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WO2015135461A1 - Dérivé de dihydrobenzofurane-pipéridine-cétone substitué, sa préparation et son utilisation - Google Patents

Dérivé de dihydrobenzofurane-pipéridine-cétone substitué, sa préparation et son utilisation Download PDF

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Publication number
WO2015135461A1
WO2015135461A1 PCT/CN2015/073932 CN2015073932W WO2015135461A1 WO 2015135461 A1 WO2015135461 A1 WO 2015135461A1 CN 2015073932 W CN2015073932 W CN 2015073932W WO 2015135461 A1 WO2015135461 A1 WO 2015135461A1
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Prior art keywords
substituted
group
pharmaceutically acceptable
compound
stereoisomer
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PCT/CN2015/073932
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English (en)
Chinese (zh)
Inventor
魏用刚
邱关鹏
郑苏欣
刘建余
钱枚林
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四川海思科制药有限公司
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Priority to CN201580002731.2A priority Critical patent/CN105793264B/zh
Publication of WO2015135461A1 publication Critical patent/WO2015135461A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a substituted dihydrobenzofuran-piperidine-methanone derivative represented by the formula (A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a process for producing the same, and a medicament containing the same Compositions and uses in the manufacture of a medicament for the treatment of cancer-related diseases.
  • the invention provides a series of inhibitors of the Wnt signaling pathway. These inhibitors are capable of inhibiting tumor cell proliferation and preventing tumor metastasis.
  • the Wnt signaling pathway is a key regulator in various cellular processes, including maintenance of stem cells, determination of stem cell fate, and control of cell cycle (Huang, Xie et al, 2006, J Immunol, 176, 4880-4887). It plays an important role in the development and maintenance of adult homeostasis, and also exhibits an abnormal activation state in many types of tumors.
  • the classical Wnt signaling pathway is regulated by the stability of its major participant, catenin ⁇ -catenin. The stability of ⁇ -catenin is controlled by the destruction of the complex. --catenin has many important biological functions. On the cell membrane, ⁇ -catenin is linked to cadherin E-cadherin and participates in the formation of adhesion junctions.
  • ⁇ -catenin In cytoplasm, ⁇ -catenin is capable of forming downstream ⁇ -catenin destruction complexes with APC, AXIN, GSK3 and CK1.
  • Wnt signaling pathway When the Wnt signaling pathway is not activated, the ⁇ -catenin in the cytosol is degraded by the phosphorylation of the complex.
  • Wnt activates the Wnt signaling pathway, the ⁇ -catenin destruction complex degrades, resulting in the accumulation of stable ⁇ -catenin after entering the nucleus, causing Wnt pathway target genes (such as c-myc, cyclin D, Axin2, and Nkd1). Transcriptional activation.
  • the Tankyrase protein is a multifunctional poly(ADP-ribose) polymerase (PRAP) that utilizes NAD+ as a substrate to transfer ADP-ribose polymers to target proteins for post-translational modification.
  • PRAP poly(ADP-ribose) polymerase
  • Tankyrase is able to directly bind to Axin protein to regulate its stability. Studies have shown that inhibition of Tankyrase can stabilize Axin to degrade ⁇ -catenin and inhibit Wnt signaling pathway (Huang, Mishina et al, 2009, Nature, 461, 614-620).
  • the tankyrase subtype can react with a highly conserved sequence of Axin to promote the degradation of Axin via the ubiquitin-protease pathway.
  • Axin has important regulatory roles in a wide range of physiological processes, including differentiation of glioma progenitor cells during remyelination (Fancy, Harrington et al., 2011, Nat Neurosci, 14, 1009-1016) and pulmonary fibrosis Transformation of the epithelium into the stroma (Ulsamer, Wei et al, 2012, J Biol Chem, 287, 5164-5172). Inhibition of Tankyrase can stabilize Axin and inhibit Wnt pathway signaling, and this process can be used to develop a treatment for disorders associated with Wnt signaling.
  • Tankyrase has multiple chaperones, including TRF1, a double-stranded telomere repeat binding protein; NuMA, a protein that plays an important role in mitotic spindle assembly; IRAP, a membrane protein associated with insulin-responsive glucose uptake And Mcl-1, a pro-apoptotic protein.
  • TRF1 a double-stranded telomere repeat binding protein
  • NuMA a protein that plays an important role in mitotic spindle assembly
  • IRAP a membrane protein associated with insulin-responsive glucose uptake
  • Mcl-1 a pro-apoptotic protein.
  • Tankyrase proteins In addition to regulating the Wnt signaling pathway, Tankyrase proteins have a variety of biological functions by interacting with various proteins. Tankyrase releases TRF1 from telomeres, causing telomeres to contact telomerase.
  • Tankyrase is able to positively regulate telomerase elongation of telomeres (Cook, Dynek et al, 2002
  • Tankyrase can be used as a target for tumor therapy by inhibiting telomerase access to telomeres and inhibiting tumors.
  • Inhibitors of Tankyrase can be used as effective tumor treatments to inhibit a variety of tumors, including leukemia, lymphoma, multiple myeloma, lung cancer and breast cancer.
  • Tankyrase also plays an important role in cell mitosis: (1) regulates the regulation of NuMA in the mitosis on the spindle pole (Chang, Dynek et al, 2005, Biochem J, 391, 177-184); (2) regulates the spindle Assembly and structure of bodies (Chang, Jacobson et al, 2004, Nature, 432, 645-649); (3) maintenance of dissociation of sister chromatids (Dynek and Smith, 2004, Science, 304, 97-100).
  • Tankyrase1 is an important gene required for centrosome aggregation, and tumor cells have redundant centrosomes to inhibit multipolar mitosis and undergo bipolar mitosis (Kwon, Godinho et al., 2008, Genes Dev, 22, 2189-2203). ). Therefore, inhibition of Tankyrase can be developed into tumors that inhibit centrosome expansion, including various solid tumors and hematological cancers such as breast cancer, bladder cancer, lung cancer, colon cancer, and leukemia.
  • Tankyrase Some synthetic inhibitors of Tankyrase have been disclosed in existing studies. Some of these studies have found that inhibitors of Tankyrase are capable of blocking Wnt signaling in APC-mutated colon cancer cells (Chen, Dodge et al, 2009, Nat Chem Biol, 5, 100-107; Huang, Mishina et al, 2009, Nature, 461, 614-620) and Wnt signaling in breast cancer (Bao, Christova et al, 2012, PLoS One, 7, e48670). Although the Wnt signaling pathway is a highly potential target for anti-tumor therapy, there are currently fewer effective tankyrase inhibitors.
  • WO2013012723 describes novel 2-piperidin-2-yl-acetamide derivatives and their use as Tankyrase inhibitors for the treatment of diseases associated with Wnt, Tankyrase1 and Tankyrase2, such as cancer.
  • X is NH or O
  • Y is CH or N
  • R 1a and R 1b are alkyl groups or together form a 5- to 7-membered ring which may be substituted
  • R 2 is H or an alkyl group
  • R 3 is H, an alkyl group, An alkynyl group or the like
  • R 5 is a benzene, a 2,3-dihydrobenzofuran, a quinoline or the like which may be substituted.
  • the specific description in this patent is not considered to be part of the present invention and its structure is as follows:
  • WO2013008217 describes novel 4-piperidine derivatives and their use as Tankyrase inhibitors for the treatment of diseases associated with Wnt, Tankyrase 1 and Tankyrase 2, such as cancer.
  • R 1 is a substitutable phenyl group, a 5-membered heterocyclic ring, an 8- to 10-membered heterocyclic ring or the like
  • R 4 is H or a substitutable phenyl group.
  • WO2013010092 describes a novel 4-oxo-3,5,7,8-tetrahydro-4H-pyrano[4,3-d]pyrimidine derivative and its use as a Tankyrase inhibitor for treatment with Wnt , Tankyrase1 and Tankyrase2 related diseases, such as cancer.
  • R 1 is H or a substitutable alkyl group
  • R 2 is R 3 -alkenyl-C(O)-
  • R 3 is a phenyl group, a 6-membered heteroaryl ring or an anthracene which may be substituted.
  • the object of the present invention is to provide a novel and effective Tankyrase inhibitor, and a use for treating a cancer-related disease, wherein the cancer-related diseases include bladder cancer, colon cancer, ovarian cancer, melanoma, leukemia, lymphoma , multiple myeloma, lung cancer and breast cancer.
  • the cancer-related diseases include bladder cancer, colon cancer, ovarian cancer, melanoma, leukemia, lymphoma , multiple myeloma, lung cancer and breast cancer.
  • the present invention provides a compound represented by the formula (A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein:
  • R 1a and R 1b are each independently selected from H, C 1-6 alkyl or C 1-6 alkoxy, and the alkyl and alkoxy are optionally further from 0 to 4 selected from F, Cl, Br. Substituted by a substituent of I, cyano, hydroxy, carboxy, amino or nitro;
  • R 2 , R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, Br, I, cyano, hydroxy, carboxy, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy,
  • the alkyl group and the alkoxy group are optionally further substituted with from 0 to 4 substituents selected from the group consisting of F, Cl, Br, I, cyano, hydroxy, carboxy, amino or nitro;
  • R 5 , R 6 , R 7 and R 8 are each independently selected from H or C 1-6 alkyl.
  • a preferred embodiment of the invention a compound of the formula (A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of a compound represented by the formula (I), a stereoisomer thereof Or pharmaceutically acceptable salts:
  • a preferred embodiment of the invention a compound of the formula (A) or the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from a 6-membered carbocyclic ring and a 5-membered heterocyclic ring.
  • R 1a and R 1b are each independently selected from H, C 1-4 alkyl or C 1-4 alkoxy, and the alkyl and alkoxy groups are further further selected from 0 to 4 selected from F, Cl, Br. Substituted by a substituent of I, cyano, hydroxy, carboxy, amino or nitro.
  • a preferred embodiment of the invention a compound of the formula (A) or the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the following structures which are substituted or unsubstituted One:
  • R 1a and R 1b are each independently selected from H, C 1-4 alkyl or C 1-4 alkoxy, and the alkyl and alkoxy groups are further further selected from 0 to 4 selected from F, Cl, Br. Substituted with a cyano or hydroxy substituent;
  • a preferred embodiment of the invention a compound of the formula (A) or the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the following structures which are substituted or unsubstituted One: Preferred substituted or unsubstituted
  • optionally further 1 to 4 are selected from the group consisting of F, Cl, Br, cyano, hydroxy, carboxy, amino, nitro, methyl, ethyl, trifluoromethyl, methoxy or ethoxy
  • substituents selected from the group consisting of F, Cl, Br, cyano, methyl, ethyl or trifluoromethyl.
  • R 1 is selected from the following structures which are substituted or unsubstituted One: When substituted, optionally further substituted with from 1 to 4 substituents selected from the group consisting of F, Cl, cyano, methyl, trifluoromethyl or methoxy;
  • R 2 , R 3 and R 4 are each independently selected from H, F, Cl or Br;
  • R 5 , R 6 , R 7 and R 8 are each independently H.
  • a preferred embodiment of the invention a compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of a compound represented by the formula (II), a stereoisomer thereof Or pharmaceutically acceptable salts:
  • a preferred embodiment of the invention a compound of the formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein:
  • R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, trifluoromethyl, methyl, ethyl, methoxy or ethoxy, preferably H, F, Cl or Br, more Preferred H or F
  • R 5 , R 6 , R 7 and R 8 are each independently selected from H, methyl or ethyl, preferably H.
  • a preferred embodiment of the invention a compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from, but not limited to, one of the following structures:
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, and a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides a compound of the present invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, Or the use of the pharmaceutical composition of the present invention for the preparation of a medicament for treating cancer.
  • the present invention provides a method of treating cancer comprising administering a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as hereinbefore described, or as described above in the present invention Pharmaceutical composition.
  • the present invention relates to the substitution of a plurality of substituents, which may be the same or different.
  • the present invention relates to the inclusion of a plurality of heteroatoms, each of which may be the same or different.
  • the elements carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and derivatives of the present invention include their isotopic conditions, and the elements carbon and hydrogen involved in the groups and derivatives of the present invention.
  • oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C and 14 C, and the hydrogen isotopes include strontium (H), strontium (D, also known as Heavy hydrogen), strontium (T, also known as super heavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, the fluorine isotope 19 F, the chlorine isotope includes 35 Cl and 37 Cl, and the bromine isotopes include 79 Br and 81 Br.
  • alkyl refers to a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms. Preference is given to alkyl groups having 1 to 10 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, positive a mercapto group, and various branched isomers thereof; more preferred are lower alkyl groups having 1 to 4 carbon atoms, and non-limiting examples include methyl, ethyl, propyl, isopropyl, and Butyl, isobutyl or tert-butyl.
  • Alkoxy means an -O-alkyl group wherein alkyl is as defined above.
  • the alkoxy group may be substituted or unsubstituted, and non-limiting examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy or
  • the hexyloxy group preferably has a 1 to 12 member alkoxy group.
  • Carbocycle means a saturated or unsaturated aromatic ring or a non-aromatic ring.
  • the aromatic ring or non-aromatic may be a single ring of 3 to 8 members, a 4 to 12 membered double ring or a 10 to 15 membered three ring system.
  • Linked to a bridged or spiro ring non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclopentene, ring Hexadiene, cycloheptatriene, phenyl, naphthyl, benzocyclopentyl, bicyclo[3.2.1]octyl, bicyclo[5.2.0]decyl, tricyclo[5.3.1.1] Dodecyl, adamantyl or spiro[3.3]heptyl and the like.
  • Heterocycle means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, and the aromatic and non-aromatic rings may be a 3 to 8 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered member.
  • a tricyclic system consisting of at least one hetero atom selected from N, O or S, preferably a 3 to 10 membered heterocyclic ring, and optionally substituted N, S in the heterocyclic ring can be oxidized to various oxidation states.
  • the heterocyclic ring can be attached to a hetero atom or a carbon atom.
  • the heterocyclic ring may be attached to a bridged or spiro ring, and non-limiting examples include, ethylene oxide, aziridine, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxane, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl , pyridazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiane, dihydrofuran, dihydropyran, dithiapentane, tetrahydrofuran, Tetrahydropyrrolyl, tetrahydroimidazole, tetrahydrothiazole, tetrahydropyran,
  • Amino means -NH 2, may be substituted or unsubstituted. When substituted, the substituent is preferably 1 to 3, independently selected from alkyl, alkenyl, alkynyl, alkoxy, Thio, hydroxy, amino, alkylamino, alkyl acylamino, heterocycloalkyl, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, hydroxyalkyl, carboxylic acid or Carboxylic acid ester.
  • Aryl means a substituted or unsubstituted 6 to 14 membered all carbon monocyclic or fused polycyclic group having a polycyclic group of a conjugated ⁇ -electron system, preferably a 6 to 10 membered aromatic ring, Non-limiting examples include phenyl or naphthyl; the aryl group may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, and the moiety attached to the parent structure is an aryl group, non-limiting examples of which include benzo Furan, benzocyclopentyl or benzothiazole.
  • Heteroaryl means a substituted or unsubstituted 5 to 15 membered aromatic ring and contains 1 to 3 heteroatoms selected from N, O or S heteroatoms, preferably 5 to 10 members, and non-limiting heteroaryl groups. Examples include pyridyl, furyl, thienyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzofuran, benzimidazole, benzopyridine or pyrrolopyridine, and the like.
  • Natural or pharmaceutically acceptable amino acids The basic skeleton of a protein molecule is an amino acid sequence, and there are 20 basic amino acids constituting a protein. These 20 basic amino acids are the basis for biological late modification of proteins, and in addition, based on these basic amino acids. The organism also synthesizes amino acid types derived from hydroxyproline, hydroxylysine, etc. These biosynthesized amino acids are collectively referred to as “natural amino acids”; artificially synthesized are “unnatural amino acids”. "Pharmaceutically acceptable amino acid” refers to a pharmaceutically acceptable natural or unnatural amino acid.
  • “Pharmaceutically acceptable salt” means a pharmaceutically acceptable salt of a non-toxic acid or base, including salts of inorganic acids and bases, organic acids and bases.
  • Crystal refers to a combination of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, of which API and CCF The pure state is solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-component eutectic formed by a neutral solid with a salt or solvate.
  • the "eutectic former” includes, but is not limited to, various pharmaceutically acceptable acid, base, nonionic compounds.
  • Stepoisomer refers to isomers resulting from the spatial arrangement of atoms in a molecule, including cis and trans isomers, enantiomers and conformational isomers.
  • “Pharmaceutical composition” means a derivative of one or more of the above-mentioned derivatives or physiological/pharmaceutically acceptable salts or prodrugs thereof and other chemical components, other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
  • Prodrug means a derivative of the invention which can be converted to biological activity under physiological conditions or by solvolysis. Things. Prodrugs of the invention are prepared by modifying functional groups in the derivative which can be removed by conventional procedures or in vivo to provide the parent compound.
  • a prodrug includes a compound formed by attaching a hydroxyl group, an amino group or a thiol group to any group in the derivative of the present invention. When a prodrug of the derivative of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free form. Hydroxyl group, free amino group or free sulfhydryl group. Examples of prodrugs include, but are not limited to, compounds formed by the hydroxyl or amino functional groups of the derivatives of the invention with formic acid, acetic acid or benzoic acid.
  • aryl substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the aryl group is substituted with an alkyl group and the case where the aryl group is not substituted with an alkyl group.
  • Substituted or unsubstituted refers to a situation in which a group may be substituted or unsubstituted, and if it is not indicated in the present invention that a group may be substituted, it means that the group is unsubstituted.
  • “As a choice” means that the scheme after “as a choice” is a side-by-side relationship with the scheme before “as a choice” rather than a further selection in the previous scheme.
  • substitution refers to the case where one or more hydrogen atoms in a group are substituted by another group, and if the group is substituted by a hydrogen atom, the group formed is the same as the group substituted by a hydrogen atom.
  • the group is substituted, for example, amino, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic, 3 to 6 membered heterocyclic ring, optionally further from 0 to 4 selected from H
  • substituent of F, Cl, Br, I, hydroxy, cyano, amino, C 1-4 alkyl or C 1-4 alkoxy the groups formed include, but are not limited to, methyl, chloromethyl, Trichloromethyl, hydroxymethyl, -CH 2 OCH 3 , -CH 2 SH, -CH 2 CH 2 CN, -CH 2 NH 2 , -NHOH, -NHCH 3 , -OCH 2 Cl, -OCH 2 OCH 2 CH 3 , -
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • the NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethylsilane (TMS).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 4.6 mm).
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.20mm.
  • the specification for thin layer chromatography separation and purification is 0.4mm. ⁇ 0.5mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anike Chemical, Shanghai Demo, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • reaction was carried out under a nitrogen atmosphere.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature.
  • the room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.
  • N,N'-carbonyldiimidazole (21.0 g, 0.13 mol) was dissolved in anhydrous dichloromethane (200 mL), and 1-t-butoxycarbonylpiperidine-4-carboxylic acid (1A) (23.0 g, A 0.10 mmol) solution of anhydrous dichloromethane (100 mL) was stirred for 30 minutes, and dimethylhydroxylamine hydrochloride (12.7 g, 0.13 mol) was added portionwise, and reacted at room temperature for 3 hours.
  • 1-t-butoxycarbonylpiperidine-4-carboxylic acid (1A) 23.0 g, A 0.10 mmol
  • dimethylhydroxylamine hydrochloride (12.7 g, 0.13 mol) was added portionwise, and reacted at room temperature for 3 hours.
  • tert-Butyl 4-methoxy(methyl)carbamoyl)piperidine-1-carboxylate (4.0 g, 0.012 mol) was dissolved in anhydrous dichloromethane (50 mL) Trifluoroacetic acid (13.7 g, 0.12 mol) was added, and the mixture was reacted at room temperature for 4 hours. Water (50 mL) was added to the reaction mixture, and the mixture was evaporated. -Dihydrobenzofuran-5-yl)(piperidin-4-yl)methanone (1D), pale yellow solid (1.2 g, yield 43%).
  • Step 6 2-[[3-[4-(2,3-Dihydrobenzofuran-5-carbonyl)-1-piperidinyl]-2-oxo-pyrrolidin-1-yl]methyl ]-3,5,7,8-tetrahydropyrano[4,3-d]pyrimidin-4-one (Compound 1)
  • Step 2 4-(6-Fluoro-2,3-dihydrobenzofuran-7-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (3C)
  • Step 5 2-[[3-[4-(6-Fluoro-2,3-dihydrobenzofuran-7-carbonyl)-1-piperidinyl]-2-oxo-pyrrolidine-1- Methyl]-3,5,7,8-tetrahydropyrano[4,3-d]pyrimidin-4-one (Compound 3)
  • Triethylamine (4.20 g, 41.5 mmol) and 2-chloroethyl hydrazine (3.00) were added to a solution of methyl 2-oxocyclopentanecarboxylate (5A) (7.10 g, 49.9 mmol) in methanol (150 mL). g, 0.649 mmol), and reacted at room temperature for 5 hours after the addition. After completion of the reaction, water (200 mL) was added, and the mixture was evaporated.
  • Tetrahydrofuran in the compound 3-(4-(2,3-dihydrobenzofuran-5-carbonyl)piperidin-1-yl)pyrrolidin-2-one (1G) (0.314 g, 1.00 mmol) (10 mL) was added 2-(chloromethyl)-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one (5B) (0.400 g, 2.17 mmol). Thereafter, sodium hydride (0.100 g, 4.17 mmol) was added in portions, and the mixture was heated to 80 ° C for 1 hour. After cooling to zero, methanol (5 mL) was added to quench the reaction, and the residue was concentrated with silica gel.
  • the third step 5-((2-bromoethyl)thio)-4H-1,2,4-triazole-3-ammonia (6E)
  • the starting material 3-amino-5-mercapto-1,2,4-triazole (6D) (2.320 g, 19.98 mmol) was dissolved in methanol (25 mL) Sodium methoxide (1.079 g, 19.98 mmol) was added, and 1,2-dibromoethane (30.02 g, 159.8 mmol) was added, and the mixture was reacted at room temperature for 3.5 hours. After the reaction was completed, the title compound (5-(2-bromoethyl)) was obtained.
  • Test Example 1 Inhibition of Wnt signaling pathway by compounds tested by reporter gene assay
  • Super-TOpFlash is a luciferase reporter gene system that specifically responds to the wnt signaling pathway.
  • the Super-TOpFlash (STF) plasmid was transferred into HEK293 cells, and the reporter gene detection method was used to reflect the inhibition of the activity of the compound on the intracellular wnt signaling pathway.
  • the continuously cultured HEK293 cells were cultured in a six-well plate and incubated at 37 ° C in a 5% CO 2 carbon dioxide incubator overnight; when the cells reached 90% confluence, the reporter plasmid was transfected into the cells using Lipofectamine 2000 (Invitrogen) transfection reagent.
  • the cells were plated into 96-well plates at 10,000 cells per well, and cultured overnight at 37 ° C in a 5% CO 2 carbon dioxide incubator, and the test compound was added the next day.
  • the compound was dissolved in DMSO, the highest concentration was 10 ⁇ M, and the cell culture medium was diluted 5 times, 10 concentrations, and 50% wnt3A conditioned medium was added to each well, and cultured in a 5% CO 2 carbon dioxide incubator for 24 hours at 37 ° C, using fluorescence.
  • the fluorescence intensity was measured by a Luciferase Assay System Freezer Pack (Promega, Cat. #E4530) and a Perkin Elmer Envision plate reader, and the IC 50 value was calculated.
  • the test results are shown in Table 1.
  • the compounds of the present invention have significant inhibitory activity on the wnt signaling pathway.

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Abstract

La présente invention concerne un dérivé de dihydrobenzofurane-pipéridine-cétone substitué, sa préparation et son utilisation. En particulier, la présente invention concerne un dérivé de dihydrobenzofurane-pipéridine-cétone substitué représenté par la formule générale (A), un stéréoisomère ou un sel pharmaceutiquement acceptable associé, le procédé de préparation associé, des compositions pharmaceutiques les comprenant, ainsi qu'une utilisation dans la préparation de médicaments pour traiter des maladies associées au cancer.
PCT/CN2015/073932 2014-03-10 2015-03-10 Dérivé de dihydrobenzofurane-pipéridine-cétone substitué, sa préparation et son utilisation WO2015135461A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004033427A1 (fr) * 2002-10-11 2004-04-22 Astrazeneca Ab Derives de piperidine 1,4 disubstituee et leur utilisation en tant qu'inhibiteurs de 11-betahsd1
WO2005108360A1 (fr) * 2004-05-07 2005-11-17 Janssen Pharmaceutica N.V. Utilisation de derives de pyrrolidin-2-one et de piperidin-2-one comme inhibiteurs de la 11-beta-hydroxysteroide deshydrogenase
WO2007127726A2 (fr) * 2006-04-25 2007-11-08 Eli Lilly And Company Inhibiteurs de la 11-bêta-hydroxystéroïde déshydrogénase 1
WO2013008217A1 (fr) * 2011-07-13 2013-01-17 Novartis Ag Composés de 4-pipéridinyle utiles comme inhibiteurs de la tankyrase
WO2013012723A1 (fr) * 2011-07-13 2013-01-24 Novartis Ag Nouveaux composés 2-piperidin-1-yl-acetamide utilisables en tant qu'inhibiteurs de tankyrase
WO2013134079A1 (fr) * 2012-03-05 2013-09-12 Amgen Inc. Composés d'oxazolidinone et leurs dérivés
WO2014036022A1 (fr) * 2012-08-29 2014-03-06 Amgen Inc. Composés quinazolinones et leurs dérivés

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004033427A1 (fr) * 2002-10-11 2004-04-22 Astrazeneca Ab Derives de piperidine 1,4 disubstituee et leur utilisation en tant qu'inhibiteurs de 11-betahsd1
WO2005108360A1 (fr) * 2004-05-07 2005-11-17 Janssen Pharmaceutica N.V. Utilisation de derives de pyrrolidin-2-one et de piperidin-2-one comme inhibiteurs de la 11-beta-hydroxysteroide deshydrogenase
WO2007127726A2 (fr) * 2006-04-25 2007-11-08 Eli Lilly And Company Inhibiteurs de la 11-bêta-hydroxystéroïde déshydrogénase 1
WO2013008217A1 (fr) * 2011-07-13 2013-01-17 Novartis Ag Composés de 4-pipéridinyle utiles comme inhibiteurs de la tankyrase
WO2013012723A1 (fr) * 2011-07-13 2013-01-24 Novartis Ag Nouveaux composés 2-piperidin-1-yl-acetamide utilisables en tant qu'inhibiteurs de tankyrase
WO2013134079A1 (fr) * 2012-03-05 2013-09-12 Amgen Inc. Composés d'oxazolidinone et leurs dérivés
WO2014036022A1 (fr) * 2012-08-29 2014-03-06 Amgen Inc. Composés quinazolinones et leurs dérivés

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