二氢吲哚 -2-酮 10a (8 g, 31.3 mmol)溶解于 100 mL氯仿中， 搅拌下加入 (U-二甲氧基乙基)-二甲胺 (9.2 g, 69 mmol), 加热回流 4.5 小时。 TLC 跟踪反应至原料消失， 在减压下浓缩反应液， 用硅胶柱色谱法纯化所 得残余物， 得到 (Z)-3-(l-二甲氨基亚乙基) -1-(3,4-二甲苯基) -5-氟 -1 ,3-二氢吲哚 -2- 酮 10b(9.52 g， 绿色固体)。 产率： 93.6%。  (Z)-3-(l-dimethylaminoethylidene) small (3,4-dimethylphenyl)-5-fluoro-1,3-dihydroindol-2-one (3,4-di Tolyl)-5-fluoro-1,3-dihydroindol-2-one 10a (8 g, 31.3 mmol) was dissolved in 100 mL of chloroform, and (U-dimethoxyethyl)-di was added with stirring. Methylamine (9.2 g, 69 mmol) was heated to reflux for 4.5 hours. The reaction was traced to the disappearance of the material by TLC, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford (Z)-3-(l-dimethylaminoethylidene)-1-(3,4- Xylyl) -5-fluoro-1,3-indan-2-one 10b (9.52 g, green solid). Yield: 93.6%.
MS m/z (ESI):325[M+l]  MS m/z (ESI): 325 [M+l]
!H NMR(400M Hz, OMSO-d6): 57.257(d,l H,J=8.0 Hz), 7.163(d,lH,J=7.6 Hz),!H NMR (400 M Hz, OMSO-d 6 ): 57.257 (d, l H, J = 8.0 Hz), 7.163 (d, lH, J = 7.6 Hz),
7.158(s,lH), 6.926(s,lH), 6.77(s,lH), 6.639(d,lH,J=7.2 Hz), 2.950(s,3H), 2.793(s,3H),7.158(s,lH), 6.926(s,lH), 6.77(s,lH), 6.639(d,lH,J=7.2 Hz), 2.950(s,3H), 2.793(s,3H),
2.281(s,6H), 1.965(s,3H) 2.281(s,6H), 1.965(s,3H)
第三歩  Third
4- [(咪 1 -硫羰基)-甲氨基] -苯甲酸甲酯  4-[(Mid 1 -thiocarbonyl)-methylamino]-benzoic acid methyl ester
将 4-甲氨基苯甲酸甲酯 10c(100 mg, 0.605 mmol)和 Ν,Ν，-硫羰基二咪唑 （162 mg, 0.908 mmol)溶解于 15 mL二氯甲烷中， 室温反应 4天。 TLC跟踪反应至原料 消失，用硅胶色谱法纯化，得到 4- [(咪唑- 1 -硫羰基)-甲氨基] -苯甲酸甲酯 10d(l 30 mg, 黄色油状液体)。 产率： 77.8%。 Methyl 4-methylaminobenzoate 10c (100 mg, 0.605 mmol) and hydrazine, hydrazine, -thiocarbonyldiimidazole (162 Mg, 0.908 mmol) was dissolved in 15 mL of dichloromethane and allowed to react at room temperature for 4 days. The reaction was quenched by TLC to dryness eluting with silica gel elution elution elution elution elution elution elution Yield: 77.8%.
MS m/z (ESI):276[M+1] MS m/z (ESI): 276 [M+1]
Ή NM (400M Hz,CD3OD): 57.998(d, 2H, J=8.8 Hz),7.854(s,lH), 7.334(d, 2H, J=8.8 Hz)，7.171 (s, 1 H),6.774(s, 1 H),3.903(s,3H),3.867(s,3H) Ή NM (400M Hz, CD 3 OD): 57.998(d, 2H, J=8.8 Hz), 7.854(s,lH), 7.334(d, 2H, J=8.8 Hz), 7.171 (s, 1 H), 6.774(s, 1 H), 3.903(s, 3H), 3.867(s, 3H)
第四步  the fourth step
4-(N-甲基肼硫酰氨基)苯甲酸甲酯  Methyl 4-(methyl-methylsulfonylamino)benzoate
将 50%水合肼溶液 (27 μL, 0.27 mmol)溶解于 5 mL四氢呋喃中， 搅拌下滴加 4- [(咪唑 - 硫羰基) -甲氨基] -苯甲酸甲酯 10d (100 mg, 0.363 mmol) 的 10 mL四氢呋 喃溶液， 室温反应 1 小吋。 TLC跟踪反应至原料消失， 减压下浓缩反应液， 用硅 胶色谱法纯化所得残余物， 得到 4-(N-甲基肼硫酰氨基)苯甲酸甲酯 10e(69 mg, 白 色固体)。 产率： 79.3%。  The 50% hydrazine hydrate solution (27 μL, 0.27 mmol) was dissolved in 5 mL of tetrahydrofuran, and 4-[(imidazolium-thiocarbonyl)-methylamino]-benzoic acid methyl ester 10d (100 mg, 0.363 mmol) was added dropwise with stirring. A 10 mL solution of tetrahydrofuran was reacted at room temperature for 1 hour. The reaction was quenched with EtOAc (EtOAc). Yield: 79.3%.
MS m/z (ESI):240[M+l] MS m/z (ESI): 240 [M+l]
Ή NMR (400M Hz, CD3OD): 58.102(d, 2H, J=6.8 Hz),7.370(d, 2H, J=6.4 Hz), NMR NMR (400 M Hz, CD 3 OD): 58.102 (d, 2H, J = 6.8 Hz), 7.370 (d, 2H, J = 6.4 Hz),
3.936(s,3H), 3.577(s,3H) 3.936(s,3H), 3.577(s,3H)
第五步  the fifth step
(Z)— 4-(2-(l -(l-(3,4-二甲苯基) -5-氟 -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基) -N-甲基肼硫 酰氨基)苯甲酸甲酯  (Z)-4-(2-(l-(l-(3,4-Dimethylphenyl)-5-fluoro-2-oxo-1,3-dihydroindol-3-ylidene)ethyl -N-methylsulfonylamino)benzoic acid methyl ester
将 (Z)-3-(l-二甲氨基亚乙基) -1-(3,4-二甲苯基) -5-氟 -1 ,3-二氢吲哚 -2-酮 10b (373 mg, 1.15 mmol)和 4-(N-甲基肼硫酰氨基)苯甲酸甲酯 10e (250 mg, 1.05 mmol)溶解 于 5 mL乙酸的乙醇溶液 (5g乙酸溶解于 50 mL乙醇)中， 室温反应过夜。 TLC跟踪 反应至原料消失， 过滤， 滤饼用乙醇洗涤 (5 mLx2)， 干燥， 得到 (Z)-4-(2-(l- (1-(3,4- 二甲苯基) -5-氟 -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基) -N-甲基肼硫酰氨基)苯甲酸甲酯 10f(389 mg, 灰色固体）。 产率： 71.6%。  (Z)-3-(l-Dimethylaminoethylidene)-1-(3,4-dimethylphenyl)-5-fluoro-1,3-dihydroindol-2-one 10b (373 mg , 1.15 mmol) and methyl 4-(N-methylsulfonylamino)benzoate 10e (250 mg, 1.05 mmol) dissolved in 5 mL of acetic acid in ethanol (5 g of acetic acid dissolved in 50 mL of ethanol), reacted at room temperature overnight. TLC followed the reaction until the disappearance of the starting material, filtration, and the filter cake was washed with ethanol (5 mL×2) and dried to give (Z)-4-(2-(1-(3,4-dimethylphenyl)-5-fluoro Methyl 2-oxo-1,3-dihydroindole-3-ylidene)ethyl)-N-methylsulfonylamino)benzoate 10f (389 mg, m.p.). Yield: 71.6%.
Ή NMR(400M Hz, OMSO-d6): 511.60(s, IH), 9.8 l(s, IH), 8.05(d, 2H, J=8.4 Hz), 7.56(d， 2H, J=8.4 Hz), 7.28(m, 2H), 7.17(s, IH), 7.11(m, IH), 6.80(m, IH), 6.72(m,lH): 3.88(s, 3H), 3.59(s, 3H), 2.40(s, 3H), 2.30(s, 3H), 2.29(s,3H) NMR NMR (400 M Hz, OMSO-d 6 ): 511.60 (s, IH), 9.8 l (s, IH), 8.05 (d, 2H, J = 8.4 Hz), 7.56 (d, 2H, J = 8.4 Hz) , 7.28(m, 2H), 7.17(s, IH), 7.11(m, IH), 6.80(m, IH), 6.72(m,lH) : 3.88(s, 3H), 3.59(s, 3H), 2.40(s, 3H), 2.30(s, 3H), 2.29(s,3H)
第六步  Step 6
(Z)-4-(2-(l-( (3,4-二甲苯基) -5-氟 -2-氧代 -1，3-二氢吲哚 -3-亚基)乙基) -N-甲基肼硫 酰氨基)苯甲酸  (Z)-4-(2-(l-((3,4-Dimethylphenyl)-5-fluoro-2-oxo-1,3-dihydroindole-3-ylidene)ethyl) - N-methylsulfonylamino)benzoic acid
将 (Z)-4-(2-(l-( (3,4-二甲苯基) -5-氟 -2-氧代- 1，3-二氢吲哚 -3-亚基)乙基) -N-甲基 肼硫酰氨基)苯甲酸甲酯 10f (370 mg, 0.714 mmol)溶解于 2 mL甲醇中，搅拌下加入 氢氧化钠溶液 (lN, 2 mL)， 加热回流反应 5小时。 TLC跟踪反应至原料消失， 将反 应液冷却至室温， 加入 5 mL水和 5 mL乙醚， 水相用盐酸 (1 N, 5 mL)调节 pH=2〜 3， 用乙酸乙酯萃取， 合并的有机相依次用饱和食盐水洗涤 (5 mLx2)， 无水硫酸钠 千燥， 过滤， 减压下浓缩， 用硅胶色谱法纯化所得残余物， 得到标题产物 (Z)-4-(2-(l -(l-(3，4-二甲苯基) -5-氟- 2-氧代 -】,3-二氢吲哚 -3-亚基）乙基) -N-甲基肼硫 酰氨基)苯甲酸 10(140 mg, 灰黄色固体)。 产率： 38.9%。 (Z)-4-(2-(l-((3,4-Dimethylphenyl)-5-fluoro-2-oxo-1,3-dihydroindol-3-yl)ethyl) Methyl-N-methylsulfonylamino)benzoate 10f (370 mg, 0.714 mmol) was dissolved in 2 mL of methanol, and sodium hydroxide solution (1N, 2 mL) was added with stirring, and the mixture was heated and refluxed for 5 hours. TLC followed the reaction until the disappearance of the starting material, the reaction solution was cooled to room temperature, 5 mL of water and 5 mL of diethyl ether were added, and the aqueous phase was adjusted to pH 2 to 3 with hydrochloric acid (1 N, 5 mL), and extracted with ethyl acetate. The phases were washed with brine (5 mL EtOAcq. (Z)-4-(2-(l-(l-(3,4-dimethylphenyl)-5-fluoro-2-oxo-],3-dihydroindole-3-ylidene)ethyl -N-methylsulfonylamino)benzoic acid 10 (140 mg, off-yellow solid). Yield: 38.9%.
MS m/z (ESI):503[M-l] MS m/z (ESI): 503 [M-l]
' H NMR(400M HZ, DMSO-C/6): 613.06(S, lH), 1 1.58(S, lH), 9.75(S, lH), 8.05(S, 2H, J=8.4 Hz), 7.54(d, 2H, J=8.4 Hz), 7.29(m, 2H), 7, 18(s, 1 H), 7.10(m, 1 H), 6.8 l(m, 1H), 6.72(m, 1 H), 3.60(s, 3H), 3.40(s, 3H), 2.30(s, 3H), 2.29(s, 3H) 实施例】 1 'H NMR (400M HZ, DMSO-C/ 6 ): 613.06 (S, lH), 1 1.58 (S, lH), 9.75 (S, lH), 8.05 (S, 2H, J = 8.4 Hz), 7.54 ( d, 2H, J=8.4 Hz), 7.29(m, 2H), 7, 18(s, 1 H), 7.10(m, 1 H), 6.8 l(m, 1H), 6.72(m, 1 H) , 3.60(s, 3H), 3.40(s, 3H), 2.30(s, 3H), 2.29(s, 3H) Example] 1
(Z)- 4- (2-Π -( 1- 4-二甲苯基) -2-氧代 - U-二氢吲哚 -3-亚基)乙基) -N-甲基肼硫酰氨  (Z)- 4-(2-Π-(1-4-Dimethylphenyl)-2-oxo-U-dihydroindole-3-ylidene)ethyl)-N-methylsulfonylamide
Figure imgf000028_0001
Figure imgf000028_0001
第一步  First step
(Z)-4— ( ( ( (3,4—二甲苯基)—2_氧代—1,3—二氢吲哚—3-亚基)乙基) -N-甲基肼硫酰氨 基)苯甲酸甲酯 (Z) -4- (((( 3,4- dimethylphenyl) - 2 _ oxo-1,3-dihydro-indol-3-ylidene) ethyl) -N- methylhydrazine sulfamido Methyl benzoate
将 (Z)-3-(l-二甲氨基亚乙基)小 (3,4-二甲苯基) -1,3-二氢吲哚 -2-酮 2c (320 mg, 1.04 mmol)和 4- (N-甲基肼硫酰氨基)苯甲酸甲酯 10e (225 mg, 0.95 mmol)溶解于 4 mL乙酸的乙醇溶液 (5g乙酸溶解于 50 mL乙醇)中， 室温反应过夜。 TLC跟踪反应 至原料消失， 过滤， 滤饼用乙醇洗涤 (5 mLx2)， 干燥， 得到 (Z)-4-(2-(l-(l-(3，4-二甲 苯基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基) -N-甲基肼硫酰氨基)苯甲酸甲酯 lla(277 mg, 黄色固体)。 产率： 53.1%。  (Z)-3-(l-Dimethylaminoethylidene) small (3,4-dimethylphenyl)-1,3-dihydroindol-2-one 2c (320 mg, 1.04 mmol) and 4 - (N-methylsulfonylamino)benzoic acid methyl ester 10e (225 mg, 0.95 mmol) was dissolved in 4 mL of acetic acid in ethanol (5 g of acetic acid dissolved in 50 mL of ethanol) and allowed to react overnight at room temperature. TLC followed the reaction until the disappearance of the starting material, filtration, and the filter cake was washed with ethanol (5 mL×2) and dried to give (Z)-4-(2-(l-(3,4-dimethylphenyl)-2-oxyl Methyl-1,3-dihydroindol-3-ylidene)ethyl)-N-methylsulfonylamino)benzoate lla (277 mg, yellow solid). Yield: 53.1%.
Ή NMR(400M Hz, DMSO- c/6): 611.44(s, 1H), 9.70(s, 1H), 8.04(d, 2H, J=8.4 Hz), 7.54(d, 2H, J=8.4 Hz), 7.47(m, 1H), 7.3 l(d, 1 H, J=8.0 Hz), 7.18(s, 1H), 7.11(m, 1H), 7.0 l(m, 2H), 6.78(m, 1H), 3.88(s, 3H)， 3.60(s, 3H), 2.40(s, 3H), 2,30(s, 3H), 2.29(s, 3H) NMR (400 M Hz, DMSO-c/ 6 ): 611.44 (s, 1H), 9.70 (s, 1H), 8.04 (d, 2H, J = 8.4 Hz), 7.54 (d, 2H, J = 8.4 Hz) , 7.47(m, 1H), 7.3 l(d, 1 H, J=8.0 Hz), 7.18(s, 1H), 7.11(m, 1H), 7.0 l(m, 2H), 6.78(m, 1H) , 3.88(s, 3H), 3.60(s, 3H), 2.40(s, 3H), 2,30(s, 3H), 2.29(s, 3H)
第二步  Second step
(Z)-4-(2-G-(l -(3,4-=甲苯基) -2-氧代 -1 ,3-二氢吲哚 -3-亚基)乙基) -N-甲基肼硫酰氨 基)苯甲酸 (Z)-4-(2-G-(l-(3,4-=Tolyl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)-N-A Thioamide Benzoic acid
将 (Z)-4- (2-(1 -(1 -(3,4-二甲苯基)- 2-氧代- 1,3-二氢吲哚 -3-亚基)乙基) -N-甲基肼硫 酰氨基)苯甲酸甲酯 11a (277 mg, 0.55 mmol)溶解于 3 mL甲醇中， 搅拌下加入氢氧 化钠溶液 (1N, 3 mL)， 加热 50°C反应 3小时。 TLC跟踪反应至原料消失， 将反应液 冷却至室温， 加入 5 mL水和 5 mL乙醚， 水相用盐酸 (1N, 5 mL)调节 pH=3， 用乙 酸乙酯萃取， 合并的有机相依次用饱和食盐水洗涤 (5 mLx2)， 无水硫酸钠干燥， 过 滤，减压下浓缩，用乙酸乙酯和正己垸重结晶纯化，得到标题产物 (Z)-4-(2-(l-(l-(3,4- 二甲苯基) -2-氧代- 1 ,3-二氢吲哚 -3-亚基)乙基) -N-甲基肼硫酰氨基)苯甲酸 11( 100 mg: 黄色固体)。 产率： 37.3%。 (Z)-4-(2-(1 -(1 -(3,4-Dimethylphenyl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)-N Methyl-methylsulfonylamino)benzoate 11a (277 mg, 0.55 mmol) was dissolved in 3 mL of methanol, and sodium hydroxide solution (1 N, 3 mL) was added with stirring, and the mixture was heated at 50 ° C for 3 hours. TLC followed the reaction until the disappearance of the starting material, the reaction solution was cooled to room temperature, 5 mL of water and 5 mL of diethyl ether were added, the aqueous phase was adjusted to pH 3 with hydrochloric acid (1N, 5 mL), and extracted with ethyl acetate. The mixture was washed with brine (5 mL EtOAc) -(3,4-dimethylphenyl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)-N-methylsulfonylamino)benzoic acid 11 ( 100 mg : Yellow solid). Yield: 37.3%.
MS m/z (ESI):486[M-l] MS m/z (ESI): 486 [M-l]
Ή NMR(400M Hz, DMSO- 6): δΐ 1.44(s, 1H), 9.70(s, 1H), 8.04(d, 2H, J=8.4 Hz), 7.54(d, 2H, J=8.4 Hz), 7.47(m, lH), 7.31 (d, 1H, J=8.0 Hz), 7.18(s, 1H), 7.1 l(m, 1H)， 7.01 (m, 2H)， 6.78(m， 1H), 3.60(s, 3H)， 2.40(s, 3H), 2,30(s, 3H), 2.29(s, 3H) 实施例 12 NMR NMR (400 M Hz, DMSO- 6 ): δ ΐ 1.44 (s, 1H), 9.70 (s, 1H), 8.04 (d, 2H, J = 8.4 Hz), 7.54 (d, 2H, J = 8.4 Hz), 7.47(m, lH), 7.31 (d, 1H, J=8.0 Hz), 7.18(s, 1H), 7.1 l(m, 1H), 7.01 (m, 2H), 6.78(m, 1H), 3.60( s, 3H), 2.40(s, 3H), 2,30(s, 3H), 2.29(s, 3H) Example 12
(Ζ)-4-(2-Π -(5-氟 -2-氧代 -1-对甲苯基 -1,3-二氢吲哚 -3-亚基)乙基) -N-甲基肼硫酰氨 基)苯甲酸  (Ζ)-4-(2-Π-(5-fluoro-2-oxo-1-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl)-N-methylindole Sulfurylamino)benzoic acid
Figure imgf000029_0001
Figure imgf000029_0001
12  12
第一步  First step
(Z)-4-(2-(l-(5-氟 -2-氧代 -1-对甲苯基 -1,3-二氢吲哚 -3-亚基)乙基) -N-甲基肼硫酰氨基) 苯甲酸甲酯  (Z)-4-(2-(l-(5-fluoro-2-oxo-1-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl)-N-methyl Methyl benzoylamino) benzoic acid methyl ester
将 (Z)-3-(l-二甲氨基亚乙基) -5-氟- 1-对甲苯基 -1,3-二氢吲哚 -2-酮 6c (350 mg, 1.13 mmol)和 4-(N-甲基肼硫酰氨基)苯甲酸甲酯 10e (256 mg, 1.07 mmol)溶解于 0.13 mL乙酸和 4 mL甲醇的混合溶液中， 窒温反应过夜。 TLC跟踪反应至原料消 失， 过滤， 滤饼用甲醇洗涤 (5 mLx2), 干燥， 得到 (Z)-4-(2-(l-(5-氟 -2-氧代 -1-对甲 苯基 -1,3-二氢吲哚 -3-亚基)乙基) -N-甲基肼硫酰氨基)苯甲酸甲酯 12a(400 mg, 灰色 固体)。 产率： 74.2%。 (Z)-3-(l-Dimethylaminoethylidene)-5-fluoro-1-p-tolyl-1,3-dihydroindol-2-one 6c (350 mg, 1.13 mmol) and 4 Methyl (N-methylsulfonylamino)benzoate 10e (256 mg, 1.07 mmol) was dissolved in a mixture of 0.13 mL of acetic acid and 4 mL of methanol, and then reacted overnight. TLC followed the reaction until the disappearance of the starting material, filtration, washing the cake with methanol (5 mL×2), and drying to give (Z)-4-(2-(l-(5-fluoro-2-oxo-1-pair) Phenyl-1,3-dihydroindole-3-ylidene)ethyl)-N-methylsulfonylamino)benzoic acid methyl ester 12a (400 mg, m.p.). Yield: 74.2%.
MS m/z (ESl):505[M+l]  MS m/z (ESl): 505 [M+l]
'H NMR(400M HZ, DMSO-C/6): 611.60(S, I H), 9.81(S,】H), 8.05(d, 2H, J=8.8 Hz), 7.56(d, 2H, J=8.4 Hz), 7.36(d, 2H, J=8.4 Hz), 7.29(d, 3H, J=8.4 Hz), 6.78(m, 2H), 3.88(s, 3H), 3.60(s, 3H), 2.40(s, 6H) 'H NMR (400 M HZ, DMSO-C/ 6 ): 611.60 (S, IH), 9.81 (S, H), 8.05 (d, 2H, J = 8.8 Hz), 7.56 (d, 2H, J = 8.4 Hz), 7.36(d, 2H, J=8.4 Hz), 7.29(d, 3H, J=8.4 Hz), 6.78(m, 2H), 3.88(s, 3H), 3.60(s, 3H), 2.40( s, 6H)
第二步  Second step
(Z)— 4— (2— (l-(5-氟 -2—氧代— μ对甲苯基—1 ,3—二氢吲哚— 3_亚基)乙基) -N-甲基肼硫酰氨基) 苯甲酸 (Z) - 4 - (2 - (l- (5 - fluoro - 2 - oxo - μ p-tolyl-1,3-dihydro-indol---3 _ ylidene) ethyl) - N - methylhydrazine Sulfurylamino) benzoic acid
将 (Z)-4-(2-(l-(5-氟 -2-氧代 -1-对甲苯基- 1，3-二氢吲哚 -3-亚基)乙基) -N-甲基肼硫 酰氨基)苯甲酸甲酯 12a (400 mg, 0.79 mmol)溶解于 3 mL甲醇中， 搅拌下加入氢氧 化钠溶液 (1N, 3 mL),室温反应过夜。 TLC跟踪反应至原料消失，用盐酸 (1N, 5 mL) 调节 pH=2〜3， 用乙酸乙酯萃取， 合并的有机相依次用饱和食盐水洗涤 (5 mLx2)， 无水硫酸钠干燥， 过滤， 减压下浓缩， 用乙酸乙酯和正己垸重结晶纯化， 得到标 题产物 (Z)-4-(2-(l-(5-氟 -2-氧代小对甲苯基 -1,3-二氢吲哚 -3-亚基)乙基) -N-甲基肼硫 酰氨基)苯甲酸 12(200 mg， 浅黄色固体)。 产率： 40.8%。  (Z)-4-(2-(l-(5-fluoro-2-oxo-1-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl)-N-A Methyl thiolamino)benzoic acid methyl ester 12a (400 mg, 0.79 mmol) was dissolved in 3 mL of methanol, and then sodium hydroxide solution (1 N, 3 mL) was added and stirred at room temperature overnight. TLC followed the reaction to the disappearance of the starting material, the pH was adjusted to 2~3 with hydrochloric acid (1N, 5 mL), and extracted with ethyl acetate. The combined organic phases were washed sequentially with brine (5 mL×2), dried over anhydrous sodium sulfate Concentration under reduced pressure and purification by ethyl acetate and hexanes to afford the title product (Z)-4-(2-(5-fluoro-2-oxo-p-tolyl-l-1,3- Indoline-3-ylidene)ethyl)-N-methylsulfonylamino)benzoic acid 12 (200 mg, pale yellow solid). Yield: 40.8%.
Ή NMR(400M Hz, DMSO-^6): 511.60(s, 1H), 9.76(s, 1H), 8.04(d, 2H, J=8.4 Hz), 7.53(d, 2H, J=8.0 Hz), 7.36(d, 2H, J=8.0 Hz), 7.30(m, 3H), 6.75(m, 2H), 3.60(s, 3H), 2.40(s, 6H) NMR NMR (400 M Hz, DMSO-^ 6 ): 511.60 (s, 1H), 9.76 (s, 1H), 8.04 (d, 2H, J = 8.4 Hz), 7.53 (d, 2H, J = 8.0 Hz), 7.36(d, 2H, J=8.0 Hz), 7.30(m, 3H), 6.75(m, 2H), 3.60(s, 3H), 2.40(s, 6H)
实施例 13  Example 13
(Ζ)-4-(2-(1-Π-(2.3-二氢 -IH-茚 -5-基) -2-氧代 -U-二氢吲哚 -3-亚基)乙基)肼硫酰氨  (Ζ)-4-(2-(1-Π-(2.3-Dihydro-IH-indol-5-yl)-2-oxo-U-dihydroindole-3-ylidene)ethyl)anthracene Sulfurylamine
Figure imgf000030_0001
Figure imgf000030_0001
第一步  First step
5-碘 -2,3-二氢 -1H-茚  5-iodo-2,3-dihydro-1H-indole
将 2,3-二氢 -1H-茚 -5-胺 13a(11.73 g, 88.2 mmol)溶解于 50 mL乙腈中， 搅拌下 加入盐酸 (2N, 100 mL), 冰水浴冷却后加入亚硝酸钠 (6.87 g, 99.6 mmol)， 20分钟后 加入碘化钾 (31.3 g, 188.6 mmol), 冰水浴下冷却， 搅拌反应过夜。 TLC跟踪反应至 原料消失，将反应液用正己垸萃取 (150 mLx2)，合并的有机相依次用饱和亚硫酸钠 溶液洗涤 (100 mL), 饱和碳酸氢钠溶液洗涤 (100 mL), 合并的有机相依次用无水硫 酸钠干燥， 过滤， 减压下浓缩滤液， 残留物通过硅胶柱色谱法纯化， 得到 5-碘 -2,3- 二氢 -1H-茚 13b(18.57 g, 浅粉色油状液体)。 2,3-Dihydro-1H-indole-5-amine 13a (11.73 g, 88.2 mmol) was dissolved in 50 mL of acetonitrile with stirring Hydrochloric acid (2N, 100 mL) was added. After cooling in ice-water bath, sodium nitrite (6.87 g, 99.6 mmol) was added. After 20 minutes, potassium iodide (31.3 g, 188.6 mmol) was added, and the mixture was cooled in an ice water bath, and the reaction was stirred overnight. TLC followed the reaction to the disappearance of the starting material, and the reaction mixture was extracted with n-hexane (150 mL×2). The combined organic phases were washed with saturated sodium sulfite solution (100 mL) and washed with saturated sodium hydrogen carbonate solution (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated tolululululululululululululululululululululululululululululululululululululululululululululululu
产率： 86.3 %。 Yield: 86.3 %.
'H NMR(400M HZ, CDC13): 57.61 (S, lH), 7.49(d, 1H, J=8.0 Hz), 7.02(d, 1H, J=8.0 Hz),'H NMR (400M HZ, CDC1 3 ): 57.61 (S, lH), 7.49 (d, 1H, J = 8.0 Hz), 7.02 (d, 1H, J = 8.0 Hz),
2.93(m, 4H), 2.11(m, 2H) 2.93(m, 4H), 2.11(m, 2H)
第二步  Second step
l-(2,3-二氢 -1H-茚 -5-基) -1,3-二氢吲哚 -2-酮  L-(2,3-Dihydro-1H-indole-5-yl)-1,3-dihydroanthracene-2-one
将 1 ,3-二氢吲哚 -2-酮 lc(480 mg, 3.60 mmol)和 5-碘- 2,3-二氢 -1H-茚 13b(800 mg, 1 ,3-Dihydroindol-2-one lc (480 mg, 3.60 mmol) and 5-iodo-2,3-dihydro-1H-indole 13b (800 mg,
3.28 mmol)溶解于 10 mL乙腈中， 搅拌下加入碳酸钾 (997 mg, 7.21 mmol), 碘化亚 铜 (62.5 mg, 0.33 mmol)和 Ν,Ν'-二甲基 -1,2-乙二胺 (58 mg, 0.65 mmol), 于 80°C下搅 拌反应 4小时。 TLC跟踪反应至原料消失， 冷却反应液至室温， 过滤， 减压下浓 缩滤液， 用硅胶柱色谱法纯化所得残留物， 得到 1-(2,3-二氢 -1H-茚 -5-基)- 1,3-二氢 吲哚 -2-酮 13c(500 mg, 黄色油状液体)。 3.28 mmol) was dissolved in 10 mL of acetonitrile, and potassium carbonate (997 mg, 7.21 mmol), cuprous iodide (62.5 mg, 0.33 mmol) and hydrazine, Ν'-dimethyl-1,2-ethane were added with stirring. The amine (58 mg, 0.65 mmol) was stirred at 80 ° C for 4 hours. The reaction was traced to the disappearance of the starting material by TLC. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1-(2,3-dihydro-1H-indol-5-yl) - 1,3-dihydroindol-2-one 13c (500 mg, yellow oily liquid).
产率： 61.2%。 Yield: 61.2%.
MS m/z (ESI):250.2[M+l]  MS m/z (ESI): 250.2 [M+l]
'H NMR(400M HZ, CDC13): 67.39(d, 1H, J=7.6 Hz), 7.34(d, 1H, J=7.6 Hz), 7.28(s, 1H)，'H NMR (400M HZ, CDC1 3 ): 67.39 (d, 1H, J = 7.6 Hz), 7.34 (d, 1H, J = 7.6 Hz), 7.28 (s, 1H),
7.23(t, 1H, J=7.6 Hz), 7.18(d, 1H, J=7.6 Hz), 7.08(t, 1H, J=7.6 Hz), 6.80(d, 1H, J=8.07.23(t, 1H, J=7.6 Hz), 7.18(d, 1H, J=7.6 Hz), 7.08(t, 1H, J=7.6 Hz), 6.80(d, 1H, J=8.0
Hz), 3.74(s, 2H), 3.00(m, 4H), 2.17(m, 2H) Hz), 3.74(s, 2H), 3.00(m, 4H), 2.17(m, 2H)
第三步  third step
(¾小(2,3-二氢 -1H-茚 -5-基) -3-(l- (二甲氨基)亚乙基 )-1,3-二氢吲哚 -2-酮 将 1-(2,3-二氢 -1H-茚 -5-基)- 1,3-二氢吲哚- 2-酮 13c(500 mg, 2.01 mmol)和 1,1- l 甲氧基 -Ν,Ν-二甲基乙胺 (535 mg, 4.02 mmol)溶解于 10 mL氯仿中， 于 70°C下回流 反应 2小时。 TLC跟踪反应至原料消失， 减压下浓缩反应液， 用硅胶柱色谱法纯 化所得残留物， 得到 (Z)-l-(2,3-二氢 -1H-茚 -5-基) -3-(1- (二甲氨基)亚乙基 )-1,3-二氢 吲哚 -2-酮 13d(420 mg, 黄色固体)。  (3⁄4 small (2,3-dihydro-1H-indol-5-yl)-3-(l-(dimethylamino)ethylidene)-1,3-dihydroindol-2-one will be 1- (2,3-Dihydro-1H-indol-5-yl)-1,3-dihydroindole-2-one 13c (500 mg, 2.01 mmol) and 1,1-l methoxy-indole, hydrazine -Dimethylethylamine (535 mg, 4.02 mmol) was dissolved in 10 mL of chloroform and refluxed at 70 ° C for 2 hours. The reaction was quenched by TLC, and the mixture was concentrated under reduced pressure and purified by silica gel column chromatography. The residue thus obtained gives (Z)-l-(2,3-dihydro-1H-indol-5-yl)-3-(1-(dimethylamino)ethylidene)-1,3-dihydroindole. Indole-2-one 13d (420 mg, yellow solid).
产率: 65.6%。 Yield: 65.6%.
MS m/z (ESI):319.4[M+l]  MS m/z (ESI): 319.4 [M+l]
Ή NMR(400M Hz, CDC13): S7.35(m, 3H), 7.22(d, 1H, J=8.0 Hz), 7.00(m, 2H)， 6.90(s, 1H), 3.37(s, 4H), 3.25(s, 2H), 3.01 (m, 4H), 2.87(s, 1H), 2.68(s, 2H), 2.18(m, 2H) NMR NMR (400M Hz, CDC1 3 ): S7.35 (m, 3H), 7.22 (d, 1H, J = 8.0 Hz), 7.00 (m, 2H), 6.90 (s, 1H), 3.37 (s, 4H) ), 3.25(s, 2H), 3.01 (m, 4H), 2.87(s, 1H), 2.68(s, 2H), 2.18(m, 2H)
第四歩  Fourth
(Z)-4-(2-(l-(l-(2,3-二氢 -1H-茚 -5-基) -2-氧代- 1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基) 苯甲酸乙酯 (Z)-4-(2-(l-(l-(2,3-dihydro-1H-indol-5-yl)-2-oxo-1,3-dihydroindole-3-ylidene) Ethyl) sulfonylamino) ethyl benzoate
将 (Z)-l -(2,3-二氢 -1 H-茚 -5-基)- 3-( 二甲氨基）亚乙基 )-1 ,3-二氢吲哚 -2-酮 13d(450 mg, 1.42 mmol)溶解于 10 mL异丙醇中， 搅拌下加入 4- (肼硫酰氨基)苯甲 酸乙酯 2e(339 mg, 1.42 mmol)和 1.5 mL乙酸， 于 85°C下加热回流反应 20分钟， 减压下浓缩反应液，用硅胶柱色谱法纯化所得残余物， 得到 (Z)- 4-(2-(1 -(1-(2,3-二氢 -1H-茚 -5-基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸乙酯 13e(320 mg,黄色固体)。 产率： 41.9%。 (Z)-l-(2,3-Dihydro-1 H-indol-5-yl)-3-(dimethylamino)ethylidene-1,3-dihydroindol-2-one 13d (450 mg, 1.42 mmol) was dissolved in 10 mL of isopropanol, and ethyl 4-(decylsulfonyl)benzoate 2e (339 mg, 1.42 mmol) and 1.5 mL of acetic acid were added with stirring, at 85 ° C The mixture was heated under reflux for 20 minutes, and the reaction mixture was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -5-yl)-2-oxo-1,3-dihydroindol-3-ylidene)ethyl) sulfonylamino)benzoic acid ethyl ester 13e (320 mg, yellow solid). Yield: 41.9%.
MS m/z (ESI):513.1 [M+1] MS m/z (ESI): 513.1 [M+1]
第五步  the fifth step
(Z)- 4-(2-(1-(1-(2,3-二氢 -1H-茚 -5-基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基) 苯甲酸  (Z)- 4-(2-(1-(1-(2,3-Dihydro-1H-indol-5-yl)-2-oxo-1,3-dihydroindole-3-ylidene) Ethyl) sulfonylamino) benzoic acid
将 (Z)-4-(2-(l-(l-(2,3-二氢 -1H-茚 -5-基) -2-氧代 -1 ,3-二氢吲哚- 3-亚基)乙基)肼硫 酰氨基)苯甲酸乙酯 13e(285 mg, 0.56 mmol)溶解于 20 mL甲醇中，搅拌下加入氢氧 化钠溶液 (lN, 2 mL)， 于 90Ό下搅拌回流反应 4小时。 TLC跟踪反应至原料消失， 冷却反应液至室温， 滴加浓盐酸调 pH=2〜3， 析出大量黄色固体， 过滤， 依次用 水洗涤（2 mL) , 甲醇洗涤（2 mL) , 固体在真空下干燥， 得到标题产物 (Z)- 4-(2-(1-(1 -(2,3-二氢 -1H-茚 -5-基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基) 苯甲酸 13(60 mg, 淡黄色固体)。 产率： 22.3 %。  (Z)-4-(2-(l-(l-(2,3-Dihydro-1H-indol-5-yl)-2-oxo-1,3-dihydroindole-3-A) Ethyl ethyl sulfonylamino)benzoic acid ethyl ester 13e (285 mg, 0.56 mmol) was dissolved in 20 mL of methanol, stirred with sodium hydroxide solution (1N, 2 mL), and stirred at 90 Torr under reflux. hour. TLC followed the reaction until the disappearance of the starting material, the reaction solution was cooled to room temperature, and concentrated hydrochloric acid was added dropwise to adjust the pH to 2~3, and a large amount of yellow solid was precipitated, which was filtered, washed with water (2 mL), and then washed with methanol (2 mL). Drying to give the title product (Z) 4-(2-(1-(1 -(2,3-dihydro-1H-indol-5-yl)-2-oxo-1,3-dihydroindole) -3-ylidene)ethyl)sulfonylamino)benzoic acid 13 (60 mg, pale yellow solid). Yield: 22.3%.
MS m/z (ESI):483.4[M-l] MS m/z (ESI): 483.4 [M-l]
'H NMR(400M HZ, DMSO-i¾:S11.37(br,lH), 10.38(br,lH), 10.28(br,lH), 7.91(d, 2H, J=4 Hz), 7.72(d,2H, J=8 Hz), 7.54(s,lH), 7.40(d,lH,J=4 Hz), 7.25(s,lH),  'H NMR (400M HZ, DMSO-i3⁄4: S11.37 (br, lH), 10.38 (br, lH), 10.28 (br, lH), 7.91 (d, 2H, J = 4 Hz), 7.72 (d, 2H, J=8 Hz), 7.54(s,lH), 7.40(d,lH,J=4 Hz), 7.25(s,lH),
7.14(d,lH,J=8 Hz) 7.02(s,2H) 6.78(d,lH,J=8 Hz) 2.95(m,4H) 2.51(s,3H) 2.10(m,2H) 实施例 14 7.14 (d, lH, J = 8 Hz) 7.02 (s, 2H) 6.78 (d, lH, J = 8 Hz) 2.95 (m, 4H) 2.51 (s, 3H) 2.10 (m, 2H) Example 14
(Z 4-i2-G-n- 3-二氢 -1H-茚 -5-基) -5-氟 -2-氧代 -U-二氢吲哚 -3-亚基)乙基)肼硫 酰氨基)苯甲酸  (Z 4-i2-Gn-3-Dihydro-1H-indol-5-yl)-5-fluoro-2-oxo-U-indoline-3-ylidene)ethyl)sulfonylamino Benzoic acid
Figure imgf000032_0001
Figure imgf000032_0001
Figure imgf000033_0001
第一步
Figure imgf000033_0001
first step
5-氟 -l-(2,3-二氢 -1H-茚 -5-基) -1,3-二氢吲哚 -2-酮 将 5-氟 -1,3-二氢吲哚 -2-酮 6a(790 mg, 5.22 mmol)和 5-碘 -2,3-二氢 -1H-茚 5-fluoro-l-(2,3-dihydro-1H-indol-5-yl)-1,3-dihydroindol-2-one 5-fluoro-1,3-dihydroindole-2 -ketone 6a (790 mg, 5.22 mmol) and 5-iodo-2,3-dihydro-1H-indole
13b(1.4 mg, 5.74 mmol)溶解于 20 mL乙腈中， 搅拌下依次加入碳酸钾 (L58g, 11.45 mmol) , 碘化亚铜 (220 mg, 1.15 mmol)和 Ν,Ν，-二甲基 -1,2-乙二胺 (200 mg, 2.3 mmol), 于 85°C下搅拌回流反应 2.5小时。 TLC跟踪反应至原料消失， 冷却反应液 至室温， 用 2N盐酸调 pH-5〜6， 加入 50 mL乙酸乙酯和 50 mL水， 过滤， 萃取 滤液， 合并的有机相依次用水洗涤 (20 mLx2)， 饱和食盐水洗涤 (20 mLx2)， 无水硫 酸锾干燥， 过滤， 减压下浓缩， 用硅胶柱色谱法纯化所得残余物， 得到 5-氟 -1-(2,3- 二氢- 1H-茚- 5-基 )-1,3-二氢吲哚 -2-酮 14a(lg, 淡黄色固体)。 13b (1.4 mg, 5.74 mmol) was dissolved in 20 mL of acetonitrile, and potassium carbonate (L58g, 11.45 mmol), cuprous iodide (220 mg, 1.15 mmol) and hydrazine, hydrazine, and dimethyl-1 were sequentially added with stirring. 2-Ethylenediamine (200 mg, 2.3 mmol) was stirred and refluxed at 85 ° C for 2.5 hours. TLC followed the reaction until the disappearance of the starting material, the reaction mixture was cooled to room temperature, pH-5~6 was adjusted with 2N hydrochloric acid, 50 mL of ethyl acetate and 50 mL of water were added, filtered, and the filtrate was extracted. The combined organic phases were washed with water (20 mL×2) The mixture was washed with saturated brine (20 mL×2), EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj茚-5-yl)-1,3-dihydroindol-2-one 14a (lg, pale yellow solid).
产率： 71.4%。 Yield: 71.4%.
MS m/z (ESI):268.5[M+l]  MS m/z (ESI): 268.5 [M+l]
第二步  Second step
(Z)-l-(2,3-二氢 -1H-茚 -5-基) -5-氟 -3- (1- (二甲氨基)亚乙基 )-1,3-二氨吲哚 -2-酮 将 5-氟小(2，3-二氢 -1H-茚 -5-基) -1,3-二氢吲哚- 2-酮 14a(lg, 3.75 mmol)和 1 ,1- 二甲氧基 -Ν,Ν-二甲基乙胺 (996 mg, 7.49 mmol)溶解于 15 mL氯仿中， 于 90°C下回 流搅拌反应 2.5小时。 TLC跟踪反应至原料消失， 减压下浓缩反应液， 用硅胶柱色 谱法纯化所得残留物， 得到 (Z)-l-(2,3-二氢 -1H-茚 -5-基) -5-氟 -3-(1- (二甲氨基)亚乙 基) -1,3-二氢吲哚 -2-酮 14b(lg, 浅黄绿色固体)。  (Z)-l-(2,3-Dihydro-1H-indol-5-yl)-5-fluoro-3-(1-(dimethylamino)ethylidene)-1,3-diaminopurine 2-keto-5-fluorosuccinic (2,3-dihydro-1H-indol-5-yl)-1,3-dihydroindole-2-one 14a (lg, 3.75 mmol) and 1, 1- Dimethoxy-oxime, hydrazine-dimethylethylamine (996 mg, 7.49 mmol) was dissolved in 15 mL of chloroform, and the reaction was stirred under reflux at 90 ° C for 2.5 hours. The reaction was traced to the disappearance of the material by TLC, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford (Z)-l-(2,3-dihydro-1H-indol-5-yl)-5- Fluor-3-(1-(dimethylamino)ethylidene)-1,3-dihydroindol-2-one 14b (lg, pale yellow-green solid).
产率： 79.4% Yield: 79.4%
MS m/z (ESI):337.4[M+l]  MS m/z (ESI): 337.4 [M+l]
1H NMR(400M Hz, CDC13): 67.37(m, 2H), 7.21(d, 1H, J=8.0 Hz), 7.02(s, 1H), 6.71(s, 1H), 6.68(d, 1H, J=7.8 Hz),3.38(s, 3H), 2.98(m, 4H), 2.55(s, 3H), 2.19(m, 2H), 1.71(s, 3H) 1H NMR (400M Hz, CDC1 3 ): 67.37 (m, 2H), 7.21 (d, 1H, J = 8.0 Hz), 7.02 (s, 1H), 6.71 (s, 1H), 6.68 (d, 1H, J =7.8 Hz), 3.38(s, 3H), 2.98(m, 4H), 2.55(s, 3H), 2.19(m, 2H), 1.71(s, 3H)
第三步  third step
(Z)-4-(2-(l-G-(2,3-二氢 -1H-茚 -5-基) -5-氟 -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰 氨基)苯甲酸乙酯 (Z)-4-(2-(lG-(2,3-dihydro-1H-indol-5-yl)-5-fluoro-2-oxo-1,3-dihydroindol-3- Ethyl) sulfonyl Amino)ethyl benzoate
将 (Z)4-(2,3-二氢- 1H-茚 -5-基) -5-氟 -3-(1- (二甲氨基)亚乙基 )-1,3-二氢吲哚 -2-酮 14b(467 mg, 1.39 mmol)溶解于 20 mL异丙醇中， 搅拌下加入 4- (肼硫酰氨基)苯甲 酸乙酯 2e(332 mg, 1.39 mmol)和 1.5 mL乙酸， 于 75°C下搅拌反应 45分钟。 TLC 跟踪反应至原料消失， 减压下浓缩反应液， 用硅胶柱色谱法纯化所得残余物， 得 到 (Z)-4-(2-(l -(l -(2,3-二氢 -1H-茚 -5-基) -5-氟 -2-氧代 -1 ,3-二氢吲哚 -3-亚基)乙基)肼硫 酰氨基)苯甲酸乙酯 14c(365 mg, 黄色固体)。 产率： 53.2 %。  (Z) 4-(2,3-Dihydro-1H-indol-5-yl)-5-fluoro-3-(1-(dimethylamino)ethylidene-1,3-dihydroindole 2-ketone 14b (467 mg, 1.39 mmol) was dissolved in 20 mL of isopropanol, and ethyl 4-(decylsulfonyl)benzoate 2e (332 mg, 1.39 mmol) and 1.5 mL of acetic acid were added with stirring. The reaction was stirred at 75 ° C for 45 minutes. The reaction was traced to the disappearance of the starting material by TLC, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford (Z)-4-(2-(l-(2,3-dihydro-1H-)茚-5-yl)-5-fluoro-2-oxo-1,3-dihydroindole-3-ylideneethyl)ethyl sulfonylamino)benzoate 14c (365 mg, yellow solid) . Yield: 53.2%.
MS m/z (ESI):531 .0[M+l]  MS m/z (ESI): 531.0 [M+l]
第四步  the fourth step
(Z)-4-(2-(l -(l -(2,3-二氢 -1H-茚 -5-基) -5-氟 -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰 氨基)苯甲酸  (Z)-4-(2-(l-(l-(2,3-dihydro-1H-indol-5-yl)-5-fluoro-2-oxo-1,3-dihydroindole- 3-sub)ethyl) sulfonylamino)benzoic acid
将 (Ζ)-4-(2-(1-(μ(2,3-二氢 -1H-茚 -5-基) -5-氟 -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基) 肼硫酰氨基)苯甲酸乙酯 14C(360 mg, 0.68 mmol)溶解于 25 mL甲醇中，搅拌下加入 氢氧化钠溶液 (1N, 2.8 mL), 于 85 °C下搅拌回流反应 3小时。 TLC跟踪反应至原料 消失， 冷却反应液至室温， 滴加浓盐酸调 pH=2〜3， 析出大量固体， 过滤， 用甲 醇洗涤 (2 mLx2) , 固体在真空下干燥， 得到标题产物 (Z)-4-(2-(l-(l-(2,3-二氢 -1H- 茚 -5-基) -5-氟 -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸 14(200 mg, 黄 色粉末)。 产率： 58.7%。 (Ζ)-4-(2-(1-(μ(2,3-dihydro-1H-indol-5-yl)-5-fluoro-2-oxo-1,3-dihydroindole- Ethyl 3-(ethylidene)ethyl)sulfonylamino)benzoate 14 C (360 mg, 0.68 mmol) was dissolved in 25 mL of methanol and stirred with sodium hydroxide (1N, 2.8 mL) at 85 ° The reaction was stirred under reflux for 3 hours at C. TLC followed the reaction to the disappearance of the starting material, the reaction mixture was cooled to room temperature, and concentrated hydrochloric acid was added dropwise to adjust the pH to 2 to 3 to precipitate a large amount of solid, which was filtered, washed with methanol (2 mL×2), and the solid was dried under vacuum to give the title product (Z) 4-(1-(l-(l-(2,3-dihydro-1H-indol-5-yl)-5-fluoro-2-oxo-1,3-dihydroindol-3-) Ethyl)ethyl)sulfonylamino)benzoic acid 14 (200 mg, yellow powder). Yield: 58.7%.
MS m/z (ESI):501.1 [M-l]  MS m/z (ESI): 501.1 [M-l]
Ή NMR(400M Hz, DMSO-i/6): 811.53(br, 1H), 10.44(br, 1H)， 10.36(br, 1H), 7.91(d, 2H,J=8.0 Hz), 7.72(d, 2H,J=8.0 Hz), 7.36(m, 2H), 7.24(s, 1H), 7.13(d, 1H,J=8.0 Hz), 6.84(t, 1H, J=8.4 Hz), 6.74(d, 1H,J=8.0 Hz), 2.93(m, 4H), 2.71(s, 3H), 2.10(m, 2H) 实施例 15 NMR (400 M Hz, DMSO-i/ 6 ): 811.53 (br, 1H), 10.44 (br, 1H), 10.36 (br, 1H), 7.91 (d, 2H, J = 8.0 Hz), 7.72 (d, 2H, J=8.0 Hz), 7.36(m, 2H), 7.24(s, 1H), 7.13(d, 1H, J=8.0 Hz), 6.84(t, 1H, J=8.4 Hz), 6.74(d, 1H, J=8.0 Hz), 2.93 (m, 4H), 2.71 (s, 3H), 2.10 (m, 2H) Example 15
(Ζ)-3-(2-Π -(1-(3,4-二甲苯基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲  (Ζ)-3-(2-Π-(1-(3,4-Dimethylphenyl)-2-oxo-1,3-dihydroindol-3-ylidene)ethyl)phosphonylamino Benzyl
Figure imgf000034_0001
Figure imgf000034_0001
(Ζ)-3-(2- ( (1-(3,4-二甲苯基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲 酸甲酯 将 (Z)-3-0二甲氨基亚乙基) -l-(3，4-二甲苯基) -1,3-二氢吲哚 -2-酮 2c(250 mg, 0.82 mmol)溶解于 20 mL 无水乙醇中， 搅拌下加入 3- (肼硫酰氨基：)苯甲酸甲酯 lb(147 mg, 0.65 mmol)和 1 mL乙酸， 加热搅拌回流反应 1小时。 TLC跟踪反应至 原料消失， 减压下浓缩反应液， 用硅胶柱色谱法纯化所得残余物， 得到 (Z)-3-(2-(l-(l -(3,4-二甲苯基) -2-氧代 -1,3-二氢吲哚- 3-亚基）乙基)肼硫酰氨基)苯甲 酸甲酯 15a(128 mg, 黄褐色油状液体)。 产率： 32.1 %。 (Ζ)-3-(2-((1-(3,4-Dimethylphenyl)-2-oxo-1,3-dihydroindol-3-ylidene)ethyl)sulfonylamino) Methyl benzoate (Z)-3-0 Dimethylaminoethylidene-1 -(3,4-dimethylphenyl)-1,3-dihydroindol-2-one 2c (250 mg, 0.82 mmol) was dissolved in In 20 mL of absolute ethanol, 3-(decylsulfonylamino)benzoic acid methyl ester lb (147 mg, 0.65 mmol) and 1 mL of acetic acid were added with stirring, and the mixture was stirred under reflux with heating for 1 hour. The reaction was quenched by TLC until the material disappeared, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford (Z)-3-(2-(l-(l-(3,4-dimethylphenyl)) Methyl 2-oxo-1,3-dihydroindole-3-ylidene)ethyl)sulfonylamino)benzoate 15a (128 mg, a tan oily liquid). Yield: 32.1%.
MS m/z (ESI):487.0[M+l] MS m/z (ESI): 487.0 [M+l]
'H NMR(400M HZ, DMSO-c 6):511.40(br,lH), 10.35(br,lH), 10.23(br,lH), 8.16(s,lH) 7.89(d,lH,J=8.0 Hz),7.82(d,lH,J=7.2 Hz),7.61 (m,2H),7.40(d, 1 H,J=7.6 Hz),7.23(s,lH) 7.13(m, 3H), 6.85(m,lH),3.42(s,3H), 2.57(s,3H),2.38(s,6H),2.37(s,6H) 'H NMR (400M HZ, DMSO-c 6 ): 511.40 (br, lH), 10.35 (br, lH), 10.23 (br, lH), 8.16 (s, lH) 7.89 (d, lH, J = 8.0 Hz ), 7.82 (d, lH, J = 7.2 Hz), 7.61 (m, 2H), 7.40 (d, 1 H, J = 7.6 Hz), 7.23 (s, lH) 7.13 (m, 3H), 6.85 (m) , lH), 3.42 (s, 3H), 2.57 (s, 3H), 2.38 (s, 6H), 2.37 (s, 6H)
第二步  Second step
(Z)-3-(2-(l-(l-(3，4-二甲苯基) -2-氧代- 1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲 酸  (Z)-3-(2-(l-(l-(3,4-dimethylphenyl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)phosphonyl Amino)benzoic acid
将 (Z)-3-(2-(l-(l-(3,4-二甲苯基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基) 苯甲酸甲酯15a(128 mg, 0.26 mmol)溶解于10 mL无水甲醇中， 加入氢氧化钠溶液 (1N, 0.79 mL), 室温下搅拌反应 0.5小时后， 加热回流反应。 TLC跟踪反应至原料 消失， 将反应液冷至室温， 加入浓盐酸调节 pH=2〜3， 有大量固体析出， 过滤， 滤饼用甲醇洗涤 (2 mLx3), 固体在真空下干燥， 得到标题产物 (Z)-3-(2-(l-(l-(3,4- 二甲苯基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸 15(38 mg, 淡黄色 固体)。 产率： 31.1 %。  (Z)-3-(2-(l-(l-(3,4-dimethylphenyl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)sulfonium sulphide Methylaminobenzoate 15a (128 mg, 0.26 mmol) was dissolved in 10 mL of anhydrous methanol, and then sodium hydroxide solution (1N, 0.79 mL) was added, and the mixture was stirred at room temperature for 0.5 hr. TLC followed the reaction until the disappearance of the starting material, the reaction solution was cooled to room temperature, concentrated hydrochloric acid was added to adjust pH = 2 to 3, a large amount of solid was precipitated, filtered, and the filter cake was washed with methanol (2 mL x 3), and the solid was dried under vacuum to give the title product. (Z)-3-(2-(l-(l-(3,4-dimethylphenyl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)phosphonyl Amino)benzoic acid 15 (38 mg, pale yellow solid). Yield: 31.1%.
MS m/z (ESI):472.9[M+l] MS m/z (ESI): 472.9 [M+l]
Ή NMR(400M Hz, DMSO-t¾: 5113.08(br,lH),1.40(br,lH),10.35(br,lH),  NMR NMR (400 M Hz, DMSO-t3⁄4: 5113.08 (br, lH), 1.40 (br, lH), 10.35 (br, lH),
10.25(br,lH),8.16(s,lH), 7.89(d,lH,J=8.0 Hz),7.82(d,lH,J=7.2 Hz),7.56(m,2H), 7.40(d,lH,J=7.6 Hz),7.19(m,lH),7.12(t,2H, J=7.6 Hz), 6.95(m, 2H), 3.42(s, 3H), 2.38(s,6H) 实施例 16 10.25(br,lH), 8.16(s,lH), 7.89(d,lH,J=8.0 Hz), 7.82(d,lH,J=7.2 Hz), 7.56(m,2H), 7.40(d,lH , J = 7.6 Hz), 7.19 (m, lH), 7.12 (t, 2H, J = 7.6 Hz), 6.95 (m, 2H), 3.42 (s, 3H), 2.38 (s, 6H) Example 16
(Ζ)-4-(2-α-Π- 4-二甲苯基) -5-氟 -2-氧代 -U-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)  (Ζ)-4-(2-α-Π-4-dimethylphenyl)-5-fluoro-2-oxo-U-indoline-3-yl)ethyl)sulfonylamino)
Figure imgf000035_0001
Figure imgf000035_0001
Figure imgf000036_0001
第一步
Figure imgf000036_0001
first step
(Z)-4-(2- ( (l-(3,4-二甲苯基) -5-氟 -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基） 苯甲酸乙酯  (Z)-4-(2-((l-(3,4-Dimethylphenyl)-5-fluoro-2-oxo-1,3-dihydroindol-3-ylidene)ethyl)indole Sulfurylamino) ethyl benzoate
将 (Z)-3-(l-二甲氨基亚乙基)小 (3,4-二甲苯基) -5-氟 二氢吲哚 -2-酮 10b(550 mg, 1.7 mmol)溶解于 20 mL无水乙醇中， 搅拌下加入 4- (肼硫酰氨基)苯甲酸乙酯 2e(406 mg, 1.7 mmol)和 1 mL乙酸，回流反应 2.5小时。 TLC跟踪反应至原料消失， 将反应液冷至室温， 有固体析出， 过滤， 滤饼用无水乙醇洗涤 (5 mLx3)， 固体在真 空下干燥， 得到 (Z)-4-(2-(l-(l-(3,4-二甲苯基) -5-氟 -2-氧代 -1,3-二氢吲哚 -3-亚基)乙 基)肼硫酰氨基)苯甲酸乙酯 16a(300 mg, 淡黄色固体)。 产率： 34.1 %。  (Z)-3-(l-Dimethylaminoethylidene) small (3,4-dimethylphenyl)-5-fluoroindan-2-one 10b (550 mg, 1.7 mmol) was dissolved in 20 In mL of absolute ethanol, ethyl 4-(decylsulfonyl)benzoate 2e (406 mg, 1.7 mmol) and 1 mL of acetic acid were added with stirring, and the mixture was refluxed for 2.5 hours. TLC followed the reaction until the disappearance of the starting material, the reaction solution was cooled to room temperature, a solid precipitated, filtered, and the filter cake was washed with anhydrous ethanol (5 mL×3), and the solid was dried under vacuum to give (Z)-4-(2-(l) -(l-(3,4-Dimethylphenyl)-5-fluoro-2-oxo-1,3-dihydroindol-3-ylidene)ethyl)sulfonylamino)benzoate ethyl ester 16a (300 mg, light yellow solid). Yield: 34.1%.
MS m/z (ESI):519.1[M+l] MS m/z (ESI): 519.1 [M+l]
t  t
一少  One less
(Z)-4- (2-(1-(1-(3,4-二甲苯基) -5-氟 -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基） 苯甲酸  (Z)-4-(2-(1-(1-(3,4-Dimethylphenyl)-5-fluoro-2-oxo-1,3-dihydroindol-3-ylidene)ethyl )sulfonylamino)benzoic acid
将 (Z)- 4-(2-(1-(1-(3,4-二甲苯基) -5-氟 -2-氧代- U-二氢吲哚 -3-亚基)乙基)肼硫酰 氨基)苯甲酸乙酯 16a(200 mg, 0.39 mmol)溶解于 10 mL无水甲醇中，搅拌下加入氢 氧化钠溶液 (1N,1.5 mL), 搅拌回流反应 4小时。 TLC跟踪反应至原料消失， 冷却 反应液至室温， 加入浓盐酸调节 pH=6， 析出大量固体， 过滤， 用二氯甲垸洗涤 (5 mLx4), 固体在真空下干燥， 得到标题产物 (Z)-4-(2-(l-(l-(3,4-二甲苯基) -5-氟 -2-氧 代 -1,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸 16(90 mg, 淡黄色固体)。 产率： 47.1 %。  (Z)- 4-(2-(1-(1-(3,4-Dimethylphenyl)-5-fluoro-2-oxo-U-indoline-3-ylidene)ethyl) Ethyl sulfonylamino)benzoate 16a (200 mg, 0.39 mmol) was dissolved in 10 mL of anhydrous methanol, and sodium hydroxide solution (1 N, 1.5 mL) was added with stirring, and the mixture was stirred and refluxed for 4 hours. TLC followed the reaction to the disappearance of the starting material, the reaction mixture was cooled to room temperature, concentrated hydrochloric acid was added to adjust pH = 6 to precipitate a large amount of solid, which was filtered, washed with dichloromethane (5 mL x 4), and the solid was dried under vacuum to give the title product (Z) 4-(1-(l-(l-(3,4-dimethylphenyl)-5-fluoro-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)sulfonium sulphide Amido benzoic acid 16 (90 mg, pale yellow solid). Yield: 47.1%.
MS m/z (ESI):489.3[M-l]  MS m/z (ESI): 489.3 [M-l]
'H NMR(400M HZ, DMSO- 6): 611.52(br,lH), 10.43(br, lH),10.39(br, 1H), 7.92(t,2H, J=8.4 Hz), 7.73(m, 2H), 7.33(m, 2H), 7.18(s,l H), 7.12(d,lH, J=8.0 Hz), 6.84(t,lH, J=7.6 Hz), 6.37(m, 1H), 2.50(s, 3H), 3.32(s, 6H) 实施例 17 'H NMR (400M HZ, DMSO- 6 ): 611.52 (br, lH), 10.43 (br, lH), 10.39 (br, 1H), 7.92 (t, 2H, J = 8.4 Hz), 7.73 (m, 2H) ), 7.33(m, 2H), 7.18(s,l H), 7.12(d,lH, J=8.0 Hz), 6.84(t,lH, J=7.6 Hz), 6.37(m, 1H), 2.50( s, 3H), 3.32(s, 6H) Example 17
(Z)-4-(N-甲基 -2-0 -(2-氧代 -1 -对甲苯基 -1 ,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯
Figure imgf000037_0001
(Z)-4-(N-methyl-2-0-(2-oxo-1-p-tolyl-1,3-dihydroindole-3-ylidene)ethyl)phosphonylamino) benzene
Figure imgf000037_0001
第一步  First step
(Z)-4-(N-甲基- 2-(1 -(2-氧代 - 1-对甲苯基 -1 ,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯 甲酸甲酯  (Z)-4-(N-methyl-2-(1-(2-oxo-1-phenyl-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl) sulfonylamino Methyl benzoate
将 (Z)-3-(l-二甲氨基亚乙基)- 1-(4-甲苯基 )-1,3-二氢吲哚- 2-酮 3b(250 mg, 0.856 mmol)溶解于 2 mL乙醇中，搅拌下加入 4-(N-甲基肼硫酰氨基)苯甲酸甲酯 10e(186 mg, 0.78 mmol)和 0.15 mL乙酸， 升温至 60°C搅拌反应 3小时。 TLC跟踪反应至原 料消失， 冷却反应液至室温， 减压下浓缩反应液， 向残余物中加入 5 mL乙酸乙酯 禾口 5 mL水， 分液， 有机相用饱和食盐水 (5 mL)洗涤， 合并的有机相依次用无水硫 酸镁干燥，过滤，减压下浓缩滤液，用硅胶柱色谱法纯化所得残余物，得到 (Z 4-(N- 甲基- 2-(1 -(2-氧代 - 对甲苯基 -1 ,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯甲酸甲酯 17a(300 mg, 黄色固体）。 产率： 79.2 %。  (Z)-3-(l-Dimethylaminoethylidene)-1-(4-methylphenyl)-1,3-dihydroindole-2-one 3b (250 mg, 0.856 mmol) was dissolved in 2 In mL ethanol, methyl 4-(N-methylsulfonylamino)benzoate 10e (186 mg, 0.78 mmol) and 0.15 mL of acetic acid were added with stirring, and the mixture was heated to 60 ° C and stirred for 3 hours. TLC followed the reaction to the disappearance of the starting material, the reaction mixture was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure. 5 mL of ethyl acetate and 5 mL of water were added to the residue, and the mixture was separated and the organic phase was washed with saturated brine (5 mL) The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated, evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjj Methyl oxo-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl)sulfonylamino)benzoate 17a (300 mg, yellow solid). Yield: 79.2 %.
第二步  Second step
(Z)— 4_(N-甲基 -2-(1-(2-氧代 -1-对甲苯基 -1 ,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨基)苯 甲酸 (Z)— 4 _(N-methyl-2-(1-(2-oxo-1-p-tolyl-1,3-dihydroindole-3-ylidene)ethyl)phosphonylamino )benzoic acid
将 (Z)-4-(N-甲基 -2-(1-(2-氧代 -1-对甲苯基 -1 ,3-二氢吲哚 -3-亚基)乙基)肼硫酰氨 基)苯甲酸甲酯 17a(300 mg, 0.62 mmol)溶解于 2 mL甲醇中，加入氢氧化钠溶液 (IN, 2 mL) , 于 50°C下反应 3小时。 TLC跟踪反应至原料消失， 减压下蒸掉甲醇， 加入 2 mL水， 用乙醚萃取 (5 mLx2)， 水相用 IN盐酸调节 pH=6， 析出大量黄色固体， 过滤， 滤饼用水洗涤 (2 mLx2)， 粗品用甲醇 -水重结晶， 固体在真空下干燥， 得到 标题产物 (Z)-4-(N-甲基 -2-(1-(2-氧代 -1 -对甲苯基 -1 ,3-二氢吲哚 -3-亚基)乙基)肼硫酰 氨基)苯甲酸 17(70 mg, 黄色粉末)。 产率： 24.1 %。  (Z)-4-(N-methyl-2-(1-(2-oxo-1-p-tolyl-1,3-dihydroindol-3-ylidene)ethyl)phosphonyl Amino)methyl benzoate 17a (300 mg, 0.62 mmol) was dissolved in 2 mL of methanol, and sodium hydroxide solution (IN, 2 mL) was added and reacted at 50 ° C for 3 hours. TLC followed the reaction until the disappearance of the starting material. The methanol was evaporated under reduced pressure. 2 mL of water was added and extracted with diethyl ether (5 mL×2). The aqueous phase was adjusted to pH=6 with IN hydrochloric acid to precipitate a large amount of yellow solid, which was filtered and washed with water (2) The crude product was recrystallized from methanol-water, and the solid was dried in vacuo to give the title product (Z)-4-(N-methyl-2-(1-(2-oxo-1-p-tolyl-1) , 3-dihydroindole-3-ylidene)ethyl)sulfonylamino)benzoic acid 17 (70 mg, yellow powder). Yield: 24.1%.
MS m/z (ESI):473.0[M+l]  MS m/z (ESI): 473.0 [M+l]
1H NMR(400M Hz, OMSO-d6): 512.78(br, 1H), 11.50(br, 1H), 9.71 (br, 1H), 8.0 l(d, 2H, J=7.2 Hz), 7.50(m, 3H), 7.42(d, 2H, J=8.0 Hz), 7.36(d, 2H, J=8.0 Hz), 7.00(m, 2H), 6.78(d, 1H, J=8.0 Hz), 3.63(s, 3H), 2.41 (s, 3H), 2.40(s, 3H) 实施例 18 1H NMR (400M Hz, OMSO-d 6 ): 512.78 (br, 1H), 11.50 (br, 1H), 9.71 (br, 1H), 8.0 l (d, 2H, J = 7.2 Hz), 7.50 (m, 3H), 7.42(d, 2H, J=8.0 Hz), 7.36(d, 2H, J=8.0 Hz), 7.00(m, 2H), 6.78(d, 1H, J=8.0 Hz), 3.63(s, 3H), 2.41 (s, 3H), 2.40(s, 3H) Example 18
(Z)-4-(2-(\ -(] - 3-二氢- 1 H-茚 -5-基) -2-氧代- 1 ,3-二氢吲哚 -3-亚基)乙基) -N-甲基肼
Figure imgf000038_0001
(Z)-4-(2-(\-(]-3-Hydrogen-1H-indol-5-yl)-2-oxo-1,3-dihydroindole-3-ylidene) -N-methyloxime
Figure imgf000038_0001
第一步  First step
(Z)-4- (2-(1-(1- (2,3-二氢 -1H-茚 -5-基) -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基) -N-甲基肼 硫酰氨基)苯甲酸甲酯  (Z)-4-(2-(1-(1-(2,3-Dihydro-1H-indol-5-yl)-2-oxo-1,3-dihydroindole-3-ylidene) Ethyl)-N-methylsulfonylamino)benzoic acid methyl ester
将 (Z)-l-(2,3-二氢 -1H-茚 -5-基) -3-(1- (二甲氨基）亚乙基 )-1,3-二氢吲哚- 2-酮 13d(295 mg,0.93 mmol) 溶解于 3 mL甲醇中， 搅拌下加入 4-(N-甲基肼硫酰氨基) 苯甲酸甲酯 10e(210 mg, 0.88 mmol)和 0.16 mL乙酸， 室温下搅拌反应过夜。 TLC 跟踪反应至原料消失， 析出大量固体， 过滤， 滤饼用甲醇洗涤 (5 mLx3)， 固体在真 空下干燥， 得到 (Z)-4-(2-(l-(l- (2,3-二氢 -1H-茚 -5-基) -2-氧代 -1，3-二氢吲哚 -3-亚基) 乙基) -N-甲基肼硫酰氨基)苯甲酸甲酯 18a(230 mg, 灰色固体)。 产率： 48.2 %。 MS m/z (ESI):510.9[M-l]  (Z)-l-(2,3-Dihydro-1H-indol-5-yl)-3-(1-(dimethylamino)ethylidene)-1,3-dihydroindole-2- Ketone 13d (295 mg, 0.93 mmol) was dissolved in 3 mL of methanol, and 4-(N-methylsulfonylamino)benzoic acid methyl ester 10e (210 mg, 0.88 mmol) and 0.16 mL of acetic acid were added with stirring, at room temperature The reaction was stirred overnight. TLC followed the reaction until the starting material disappeared, a large amount of solid was precipitated, filtered, and the filter cake was washed with methanol (5 mL×3), and the solid was dried under vacuum to give (Z)-4-(2-(l-(l-(2,3-) Dihydro-1H-indol-5-yl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)-N-methylsulfonylamino)benzoic acid methyl ester 18a ( 230 mg, gray solid). Yield: 48.2%. MS m/z (ESI): 510.9 [M-l]
第二步  Second step
(Z)-4-(2-(l-(l-(2,3-二氢 -1 H-茚 -5-基) -2-氧代 -1,3-二氢吲哚- 3-亚基)乙基) -N-甲基肼 硫酰氨基)苯甲酸  (Z)-4-(2-(l-(l-(2,3-Dihydro-1 H-indol-5-yl)-2-oxo-1,3-dihydroindole-3-A Ethyl)ethyl-N-methylsulfonylamino)benzoic acid
将 (Z)-4- (2-(1- (1-(2,3-二氢 -1H-茚 -5-基) -2-氧代 -1,3-二氢吲哚- 3-亚基）乙基) -N- 甲基肼硫酰氨基)苯甲酸甲酯 18a(230 mg, 0.45 mmol)溶解于 2 mL甲醇中， 搅拌下 加入氢氧化钠溶液 (lN, 2 mL)， 室温下搅拌反应过夜。 TLC跟踪反应至原料消失， 用 1N盐酸调节 pH=2〜3， 过滤， 滤饼用正己垸 -乙酸乙酯重结晶， 得到标题产物 (Z)-4-(2-(l -(l-(2,3-二氢 -1H-茚 -5-基) -2-氧代 -1 ,3-二氢吲哚 -3-亚基）乙基) - N-甲基肼 硫酰氨基)苯甲酸 18(100 mg, 灰色固体)。 产率： 44.6%。  (Z)-4-(2-(1-(1-(2,3-Dihydro-1H-indol-5-yl)-2-oxo-1,3-dihydroindole-3-A) Ethyl)ethyl)-N-methylsulfonylamino)benzoic acid methyl ester 18a (230 mg, 0.45 mmol) was dissolved in 2 mL of methanol and stirred with sodium hydroxide solution (1 N, 2 mL) at room temperature The reaction was stirred overnight. TLC followed the reaction to the disappearance of the starting material, and the pH was adjusted to 2 to 3 with 1N hydrochloric acid, and filtered, and the filter cake was recrystallized from n-hexane-ethyl acetate to give the title product (Z)-4-(2-(l-(l-( 2,3-Dihydro-1H-indol-5-yl)-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)-N-methylsulfonylamino)benzoic acid 18 (100 mg, gray solid). Yield: 44.6%.
MS m/z (ESI):497.0[M-l] MS m/z (ESI): 497.0 [M-l]
Ή NMR(400M Hz, OMSO-d6): 511.44(s, 1H), 9.7 l(s, 1H), 8.04(d, 2H, J=8.8 Hz), 7.53(d, 2H, J=8.4 Hz), 7.47(m, 1H), 7.39(d, 1H, J=8.0 Hz), 7.24(s, 1H), 7.13(d, 1H, J=7.6 Hz), 7.01 (m, 2H), 6.77(m, 1H), 3.60(s, 3H)， 2.94(t, 4H, J=5.6 Hz), 2.40(s, 3H), 2.10(m, 2H) 实施例 19 NMR NMR (400 M Hz, OMSO-d 6 ): 511.44 (s, 1H), 9.7 l (s, 1H), 8.04 (d, 2H, J = 8.8 Hz), 7.53 (d, 2H, J = 8.4 Hz) , 7.47(m, 1H), 7.39(d, 1H, J=8.0 Hz), 7.24(s, 1H), 7.13(d, 1H, J=7.6 Hz), 7.01 (m, 2H), 6.77(m, 1H), 3.60(s, 3H), 2.94(t, 4H, J=5.6 Hz), 2.40(s, 3H), 2.10(m, 2H) Example 19
(2)-4-(2-(1-( -(2，3-二氢-11^-茚-5-基)-5-氟-2-氧代-1 ,3-二氢吲哚-3-亚基)乙基)^-甲 基肼硫酰氨基)苯甲酸
Figure imgf000039_0001
第一步 (2) 4-(2-(1-(2,3-Dihydro-11^-indol-5-yl)-5-fluoro-2-oxo-1,3-dihydroindole- 3-ylidene)ethyl)^-methylsulfonylamino)benzoic acid
Figure imgf000039_0001
first step
(Z)-4-(2-(l-(l-(2,3-二氢- 1H-茚 -5-基) -5-氟 -2-氧代 -1 ,3-二氢吲哚 -3-亚基)乙基) -N-甲 基肼硫酰氨基)苯甲酸甲酯  (Z)-4-(2-(l-(l-(2,3-dihydro-1H-indol-5-yl)-5-fluoro-2-oxo-1,3-dihydroindole- Methyl 3-phenyl)ethyl)-N-methylsulfonylamino)benzoate
将 (Z)小 (2,3-二氢 -1H-茚 -5-基) -5-氟 -3-(1- (二甲氨基)亚乙基 )-1,3-二氢吲哚 -2-酮 14b(270 mg,0.74 mmol) 溶解于 3 mL甲醇中， 搅拌下加入 4-(N-甲基肼硫酰氨基) 苯甲酸甲酯 10e(167 mg, 0.70 mmol)和 0.09 mL乙酸， 室温下搅拌反应过夜。 TLC 跟踪反应至原料消失， 析出大量固体， 过滤， 滤饼用甲醇洗涤 (5 mLx3)， 固体在真 空下千燥， 得到 (Z)-4-(2-(l-(l-(2，3-二氢- 1H-茚 -5-基) -5-氟 -2-氧代 -1,3-二氢吲哚- 3- 亚基)乙基) -N-甲基肼硫酰氨基)苯甲酸甲酯 19a(240 mg, 黄色固体)。产率： 64.7%。 MS m/z (ESI):528.8[M-l]  (Z) Small (2,3-dihydro-1H-indol-5-yl)-5-fluoro-3-(1-(dimethylamino)ethylidene)-1,3-dihydroindole- 2-ketone 14b (270 mg, 0.74 mmol) was dissolved in 3 mL of methanol, and then 4-(N-methylsulfonylamino)benzoic acid methyl ester 10e (167 mg, 0.70 mmol) and 0.09 mL of acetic acid were added with stirring. The reaction was stirred at room temperature overnight. TLC followed the reaction until the starting material disappeared, a large amount of solid was precipitated, filtered, and the filter cake was washed with methanol (5 mL×3), and the solid was dried under vacuum to obtain (Z)-4-(2-(l-(l-(2,3) -dihydro-1H-indol-5-yl)-5-fluoro-2-oxo-1,3-dihydroindole-3-ylideneethyl)-N-methylsulfonylamino)benzene Methyl formate 19a (240 mg, yellow solid). Yield: 64.7%. MS m/z (ESI): 528.8 [M-l]
第二步  Second step
(Z)-4- (2-(1-(1 -(2,3-二氢 -1H-茚 -5-基) -5-氟 -2-氧代 -1,3-二氢吲哚 -3-亚基)乙基) -N-甲 基肼硫酰氨基)苯甲酸  (Z)-4-(2-(1-(1 -(2,3-dihydro-1H-indol-5-yl)-5-fluoro-2-oxo-1,3-dihydroindole- 3-subphenyl)ethyl)-N-methylsulfonylamino)benzoic acid
将 (Z)-4- (2- ( (1-(2,3-二氢 -1H-茚 -5-基) -5-氟 -2-氧代 -1,3-二氢吲哚 -3-亚基）乙 基) 甲基肼硫酰氨基)苯甲酸甲酯 19a(240 mg, 0.45 mmol)溶解于 3 mL甲醇中， 搅拌下加入氢氧化钠溶液 (IN, 3 mL), 室温下搅拌反应过夜。 TLC跟踪反应至原料 消失， 用 1N盐酸调节 pH=2〜3， 过滤， 滤饼用正己烷 -乙酸乙酯重结晶， 得到标 题产物 (Z)-4-(2-(l -(l-(2,3-二氢 -1H-茚- 5-基) -5-氟 -2-氧代- 1 ,3-二氢吲哚 -3-亚基）乙 基) 甲基肼硫酰氨基)苯甲酸 19(120 mg, 黄色固体)。 产率： 51.6%。  (Z)-4-(2-((1-(2,3-Dihydro-1H-indol-5-yl)-5-fluoro-2-oxo-1,3-dihydroindole-3) -yetyl)ethyl)methyl sulfonylamino)benzoic acid methyl ester 19a (240 mg, 0.45 mmol) was dissolved in 3 mL of methanol, stirred with sodium hydroxide solution (IN, 3 mL), stirred at room temperature The reaction was overnight. TLC followed the reaction until the disappearance of the starting material, pH was adjusted to pH 2 to 3 with 1N hydrochloric acid, filtered, and the filter cake was recrystallized from n-hexane-ethyl acetate to give the title product (Z)-4-(2-(l-(l-( 2,3-Dihydro-1H-indole-5-yl)-5-fluoro-2-oxo-1,3-dihydroindole-3-ylidene)ethyl)methylsulfonylamino)benzene Formic acid 19 (120 mg, yellow solid). Yield: 51.6%.
MS m/z (ESI):514.9[M-l] MS m/z (ESI): 514.9 [M-l]
Ή NMR(400M Hz, DMSO-i 6): 511.58(s, 1H), 9.75(s, 1H), 8.04(d, 2H, .1=7.6 Hz), 7.54(d, 2H, J=8.4 Hz), 7.39(d, 1H, J=8.0 Hz), 7.29(m, 1 H), 7.24(s, 1H), 7.12(m, 1H), 6.8 l(m, 1H), 6.73(m, 1 H), 3.60(s, 3H), 2,93(t, 4H, J=7.6 Hz), 2.39(s, 3H), 2.10(m, 2H) 实施例 20 NMR NMR (400 M Hz, DMSO-i 6 ): 511.58 (s, 1H), 9.75 (s, 1H), 8.04 (d, 2H, .1 = 7.6 Hz), 7.54(d, 2H, J=8.4 Hz), 7.39(d, 1H, J=8.0 Hz), 7.29(m, 1 H), 7.24(s, 1H), 7.12(m, 1H), 6.8 l(m , 1H), 6.73 (m, 1 H), 3.60 (s, 3H), 2,93 (t, 4H, J = 7.6 Hz), 2.39 (s, 3H), 2.10 (m, 2H) Example 20
(ZV4-(N'-n-n-(3,4-二甲苯基) -3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基卜乙基 肼硫酰 氨基) -苯甲酸 ( ZV4-(N'-nn-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylideneethylsulfonylamino)-benzene Formic acid
Figure imgf000040_0001
第一歩
Figure imgf000040_0001
First
2-(3 ,4-二甲苯基) -5-甲基 -2,4-二氢吡唑 -3-酮 采用公知的方法 [Redox Report, 8(3), 151 -155; 2003] , 将 (3,4-二甲苯基)-肼盐酸 盐20a (10.36 g, 60 mmol)溶解于 150 mL乙醇中， 加热反应液至 95 °C， 搅拌下加入 乙酰乙酸乙酯 (8.58 g, 66 mmol)的 50 mL乙醇溶液， 在 90Ό下反应 2小时。 TLC跟 踪反应至原料消失， 冷却至室温， 减压下浓缩， 用硅胶色谱法纯化所得残余物， 得到 2-(3,4-二甲苯基) -5-甲基 -2,4-二氢吡唑 -3-酮 20b(6.04 g, 淡黄色固体)。 产率： 49.8%。  2-(3,4-Dimethylphenyl)-5-methyl-2,4-dihydropyrazol-3-one is carried out by a known method [Redox Report, 8(3), 151-155; 2003], (3,4-Dimethylphenyl)-hydrazine hydrochloride 20a (10.36 g, 60 mmol) was dissolved in 150 mL of ethanol. The reaction mixture was warmed to 95 ° C, and ethyl acetoacetate (8.58 g, 66 mmol) was added with stirring. The 50 mL ethanol solution was reacted at 90 Torr for 2 hours. The reaction was quenched by TLC until the title material disappeared, cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel chromatography to give 2-(3,4-dimethylphenyl)-5-methyl-2,4-dihydropyridin. Zylin-3-one 20b (6.04 g, pale yellow solid). Yield: 49.8%.
MS m/z (ESI):203[M+l]  MS m/z (ESI): 203 [M+l]
第二歩  Second
(Z)-4-(l -二甲氨基亚乙基 )-2-(3,4-二甲苯基 )-5-甲基 -2,4-二氢吡唑 -3-酮 将 (1,1-二甲氧基乙基) -二甲胺 (2.37 g, 17.8 mmol)溶解于 40 mL氯仿中， 搅拌下 加入 2-(3,4-二甲苯基) -5-甲基 -2,4-二氢吡唑 -3-酮 20b (1.8 g, 8.9 mmol)，加热回流 0.5 小时。 TLC 跟踪反应至原料消失， 减压下浓缩反应液， 用硅胶色谱法纯化所得残 留物， 得到 (Z)-4-(l-二甲氨基亚乙基) -2-(3,4-二甲苯基) -5-甲基 -2,4-二氢吡唑 -3-酮 20c(2.0 g, 黄色固体)。 产率： 83.3%。 MS m/z (ESI):272[M+l] (Z)-4-(l-dimethylaminoethylidene)-2-(3,4-dimethylphenyl)-5-methyl-2,4-dihydropyrazol-3-one (1, 1-Dimethoxyethyl)-dimethylamine (2.37 g, 17.8 mmol) was dissolved in 40 mL of chloroform, and 2-(3,4-dimethylphenyl)-5-methyl-2,4 was added with stirring. -Dihydropyrazol-3-one 20b (1.8 g, 8.9 mmol), heated to reflux for 0.5 h. The reaction was traced to the disappearance of the material by TLC, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford (Z)-4-(1-dimethylaminoethylidene)-2-(3,4-xylene -5-Methyl-2,4-dihydropyrazol-3-one 20c (2.0 g, yellow solid). Yield: 83.3%. MS m/z (ESI): 272 [M+l]
1 H NMR(400M Hz, CDC13): δ 1 1.39(br, 1H ),10.35(br,lH ),10.6(br, 1 H),8 · 16(s, 1 H), 7.82(d,lH,J=8.4 Hz), 7.75(d,l H, J=7.6 Hz),7.63(m,2H),7.57(m,2H), 7.53(d,lH, J=7.6 Hz),7.13(m,3H),6.68(t,lH, J=4.8 Hz),3.42(s, 3H),2.38(s,6H) 1 H NMR (400 M Hz, CDC1 3 ): δ 1 1.39 (br, 1H ), 10.35 (br, lH ), 10.6 (br, 1 H), 8 · 16 (s, 1 H), 7.82 (d, lH) , J = 8.4 Hz), 7.75 (d, l H, J = 7.6 Hz), 7.63 (m, 2H), 7.57 (m, 2H), 7.53 (d, lH, J = 7.6 Hz), 7.13 (m, 3H), 6.68 (t, lH, J = 4.8 Hz), 3.42 (s, 3H), 2.38 (s, 6H)
第三步  third step
4-肼硫酰氨基 -苯甲酸甲酯  4-sulfonylamino-benzoic acid methyl ester
将 4-异硫氰酸酯基苯甲酸甲酯 20d (4 g, 19.3 mmol)溶解于 50 mL乙醇中， 加 入 50%水合肼溶液 (3.86 mL, 38.6 mmol), 80°C反应 30分钟。 TLC跟踪反应至原料 消失， 将反应液冷却至室温， 过滤， 滤饼用乙醇洗涤 (5 mL), 真空下干燥， 得到 4- (肼硫酰氨基)苯甲酸甲酯 20e (4.0 g, 白色固体)。 产率： 86.9%。  Methyl 4-isothiocyanate benzoate 20d (4 g, 19.3 mmol) was dissolved in 50 mL of ethanol, and a 50% hydrazine hydrate solution (3.86 mL, 38.6 mmol) was added and reacted at 80 ° C for 30 minutes. The reaction was quenched by TLC until the title material disappeared. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethanol (5 mL) and dried under vacuum to give methyl 4-(sulfonylamino)benzoate 20e (4.0 g, white solid ). Yield: 86.9%.
MS m/z (ESI):240[M+1] MS m/z (ESI): 240 [M+1]
Ή NMR(400M Hz, CD3OD): 68.10(d,2H,J=6.8 Hz),7.37(d,2H, J=6.4 Hz), 3.577(s,3H) 第四步  NMR NMR (400M Hz, CD3OD): 68.10 (d, 2H, J = 6.8 Hz), 7.37 (d, 2H, J = 6.4 Hz), 3.577 (s, 3H)
(Ζ)_4_(Ν'— { 1-[1-(3,4-二甲苯基) -3-甲基 -5-氧代- 1,5-二氢吡唑 -4-亚基] -乙基 }-肼硫酰 氨基) -苯甲酸甲酯 (Ζ) _ 4 _(Ν'- { 1-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene] -ethyl}-sulfonylamino)-methyl benzoate
将 (Z)-4-(l -二甲氨基亚乙基 )-2- (3,4-二甲苯基 )-5-甲基 -2,4-二氢吡唑 -3-酮 20c(210 mg, 0.77 mmol)溶解于 15 mL无水乙醇中，搅拌下加入 4- (肼硫酰氨基)苯甲 酸甲酯 20e (220 mg, 0.92 mmol)和 1 mL乙酸， 加热回流 45分钟。 TLC跟踪反应 至原料消失， 趁热过滤， 固体在真空下干燥， 得到 (Z)- 4-(Ν'-{ 1-[1- (3,4-二甲苯基) -3- 甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基] -乙基 }-肼硫酰氨基) -苯甲酸甲酯 20f (300 mg, 黄 色固体)。 产率： 85.5%。  (Z)-4-(l-Dimethylaminoethylidene)-2-(3,4-dimethylphenyl)-5-methyl-2,4-dihydropyrazol-3-one 20c (210 The mg, 0.77 mmol) was dissolved in 15 mL of absolute ethanol, and methyl 4-(sulfonylamino)benzoate 20e (220 mg, 0.92 mmol) and 1 mL of acetic acid were added with stirring, and the mixture was heated to reflux for 45 min. The reaction was traced by TLC until the starting material disappeared. The mixture was filtered while hot, and the solid was dried under vacuum to give (Z)- 4-(1-(3,4-dimethylphenyl)-3-methyl-5 -Oxo-1,5-dihydropyrazole-4-ylidene]-ethyl}-sulfonylamino)-benzoic acid methyl ester 20f (300 mg, yellow solid). Yield: 85.5%.
MS m/z (ESI):466[M+l] MS m/z (ESI): 466 [M+l]
'H NMR(400M Hz,DMSO- 6): 6110.38(br,2H),7.90(d,2H, J=7.6 Hz), 7.8 l(t, 3H, J=8.0 Hz),7.51 (d, 1 H, J=7.2 Hz),7.14(d, 1 H, J=8.4 Hz),4.35(q,2H),2.55(s,3H),2.41 (s,3H) 2.33(s,3H), 2.21(s, 3H), 1.31 (q,3H) 'H NMR (400 M Hz, DMSO- 6 ): 6110.38 (br, 2H), 7.90 (d, 2H, J = 7.6 Hz), 7.8 l (t, 3H, J = 8.0 Hz), 7.51 (d, 1 H , J = 7.2 Hz), 7.14 (d, 1 H, J = 8.4 Hz), 4.35 (q, 2H), 2.55 (s, 3H), 2.41 (s, 3H) 2.33 (s, 3H), 2.21 (s , 3H), 1.31 (q, 3H)
第五歩  Fifth
(Z)-4— (N'-{ 1— [l-(3,4-二甲苯基) -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基] -乙基 }-肼硫酰 氨基) -苯甲酸 (Z )- 4 — (N'-{ 1 - [l-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene] -ethyl}-sulfonylamino)-benzoic acid
将 (Ζ)-4-(Ν'-{ 1 -[1-(3,4-二甲苯基) -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基] -乙基 } -肼 硫酰氨基) -苯甲酸甲酯 20f (280 mg, 0.6 mmol)溶解于 15 mL乙醇中，搅拌下加入氢 氧化钠溶液(lN，2.4 mL )， 加热回流 3小时。 TLC跟踪反应至原料消失， 过滤， 滤 液用盐酸 (lN, 3 mL)调节 pH=3， 搅拌 30分钟， 静置， 过滤， 固体依次用二氯甲烷 洗涤 (10 mLx3)，正己垸洗涤 (15 mLx3),干燥，得到 (Z)-4-(N'-{ 1-[1-(3,4-二甲苯基) -3- 甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基] -乙基 } -肼硫酰氨基)-苯甲酸 20(100 mg, 黄色固 体)。 产率： 38.2%。  (Ζ)-4-(Ν'-{ 1 -[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene ]-Ethyl}-sulfonylamino)-benzoic acid methyl ester 20f (280 mg, 0.6 mmol) was dissolved in 15 mL of ethanol, and sodium hydroxide solution (1N, 2.4 mL) was added under stirring, and the mixture was heated to reflux for 3 hours. TLC followed the reaction until the disappearance of the starting material, filtration, the filtrate was adjusted to pH = 3 with hydrochloric acid (1N, 3 mL), stirred for 30 min, allowed to stand, filtered, and the solid was washed with dichloromethane (10 mL×3) and washed with hexane (15 mL×3) ), dried to give (Z)-4-(N'-{ 1-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazole- 4-Subphenyl]-ethyl}-guanidinoylamino)-benzoic acid 20 (100 mg, yellow solid). Yield: 38.2%.
MS m/z (ESI):438[M+l]  MS m/z (ESI): 438 [M+l]
'H NMR(400M HZ, DMSO-i 6): 610.63(br, 2H),7.91 (d,2H,J=8.8 Hz),7.75(m,3H), 7.67(d,lH, J=8.0 Hz),7.15(d,lH, J=8.4 Hz),2.54(s, 3H),2.41(s, 3H),2.21(s,6H) 实施例 21 'H NMR (400M HZ, DMSO-i 6 ): 610.63 (br, 2H), 7.91 (d, 2H, J = 8.8 Hz), 7.75 (m, 3H), 7.67 (d, lH, J = 8.0 Hz), 7.15 (d, lH, J = 8.4 Hz), 2.54 (s, 3H), 2.41 (s, 3H), 2.21 (s, 6H) Example 21
(Z 4— {N'-「1-(1-茚满 -5-基 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -乙基 肼硫酰氨 (Z 4 — { N'-"1-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-ethyl sulfonium Amide
基 苯甲酸  Benzoic acid
Figure imgf000042_0001
第一歩
Figure imgf000042_0001
First
5-肼基茚满盐酸盐  5-mercaptopurine hydrochloride
冰水浴下将 5-氨基茚满 21a (6 g, 45 mmol)溶解于盐酸 (2N,50 mL)中， 搅拌下滴 加 15 mL亚硝酸钠溶液 (3.4 g, 50 mmol), 搅拌 30分钟。 冰盐浴下将二水合氯化亚 锡 (30.6 g, 135 mmol)溶解于 20 mL浓盐酸中，加入到上述溶液中，室温反应 1小时。 用氢氧化钠溶液 (3N, 30 mL)调节 pH=10， 加入 30 mL乙酸乙酯， 用硅胶过滤， 滤 液用乙酸乙酯萃取 (20 mLx3)， 合并有机相依次用无水硫酸钠干燥， 过滤， 减压下 浓缩溶液至 400 mL， 加入氯化氢乙酸乙酯溶液 (6.6N, 7 mL)， 析出固体， 过滤， 固 体在真空下干燥， 得到 5-肼基茚满盐酸盐 21b(1.24 g, 灰色固体)。 产率： 14.9%。  5-Aminoindan 21a (6 g, 45 mmol) was dissolved in hydrochloric acid (2N, 50 mL) under ice-water bath, and 15 mL of sodium nitrite solution (3.4 g, 50 mmol) was added dropwise with stirring, and stirred for 30 minutes. In a ice salt bath, stannous chloride dihydrate (30.6 g, 135 mmol) was dissolved in 20 mL of concentrated hydrochloric acid, and added to the above solution, and reacted at room temperature for 1 hour. The pH was adjusted to 10 with sodium hydroxide solution (3N, 30 mL), EtOAc (EtOAc)EtOAc. The solution was concentrated to 400 mL under reduced pressure. EtOAc (EtOAc, EtOAc (EtOAc) Gray solid). Yield: 14.9%.
第二步  Second step
2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮  2-indan-5-yl-5-methyl-2,4-dihydropyrazole-3-one
将 5-肼基茚满盐酸盐 21b (1.5 g, 8.2 mmol)溶解于 25 mL乙酸中， 在 70°C下滴 加乙酰乙酸乙酯 (1.06 g, 8.2 mmol)的 8 mL乙酸溶液， 反应 30分钟。 TLC跟踪反应 至原料消失， 冷却至室温， 减压下浓缩， 用硅胶色谱法纯化所得残留物， 得到 2- 茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 21c(0.35 g, 褐色固体)。 产率： 20.1%。  Dissolve 5-mercaptopurine hydrochloride 21b (1.5 g, 8.2 mmol) in 25 mL of acetic acid, and add ethyl acetoacetate (1.06 g, 8.2 mmol) in 8 mL of acetic acid at 70 ° C. 30 minutes. The reaction was quenched by TLC until the title material disappeared, cooled to room temperature, concentrated under reduced pressure, and the residue obtained was purified by silica gel chromatography to give 2-indane-5-yl-5-methyl-2,4-dihydropyrazole-3 - Ketone 21c (0.35 g, brown solid). Yield: 20.1%.
MS m/z (ESI):215[M+l] MS m/z (ESI): 215 [M+l]
'H NMR(400M HZ, CDC13): δ 7.70(s,lH),7.59-7.61(d,lH,J=8 Hz),7.24-7.26(d,J=8 Hz, lH),3.44(s,2H),2.90-2.97(m,4H),2.21(s,3H),2.07-2.14(m,2H) 'H NMR (400M HZ, CDC1 3 ): δ 7.70 (s, lH), 7.59-7.61 (d, lH, J = 8 Hz), 7.24 - 7.26 (d, J = 8 Hz, lH), 3.44 (s , 2H), 2.90-2.97 (m, 4H), 2.21 (s, 3H), 2.07-2.14 (m, 2H)
第三步  third step
(Z)-4- ( 二甲氨基亚乙基 )-2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 将 2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 21c (300 mg, 1.4 mmol)溶解于 20 mL 氯仿中， 搅拌下加入 (1,1-二甲氧基乙基)-二甲胺 (373 mg， 2.8 mmol)， 加热回流 45 分钟。 TLC 跟踪反应至原料消失， 减压下浓缩反应液， 用硅胶色谱法纯化所得残 留物， 得到 (Z)-4-(l -二甲氨基亚乙基 )-2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 21d(308 mg, 黄色固体)。 产率： 77.8%。 (Z)-4-(dimethylaminoethylidene)-2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 2-indan-5-yl -5-Methyl-2,4-dihydropyrazol-3-one 21c (300 mg, 1.4 mmol) dissolved in 20 mL In chloroform, (1,1-dimethoxyethyl)-dimethylamine (373 mg, 2.8 mmol) was added under stirring, and the mixture was heated to reflux for 45 min. The reaction was traced to the disappearance of the material by TLC, and the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography to afford (Z)-4-(l-dimethylaminoethylidene)-2-indan-5-yl- 5-Methyl-2,4-dihydropyrazol-3-one 21d (308 mg, yellow solid). Yield: 77.8%.
MS m/z (ESI):284[M+l] MS m/z (ESI): 284 [M+l]
Ή NMR(400M Hz, CDC13): 67.86(s,lH), 7.77(dd,lH, J, =8.4 Hz, J2=2.0 Hz), NMR NMR (400 M Hz, CDC1 3 ): 67.86 (s, lH), 7.77 (dd, lH, J, = 8.4 Hz, J 2 = 2.0 Hz),
7.23(d,lH, J=8.4 Hz),3.43(s,6H),2.93(m,4H),2.50(s,3H),2.36(s,3H),2.16 (m,2H) 7.23 (d, lH, J = 8.4 Hz), 3.43 (s, 6H), 2.93 (m, 4H), 2.50 (s, 3H), 2.36 (s, 3H), 2.16 (m, 2H)
第四步  the fourth step
(Z)-4-{N'-[l- (1-茚满 -5-基 -3-甲基 -5-氧代 -1，5-二氢吡唑 -4-亚基) -乙基] -肼硫酰氨基 } - 苯甲酸甲酯  (Z)-4-{N'-[l-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-ethyl ] - sulfoximine amino group - methyl benzoate
将 (Z)-4-(l-二甲氨基亚乙基) -2-茚满 -5-基 -5-甲基- 2,4-二氢吡唑 -3-酮 21d (300 mg, 1.06 mmol)溶解于 20 mL无水乙醇中， 搅拌下加入 4- (肼硫酰氨基)苯甲酸甲酯 20e (253 mg, 1.06 mmQl)和 1 mL乙酸， 加热回流 1小时。 TLC跟踪反应至原料消 失， 将反应液冷却至室温， 过滤， 滤饼用乙醇洗涤 (5 mLx3), 真空下干燥， 得到 (Ζ)-4-{Ν'- [1-(1-茚满 -5-基 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -乙基] -肼硫酰氨基 } - 苯甲酸甲酯 21e (324 mg, 淡黄色固体)。 产率： 64.0%。  (Z)-4-(l-Dimethylaminoethylidene)-2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 21d (300 mg, 1.06 Methyl acetate was dissolved in 20 mL of absolute ethanol, and methyl 4-(decylsulfonyl)benzoate 20e (253 mg, 1.06 mm Ql) and 1 mL of acetic acid were added with stirring, and the mixture was heated to reflux for 1 hour. TLC followed the reaction until the disappearance of the starting material, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with ethanol (5 mL×3) and dried under vacuum to give (Ζ)-4-{Ν'- [1-(1-茚满- 5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-ethyl]-sulfonylamino}-benzoic acid methyl ester 21e (324 mg, light yellow solid). Yield: 64.0%.
MS m/z (ESI):476[M-l] MS m/z (ESI): 476 [M-l]
'H NMR(400M HZ, OMSO-d6): 510.38(br, 1H), 10.34(br, 1H), 7.93(d,2H, J=8.8 Hz), 7.78(m,3H), 7.70(d,lH, J=8.8 Hz), 7.24(d,lH, J=8.0 Hz),l 2.87(m,4H), 2.46(s, 3H) 2.38(s, 3H) 2.06(m, 2H) 1.34(s, 3H) 'H NMR (400M HZ, OMSO-d 6 ): 510.38 (br, 1H), 10.34 (br, 1H), 7.93 (d, 2H, J = 8.8 Hz), 7.78 (m, 3H), 7.70 (d, lH, J=8.8 Hz), 7.24(d,lH, J=8.0 Hz), l 2.87(m,4H), 2.46(s, 3H) 2.38(s, 3H) 2.06(m, 2H) 1.34(s, 3H)
第五步  the fifth step
(Z)-4-{N'-[l-(l-茚满 -5-基 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基)-乙基] -肼硫酰氨基 苯甲酸  (Z)-4-{N'-[l-(l-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-ethyl - thiolaminobenzoic acid
将 (Ζ)-4-{Ν'-[1 -(1-茚满 -5-基- 3-甲基 -5-氧代 -1，5-二氢吡唑 -4-亚基) -乙基]-肼硫酰 氨基}-苯甲酸甲酯21e (300 mg, 0.63 mmol；)溶解于 15 mL乙醇中， 搅拌下加入氢氧 化钠溶液(l N, 2.5 rnL )， 加热回流 1.5小时。 TLC跟踪反应至原料消失， 过滤， 滤 液用盐酸 (1 N, 4 mL)调节 pH=3， 过滤， 固体倒入 15 mL二氯甲垸和甲醇 (5:1)的混 和溶剂中， 过滤， 固体在真空下干燥， 得到标题产物 (Ζ)-4-{Ν'-[1-(1-茚满 -5-基- 3- 甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -乙基] -肼硫酰氨基 }-苯甲酸 21 (107 mg, 淡黄色 固体)。 产率： 37.8%。  (Ζ)-4-{Ν'-[1 -(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-B Methyl]-hydrazinylamino}-methyl benzoate 21e (300 mg, 0.63 mmol;) was dissolved in 15 mL of ethanol, and sodium hydroxide solution (1 N, 2.5 rnL) was added with stirring, and the mixture was heated to reflux for 1.5 hours. TLC followed the reaction until the disappearance of the starting material, filtration, the filtrate was adjusted to pH=3 with hydrochloric acid (1 N, 4 mL), filtered, and poured into 15 mL of mixed solvent of dichloromethane and methanol (5:1), filtered, solid Drying under vacuum gave the title product (Ζ)-4-{Ν'-[1-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydropyrazole- 4-Subphenyl)-ethyl]-guanidinoylamino}-benzoic acid 21 (107 mg, pale yellow solid). Yield: 37.8%.
MS rn/z (ESI):450[M+1] MS rn/z (ESI): 450 [M+1]
Ή NMR(400M Hz, OMSO-d6): 612.63(br,2H), 10.37(br,2H), 8.19(d,2H, J=8.8 Hz) 7.80(s, H), 7.73(m,3H), 7.23(d,lH, J=8.4 Hz), 2.87(m,4H), 2.25(s,3H), 2.40(s, 3H), 2.04(m, 2H) 实施例 22 NMR NMR (400M Hz, OMSO-d 6 ): 612.63 (br, 2H), 10.37 (br, 2H), 8.19 (d, 2H, J = 8.8 Hz) 7.80 (s, H), 7.73 (m, 3H) , 7.23 (d, lH, J = 8.4 Hz), 2.87 (m, 4H), 2.25 (s, 3H), 2.40 (s, 3H), 2.04 (m, 2H) Example 22
(Ζ)-4-(Ν'-{ 1-「1-(3,4-二甲苯基) -3-甲基 -5-氧代- 1,5-二氢吡唑 -4-亚基 1-乙基 }-肼硫酰 甲氨基) -苯甲酸 (Ζ) - 4 -(Ν'-{ 1-"1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene 1 -ethyl}-sulfonyl Methylamino)-benzoic acid
Figure imgf000044_0001
Figure imgf000044_0001
第一步  First step
(Ζ)-4-(Ν'-{1-[1-(3，4-二甲苯基) -3-甲基 -5-氧代 -1，5-二氢吡唑 -4-亚基] -乙基 } -肼硫酰 甲氨基) -苯甲酸甲酯  (Ζ)-4-(Ν'-{1-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene] -ethyl}-sulfonylmethylamino)-methyl benzoate
将 (Z)-4- ( 二甲氨基亚乙基 )-2- (3,4-二甲苯基) -5-甲基 -2,4-二氫吡唑 -3-酮 20c (300 mg, 1.1 mmol)溶解于 20 mL甲醇中， 搅拌下加入 4-(N-甲基肼硫酰氨基；)苯甲 酸甲酯 10e (265 mg, 1.1 mmol)和 1 mL乙酸， 加热回流反应 1.5小时。 TLC跟踪 反应至原料消失， 将反应液冷却至室温， 过滤， 滤饼用乙醇洗涤 (5 mLx2)， 真空下 千燥， 得到 (Z)-4- (N'-{ 1-[1-(3，4-二甲苯基) -3-甲基- 5-氧代 -1,5-二氢吡唑 -4-亚基] -乙 基} -肼硫酰甲氨基) -苯甲酸甲酯 22a(381 mg, 黄色固体)。 产率： 74.4%。  (Z)-4-(Dimethylaminoethylidene)-2-(3,4-dimethylphenyl)-5-methyl-2,4-dihydropyrazol-3-one 20c (300 mg, 1.1 mmol) was dissolved in 20 mL of methanol, and 4-(N-methylsulfonylaminoamide;) methyl benzoate 10e (265 mg, 1.1 mmol) and 1 mL of acetic acid were added with stirring, and the mixture was heated and refluxed for 1.5 hours. TLC followed the reaction until the starting material disappeared. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with ethanol (5 mL×2) and dried under vacuum to give (Z)-4-(N'-{ 1-[1-(3 , 4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-ethyl}-sulfonylmethylamino)-benzoic acid methyl ester 22a ( 381 mg, yellow solid). Yield: 74.4%.
MS m/z (ESI):466[M+1] MS m/z (ESI): 466 [M+1]
第二步  Second step
(Z)-4— (Ν'-μ-[1-(3,4-二甲苯基) -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基] -乙基 } -肼硫酰 甲氨基) -苯甲酸 (Z) - 4 - (Ν'-μ-[1-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene] - Ethyl}-sulfonylmethylamino)-benzoic acid
将 (Z)-4-(N'- -[l-(3,4-二甲苯基) -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基] -乙基 } -肼 硫酰甲氨基) -苯甲酸甲酯 22a (300 mg, 0.64 mmol)溶解于 20 mL甲醇中， 搅拌下加 入氢氧化钠溶液 (1N, 3.5 mL)， 加热回流反应 2小时。 TLC跟踪反应至原料消失， 将反应液冷却至室温， 过滤， 滤液在冰浴下用盐酸 (1N, 5 mL)调节 pH=3 , 过滤， 滤饼倒入 20 mL二氯甲垸和甲醇 (5:1)的混和溶剂中， 搅拌， 过滤， 滤饼用二氯甲 烷洗涤 (2 mLx3), 干燥， 得到标题产物 (Ζ)-4-(Ν'-{ 1-[1-(3,4-二甲苯基) -3-甲基- 5-氧 代 -1,5-二氢吡唑 -4-亚基] -乙基 肼硫酰甲氨基)-苯甲酸 22(120 mg, 淡黄色固体)。产 率： 19.1%。  (Z)-4-(N'--[l-(3,4-Dimethylphenyl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene] - Ethyl}-sulfonylmethylamino)-benzoic acid methyl ester 22a (300 mg, 0.64 mmol) was dissolved in 20 mL of methanol, and sodium hydroxide solution (1N, 3.5 mL) was added under stirring, and the mixture was heated and refluxed for 2 hours. TLC followed the reaction until the disappearance of the starting material, the reaction solution was cooled to room temperature, filtered, and the filtrate was adjusted to pH = 3 with hydrochloric acid (1 N, 5 mL) in an ice bath, filtered, and the filter cake was poured into 20 mL of dichloromethane and methanol. :1) In a mixed solvent, stirred, filtered, and the filter cake was washed with dichloromethane (2 mL×3) and dried to give the title product (Ζ)-4-(Ν'-{ 1-[1-(3,4- Xylyl)-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene]-ethylsulfonylmethylamino)-benzoic acid 22 (120 mg, pale yellow solid) . Yield: 19.1%.
MS m/z (ESI):450[M-l] Ή NMR(400M Hz, OMSO-d6): S8.03(d,2H, J=8.4 Hz), 57.74(s,lH ), 67.68(d,lH, J=8.0 Hz), 57.54(d, 2H, J=8.0 Hz), 67.13(d,lH, J=8.4 Hz),53.59(s, 3H) 52.32(s, 6H) 52.22(s, 6H) MS m/z (ESI): 450 [Ml] NMR NMR (400M Hz, OMSO-d 6 ): S8.03 (d, 2H, J = 8.4 Hz), 57.74 (s, lH ), 67.68 (d, lH, J = 8.0 Hz), 57.54 (d, 2H , J=8.0 Hz), 67.13 (d, lH, J=8.4 Hz), 53.59(s, 3H) 52.32(s, 6H) 52.22(s, 6H)
实施例 23  Example 23
iZV4-{N'-ri-(l-茚满 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -乙基 1-肼硫酰甲氨基 苯 i Z V4-{N'-ri-(l-indan-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-ethyl 1-indolesulfonylamino benzene
Figure imgf000045_0001
Figure imgf000045_0001
23 第一步  23 first step
(Ζ)-4-{Ν'-[1 -(1-茚满 -3-甲基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基) -乙基] -肼硫酰甲氨基} -苯 甲酸甲酯 ( Ζ )-4-{Ν'-[1 -(1-indan-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-ethyl]-indole sulfur Acylmethylamino}-benzoic acid methyl ester
将 (Z)-4-(l-二甲氨基亚乙基) -2-茚满 -5-基 -5-甲基 -2,4-二氢吡唑 -3-酮 21d (418 mg, 1.153 mmol)和 4-(N-甲基肼硫酰氨基)苯甲酸甲酯 10e(281 mg, 1.048 mmol)溶解 于 10 mL无水乙醇中， 室温反应 3小时。 TLC跟踪反应至原料消失， 过滤， 滤饼 用乙醇 (5 mL)洗涤， 正己垸洗涤 (5 mLx2)， 干燥， 得到 (Z)-4- {N'-[l-(l -茚满 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -乙基]-肼硫酰甲氨基 } -苯甲酸甲酯 23a(468 mg, 黄色 固体)。 产率： 93.6%。  (Z)-4-(l-Dimethylaminoethylidene)-2-indan-5-yl-5-methyl-2,4-dihydropyrazol-3-one 21d (418 mg, 1.153 Methyl) 4-(N-methylsulfonylamino)benzoic acid methyl ester 10e (281 mg, 1.048 mmol) was dissolved in 10 mL of anhydrous ethanol and allowed to react at room temperature for 3 hours. TLC followed the reaction until the disappearance of the starting material, filtration, the filter cake was washed with ethanol (5 mL), washed with hexane (5 mL×2) and dried to give (Z)-4-{N'-[l-(l-茚满-3 -Methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-ethyl]-phosphonomethylamino}-benzoic acid methyl ester 23a (468 mg, yellow solid). Yield: 93.6%.
MS m/z (ESI):476[M-l] MS m/z (ESI): 476 [M-l]
第二步  Second step
(Ζ)-4-{Ν'-[1-(1-茚满 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基) -乙基]-肼硫酰甲氨基 } -苯 甲酸  (Ζ)-4-{Ν'-[1-(1-indan-3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-ethyl]-indole sulfur Acylmethylamino}-benzoic acid
将 (Ζ)-4-{Ν'-[1-(1-茚满 -3-甲基 -5-氧代 -1,5-二氢吡唑 -4-亚基)-乙基] -肼硫酰甲氨 基) -苯甲酸甲酯 23a (388 mg, 0.81 mmol)溶解于 3.5 mL甲醇中，加入氢氧化钠溶液 (1N,3.5 mL), 室温反应 3小时。 TLC跟踪反应至原料消失， 用 1N盐酸调节 pH=5， 过滤， 滤饼用正己垸洗涤 (5 mLx2)， 干燥， 得到标题产物 (Ζ)-4-{Ν'-[1 -(1-茚满- 3-甲 基 -5-氧代 -1 ,5-二氢吡唑 -4-亚基)-乙基] -肼硫酰甲氨基 苯甲酸 23(120 mg, 黄色固 体)。 产率： 31.8%。 (Ζ)-4-{Ν'-[1-(1-indan-3-methyl-5-oxo-1,5-dihydropyrazol-4-ylidene)-ethyl]-oxime Sulfurylmethylamino)-benzoic acid methyl ester 23a (388 mg, 0.81 mmol) was dissolved in 3.5 mL of methanol, and then sodium hydroxide solution (1 N, 3.5 mL) was added and allowed to react at room temperature for 3 hours. TLC followed the reaction until the disappearance of the starting material, pH = 5 was adjusted with 1N hydrochloric acid, filtered, and the filter cake was washed with n-hexane (5 mL×2) and dried to give the title product (Ζ)-4-{Ν'-[1 -(1-茚3-(3-methyl-5-oxo-1,5-dihydropyrazole-4-ylidene)-ethyl]-indolesulfonylaminobenzoic acid 23 (120 mg, yellow solid Body). Yield: 31.8%.
MS m/z (ESI):462[M-l] MS m/z (ESI): 462 [M-l]
Ή NMR(400M Hz,DMSO- : 612.41(br,lH), 9.88(br,lH), 8.03(d,2H, J=8.4 Hz), 7.81(s,lH), 7.72(d,lH, J=8.4 Hz), 7.54(d,2H, J=8.4 Hz), 7.21(d,lH, J=8.4 Hz), 3.59(s,3H,), 2.90~2.82(m, 4H), 2.32(s, 3H), 2.27(s, 3H), 2.07~2.00(m, 2H) 测试例：  NMR NMR (400 M Hz, DMSO-: 612.41 (br, lH), 9.88 (br, lH), 8.03 (d, 2H, J = 8.4 Hz), 7.81 (s, lH), 7.72 (d, lH, J = 8.4 Hz), 7.54 (d, 2H, J = 8.4 Hz), 7.21 (d, lH, J = 8.4 Hz), 3.59 (s, 3H,), 2.90~2.82 (m, 4H), 2.32 (s, 3H) ), 2.27(s, 3H), 2.07~2.00(m, 2H) Test example:
生物学评价  Biological evaluation
测试例 1 Test example 1
TPO系列化合物对 32D-Mpl细胞中 STAT3的激活作用  Activation of STAT3 in 32D-Mpl cells by TPO series compounds
1. 摘要  Summary
观察 TPO系列化合物 (实施例 7)对体外培养的已转染 TPO受体 Mpl的 32D-Mpl小 鼠前淋巴 B细胞中 STAT3的激活作用。 用不同浓度的实施例 7化合物以及 TPO- EoA 处理细胞后， 用 Western blot方法评价并比较其作用大小。 实验发现实施例 7的活 性与 TPO-EoA相当。  The TPO series of compounds (Example 7) was observed for activation of STAT3 in 32D-Mpl mouse prolymphocytes B cells transfected with TPO receptor Mpl in vitro. After treatment of the cells with different concentrations of the compound of Example 7 and TPO-EoA, the effect was evaluated by Western blot. It was found by experiment that the activity of Example 7 is comparable to that of TPO-EoA.
2. 试验目的：  2. Test purpose:
评价 TPO系列化合物实施例 7对 32D-Mpl细胞中 STAT3的激活作用大小。 The magnitude of activation of STAT3 in 32D-Mpl cells by TPO series compound Example 7 was evaluated.
3. 试验试剂、 药物及仪器： 3. Test reagents, drugs and instruments:
RPMI-1640购自 Gibco BRL公司； 胎牛血清购自 Hyclone公司； 抗 STAT3磷酸化 抗体购自 Cell signaling公司； 抗兔 lgG二抗， 硝酸纤维素膜， 以及 ECL检测试剂盒 购自 Amershan公司； 其他试剂购自 Sigma公司  RPMI-1640 was purchased from Gibco BRL; fetal bovine serum was purchased from Hyclone; anti-STAT3 phosphorylated antibody was purchased from Cell signaling; anti-rabbit lgG secondary antibody, nitrocellulose membrane, and ECL detection kit were purchased from Amershan; Reagents were purchased from Sigma
4. 试验方法：  4. Test method:
32D-Mpl细胞用实施例 7化合物处理， 然后， 收集并裂解细胞， 定蛋白到相同 的量。 蛋白变性后， 进行 SDS-PAGE, 转移到硝酸纤维素膜， 分别与抗 STAT3磷酸 化抗体 (一抗 抗兔 IgG抗体 (二抗)杂交， 最后用 ECL试剂盒检测， X光片曝光。 根 据相应蛋白条带的大小及密度， 评价实施例 7化合物对 STAT3的激活程度。  The 32D-Mpl cells were treated with the compound of Example 7, and then, the cells were collected and lysed, and the proteins were fixed to the same amount. After denaturation of the protein, SDS-PAGE was performed, transferred to a nitrocellulose membrane, and hybridized with an anti-STAT3 phosphorylated antibody (an anti-rabbit IgG antibody (secondary antibody), and finally detected by an ECL kit, and the X-ray film was exposed. The size and density of the protein bands were evaluated for the degree of activation of STAT3 by the compound of Example 7.
5. 结果：  5. Results:
化合物 TPO活性 EC5()值
Figure imgf000046_0001
测试例 2 Compound TPO activity EC 5 () value
Figure imgf000046_0001
Test example 2
TPO系列化合物对 BAF3-TPOR细胞的增殖作用  Proliferation of BAF3-TPOR cells by TPO series compounds
1. 材料和方法： 1. Materials and methods:
a. RPM1 Medium 1640,Powder,10* lL, 含 HEPES (Gibco Catalog no.23400021) b. FBS胎牛血清 ( Gibco Catalog no.10099-141 ) a. RPM1 Medium 1640, Powder, 10* lL, with HEPES (Gibco Catalog no.23400021) b. FBS fetal bovine serum ( Gibco Catalog no.10099-141 )
c. PENICILLIN STREPTOMYCIN SOL ( Gibco Catalog no. 15140-122 ) c. PENICILLIN STREPTOMYCIN SOL ( Gibco Catalog no. 15140-122 )
d. Geneticin(G418) ( Gibco Catalog no.11811 -098 ) d. Geneticin(G418) ( Gibco Catalog no.11811 -098 )
e. recombinant mouse 1L-3 ( chemicon Catalog no.ILOl 5 ) e. recombinant mouse 1L-3 ( chemicon Catalog no.ILOl 5 )
f. Huma Thrombopoietin R Mab (TPO ) (R&D Catalog no.MAB1016 ) f. Huma Thrombopoietin R Mab (TPO) (R&D Catalog no.MAB1016 )
g. DMSO (AppliChem Catalog no.A3672 ) g. DMSO (AppliChem Catalog no.A3672 )
h. QuikChange® Multi Site Directed Mutagenesis Kit, 10 Runs (Stratagene ST200515) i. Cell Counting Kit-8 (同仁化学研究所 Catalog no.CK04-13 ) h. QuikChange® Multi Site Directed Mutagenesis Kit, 10 Runs (Stratagene ST200515) i. Cell Counting Kit-8 (Tongren Institute of Chemistry Catalog no.CK04-13 )
J, Ba/F3细胞 (协和细胞库 Catalog no.0095) J, Ba/F3 cells (Concord Cell Bank Catalog no.0095)
k. EX-EGFP-M02 (FulenGen Catalog no. EX-EGFP-M02 Control) k. EX-EGFP-M02 (FulenGen Catalog no. EX-EGFP-M02 Control)
1. EX-B0010-M02 (FulenGen Catalog no. EX-B0010-M02)  1. EX-B0010-M02 (FulenGen Catalog no. EX-B0010-M02)
2. 操作步骤： 2. Operation steps:
(1) 质粒构建：根据 Entrez Gene ID:4325, Refseq: NM— 005373提供的 TPOR基因序 歹 ij ,对购买的 EX-B0010-M02质粒（FulenGen)利用 QuikChange® Multi Site Directed (1) Plasmid construction: According to the TPOR gene sequence 歹 ij provided by Entrez Gene ID: 4325, Refseq: NM-005373, the purchased EX-B0010-M02 plasmid (FulenGen) utilizes QuikChange® Multi Site Directed
Mutagenesis Kit (Stratagene)试剂盒进行 2点突变。多点突变引物序列分别为： g49 la: 5'-gggaacttcagatcagctgggaggagccg-3 '， g491 a anti sense： The Mutagenesis Kit (Stratagene) kit performs a 2-point mutation. The multi-point mutation primer sequences are: g49 la: 5'-gggaacttcagatcagctgggaggagccg-3 ', g491 a anti sense:
5 '-cggctcctcccagctgatctgaagttccc-3 '； c9651 : 5'-caggaccatgctagctcccaaggcttcttct-3 ' , c965t_antisense: 5'-agaagaagccttgggagctagcatggtcctg-3，。 突变后质粒转化大肠卞干菌 DH5o， 经 Amp筛选出阳性克隆， 测序鉴定突变结果正确。 5 '-cggctcctcccagctgatctgaagttccc-3 '; c9651 : 5'-caggaccatgctagctcccaaggcttcttct-3 ' , c965t_antisense : 5'-agaagaagccttgggagctagcatggtcctg-3,. After the mutation, the plasmid was transformed into DH5o, and the positive clone was screened by Amp. The mutation results were confirmed by sequencing.
(2) BAF3-TPOR细胞株构建： 构建稳定高表达功能性 TPO受体的 BaF3细胞株。 将经 2点突变后的表达人 TPO受体和筛选基因 neomycin的 EX-B0010-M02质粒 25 μβ转染野生型 BaF3细胞 （ 1X107)， 转染所用仪器为 Electro Square Porator ECM830 (BTX Division of Genetronic, Inc.US), 转染条件为：250V, 18ms。通过 G418 ( Gibco, US ) 筛选获得 BAF3-TPOR稳定细胞株。 BAF3-TPOR在 RPMI1640(2) Construction of BAF3-TPOR cell line: A BaF3 cell line stably expressing a highly functional TPO receptor was constructed. The by expressing human after the 2-point mutant TPO receptor and screening gene neomycin the EX-B0010-M02 plasmid 25 μ β transfected with wild-type BaF3 cells (1X10 7), transfection instruments as Electro Square Porator ECM830 (BTX Division of Genetronic, Inc. US), transfection conditions: 250V, 18ms. The BAF3-TPOR stable cell line was obtained by G418 (Gibco, US) screening. BAF3-TPOR in RPMI1640
(Gibco, US ) 培养基， 10%FB (Gibco, US ) S， 800ng/mL G418, 5ng/mL, rmIL-3 (Chemicon, US ) 中培养。 (Gibco, US) Medium, 10% FB (Gibco, US) S, 800 ng/mL G418, 5 ng/mL, rmIL-3 (Chemicon, US).
3. 化合物筛选： 3. Compound screening:
(1) 离心清洗细胞： 取适量细胞悬液 lOOOrpm,离心 5分钟， 弃去上清， 再用 10 mL 不含 IL3的细胞培养液将细胞重新悬起， lOOOrpm,离心 5分钟， 弃去上清；(1) Centrifuge the cells by centrifugation: Take appropriate amount of cell suspension at 1000 rpm, centrifuge for 5 minutes, discard the supernatant, resuspend the cells with 10 mL of cell culture medium without IL3, centrifuge at lOOOOrpm for 5 minutes, discard the supernatant. ;
(2) 加入 lmL不含 IL3的细胞培养液将细胞吹打均匀， 取适量细胞悬液稀释后计 数； (2) Add lmL of IL3-free cell culture medium to evenly blow the cells, and take appropriate amount of cell suspension to dilute and count;
(3) 根据细胞计数结果制备密度为 100000个 /mL的细胞悬液；  (3) preparing a cell suspension having a density of 100,000 /mL based on the cell count result;
(4) 于 96-well平板中每孔加入】 ΟΟμί细胞悬液， 设置 3个复孔， 并设置空白对照 组 (Β)， 阴性对照组 (N)， TPO阳性对照组 (Ρ)和待测化合物组 (S); (4) Add 】μί cell suspension to each well of 96-well plate, set 3 duplicate wells, and set blank control group (Β), negative control group (N), TPO positive control group (Ρ) and test Compound group (S);
(5) 用 DMSO将待测化合物粉末配成 10mM的储存液， 再用 RPM11640稀释成不 同浓度： 30μΜ,10μΜ,3μΜ, Ι μΜ, 0.3μΜ, 0.1μΜ,0.03μΜ, 0.01 μΜ, 0.003μΜ, 0.001 μΜ; (5) Prepare the test compound powder into 10 mM stock solution in DMSO, and dilute it with RPM11640. Same concentration: 30μΜ, 10μΜ, 3μΜ, Ι μΜ, 0.3μΜ, 0.1μΜ, 0.03μΜ, 0.01 μΜ, 0.003μΜ, 0.001 μΜ;
(6) 每孔加入 lO L相应浓度的药液， 阳性对照孔中加入 1μί ΑΤΡΟ(10μ§/ηΛ); (6) Add 10 L of the corresponding concentration of the drug solution to each well, and add 1 μί ΑΤΡΟ (10 μ § /ηΛ) to the positive control well ;
(7) 置于 5%C02， 37°C细胞培养箱中培养 24小时； (7) Incubate in a 5% C0 2 , 37 ° C cell culture incubator for 24 hours;
(8) 每孔加入 l(^LCCK-8， 于细胞培养箱中培养 4小时；  (8) Add l(^LCCK-8) to each well for 4 hours in a cell culture incubator;
(9) 利用 VICTOR3 (Perkin Elmer 1420-120)仪器在 450nm检测 OD值。  (9) The OD value was measured at 450 nm using a VICTOR3 (Perkin Elmer 1420-120) instrument.
4. 结果分析计算： 4. Analysis of results:
(1 ) 增值率定义： [(S-B)/(P-B)] * 100%  (1) Definition of value added rate: [(S-B)/(P-B)] * 100%
S: 样品； B: 空白对照； P: 阳性对照  S: sample; B: blank control; P: positive control
(2)通过 Origin 7.0计算 EC50. (2) Calculate EC 50 by Origin 7.0.
5. 结果：  5. Results:
化合物 TPO活性 EC5o值 Compound TPO activity EC 5 o value
Figure imgf000048_0001
Figure imgf000048_0001

Claims

权利要求书： Claims:
1、 通式（I )所示的化合物或其药学上可以接受的盐、 水合物或溶剂化合物: A compound represented by the formula (I) or a pharmaceutically acceptable salt, hydrate or solvent compound thereof:
Figure imgf000049_0001
Figure imgf000049_0001
其中：  among them:
Ri 、 R2或 R3各自独立地选自氢原子或烷基， 或者 Ri, R 2 or R 3 are each independently selected from a hydrogen atom or an alkyl group, or
R2与 或 R3和其相连接的原子形成一个 4〜6元环； R 2 and R 3 and the atoms to which they are attached form a 4 to 6 membered ring;
R4选自卤素、 垸基、 四唑基、 羧基或羧酸酯；  R4 is selected from the group consisting of halogen, decyl, tetrazolyl, carboxy or carboxylic acid ester;
R5选自氢原子或垸基； R 5 is selected from a hydrogen atom or a fluorenyl group;
X选自氧原子或硫原子； 且  X is selected from an oxygen atom or a sulfur atom;
Y是一个或多个基团的 1〜4个原子空间， 选自烷基或芳基， 其中所述芳基或 院基任选地进一步被一个或多个选自卤素、 垸基或芳基的取代基所取代。  Y is 1 to 4 atomic spaces of one or more groups selected from an alkyl group or an aryl group, wherein the aryl group or the aryl group is optionally further further selected from one or more selected from halogen, decyl or aryl Substituted by a substituent.
2、根据权利要求 1所述的化合物或其药学上可以接受的盐、水合物或溶剂化合物， 其中： 2. A compound according to claim 1 or a pharmaceutically acceptable salt, hydrate or solvent compound thereof, wherein:
Y选自
Figure imgf000049_0002
Y is selected from
Figure imgf000049_0002
选自氢原子、 卤素、 垸基或芳基； 且  Selected from a hydrogen atom, a halogen, a fluorenyl group or an aryl group;
R7选自氢原子或垸基。 R 7 is selected from a hydrogen atom or a fluorenyl group.
3、 通式 ( Π )所示的化合物或其药学上可接受的盐、 水合物或溶剂化合物， 3. A compound of the formula (A) or a pharmaceutically acceptable salt, hydrate or solvent compound thereof,
Figure imgf000050_0001
Figure imgf000050_0001
( U )  ( U )
其中- among them-
R, 、 R2或 各自独立地选自氢原子或垸基， 或者 R, R 2 or each independently selected from a hydrogen atom or a fluorenyl group, or
R2与 或 R3和其相连接的原子形成一个 4〜6元环； R 2 and R 3 and the atoms to which they are attached form a 4 to 6 membered ring;
选自卤素、 垸基、 四唑基、 羧基或羧酸酯；  Selected from halogen, decyl, tetrazolyl, carboxyl or carboxylic acid esters;
R5选自氢原子或垸基； R 5 is selected from a hydrogen atom or a fluorenyl group;
R6选自氢原子、 卤素、 垸基或芳基； 且 R 6 is selected from a hydrogen atom, a halogen, a fluorenyl group or an aryl group;
X选自氧原子或硫原子。  X is selected from an oxygen atom or a sulfur atom.
4、 通式 (III)所示的化合物或其药学上可接受的盐、 水合物或溶剂化合物， 4. A compound of the formula (III) or a pharmaceutically acceptable salt, hydrate or solvent compound thereof,
Figure imgf000050_0002
其中：
Figure imgf000050_0002
among them:
R, 、 R2或 R3各自独立地选自氢原子或烷基， 或者 R, R 2 or R 3 are each independently selected from a hydrogen atom or an alkyl group, or
！^与！^ 或 R3和其相连接的原子形成一个 4〜6元环； ! ^And! ^ or R 3 and the atoms to which they are attached form a 4 to 6 membered ring;
R4选自卤素、 垸基、 四唑基、 羧基或羧酸酯；  R4 is selected from the group consisting of halogen, decyl, tetrazolyl, carboxy or carboxylic acid ester;
R5或 R7各自独立地选自氢原子或垸基； 且 R 5 or R 7 are each independently selected from a hydrogen atom or a fluorenyl group;
X选自氧原子或硫原子。  X is selected from an oxygen atom or a sulfur atom.
5、 根据权利要求 ！〜 4任一项所述的化合物或其药学上可以接受的盐、 水合物或 溶剂化合物， 其中所述的化合物选自： 5. According to the claims! Or a pharmaceutically acceptable salt, hydrate or solvent compound thereof, wherein the compound is selected from the group consisting of:
Figure imgf000051_0001
Figure imgf000051_0001
6、 通式（ I A)所示化合物， 所述化合物为合成如权利要求 1所述的通式 (； I )化合物 合成的中间体： 6. A compound of the formula (IA), which is an intermediate for the synthesis of a compound of the formula (; I) according to claim 1:
Figure imgf000051_0002
Figure imgf000051_0002
(I A)  (I A)
其中：  among them:
R4选自卤素、 垸基、 四唑基、 羧基或羧酸酯; R5选自氢原子或垸基； 且 R4 is selected from the group consisting of halogen, decyl, tetrazolyl, carboxy or carboxylic acid ester; R 5 is selected from a hydrogen atom or a fluorenyl group;
X选自氧原子或硫原子。  X is selected from an oxygen atom or a sulfur atom.
7、 通式（I B)所示化合物， 所述化合物为合成如权利要求 1所述的通式（I )化合物 合成的中间体： 7. A compound of the formula (IB) which is an intermediate for the synthesis of a compound of the formula (I) according to claim 1:
Figure imgf000052_0001
Figure imgf000052_0001
Ri , R2或 各自分别选自氢原子或垸基， 或者 Ri , R 2 or each of each selected from a hydrogen atom or a sulfhydryl group, or
！^与！^ 或 R3和其相连接的原子形成一个 4〜6元环； 且 ! ^And! ^ or R 3 and its attached atoms form a 4 to 6 membered ring;
Y是一个或多个基团的〗〜 4个原子空间， 选自烷基或芳基， 其中所述芳基或 垸基任选地进一歩被一个或多个选自卤素、 垸基或芳基的取代基所取代。  Y is 〜4 atoms of one or more groups selected from an alkyl group or an aryl group, wherein the aryl or fluorenyl group is optionally further selected from one or more selected from the group consisting of halogen, fluorenyl or aryl. Substituted by a substituent.
8、 根据权利要求 7所述的通式（I B)所示化合物， 8. The compound of the formula (I B) according to claim 7,
其中 Y选自
Figure imgf000052_0002
Where Y is selected from
Figure imgf000052_0002
选自氢原子、 卤素、 垸基或芳基； 且  Selected from a hydrogen atom, a halogen, a fluorenyl group or an aryl group;
R7选自氢原子或烷基。 R 7 is selected from a hydrogen atom or an alkyl group.
9、 制备根据权利要求 6所述的通式（I A)化合物的方法， 该方法包括:
Figure imgf000052_0003
9. A process for the preparation of a compound of the formula (IA) according to claim 6 which comprises:
Figure imgf000052_0003
( I A )  ( I A )
取代苯胺与 Ν,Ν'-Χ代羰基二咪唑反应， 得到的化合物与水合肼溶液在室温下 反应， 得到通式（ I Α)化合物， 其中 、 R5和 X如权利要求 6中所定义。 The substituted aniline is reacted with hydrazine, Ν'-deuterated carbonyl diimidazole, and the resulting compound is reacted with a hydrazine hydrate solution at room temperature to obtain a compound of the formula (I Α) wherein R 5 and X are as defined in claim 6.
10、 制备根据权利要求 7所述的通式（I B)化合物的方法， 该方法包括:
Figure imgf000053_0001
10. A process for the preparation of a compound of the formula (IB) according to claim 7, which process comprises:
Figure imgf000053_0001
( I B)  ( I B)
将二甲氨基亚乙基化合物与水合肼溶液在室温下反应， 得到通式（ I B)化合物, 其中 R2、 R3和 Y如权利要求 7中所定义。 The dimethylaminoethylidene compound is reacted with a hydrazine hydrate solution at room temperature to obtain a compound of the formula (IB) wherein R 2 , R 3 and Y are as defined in claim 7.
1 1、 制备根据权利要求 1所述的通式（I )化合物的方法， 该方法包括: 1 1. A method of preparing a compound of formula (I) according to claim 1, the method comprising:
Figure imgf000053_0002
Figure imgf000053_0002
将二甲氨基亚乙基化合物和通式（ I A)化合物在酸性条件下加热缩合得到通式 ( I )化合物， 其中 R R2、 R3、 、 、 X和 Y如权利要求 1中所定义。 The dimethylaminoethylidene compound and the compound of the formula (IA) are condensed by heating under acidic conditions to give a compound of the formula (I) wherein RR 2 , R 3 , , , X and Y are as defined in claim 1.
12、 制备根据权利要求 1所述的通式（ I )化合物的方法， 该方法包括: 12. A process for the preparation of a compound of formula (I) according to claim 1 which comprises:
Figure imgf000053_0003
Figure imgf000053_0003
( I B )  ( I B )
将通式（ I B)化合物和 X取代异氰酸苯酯在酸性条件下加热缩合，得到通式（ I ) 化合物， 其中 、 R2、 R3、 R4、 R5、 X和 Y如权利要求 1中所定义。 Heating and condensing a compound of the formula (IB) and X-substituted isocyanate under acidic conditions to obtain a compound of the formula (I) wherein R 2 , R 3 , R 4 , R 5 , X and Y are as claimed in claim 1 Defined in .
13、 根据权利要求 1〜5任一项所述的化合物或其药学上可以接受的盐、 水合物或 溶剂化合物在制备血小板生成素 (ΤΡΟ)受体激动剂中的用途。 Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for the preparation of a thrombopoietin (ΤΡΟ) receptor agonist.
14、 根据权利要求！〜 5任一项所述的化合物或其药学上可以接受的盐、 水合物或 溶剂化合物在制备治疗血小板减少症药物中的用途。 14. According to the claims! Use of a compound according to any one of 5 or a pharmaceutically acceptable salt, hydrate or solvate thereof for the manufacture of a medicament for the treatment of thrombocytopenia.
15、 一种药物组合物， 其含有治疗有效剂量的如权利要求 1〜5任一项所述的化合 物及其药学上可以接受的盐、 水合物或溶剂化合物及药学上可接受的载体。 A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 5. And a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier.
16、 根据权利要求 14所述的用途， 其中所述化合物进一歩与集落刺激因子、 细胞 因子、 趋化因子、 白细胞介素、 细胞因子受体激动剂或与它们具有相同的作用机 理的肽或小分子类物质的联合使用。 The use according to claim 14, wherein the compound further enters a colony with a colony stimulating factor, a cytokine, a chemokine, an interleukin, a cytokine receptor agonist or a peptide having the same mechanism of action or The combined use of small molecular substances.
17、 根据权利要求 15所述的药物组合物， 该组合物进一步含有治疗有效量的集落 刺激因子、 细胞因子、 趋化因子、 白细胞介素或细胞因子受体激动剂。 17. A pharmaceutical composition according to claim 15 which further comprises a therapeutically effective amount of a colony stimulating factor, a cytokine, a chemokine, an interleukin or a cytokine receptor agonist.
18、 根据权利要求 15所述的药物组合物在制备治疗血小板减少症药物的用途。 18. Use of a pharmaceutical composition according to claim 15 for the manufacture of a medicament for the treatment of thrombocytopenia.
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