WO2020071550A1 - Inhibiteur de cdk8 et utilisation associée - Google Patents

Inhibiteur de cdk8 et utilisation associée

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Publication number
WO2020071550A1
WO2020071550A1 PCT/JP2019/039376 JP2019039376W WO2020071550A1 WO 2020071550 A1 WO2020071550 A1 WO 2020071550A1 JP 2019039376 W JP2019039376 W JP 2019039376W WO 2020071550 A1 WO2020071550 A1 WO 2020071550A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
mmol
added
pharmaceutically acceptable
Prior art date
Application number
PCT/JP2019/039376
Other languages
English (en)
Japanese (ja)
Inventor
弘明 白波瀬
達哉 北尾
高橋　健司
幸倫 庄子
滋充 武田
Original Assignee
京都薬品工業株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 京都薬品工業株式会社 filed Critical 京都薬品工業株式会社
Priority to JP2020551124A priority Critical patent/JPWO2020071550A1/ja
Publication of WO2020071550A1 publication Critical patent/WO2020071550A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
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    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
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    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
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    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus

Definitions

  • the present invention relates to a compound having a cyclin dependent kinase (CDK) 8 inhibitory activity or a pharmaceutically acceptable salt thereof. Further, the present invention relates to a compound or a pharmaceutically acceptable salt thereof useful for the prevention and / or treatment of CDK8-related diseases, bone metabolism-related diseases such as osteoporosis, and cell proliferative diseases such as cancer.
  • CDK cyclin dependent kinase
  • CDK is a phosphorylase that is activated by forming a complex with the cyclin protein, and is known as a factor involved in cell cycle and transcriptional regulation.
  • CDK2, CDK4 and CDK6 are mainly involved in the cell cycle
  • CDK7, CDK8 and CDK9 are mainly involved in transcription.
  • CDK8 forms a complex with cyclin C, MED12, and MED13, and functions as a kinase that mainly controls transcription by controlling phosphorylation of the C-terminal domain of RNA polymerase II (Non-patent Documents). 1).
  • CDK8 is an oncogene in some colorectal cancer cells, and in colorectal cancer patients, the expression of CDK8 is enhanced, which activates ⁇ -catenin signal and positively regulates cell growth. It has been reported (Non-Patent Document 2). Furthermore, CDK8 is known to be involved in maintenance of undifferentiation of cancer cells and epithelial-mesenchymal transition. In addition, it has been reported that the CDK8 inhibitor Cortistatin A suppresses the growth of various cancer cells and has a remarkable effect particularly on leukemia cells (Non-Patent Document 3). Non-Patent Document 4 discloses that compounds that inhibit CDK8 are useful for treating or preventing cancer, and Patent Documents 1 to 6 disclose CDK inhibitors having anticancer activity.
  • the compounds of the present invention are also useful for diseases related to bone metabolism such as osteoporosis.
  • Therapeutic agents for osteoporosis include bone resorption inhibitors that suppress the activity of osteoclasts and bone formation promoters that activate osteoblasts.
  • calcitonin, bisphosphonate, estrogen receptor modulator and the like have been used.
  • human PTH 1-34 is used as an osteogenesis promoter, and can be used for increasing bone mass and bone density and reconstructing bone structure.
  • the period of use is limited to one and a half years to two years, and long-term subcutaneous injection is required, which makes it difficult for patients to comply.
  • Patent Documents 7 and 8 benzothiepine derivatives having an alkaline phosphatase-inducing activity
  • Patent Document 9 N-quinolylanthranilic acid derivatives
  • Patent Document 10 triazolopyridazine derivatives
  • Patent Document 11 thienopyridine derivatives
  • Patent Document 12 [5,6] heterocyclic compounds
  • Patent Document 13 aromatic compounds
  • An object of the present invention is to provide a prophylactic and / or therapeutic agent having a CDK8 inhibitory activity and preventing a CDK8-related disease, a bone metabolism-related disease such as osteoporosis, and a cell proliferative disease such as cancer. is there.
  • Another object is to provide a compound and a pharmaceutically acceptable salt which are highly safe and can be administered orally.
  • the present inventors have conducted intensive studies, and as a result, have shown a strong inhibitory effect on CDK8, and have shown that CDK8-related diseases, bone metabolism-related diseases such as osteoporosis, and cell proliferative diseases such as cancer.
  • the present inventors have found an excellent compound of the present invention that can be used as a prophylactic and / or therapeutic agent, and have completed the present invention.
  • R 4 A C 1-6 alkylcarbonyl group, a C 1-6 alkylthiocarbonyl group, a carbamoyl group, a C 1-6 alkoxycarbonyl group or a carboxy group
  • R 5 A hydrogen atom, a C 1-6 alkyl group or a halogen atom
  • R 6 A C 1-6 alkyl group, a halogen atom, an amino group, a hydroxy C 1-6 alkyl group, a carboxy C 1-6 alkyl group or a hydrogen atom (provided that T is CHCH— and U is NN—);
  • R 7 A hydrogen atom or a C 1-6 alkyl group
  • R 8 A hydrogen atom, a C 1-6 alkyl group or a C 1-6 alkylcarbonyl group
  • R 9 Hydrogen atom or C 1-6 alkyl group
  • R 1 A hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group
  • R 4 is an acetyl group, a carbamoyl group or a carboxy group
  • R 5 is a methyl group, or a pharmaceutically acceptable salt thereof.
  • R 7 is a methyl group
  • R 9 is a hydrogen atom, or a pharmaceutically acceptable salt thereof.
  • R 6 is chlorine, methyl or carboxymethyl, or the pharmaceutically acceptable salt thereof.
  • R 1 is a cyano group, a methoxy group, a methylsulfanyl group, an acetyl group, a carbamoyl group or an imidazolyl group, or a pharmaceutically acceptable compound thereof. Salt.
  • a pharmaceutical composition comprising, as an active ingredient, the compound according to any one of [1] to [22] or a pharmaceutically acceptable salt thereof.
  • a CDK8 inhibitor comprising as an active ingredient the compound according to any one of [1] to [22] or a pharmaceutically acceptable salt thereof.
  • Composition [27] A pharmaceutical composition for use in preventing or treating cancer, which comprises as an active ingredient the compound according to any one of [1] to [22] or a pharmaceutically acceptable salt thereof.
  • ⁇ Compound (I) of the present invention has excellent inhibitory activity on CDK8. Therefore, a medicament containing the compound (I) of the present invention as an active ingredient can be used as a CDK8 inhibitor, and can also be used as a CDK8-related disease, a disease associated with bone metabolism such as osteoporosis, and a cell such as cancer. It is useful as a prophylactic and / or therapeutic agent for proliferative diseases.
  • halogen atom refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C 1-6 alkyl group means a linear or branched monovalent saturated hydrocarbon group having 1 to 6 carbon atoms.
  • Examples of the “C 1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 4-methylpentyl, hexyl and the like.
  • C 3-8 cycloalkyl group means a monovalent group derived from a saturated hydrocarbon ring having 3 to 8 carbon atoms. Further, the “C 3-8 cycloalkyl group” may be cross-linked. As the “C 3-8 cycloalkyl group”, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned.
  • C 1-6 alkoxy group means a group in which the above “C 1-6 alkyl group” is bonded to an oxygen atom, that is, a linear or branched alkoxy group having 1 to 6 carbon atoms. I do.
  • Examples of the “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like. No.
  • C 1-6 alkylcarbonyl group means a monovalent group in which the above “C 1-6 alkyl group” is bonded to carbonyl.
  • Examples of the “C 1-6 alkylcarbonyl group” include, for example, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, isopentanoyl, 1-methylbutyryl, pivaloyl, hexanoyl, isohexanoyl, 3,3-dimethylbutyryl, -Ethylbutyryl, 4-methylhexanoyl, heptanoyl and the like.
  • C 1-6 alkoxy C 1-6 alkyl group means the “C 1-6 alkyl group” in the monovalent radical "C 1-6 alkoxy group” is bonded.
  • the “C 1-6 alkoxy C 1-6 alkyl group” includes, for example, methoxymethyl, 2-methoxyethyl, ethoxymethyl, 2-ethoxyethyl, 3-ethoxypropyl, 2-propoxyethyl, 2-isopropoxyethyl , 2-butoxyethyl, 2-isobutoxyethyl, sec-butoxymethyl, tert-butoxymethyl, 2-pentyloxyethyl, isopentyloxymethyl, 2-neopentyloxyethyl, 2-hexyloxyethyl and the like. .
  • C 1-6 alkylthiocarbonyl group means a monovalent group in which the above “C 1-6 alkyl group” is bonded to thiocarbonyl.
  • Examples of the “C 1-6 alkylthiocarbonyl group” include, for example, methylthiocarbonyl, ethylthiocarbonyl, propylthiocarbonyl, butylthiocarbonyl, isobutylthiocarbonyl, pentylthiocarbonyl, 3,3-dimethylbutylthiocarbonyl, 1-ethyl Butylthiocarbonyl, hexylthiocarbonyl and the like.
  • C 1-6 alkylcarbonyloxy group means a monovalent group in which the above “C 1-6 alkylcarbonyl group” is bonded to an oxygen atom.
  • Examples of the “C 1-6 alkylcarbonyloxy group” include, for example, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy, isopentanoyloxy, 1-methylbutyryloxy, pivaloyloxy, hexanoyloxy , Isohexanoyloxy, 3,3-dimethylbutyryloxy, 1-ethylbutyryloxy, 4-methylhexanoyloxy, heptanoyloxy and the like.
  • the “C 1-6 alkylcarbonylamino group” means a monovalent group in which the above “C 1-6 alkylcarbonyl group” is bonded to a nitrogen atom.
  • Examples of the “C 1-6 alkylcarbonylamino group” include methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino, tert-butylcarbonyl Amino, pentylcarbonylamino, isopentylcarbonylamino, neopentylcarbonylamino, 1-ethylpropylcarbonylamino, hexylcarbonylamino and the like.
  • C 1-6 alkylsulfonyl group is a group in which the above “C 1-6 alkyl group” is bonded to a sulfonyl group, that is, a linear or branched alkylsulfonyl group having 1 to 6 carbon atoms.
  • C 1-6 alkylsulfonyl group examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, Neopentylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl and the like can be mentioned.
  • C 1-6 alkylsulfonylamino group means a monovalent group in which the above “C 1-6 alkylsulfonyl group” is bonded to a nitrogen atom.
  • the “C 1-6 alkylsulfonylamino group” includes, for example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino, tert-butylsulfonyl Examples include amino, pentylsulfonylamino, isopentylsulfonylamino, neopentylsulfonylamino, 1-ethylpropylsulfonylamino, and hexyls
  • C 1-6 alkylsulfanyl group is a group in which the above “C 1-6 alkyl group” is bonded to a sulfur atom, that is, a linear or branched alkylsulfanyl group having 1 to 6 carbon atoms.
  • C 1-6 alkylsulfanyl group examples include methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsulfanyl, butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, pentylsulfanyl, isopentylsulfanyl, Neopentylsulfanyl, 1-ethylpropylsulfanyl, hexylsulfanyl and the like can be mentioned.
  • C 3-8 cycloalkyl group means a monovalent group derived from a saturated hydrocarbon ring having 3 to 8 carbon atoms. Further, the “C 3-8 cycloalkyl group” may be cross-linked. As the “C 3-8 cycloalkyl group”, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [1,1,1] pentyl and the like can be mentioned.
  • amino C 1-6 alkylcarbonyloxy group means a group in which an amino group is bonded to the above “C 1-6 alkylcarbonyloxy group”.
  • amino C 1-6 alkylcarbonyloxy include, for example, aminoacetyloxy, aminopropionyloxy, aminobutyryloxy, aminoisobutyryloxy, aminopentanoyloxy, aminoisopentanoyloxy, amino-1- Methylbutyryloxy, aminopivaloyloxy, aminohexanoyloxy, aminoisohexanoyloxy, amino-3,3-dimethylbutyryloxy, amino-1-ethylbutyryloxy, amino-4-methylhexanoyloxy , Aminoheptanoyloxy and the like.
  • a “mono- or di-C 1-6 alkylamino group” is a group in which one or two “C 1-6 alkyl groups” are bonded to a nitrogen atom, that is, a group having 1 to 6 carbon atoms. Means a linear or branched alkylamino group.
  • the “mono or di-C 1-6 alkylamino group” includes, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, sec-butylamino, tert-butylamino, pentylamino, Examples include isopentylamino, neopentylamino, 1-ethylpropylamino, hexylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, methylethylamino and the like.
  • C 1-6 alkoxycarbonyl group refers to a group in which the above “C 1-6 alkoxy group” is bonded to carbonyl, that is, a straight-chain or branched-chain alkoxycarbonyl group having 1 to 6 carbon atoms. means.
  • C 1-6 alkoxycarbonyl group examples include, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, Pentyloxycarbonyl, neopentyloxycarbonyl, 1-ethylpropyloxycarbonyl, hexyloxycarbonyl and the like can be mentioned.
  • C 3-8 cycloalkenylene group one or more carbon - carbon double bond
  • C 3-8 cycloalkenyl carbon atoms is derived from a hydrocarbon ring of 3-8 It means a divalent group derived from a group.
  • Examples of the C 3-8 cycloalkenyl group include 3-cyclobutenyl, 3-cyclopentenyl, 2-cyclohexenyl, 3-cyclohexenyl, 2-cycloheptenyl, 3-cycloheptenyl, 2-cyclooctenyl, 3-cyclooctenyl and the like.
  • C 6-14 aryl group means an aromatic hydrocarbon group having 6-14 carbon atoms.
  • Examples of the “C 6-14 aryl group” include phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl), acenaphthenyl, azulenyl, anthryl, phenanthryl and the like.
  • C 6-14 arylene group means a divalent group derived from a C 6-14 aryl group derived from an aromatic hydrocarbon group having 6 to 14 carbon atoms.
  • Examples of the “C 6-14 aryl group” include phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl), acenaphthenyl, azulenyl, anthryl, phenanthryl and the like.
  • hydroxy C 1-6 alkyl group is a group in which one hydroxy group is bonded to the “C 1-6 alkyl group”, for example, 1-hydroxymethyl group, 1-hydroxyethyl Group, 1-hydroxypropyl group, 2-hydroxyethyl group or 3-hydroxypropyl group.
  • hydroxy C 1-6 alkoxy group is a group in which one hydroxy group is bonded to the above “C 1-6 alkoxy group”, for example, 1-hydroxymethoxy group, 1-hydroxyethoxy group Group, 1-hydroxypropoxy group, 2-hydroxyethoxy group or 3-hydroxypropoxy group.
  • “carboxy C 1-6 alkyl group” means a group in which a carboxy group is bonded to the above “C 1-6 alkyl group”.
  • Examples of the “carboxy C 1-6 alkyl group” include, for example, carboxymethyl, carboxyethyl, carboxypropyl, carboxyisopropyl, carboxybutyl, carboxyisobutyl, carboxy-sec-butyl, carboxy-tert-butyl, carboxypentyl, carboxyiso Pentyl, carboxyneopentyl, carboxy-1-ethylpropyl, carboxyhexyl and the like.
  • the “carboxy C 1-6 alkylcarbonyloxy group” means a group in which a carboxy group is bonded to the above “C 1-6 alkylcarbonyloxy group”.
  • Examples of the “carboxy C 1-6 alkylcarbonyloxy” include, for example, carboxyacetyloxy, carboxypropionyloxy, carboxybutyryloxy, carboxyisobutyryloxy, carboxypentanoyloxy, carboxyisopentanoyloxy, carboxy-1- Methylbutyryloxy, carboxypivaloyloxy, carboxyhexanoyloxy, carboxyisohexanoyloxy, carboxy-3,3-dimethylbutyryloxy, carboxy-1-ethylbutyryloxy, carboxy-4-methylhexanoyloxy , Carboxyheptanoyloxy and the like.
  • heterocyclic group refers to a monovalent monocyclic aromatic heterocyclic group containing at least one hetero atom selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, and a fused aromatic group. It means a heterocyclic group.
  • Examples of the monocyclic aromatic heterocyclic group include a 5- or 6-membered monocyclic aromatic heterocyclic group, for example, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, Thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and the like.
  • a 5- or 6-membered monocyclic aromatic heterocyclic group for example, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, Thiadiazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl and the like.
  • fused aromatic heterocyclic group examples include a bicyclic or tricyclic fused aromatic heterocyclic group, for example, indolyl, isoindolyl, indazolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, Quinolyl, isoquinolyl, benzoxazinyl, benzothiazinyl, furo [2,3-b] pyridyl, thieno [2,3-b] pyridyl, naphthyridinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, quinolyl, carbazolyl, dibenzo Thiophenyl and the like.
  • saturated heterocyclic group refers to a saturated 5-7 membered heterocyclic group containing 1-3 sulfur atoms, oxygen atoms and / or nitrogen atoms, and includes, for example, tetrahydropyranyl, tetrahydrofuranyl, oxo Tetrahydrofuranyl, morpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, 1, 4-dioxanyl, 1,1-dioxohexahydrothiopyranyl and the like.
  • heterocyclic group— indicates a divalent group derived from a heterocyclic ring
  • examples of the monocyclic aromatic heterocyclic ring of the heterocyclic ring include furan, thiophene, pyrrole, imidazole, and pyrazole Oxazole, isoxazole, thiazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyridazine, pyrimidine and the like.
  • condensed aromatic heterocycle examples include indoline, isoindoline, indazoline, benzofuran, benzothiophene, benzimidazole, benzoxazole, benzothiazole, quinoline, isoquinoline, benzoxazine, benzothiazine, furo [2,3-b] pyridine, Thieno [2,3-b] pyridine, naphthyridine, imidazopyridine, oxazolopyridine, thiazolopyridine, quinoline, carbazole, dibenzothiophene and the like.
  • saturated heterocyclic group- represents a divalent group derived from a saturated heterocycle
  • saturated heterocycle include azetidine, tetrahydropyran, tetrahydrofuran, morpholine, thiomorpholine, 1- Oxothiomorpholine, 1,1-dioxothiomorpholine, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, piperidine, piperazine, oxazolidine, isoxazolidine, thiazolidine and the like.
  • Optionally substituted means unsubstituted or substituted by any one of 1-3. In the case of di- or tri-substitution, each substituent may be the same or different.
  • the “pharmaceutically acceptable salt” refers to a salt that can be used as a medicament.
  • the compound of the present invention When the compound of the present invention has an acidic group or a basic group, it can be converted into a basic salt or an acidic salt by reacting with a base or an acid.
  • the pharmaceutically acceptable "basic salt" of compound (I) of the present invention is preferably an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt; an alkaline earth salt such as a magnesium salt or a calcium salt.
  • Metal salts organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt; It is an amino acid salt such as a glycine salt, a lysine salt, an arginine salt, an ornithine salt, a glutamate, and an aspartate, and is preferably an alkali metal salt.
  • organic base salts such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidine salt, pyridine salt, 4-pyrrolidinopyridine salt, picoline salt
  • It is an amino acid salt such as a glycine salt, a lysine salt, an
  • the pharmaceutically acceptable "acid salt" of the compound (I) of the present invention preferably, a hydrofluoride, hydrochloride, hydrobromide, hydrogen halide such as hydroiodide
  • Inorganic salts such as acid salts, nitrates, perchlorates, sulfates and phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; benzenesulfonate Arylsulfonate such as p-toluenesulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc.
  • An organic acid salt such as a glycine salt, a lysine salt, an arginine salt, an ornithine salt, a glutamate, an aspartate, and most preferably a hydrohalide (particularly hydrochloride).
  • prevention refers to, for example, a patient who does not have the disease or symptom that is expected to have a high risk of developing due to some factor related to the disease or symptom, or who has developed the disease or symptom.
  • administering a medicament containing the compound (I) of the present invention, or after treatment of the disease or condition, to a patient who is concerned about the recurrence of the disease or condition, a compound of the present invention ( Administering a medicament comprising I).
  • Treatment is the cure of a disease or condition.
  • R 1 represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkylsulfanyl group, a C 1-6 alkylcarbonyl group, a carbamoyl group or a heterocyclic group. Show.
  • R 1 is preferably a halogen atom (eg, a chlorine atom), a cyano group, a C 1-6 alkoxy group (eg, methoxy), a C 1-6 alkylsulfanyl group (eg, methylsulfanyl), a C 1-6 alkyl
  • a carbonyl group eg, acetyl
  • a carbamoyl group or a heterocyclic group eg, imidazolyl, furyl, pyridyl
  • R 2 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group.
  • R 2 is preferably a hydrogen atom, a halogen atom (eg, a fluorine atom), a C 1-6 alkyl group (eg, methyl) or a C 1-6 alkoxy group (eg, methoxy), more preferably hydrogen.
  • Ring A is
  • R 3 represents -BDEGG [wherein B represents a C 6-14 arylene group, a C 3-8 cycloalkenylene group, -heterocyclic- or -saturated heterocyclic-, and D is Represents a single bond, —O (CH 2 ) n —, — (CH 2 ) n O— or —saturated heterocycle—, n represents an integer of any one selected from 1 to 4, and E represents Represents a single bond, -O-, -N (R 10 )-, -CO- or -CONH-, and R 10 may be substituted by a hydrogen atom or any group selected from substituent group ⁇ .
  • G is a hydrogen atom, one of C 1-6 alkyl group optionally substituted with a group selected from substituent group alpha, are selected from substituent group alpha A C 3-8 cycloalkyl group optionally substituted with any group, or any group selected from substituent group ⁇ .
  • a substituent group ⁇ is a heterocyclic group, a saturated heterocyclic group, a halogen atom, a cyano group, a C 1-6 alkylcarbonyl group, a C 1-6 alkylcarbonyloxy group, C 1-6 alkylcarbonylamino group, C 1-6 alkoxycarbonyl group, C 1-6 alkoxy C 1-6 alkyl group, hydroxy C 1-6 alkyl group, hydroxy C 1-6 alkoxy group, C 1-6 alkyl sulfonyl group, C 1-6 alkylsulfonylamino group, an aminosulfonylamino group, a carboxy group, a carboxy C 1-6 alkylcarbonyloxy group, a carbamoyl group, hydrin Alkoxy groups, C 1-6 alk
  • B is preferably a C 6-14 arylene group (eg, phenylene), a C 3-8 cycloalkenylene group (eg, cyclohexenylene), -heterocycle- (eg, pyridinediyl) or -saturated heterocycle- ( For example, piperidinediyl), more preferably,
  • D is preferably a single bond, -O (CH 2 ) n- (n is 1, 2, 3 or 4),-(CH 2 ) n O- (n is 1) Or -saturated heterocycle- (eg, azetidindiyl, pyrrolidinediyl, piperidindiyl, piperazinediyl, tetrahydropyridinediyl), more preferably a single bond, -O (CH 2 ) n- (n is 2 .) Or -saturated heterocycle- (eg, azetidindiyl, pyrrolidinediyl, piperidindiyl, piperazindiyl, tetrahydropyridinediyl).
  • -saturated heterocycle- eg, azetidindiyl, pyrrolidinediyl, piperidindiyl, piperazindiyl, tetrahydropyridinediyl.
  • E is preferably a single bond, -O-, -N (R 10 )-(R 10 is a C 1-6 alkyl group optionally substituted by a hydrogen atom or a hydroxy group (eg, methyl, ethyl) ), —CO— or —CONH—, more preferably a single bond or —O—.
  • G is preferably (1) a heterocyclic group (eg, oxazolyl, imidazolyl, tetrazolyl), a saturated heterocyclic group (eg, tetrahydrofuryl, piperazinyl, morpholinyl, tetrahydropyranyl, 1,4-dioxanyl), a halogen atom ( (Eg, fluorine atom), C 1-6 alkylcarbonyloxy group (eg, methylcarbonyloxy), C 1-6 alkylcarbonylamino group (eg, methylcarbonylamino), C 1-6 alkoxycarbonyl group (eg, ethoxycarbonyl) ), Hydroxy C 1-6 alkoxy group (eg, hydroxyethoxy), aminosulfonylamino group, carboxy group, carboxy C 1-6 alkylcarbonyloxy group (eg, carboxyethylcarbonyloxy), carbamoyl group, hydroxy group, C 1 -6 al
  • N represents 3.
  • Heterocyclic groups eg, imidazolyl, oxazolyl, pyridyl
  • saturated heterocyclic groups eg, morpholinyl, thiomorpholinyl, dioxothio
  • Ruhoriniru halogen atom (e.g., fluorine atom)
  • a cyano group C 1-6 alkylcarbonyl group (e.g., methylcarbonyl), C 1-6 alkylcarbonylamino group (e.g., methyl carbonylamino), hydroxy C 1-6 Alkyl group (eg, hydroxymethyl), C 1-6 alkylsulfonyl group (eg, methylsulfonyl), C 1-6 alkylsulfonylamino group (eg, methylsulfonylamino), carboxy group, carbamoyl group, hydroxy group, C 1 Selected from -6 alkoxy groups (eg, methoxy, ethoxy),
  • Saturated heterocyclic group which may be substituted with any of the following groups (eg, azetidinyl, tetrahydro Furyl, piperidinyl, piperazinyl, dihydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, oxopyrrolidinyl, oxopiperidinyl, oxothiomorpholinyl, dioxothiomorpholinyl, 1,4-dioxanyl, sulfolanyl) And more preferably (1) a hydroxy group, an amino group, a carboxy group, an aminosulfonylamino group, a diethylphosphono group or
  • a C 1-6 alkyl group eg, methyl, ethyl, propyl, butyl, isobutyl, isopentyl
  • (2) phenyl group e.g. methyl, ethyl, propyl, butyl, isobutyl, isopentyl
  • (3) tetrahydropyranyl group e.g. tetrahydrofuranyl
  • ( 5) a piperazinyl group or (6) a morpholinyl group eg, methyl, ethyl, propyl, butyl, isobutyl, isopentyl
  • phenyl group eg, methyl, ethyl, propyl, butyl, isobutyl, isopentyl
  • (3) tetrahydropyranyl group e.g., tetrahydrofuranyl
  • ( 5) a piperazinyl group or (6) a morpholinyl
  • R 4 represents a C 1-6 alkylcarbonyl group, a C 1-6 alkylthiocarbonyl group, a carbamoyl group, a C 1-6 alkoxycarbonyl group or a carboxy group.
  • R 4 is preferably a C 1-6 alkylcarbonyl group (eg, acetyl), a C 1-6 alkylthiocarbonyl group (eg, methylthiocarbonyl), a carbamoyl group, a C 1-6 alkoxycarbonyl group (eg, methoxycarbonyl, Ethoxycarbonyl) or a carboxy group.
  • R 5 represents a hydrogen atom, a C 1-6 alkyl group or a halogen atom.
  • R 5 is preferably a hydrogen atom, a C 1-6 alkyl group (eg, methyl) or a halogen atom (eg, chlorine atom).
  • R 6 represents a C 1-6 alkyl group, a halogen atom, an amino group, a hydroxy C 1-6 alkyl group, a carboxy C 1-6 alkyl group or a hydrogen atom (provided that T is CHCH— and U is NN— Case).
  • R 6 is preferably a C 1-6 alkyl group (eg, methyl), a halogen atom (eg, chlorine atom), an amino group, a hydroxy C 1-6 alkyl group (eg, hydroxyethyl), a carboxy C 1-6 An alkyl group (eg, carboxymethyl) or a hydrogen atom (provided that T is CHCH— and U is NN—).
  • R 7 represents a hydrogen atom or a C 1-6 alkyl group.
  • R 7 is preferably a hydrogen atom or a C 1-6 alkyl group (eg, methyl, ethyl).
  • R 8 represents a hydrogen atom, a C 1-6 alkyl group or a C 1-6 alkylcarbonyl group.
  • R 8 is preferably a hydrogen atom or a C 1-6 alkylcarbonyl group (eg, methylcarbonyl, ethylcarbonyl).
  • R 9 represents a hydrogen atom or a C 1-6 alkyl group.
  • R 9 is preferably a hydrogen atom or a C 1-6 alkyl group (eg, methyl).
  • Ring A is
  • R 4 is an acetyl, carbamoyl or carboxy group and R 5 is a methyl group;
  • Ring A is
  • R 7 is a methyl group and R 9 is a hydrogen atom; (3) Ring A is
  • Ring A is
  • R 6 is a chlorine, methyl or carboxymethyl group.
  • R 1 is a halogen atom (eg, a chlorine atom), a cyano group, a C 1-6 alkoxy group (eg, methoxy, isopropoxy), a C 1-6 alkylsulfanyl group (eg, methylsulfanyl), a C 1-6 alkyl
  • a carbonyl group eg, acetyl
  • a carbamoyl group or a heterocyclic group eg, imidazolyl, furyl, pyridyl
  • R 2 is a hydrogen atom, a halogen atom (eg, a fluorine atom), a C 1-6 alkyl group (eg, methyl) or a C 1-6 alkoxy group (eg, methoxy);
  • a ring is
  • R 3 is -BDEGG
  • B is a C 6-14 arylene group (eg, phenylene), a C 3-8 cycloalkenylene group (eg, cyclohexenylene), a -heterocycle- (eg, pyridinediyl) or a -saturated heterocycle- (eg, ⁇ lysine diyl);
  • D is a single bond, -O (CH 2 ) n- (n is 1, 2, 3 or 4),-(CH 2 ) n O- (n is 1) or -saturated
  • a heterocycle- eg, azetidindiyl, pyrrolidinediyl, piperidindiyl, piperazindiyl, tetrahydropyridinediyl);
  • E is a single bond, —O—, —N (R 10 ) — (R 10 is a hydrogen atom or a C 1-6 alkyl group optionally substituted with a
  • G is (1) a heterocyclic group (eg, oxazolyl, imidazolyl, tetrazolyl), a saturated heterocyclic group (eg, tetrahydrofuryl, piperazinyl, morpholinyl, tetrahydropyranyl, 1,4-dioxanyl), a halogen atom (eg, fluorine) Atom), a C 1-6 alkylcarbonyloxy group (eg, methylcarbonyloxy), a C 1-6 alkylcarbonylamino group (eg, methylcarbonylamino), a C 1-6 alkoxycarbonyl group (eg, ethoxycarbonyl), hydroxy C 1-6 alkoxy group (eg, hydroxyethoxy), aminosulfonylamino group, carboxy group, carboxy C 1-6 alkylcarbonyloxy group (eg, carboxyethylcarbonyloxy), carbamo
  • a heterocyclic group eg,
  • N represents 3.
  • Heterocyclic groups eg, imidazolyl, oxazolyl, pyridyl
  • saturated heterocyclic groups eg, morpholinyl, thiomorpholinyl, dioxothio
  • Ruhoriniru halogen atom (e.g., fluorine atom)
  • a cyano group C 1-6 alkylcarbonyl group (e.g., methylcarbonyl), C 1-6 alkylcarbonylamino group (e.g., methyl carbonylamino), hydroxy C 1-6 Alkyl group (eg, hydroxymethyl), C 1-6 alkylsulfonyl group (eg, methylsulfonyl), C 1-6 alkylsulfonylamino group (eg, methylsulfonylamino), carboxy group, carbamoyl group, hydroxy group, C 1 Selected from -6 alkoxy groups (eg, methoxy, ethoxy),
  • R 4 represents a C 1-6 alkylcarbonyl group (eg, acetyl), a C 1-6 alkylthiocarbonyl group (eg, methylthiocarbonyl), a carbamoyl group, a C 1-6 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl) Or a carboxy group;
  • R 5 is a hydrogen atom
  • R 3 is -BDEGG;
  • B is a C 6-14 arylene group (eg, phenylene) or -saturated heterocycle- (eg, piperidindiyl);
  • D is a single bond, -O (CH 2 ) n- (n is 1, 2, 3 or 4) or -saturated heterocycle- (eg, azetidindiyl, piperidindiyl);
  • E is a single bond or -O-;
  • G is (1) a saturated heterocyclic group (eg, morpholinyl), an aminosulfonylamino group, a carboxy group, a hydroxy group, an amino group, a mono- or di-C 1-6 alkylphosphono group (eg, diethylphosphono), and
  • N represents 3.
  • a C 1-6 alkyl group eg, methyl, ethyl, propyl, butyl
  • R 4 is a C 1-6 alkylcarbonyl group (eg, acetyl) or a carbamoyl group;
  • R 5 is a hydrogen atom or a C 1-6 alkyl group (eg, methyl);
  • R 6 is a C 1-6 alkyl group (eg, methyl);
  • R 7 is a C 1-6 alkyl group (eg, methyl);
  • R 9 is a hydrogen atom; Compound (I).
  • R 3 is -BDEGG;
  • B is a C 6-14 arylene group (eg, phenylene) or -saturated heterocycle- (eg, piperidindiyl);
  • D is a single bond, -O (CH 2 ) n- (n is 1, 2, 3 or 4),-(CH 2 ) n O- (n is 1) or -saturated
  • a heterocycle- eg, azetidindiyl, pyrrolidinediyl, piperidindiyl, piperazindiyl);
  • E is a single bond, -O- or -CO-;
  • G is (1) a saturated heterocyclic group (eg, morpholinyl), an aminosulfonylamino group, a carboxy group, a hydroxy group, an amino group, a mono- or di-C 1-6 alkylphosphono group (eg, diethylphosphono), and
  • N represents 3.
  • a C 1-6 alkyl group (eg, methyl, ethyl, propyl, butyl) optionally substituted with any group selected from (2) C 6-14 aryl (Eg, phenyl) or (3) substituted with any group selected from C 1-6 alkylcarbonyl group (eg, methylcarbonyl), carboxy group, C 1-6 alkyl group (eg, methyl), and amino group
  • An optionally substituted heterocyclic group eg, piperazinyl, piperidinyl, tetrahydropyranyl, morpholinyl
  • R 4 is a C 1-6 alkylcarbonyl group (eg, acetyl), a C 1-6 alkylthiocarbonyl group (eg, methylthiocarbonyl) or a carbamoyl group
  • R 5 is a hydrogen atom or a C 1-6 alkyl group (eg, methyl)
  • R 6 is a hydrogen atom or a C
  • Preferred specific examples of compound (I) include, for example, the compounds of Examples 1 to 21 and Examples 22 to 375 described in Tables 1-1 to 1-71 below (hereinafter, also referred to as compounds 1 to 375). Among them, (1) 3-acetyl-5,6-dimethoxy-2-methyl-1- [4- (morpholin-4-yl) phenyl] indole
  • the compound (I) of the present invention can be produced by applying various known production methods utilizing characteristics based on the basic skeleton or the type of the substituent.
  • Known methods include, for example, methods described in "ORGANIC FUNCTIONAL GROUP PREPARATIONS", 2nd edition, ACADEMIC PRESS, INC., 1989, “Comprehensive Organic Transformations”, VCH Publishers Inc., 1989.
  • it is effective in production technology to protect the functional group with an appropriate protecting group at the stage of a raw material or an intermediate, or to replace the functional group with a group that can be easily converted to the functional group. It may be.
  • Examples of such a functional group include an amino group, a hydroxyl group, a carboxyl group, and the like.
  • Examples of such a protective group include, for example, "Protective Groups in Organic Synthesis (Third Edition, 1999)” by TWGreene and PG Wuts. And the protecting group described in ", and may be appropriately selected and used depending on the reaction conditions. According to such a method, a desired compound can be obtained by introducing the substituent and carrying out the reaction, and then removing the protective group or converting it to a desired group, if necessary.
  • the prodrug of the compound of the present invention can be produced by introducing a specific group at the stage of a raw material or an intermediate, or by performing a reaction using the obtained compound of the present invention, in the same manner as the above protective group. it can.
  • the reaction can be carried out by applying a method known to those skilled in the art, such as ordinary esterification, amidation, dehydration, hydrogenation and the like.
  • a method for producing the compound of the present invention will be described.
  • the manufacturing method is not limited to the following method at all.
  • a specific production method is not described, a raw material compound in each reaction can be easily obtained and used as a commercially available product, or can be produced according to a method known per se or a method analogous thereto. .
  • the ring A of the compound (I) of the present invention is obtained by coupling the compound (a-1) with the compound (a-2).
  • Compound (a-1) used in the present production method can be produced by a method known per se.
  • R 1 , R 3 , R 5 , T and U have the same meanings as described above, and X represents a leaving group such as a halogen atom or a trifluoromethanesulfonyloxy group.
  • Step A comprises a base such as an inorganic carbonate or phosphate (eg, potassium carbonate, cesium carbonate, tripotassium phosphate), a copper compound (eg, CuBr, CuI) and a ligand (eg, N, N′-dimethylethylenediamine, 1,2-diaminocyclohexane, trans-N, N'-dimethylcyclohexane-1,2-diamine) is a nucleophilic substitution reaction using an inert solvent, compound (a-1) and compound (a- This is a step of producing an intermediate compound (a-3) of the present compound (I) from 2).
  • a base such as an inorganic carbonate or phosphate (eg, potassium carbonate, cesium carbonate, tripotassium phosphate), a copper compound (eg, CuBr, CuI) and a ligand (eg, N, N′-dimethylethylenediamine, 1,2-diaminocyclohexan
  • the amount of compound (a-2) used in Step A is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound (a-1).
  • the amount of the inorganic carbonate or phosphate to be used is generally 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (a-1).
  • the amount of the copper compound to be used is generally 0.01 to 0.3 equivalent, preferably 0.05 to 0.1 equivalent, relative to compound (a-1).
  • the amount of the ligand to be used is generally 0.01 to 0.3 equivalent, preferably 0.01 to 0.15 equivalent, relative to compound (a-1).
  • Inert solvents used are, for example, alcohols such as methanol, ethanol, propanol, 2-propanol or butanol; aromatic hydrocarbons such as benzene, toluene or xylene; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane Or ethers such as 1,2-dimethoxyethane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone or hexamethylphosphorotriamide Or methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, fluorobenzene, trichloromethylbenzene or trifluoromethylbenzene Halogenated hydrocarbons UNA, or a
  • the reaction temperature varies depending on the starting compound and the solvent used, but is usually from 0 ° C. to the reflux temperature of the reaction mixture, and preferably from room temperature to the reflux temperature of the reaction mixture.
  • the reaction time varies depending on the starting compound, the solvent used and the reaction temperature, but is usually 30 minutes to 72 hours, preferably 30 minutes to 24 hours.
  • R 4 is a C 1-6 lower alkylcarbonyl group, wherein the intermediate compound (a-3) obtained in the preparation method A is a compound (b-1) To produce the compound (b-2) of the present invention.
  • R 1 , R 3 , R 5 , T and U have the same meanings as described above, and R 11 represents C 1-6 lower alkyl.
  • Step B is a step of producing the present compound (b-2) from the compound (a-3) and the compound (b-1) in an inert solvent in the presence of titanium (IV) chloride.
  • the inert solvents used include those described above.
  • the amount of compound (b-1) used in Step B is usually 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound (a-3).
  • the amount of titanium chloride (IV) to be used is generally 1-2 equivalents, preferably 1-1.5 equivalents, relative to compound (a-3).
  • the reaction temperature varies depending on the starting compound or the solvent used, but is usually from 0 ° C to 50 ° C, preferably from 0 ° C to room temperature.
  • the reaction time varies depending on the starting compound, the solvent used and the reaction temperature, but is usually 30 minutes to 24 hours, preferably 30 minutes to 2 hours.
  • R 4 is a carbamoyl group
  • a compound (c-2) obtained by reacting the intermediate compound (a-3) obtained by the method A with chlorosulfonyl isocyanate This is a method for obtaining the present compound (c-2) from -1).
  • R 1 , R 3 , R 5 , T and U have the same meaning as described above.
  • Step C1 is a step of reacting compound (a-3) with chlorosulfonyl isocyanate in an inert solvent to produce intermediate compound (c-1).
  • Step C2 is a step of removing the chlorosulfonyl group of the intermediate compound (c-1) with acetic acid or the like to produce the present compound (c-2).
  • the inert solvents used include those described above.
  • the amount of the chlorosulfonyl isocyanate to be used in Step C1 is generally 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound (a-3).
  • the reaction temperature varies depending on the starting compound or the solvent used, but is usually from 0 ° C to 50 ° C, preferably from 0 ° C to room temperature.
  • the reaction time varies depending on the starting compound, the solvent used and the reaction temperature, but is usually 30 minutes to 24 hours, preferably 30 minutes to 2 hours.
  • R 4 is a carbamoyl group
  • a method for preparing a compound (c-2), wherein the intermediate compound (a-3) obtained by the method A is iodinated, and the intermediate compound (d-1) This is a method for obtaining the compound (c-2) of the present invention by cyanation and hydrolysis of the cyano group of the intermediate compound (d-2).
  • R 1 , R 3 , R 5 , T and U have the same meaning as described above.
  • Step D1 is a step of reacting compound (a-3) with an iodizing agent such as N-iodosuccinimide in an inert solvent to produce intermediate compound (d-1).
  • Step D2 is carried out in an inert solvent in the presence of a catalyst such as tris (dibenzylideneacetone) dipalladium (0) and 1,1′-bis (diphenylphosphino) ferrocene, by adding compound such as copper cyanide to compound (d-1).
  • a catalyst such as tris (dibenzylideneacetone) dipalladium (0) and 1,1′-bis (diphenylphosphino) ferrocene
  • This is a step of producing an intermediate compound (d-2) by reacting the cyanating agent with Step D3 is a step of subjecting the cyano group of the compound (d-2) to a hydrolysis reaction in an inert solvent to convert the cyano group into a carbamoyl group, thereby producing the compound (c-2) of the present invention.
  • the hydrolysis reaction of the cyano group can be performed according to a method known per se.
  • the inert solvents used include those described above.
  • the amount of the iodinating agent such as N-iodosuccinimide in Step D1 to be used is generally 1-2 equivalents, preferably 1-1.1 equivalents, relative to compound (a-3).
  • the reaction temperature varies depending on the starting compound or the solvent used, but is usually from 0 ° C to 50 ° C, preferably from 0 ° C to room temperature.
  • the reaction time varies depending on the starting compound, the solvent used and the reaction temperature, but is usually 30 minutes to 24 hours, preferably 30 minutes to 2 hours.
  • the amount of the cyanating agent such as copper cyanide to be used in Step D2 is generally 1 to 5 equivalents, preferably 1 to 4 equivalents, relative to compound (d-1).
  • the amount of the catalyst such as tris (dibenzylideneacetone) dipalladium (0) and 1,1′-bis (diphenylphosphino) ferrocene is usually 0.01 to 0.5 with respect to the compound (d-1).
  • the equivalent preferably 0.01 to 0.2 equivalent.
  • the reaction temperature varies depending on the starting compound or the solvent used, but is usually from 0 ° C to 50 ° C, preferably from 0 ° C to room temperature.
  • the reaction time varies depending on the starting compound, the solvent used and the reaction temperature, but is usually 30 minutes to 24 hours, preferably 30 minutes to 10 hours.
  • Compound (e-1) used in the present production method can be produced by a method known per se.
  • R 1 , R 3 , R 5 , T, U and X have the same meanings as described above, and Z represents —N (R 8 ) —, an oxygen atom or a sulfur atom.
  • Step E is a step of subjecting compound (e-1) and compound (e-2) to a coupling reaction using an organometallic catalyst in an inert solvent in the presence of a base to produce compound (e-3) of the present invention.
  • This is the step of performing This reaction may be carried out in the presence of a phosphine ligand, if necessary.
  • the inert solvents used include those described above.
  • Examples of the base include inorganic carbonates and phosphates (for example, potassium carbonate, cesium carbonate, and tripotassium phosphate).
  • Examples of the organometallic catalyst include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0), and dichlorobis (triphenylphosphine) palladium (II).
  • phosphine ligands examples include 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (BINAP), tris (2-methylphenyl) phosphine, 1,1′-bis (diphenylphosphino) ferrocene, -Dicyclohexylphosphino-2 ', 6'-dimethoxybiphenyl, 2-dicyclohexylphosphino-2', 4,6'-triisopropylbiphenyl and the like.
  • reaction conditions such as reaction temperature and reaction time vary depending on the reaction reagents and reaction solvents used, but the reaction temperature is usually -30 ° C to 150 ° C, and the reaction time is 30 minutes to 20 hours.
  • Compound (f-1) used in the present production method can be produced by a method known per se.
  • R 1 , R 3 , R 7 , T, U and X have the same meaning as described above.
  • Step F subjecting compound (f-1) and compound (e-2) to a coupling reaction using an organometallic catalyst in an inert solvent in the presence of a base to produce compound (f-2) of the present invention This can be performed under the same conditions as in the reaction of Step E described in Production Method E.
  • Compound (g-1) used in the present production method can be produced by a method known per se.
  • R 1 , R 3 , T, U and X are as defined above.
  • Step G is a step of subjecting compound (g-1) and compound (e-2) to a coupling reaction using an organometallic catalyst in an inert solvent in the presence of a base to produce compound (g-2) of the present invention. This can be performed under the same conditions as in the reaction of Step E described in Production Method E.
  • R 1 , R 3 , T, U and X have the same meaning as described above.
  • Step H comprises a base such as an inorganic carbonate or phosphate (eg, potassium carbonate, cesium carbonate, tripotassium phosphate), a copper compound (eg, CuBr, CuI) and a ligand (eg, N, N′-dimethylethylenediamine, 1,2-diaminocyclohexane, trans-N, N'-dimethylcyclohexane-1,2-diamine) is a nucleophilic substitution reaction using an inert solvent, compound (h-1) and compound (a- This is a step of producing the compound (h-2) of the present invention from 2), and can be carried out under the same conditions as in the reaction of Step A described in Production Method A.
  • a base such as an inorganic carbonate or phosphate (eg, potassium carbonate, cesium carbonate, tripotassium phosphate), a copper compound (eg, CuBr, CuI) and a ligand (eg, N, N′-di
  • Production method I comprises reacting compound (i-1) with compound (a-2), reducing the nitro group by a method known per se, and converting the amino group of compound (i-3) to chloroacetyl chloride. After the amidation, the compound (i-5) is subjected to a ring closure reaction to react the resulting compound (i-5) with the compound (i-6), whereby the ring A of the compound (I) of the present invention is formed.
  • R 1 , R 3 , R 7 , R 9 , T, U and X are as defined above.
  • Step I1 is a step of subjecting compound (i-1) and compound (a-2) to a coupling reaction using an organometallic catalyst in an inert solvent in the presence of a base to produce compound (i-2). It is. This reaction may be carried out in the presence of a phosphine ligand, if necessary, and can be carried out under the same conditions as in the reaction of Step E described in Production Method E.
  • Step I2 is a step of producing a compound (i-3) by reducing a nitro group of the compound (i-2) to an amino group by a method known per se.
  • Step I3 is a step of producing compound (i-4) by reacting chloroacetyl chloride with an amino group of compound (i-3) in an inert solvent in the presence of a base such as triethylamine.
  • Step I4 is a step of subjecting compound (i-4) to intramolecular ring closure in an inert solvent in the presence of a base such as sodium hydride to produce compound (i-5).
  • Step I5 is a step of reacting compound (i-5) in an inert solvent in the presence of a base such as sodium hydride to produce compound (i-7) of the present invention.
  • the inert solvents used include those described above.
  • the amount of chloroacetyl chloride to be used in Step I3 is generally 1 to 2 equivalents, preferably 1 to 1.2 equivalents, relative to compound (i-3).
  • the amount of the base to be used is generally 1-3 equivalents, preferably 1-1.5 equivalents, relative to compound (i-3).
  • the reaction conditions such as the reaction temperature and the reaction time vary depending on the used reaction reagent, reaction solvent and the like, but usually the reaction temperature is from -30 ° C to 50 ° C, and the reaction time is from 30 minutes to 5 hours.
  • the amount of the base to be used in Step I4 is generally 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound (i-4).
  • the reaction conditions such as the reaction temperature and the reaction time vary depending on the used reaction reagent, reaction solvent and the like, but usually the reaction temperature is from -30 ° C to 50 ° C, and the reaction time is from 30 minutes to 5 hours.
  • the amount of compound (i-6) to be used in Step I5 is generally 1 to 3 equivalents, preferably 1 to 1.5 equivalents, relative to compound (i-5).
  • the reaction conditions such as the reaction temperature and the reaction time vary depending on the used reaction reagent, reaction solvent and the like, but usually the reaction temperature is from -30 ° C to 50 ° C, and the reaction time is from 30 minutes to 5 hours.
  • Production method J comprises reacting compound (j-3) obtained from the reaction of compound (j-1) with compound (j-2) with compound (a-2), or compound (i) obtained by production method I. -4) and compound (j-2) to give compound (j-4), and subjecting compound (j-4) to a ring-closure reaction by a method known per se to give compound (I) of the present invention.
  • a ring-closure reaction by a method known per se to give compound (I) of the present invention.
  • R 1 , R 3 , R 6 , T, U and X are as defined above.
  • Step J1 is a step of reacting compound (j-1) with compound (j-2) in an inert solvent, amidating the amino group of compound (j-1) to produce compound (j-3). is there. This reaction may be performed, if necessary, in the presence of a base such as triethylamine, pyridine, 4-dimethylaminopyridine, or potassium carbonate.
  • Step J2 is a step of subjecting compound (j-3) and compound (a-2) to a coupling reaction using an organometallic catalyst in an inert solvent in the presence of a base to produce compound (j-4). It is a process.
  • Step J3 is a step of producing a compound (j-4) by reacting the compound (i-4) obtained by the production method I with the compound (j-2) in an inert solvent.
  • the reaction can be performed under the same conditions as in the reaction of Step J1.
  • Step J4 is a step of subjecting compound (j-4) to intramolecular ring closure in an inert solvent by a method known per se to produce compound (j-5) of the present invention.
  • the inert solvents used include those described above.
  • the compound (j-2) is not only in the form of a free acid, but also in a salt (eg, a salt with sodium, potassium, calcium, triethylamine, pyridine, etc.) or a reactive derivative (eg, acid chloride, acid bromide, etc.).
  • the reaction is preferably performed in the presence of a condensing agent.
  • the condensing agent include N, N'-dicyclohexylcarbodiimide N, N'-disubstituted carbodiimides such as 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N '-(4-diethylamino Carbodiimide compounds such as cyclohexyl) carbodiimide; azolide compounds such as N, N'-carbonyldiimidazole and N, N'-thionyldiimidazole are used.
  • the amount of compound (j-2) to be used in Step J1 is generally 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (j-1).
  • the amount of the base to be used is generally 1 to 5 equivalents, preferably 1 to 3 equivalents, relative to compound (j-1).
  • the reaction conditions such as the reaction temperature and the reaction time vary depending on the used reaction reagent, reaction solvent and the like, but usually the reaction temperature is from -30 ° C to 100 ° C, and the reaction time is from 30 minutes to 20 hours.
  • Compound (k-1) used in the present production method can be produced by a method known per se.
  • R 1 , R 3 , T, U and X are as defined above.
  • the inert solvent to be used includes those described above.
  • Step K is a step of subjecting compound (k-1) and compound (e-2) to a coupling reaction using an organometallic catalyst in an inert solvent in the presence of a base to produce compound (k-2) of the present invention. This can be performed under the same conditions as in the reaction of Step E described in Production Method E.
  • the compound (I) of the present invention produced by the above method may be purified to any purity by subjecting it to conventional purification means, for example, concentration, extraction, chromatography, reprecipitation, recrystallization and the like. Can be. Further, if necessary, a pharmaceutically acceptable salt thereof can be obtained by treating with an acid or a base in a suitable solvent. Further, the compound (I) of the present invention or a pharmaceutically acceptable salt thereof is allowed to stand in the air, treated with water, a water-containing solvent or another solvent (eg, alcohol, etc.), or recrystallized. As a result, water (or solvent) may be absorbed and may become hydrate (or solvate) with adsorbed water (or adsorption solvent). Such various hydrates, solvates and polymorphic compounds are also included.
  • conventional purification means for example, concentration, extraction, chromatography, reprecipitation, recrystallization and the like.
  • a pharmaceutically acceptable salt thereof can be obtained by treating with an acid or a base in a
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be, depending on the type or combination of substituents, a geometric isomer such as a cis-form or a trans-form, a tautomer or an optical isomer such as a d-form or an l-form.
  • a geometric isomer such as a cis-form or a trans-form
  • a tautomer or an optical isomer such as a d-form or an l-form.
  • various isomers such as isomers may exist
  • the compound (I) of the present invention may have all isomers, stereoisomers and mixtures of these isomers and stereoisomers in any ratio unless otherwise specified. Is also included.
  • These optical isomers and a mixture of isomers can be isolated by a known resolving means (for example, see J.
  • the compound (I) of the present invention is a labeled product, that is, one or more atoms constituting the compound (I) of the present invention are isotopes (for example, 2 H, 3 H, 13 C, 14 C, Compounds substituted with 35 S etc. are also included.
  • the present invention also includes pharmaceutically acceptable so-called prodrugs of the compound (I) of the present invention.
  • a pharmaceutically acceptable prodrug is a compound having a group that can be converted to the amino group, hydroxyl group, carboxy group, or the like of compound (I) of the present invention by hydrolysis or under physiological conditions. Examples of a group that forms such a prodrug include Prog. @Med., Vol. 5, pp. 2157-2161, 1985, and "Development of Drugs" (Hirokawa Shoten, 1990), Vol. 7, Molecular Design 163-198. It is the group described on the page.
  • the prodrug when an amino group is present in compound (I) of the present invention, a compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group Is eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation Tert-butylated compound, etc.).
  • the amino group I eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation Tert-butylated compound, etc.
  • the hydroxyl group is acylated, alkylated, phosphorylated, boronated, or the like.
  • Oxidized compounds eg, whose hydroxyl groups are acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated Is a compound or the like which is dimethylaminomethyl carbonylation.
  • the carboxy group is esterified or amidated (for example, the carboxy group is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified). Dimethylaminomethyl esterification, pivaloyloxymethyl esterification, 1-ethoxycarbonyloxyethyl esterification, 1-cyclohexyloxycarbonyloxyethyl esterification, amidation or methylamidation, etc.). No.
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof has a cyclin-dependent kinase (CDK) 8 inhibitory activity, and is useful in mammals (human, horse, cow, dog, cat, rat, mouse, hamster, etc.).
  • CDK cyclin-dependent kinase
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof includes, for example, osteoporosis, osteogenesis imperfecta, achondroplasia, fibrous ostitis (hyperparathyroidism), osteomalacia, p.
  • the compound (I) of the present invention may be used as it is or in combination with a pharmaceutically acceptable carrier, and may be orally or parenterally administered to a mammal (preferably a human) as a medicament (ie, a pharmaceutical composition). Can be administered.
  • cancers to which the compound (I) of the present invention is applied include, for example, colorectal cancer (eg, colon cancer, rectal cancer, anal cancer, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor), Lung cancer (eg, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma), mesothelioma, pancreatic cancer (eg, pancreatic ductal cancer, pancreatic endocrine tumor), pharyngeal cancer, laryngeal cancer, esophageal cancer, gastric cancer (eg, nipple) Adenocarcinoma, mucinous adenocarcinoma, adenosquamous cell carcinoma), duodenal cancer, small intestine cancer, breast cancer (eg, invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer), ovarian cancer (eg, epithelial ovarian
  • the compound (I) of the present invention is used for breast cancer, pancreatic cancer, bladder cancer, prostate cancer, esophageal cancer, gastric cancer, uterine cancer, ovarian cancer, brain tumor, colon cancer (eg, colon cancer, rectal cancer), blood cancer (for example, it is effective against at least one kind of cancer selected from the group consisting of acute myeloid leukemia, multiple myeloma), liver cancer (eg, hepatocellular carcinoma), skin cancer, lung cancer, and thyroid cancer.
  • the medicament of the present invention can be produced by a known production method generally used in the field of formulation technology (eg, a method described in the Japanese Pharmacopoeia). Further, the medicine of the present invention may contain, if necessary, excipients, binders, disintegrants, lubricants, sweeteners, surfactants, suspending agents, emulsifiers, coloring agents which are usually used in the field of pharmaceutical preparations. Additives such as preservatives, fragrances, flavoring agents, stabilizers, and thickeners can be appropriately contained in appropriate amounts.
  • the above-mentioned pharmaceutically acceptable carriers include these additives.
  • tablets can be manufactured using excipients, binders, disintegrants, lubricants, etc.
  • pills and granules can be manufactured using excipients, binders, and disintegrants.
  • Powders and capsules can be manufactured using excipients and the like
  • syrups can be manufactured using sweeteners and the like
  • emulsions and suspensions can be manufactured using suspending agents, surfactants, emulsifiers and the like.
  • excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium hydrogen carbonate, calcium phosphate, calcium sulfate.
  • binders include 5 to 10% by weight starch paste, 10 to 20% by weight gum arabic solution or gelatin solution, 1 to 5% by weight tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, and glycerin.
  • disintegrants include starch and calcium carbonate.
  • lubricants include magnesium stearate, stearic acid, calcium stearate, purified talc.
  • sweetening agents include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup.
  • surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxyl 40 stearate.
  • suspending agents include gum arabic, sodium alginate, sodium carboxymethylcellulose, methylcellulose, bentonite.
  • emulsifiers include gum arabic, tragacanth, gelatin, polysorbate 80.
  • the tablet may be added to the compound of the present invention by, for example, an excipient (eg, lactose, sucrose, starch), a disintegrant (eg, starch, carbonate) according to a method known per se. Calcium), a binder (eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose) or a lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000) and then compression-molded.
  • an excipient eg, lactose, sucrose, starch
  • a disintegrant eg, starch, carbonate
  • a binder eg, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose
  • a lubricant eg, talc, magnesium stearate, polyethylene glycol 6000
  • the injections include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, intraperitoneal injections, infusions, and the like.
  • Such injections are prepared by a method known per se, that is, by dissolving, suspending or emulsifying the compound (I) of the present invention in a sterile aqueous or oily liquid.
  • the aqueous liquid include physiological saline, isotonic liquid containing glucose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium chloride) and the like.
  • the aqueous liquid contains a suitable solubilizing agent, for example, an alcohol (eg, ethanol), a polyalcohol (eg, propylene glycol, polyethylene glycol), a nonionic surfactant (eg, polysorbate 80, HCO-50). May be.
  • the oily liquid examples include sesame oil and soybean oil.
  • the oily liquid may contain a suitable solubilizer.
  • the solubilizer include benzyl benzoate and benzyl alcohol.
  • the injection includes a buffer (eg, phosphate buffer, sodium acetate buffer), a soothing agent (eg, benzalkonium chloride, procaine hydrochloride), a stabilizer (eg, human serum albumin, polyethylene glycol). And a preservative (eg, benzyl alcohol, phenol) and the like.
  • the prepared injection solution is usually filled into an ampoule.
  • the content of the additive in the medicament of the present invention varies depending on the form of the preparation, but is usually about 1 to about 99.9% by weight, preferably about 10 to about 90% by weight, based on the whole preparation. is there.
  • the dose of the compound of the present invention or a pharmaceutically acceptable salt thereof varies depending on the administration subject, symptoms, and other factors.
  • the daily dose Is about 1 to about 1000 mg, preferably about 3 to about 300 mg, more preferably about 10 to about 200 mg of the compound of the present invention, and it is desirable to administer these once or several times.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof when used as an anticancer agent, it can be used in combination with another agent, for example, an existing anticancer agent, as long as its efficacy is not impaired.
  • the administration timing is not limited, and these may be administered to the administration subject simultaneously or at an interval.
  • the dose can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention or a pharmaceutically acceptable salt thereof and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • Existing anticancer agents include, for example, chemotherapeutic agents, hormonal therapeutic agents, immunotherapeutic agents, molecular targeted drugs, immune checkpoint inhibitors (anti-PD-1 antibody, anti-PD-L1 antibody) and the like.
  • chemotherapeutic agent for example, an alkylating agent, an antimetabolite, an anticancer antibiotic, a plant-derived anticancer agent and the like are used.
  • alkylating agent examples include, for example, nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambucil, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitobronitol, mellon Phalan, dacarbazine, ranimustine, bendamustine, procarbazine, sodium estramustine phosphate, triethylenemelamine, carmustine, lomustine, streptozocin, pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambrostine hydrochloride Pydium, fotemustine, prednimustine, bumitepa, ribomustine, temozolomide, threo Rufan, trofosf
  • antimetabolites include, for example, mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enocitabine, cytarabine, cytarabine octphosphate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, doxyfluridine, carmofur, galocitabine, emitefur, capecitabine), aminopterin, nerzarabine, leucovorin calcium, tabloid, butosin, folinate calcium, levofolinate calcium, cladribine, clofarabine, nerabrabine, emmitefurin, fludarabine, fludarabine, fludarabine Statins, pyritrexime, idoxiuridine, mitoguazone, thiazofurin and their D S formulation, or the like is used.
  • 5-FU drugs eg
  • anticancer antibiotics include, for example, actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride , Neocarzinostatin, mythramycin, sarcomycin, carcinophilin, mitotane, sorbicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and DDS preparations thereof.
  • plant-derived anticancer agent for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine, and DDS preparations thereof are used.
  • ⁇ hormone therapeutic agent '' for example, phosphestrol, diethylstilbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, guestlinone, meparttricin, Raloxifene, olmeloxifene, revolmeloxifene, antiestrogen (eg, tamoxifen citrate, toremifene citrate), pill preparation, mepithiostane, testolactone, aminoglutethimide, LH-RH agonist (eg, goserelin acetate, buserelin) , Leuprorelin), droloxifene, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitors (eg, fadrozole),
  • immunotherapeutic agent examples include biological response modifiers (e.g., picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody) and the like are used.
  • biological response modifiers e.g., picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacterium parvum, levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody
  • molecular targeted drug examples include, for example, tositumomab, ibritumomab, alemtuzumab, axitinib, bevacizumab, afatinib, osimertinib, bortezomib, bostinib, carfilzomib, cetuximab, dasatinib, denosumabuemu, edrecolibumeb, edrecolibumeb, edrecolimb Ozogamicin, imatinib, ipilimumab, lapatinib, lenalidomide, nilotinib, nimotuzumab, olaparib, panitumumab, pazopanib, pertuzumab, rituximab, ofatumumab, mogamulizumab, brentuxumabuxantumizumab,
  • Thalidomide trastuzumab, trastuzumab Mutanshin, tretinoin, vandetanib, vorinostat, Kabozanchinibu, Trametinib, Dabrafenib, crizotinib, Arekuchinibu, Serichinibu, RUXOLITINIB, Iburuchinibu, Paruboshikuribu, Riboshikuribu, Abemashikuribu, REGORAFENIB, Pirararishibu, lenvatinib, vemurafenib or the like is used.
  • the “immune checkpoint inhibitor” for example, ipilimumab, tremelimumab, nivolumab, pembrolizumab, averumab, atezolizumab, durvalumab and the like are used.
  • the two layers were separated, the aqueous layer was extracted with 200 mL of diisopropyl ether, the diisopropyl ether layers were combined, washed with 200 mL of water, and diisopropyl ether was distilled off under reduced pressure. Diisopropyl ether (50 mL) was added to the residue, 1 M hydrochloric acid (200 mL) was added under ice-cooling, and the insoluble matter was filtered off. The two layers were separated, and the diisopropyl ether layer was extracted with 40 mL of 1M hydrochloric acid, and the aqueous layers were combined and neutralized with 20 g of sodium bicarbonate.
  • the diethyl ether layer was washed with saturated saline and dried (Na 2 SO 4 ), and then diethyl ether was distilled off under reduced pressure.
  • the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 2: 1 ⁇ 1: 1 ⁇ 1: 2, V / V).
  • the solvent of the target fraction was distilled off under reduced pressure to obtain 15.3 g of a brown oil of 2- (1-phenylpiperidin-4-yloxy) ethanol.
  • the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 20: 1 ⁇ 10: 1, V / V).
  • the solvent of the target fraction was distilled off under reduced pressure to obtain 17.7 g (yield: 80%) of the title compound as a pale orange oil.
  • the methylene chloride layer was sequentially washed with 5% aqueous sodium thiosulfate, water and saturated saline, dried (Na 2 SO 4 ), and methylene chloride was distilled off under reduced pressure.
  • the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 20: 1 ⁇ 10: 1, V / V), and the solvent of the target fraction was distilled off under reduced pressure.
  • the obtained residue was purified again by column chromatography (n-hexane: ethyl acetate, 10: 1, V / V).
  • the solvent of the target fraction was distilled off under reduced pressure to obtain 22.4 g (yield: 92%) of the title compound as a pale pink powder.
  • Example 4 2.36 g (5.59 mmol) of the compound produced in (4a) was dissolved in 10 mL of toluene, and 1.07 g (5.59 mmol) of the compound produced in Example 1 (1b), 54 mg (0.28 mmol) of copper iodide 2.49 g (11.7 mmol) of pulverized tripotassium phosphate, 0.13 mL (0.84 mmol) of trans-N, N'-dimethylcyclohexane-1,2-diamine were added, and after bubbling with nitrogen for 10 minutes, 110 ° C under a nitrogen atmosphere. For 20 hours. Ethyl acetate and water were added, and the insolubles were filtered off through celite.
  • Example 4 1.78 g (3.67 mmol) of the compound prepared in (4b) was dissolved in 20 mL of methylene chloride, and 0.39 mL (5.5 mmol) of acetyl chloride and 0.61 mL (5.5 mmol) of titanium (IV) chloride were sequentially added under ice-cooling. The mixture was stirred at the same temperature for 1 hour. Water and chloroform were added to the reaction solution, the two layers were separated, and the chloroform layer was washed with water and saturated saline in this order, dried (Na 2 SO 4 ), and then chloroform was distilled off under reduced pressure.
  • the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 1 ⁇ 1: 2, V / V).
  • the solvent of the target fraction was distilled off under reduced pressure to obtain 580 mg (yield: 30%) of the title compound as a white powder.
  • 6-methoxy-2-methylindole 3.85 g (23.9 mmol), tert-butyl- (4-iodophenoxy) dimethylsilane 8.00 g (23.9 mmol), copper iodide 229 mg (1.20 mmol), trans-N, N ' -Dimethylcyclohexane-1,2-diamine 0.57 mL (3.6 mmol) and tripotassium phosphate 10.7 g (50.2 mmol) were suspended in toluene (27 mL), and nitrogen was bubbled at room temperature for 10 minutes. And stirred for 18 hours. After cooling, 80 mL of water was added to the reaction solution, and the mixture was extracted with 80 mL of ethyl acetate.
  • the ethyl acetate layer was washed successively with water and saturated saline, dried (Na 2 SO 4 ), and the ethyl acetate was distilled off under reduced pressure.
  • the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 50: 1 ⁇ 20: 1, V / V).
  • the solvent of the desired fraction was distilled off under reduced pressure to obtain 4.38 g (yield: 50%) of the title compound as a pale yellow powder.
  • the obtained powder was purified by column chromatography (n-hexane: ethyl acetate, 2: 1 ⁇ 1: 1, V / V).
  • the solvent of the target fraction was distilled off under reduced pressure to obtain 586 mg (yield: 85%) of the title compound as a pale yellow powder.
  • the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 1: 1 ⁇ 0: 1, chloroform: methanol, 20: 1, V / V).
  • the solvent of the target fraction was distilled off under reduced pressure to obtain 478 mg (yield: 90%) of the title compound as a pale yellow oil.
  • Example 7 450 mg (2.77 mmol) of the compound produced in Example 7 (7f) was dissolved in 5 mL of toluene, and 1.54 g (3.32 mmol) of the compound produced in Example 3 (3c), 27 mg (0.14 mmol) of copper iodide , 1.23 g (5.82 mmol) of ground potassium phosphate and 0.066 mL (0.42 mmol) of trans-N, N'-dimethylcyclohexane-1,2-diamine were added, and nitrogen was bubbled for 10 minutes. For 28 hours.
  • Example 7 210 mg (0.42 mmol) of the compound prepared in Example 7 (7 g) was dissolved in 2 mL of tetrahydrofuran, and 1.3 mL (1.3 mmol) of a 1.0 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran was added under ice-cooling. Then, 0.63 mL (0.63 mmol) of a 1.0 M tetra-n-butylammonium fluoride tetrahydrofuran solution was added thereto, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and extracted twice with ethyl acetate.
  • the ethyl acetate layers were combined, washed sequentially with water and a saturated saline solution, dried (Na 2 SO 4 ), and the solvent was distilled off under reduced pressure.
  • the obtained colorless oil was dissolved in 2 mL of methylene chloride, and 0.18 mL (1.3 mmol) of triethylamine and 60 ⁇ L (0.84 mmol) of acetyl chloride were added under ice-cooling, followed by stirring at the same temperature for 30 minutes.
  • the reaction solution was washed with water and saturated saline in that order, dried (Na 2 SO 4 ), and the solvent was distilled off under reduced pressure.
  • Example 7 40 mg (0.086 mmol) of the compound prepared in (7i) was dissolved in 1 mL of a mixture of methylene chloride-methanol (1: 1), and 86 ⁇ L (0.43 mmol) of 5.0 M aqueous sodium hydroxide solution was added at room temperature. The mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction solution, extracted with methylene chloride, dried (Na 2 SO 4 ), and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, which was collected by filtration to give 20 mg (yield: 56%) of a white powder of the title compound.
  • Example 8 3.49 g (5.61 mmol) of the compound produced in (8a), 1.76 g (19.6 mmol) of copper (I) cyanide, 257 mg (0.281 mmol) of tris (dibenzylideneacetone) dipalladium (0), 1, 1′-Bis (diphenylphosphino) ferrocene (544 mg, 0.982 mmol) was suspended in 1,4-dioxane (60 mL), heated under reflux for 15 hours, and then stirred at room temperature for 7 hours. After insolubles were filtered off through celite, the solvent was distilled off under reduced pressure.
  • the reaction solution was poured into 1.2 L of ice water, neutralized with potassium carbonate, extracted twice with ethyl acetate, and the organic layers were combined, washed with saturated saline, dried (Na 2 SO 4 ), and dried under reduced pressure.
  • the lower solvent was distilled off to obtain a residue containing (3,4-dimethoxyphenyl) methylamine.
  • malonic acid (8.43 g, 81.0 mmol) and phosphorus oxychloride (35.0 mL, 378 mmol) were added, and the mixture was stirred at 90 ° C for 2 hours.
  • reaction solution was poured into ice water, added with 130 mL of 5.0 M aqueous sodium hydroxide, neutralized with potassium carbonate, and extracted twice with ethyl acetate and three times with chloroform.
  • the organic layers were combined, dried (Na 2 SO 4 ), and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the obtained residue, which was collected by filtration to obtain 1.96 g (yield: 14%) of a reddish brown powder of the title compound.
  • Example 9 2.50 g (6.20 mmol) of the compound produced in (9d), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct 101 mg (0.124 mmol), 4,4, 1.35 mL (9.30 mmol) of 5,5-tetramethyl-1,3,2-dioxaborolane was suspended in 20 mL of 1,4-dioxane, and 4.32 mL (31.0 mmol) of triethylamine was added. Stir for 40 minutes. 100 mL of water was added to the reaction solution, and extracted twice with ethyl acetate.
  • the reaction solution was poured into cold water, neutralized with potassium carbonate, extracted twice with ethyl acetate, and the organic layers were combined and dried (Na 2 SO 4 ).
  • the solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue, and the mixture was collected by filtration to obtain 2.50 g of the title compound as a yellow powder. Further, the solvent of the filtrate was distilled off under reduced pressure, and the residue was purified by column chromatography (n-hexane: ethyl acetate, 5: 1, V / V) to obtain 2.02 g of a yellow powder of the title compound. .
  • the organic layer was washed successively with water and saturated saline, dried (Na 2 SO 4 ), and then the solvent was distilled off under reduced pressure.
  • the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 2: 1 ⁇ 1: 1 ⁇ 0: 1, V / V).
  • the solvent of the desired fraction was distilled off under reduced pressure to obtain 480 mg of a brown oil. 480 mg of the obtained oil was dissolved in 2.4 mL of 6.0 M hydrochloric acid and stirred at room temperature for 2 hours.
  • the reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with chloroform.
  • Example 9 415 mg (1.03 mmol) of the compound prepared in (9e) was dissolved in 4 mL of N, N-dimethylformamide, and 217 mg (1.03 mmol) of the compound prepared in Example 11 (11b), tripotassium phosphate 656 mg (3.09 mmol) and 119 mg (0.103 mmol) of tetrakis (triphenylphosphine) palladium (0) were added, and the mixture was stirred at 90 ° C for 1 hour under a nitrogen atmosphere. After cooling, the reaction solution was diluted with ethyl acetate, washed sequentially with water and saturated saline, and then dried (Na 2 SO 4 ).
  • Example 13 A solution of 17.3 g (57.1 mmol) of the compound (3) produced in (13a) in 50 mL of N, N-dimethylformamide was added dropwise, followed by stirring at 120 ° C. for 2.5 hours.
  • reaction solution was concentrated to dryness under reduced pressure, water was added to the residue, water was added to the residue, and the insoluble material was collected by filtration.
  • 12.4 g of a pale gray powder was obtained.
  • 12.4 g of the obtained light gray powder was dissolved in 150 mL of N, N-dimethylformamide, and 9.32 g (79.4 mmol) of zinc dicyanide and 4.59 g (3.97 mmol) of tetrakis (triphenylphosphine) palladium (0) were added thereto. The mixture was stirred at 90 ° C for 2.5 hours under an atmosphere.
  • the obtained residue was purified twice by column chromatography (chloroform: n-hexane, 1: 1 ⁇ 1: 0, V / V), and the solvent of the target fraction was distilled off under reduced pressure. 10 mL of a mixture of -diethyl ether (1: 3) was added, and the insolubles were collected by filtration. The obtained powder was washed with diethyl ether to obtain 1.27 g (yield: 10%) of a white powder of the title compound.
  • the reaction solution was diluted with ethyl acetate, washed sequentially with water and saturated saline, dried (Na 2 SO 4 ), and the solvent was distilled off under reduced pressure.
  • the residue was purified by column chromatography (chloroform: ethyl acetate, 1: 0 ⁇ 3: 2, V / V), the solvent of the target fraction was distilled off under reduced pressure, and 1 mL of methanol and 10 mL of diethyl ether were added to the residue. Was added and stirred at room temperature for 1 hour. The insolubles were collected by filtration to obtain 333 mg (yield: 92%) of a white powder of the title compound.
  • Example 13 To 325 mg (0.820 mmol) of the compound (5) produced in (13d) was added a solution of 68 mg (0.49 mmol) of potassium carbonate and 130 mg (1.2 mmol) of 30% aqueous hydrogen peroxide in 4 mL of dimethyl sulfoxide. And stirred at room temperature for 3.5 hours. 30 mL of water was added to the reaction solution, and the precipitate was collected by filtration and washed with 5 mL of ethanol to obtain 310 mg of a white powder. To 310 mg of the obtained white powder, 15 mL of ethanol was added, and the mixture was heated under reflux for 15 minutes, allowed to cool to room temperature, and the insoluble matter was collected by filtration.
  • Example 14 191 mg (0.896 mmol) of the compound prepared in (14c) was dissolved in 4 mL of N, N-dimethylformamide, 241 mg (2.69 mmol) of copper (I) cyanide was added, and the mixture was heated at 150 ° C. for 12 hours. Stirred. After allowing to cool, water (20 mL) and ethyl acetate (20 mL) were added, and the insoluble matter was filtered off through celite. After separating two layers of the filtrate, the aqueous layer was extracted with 20 mL of ethyl acetate.
  • Example 14 0.19 g (0.50 mmol) of the compound prepared in (14e) was dissolved in 2.5 mL of dimethyl sulfoxide, and 0.15 mL (0.75 mmol) of a 5.0 M aqueous sodium hydroxide solution and 0.068 mL of a 30% aqueous hydrogen peroxide solution were added at room temperature. (0.75 mmol), and the mixture was stirred at the same temperature for 40 minutes. After adding 20 mL of water and 10 mL of diethyl ether and stirring for 30 minutes, the precipitate was collected by filtration to obtain 135 mg (yield: 68%) of a white powder of the title compound.
  • the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1, V / V), and the solvent of the target fraction was distilled off under reduced pressure.
  • the obtained residue was purified again by column chromatography (Chromatorex NH, n-hexane: ethyl acetate, 9: 1 ⁇ 2: 3, V / V).
  • the solvent of the desired fraction was distilled off under reduced pressure to obtain 4.68 g (yield: quantitative) of the title compound as a pale yellow oil.
  • Example 16 330 mg (1.14 mmol) of the compound prepared in (16a) and 3- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) benzo [b] thiophene-5 Dissolve 486 mg of powder containing carbonitrile in 5 mL of 1,2-dimethoxyethane, and add a solution of 350 mg (3.02 mmol) of sodium carbonate in 5 mL of water and a solution of 50 mg (1.2 mmol) of lithium chloride in 0.5 mL of water. And 66 mg (0.057 mmol) of tetrakis (triphenylphosphine) palladium (0) were sequentially added, and the mixture was stirred at 70 ° C.
  • the obtained residue was purified by column chromatography (n-hexane: ethyl acetate, 10: 1, V / V), and the solvent of the target fraction was distilled off under reduced pressure.
  • the obtained residue was purified again by column chromatography (Chromatorex NH, n-hexane: ethyl acetate, 4: 1, V / V), and the solvent of the target fraction was distilled off under reduced pressure to give the title compound as a colorless oil. 0.30 g of the product (yield: 25%) was obtained.
  • 0.30 g (0.78 mmol) of the compound prepared in Example 16 (16d) was dissolved in 1.5 mL of dimethyl sulfoxide, and 0.23 mL (1.2 mmol) of 5.0 M aqueous sodium hydroxide solution and 0.12 mL of 30% aqueous hydrogen peroxide solution were added at room temperature. 1.2 mmol), and stirred for 1 hour. Then, 0.12 mL (0.60 mmol) of 5.0 M aqueous sodium hydroxide and 0.06 mL (0.67 mmol) of 30% aqueous hydrogen peroxide were added, and the mixture was stirred for 30 minutes. 10 mL of water was added, and the mixture was extracted twice with 20 mL of ethyl acetate.
  • Example 17 (17c) To a compound (743 mg, 1.38 mmol) produced in Example 17 (17c) was added 4.1 mL (4.1 mmol) of a 1.0 M tetra-n-butylammonium fluoride solution in tetrahydrofuran at room temperature, and the mixture was stirred at the same temperature for 50 minutes. After distilled off under reduced pressure of tetrahydrofuran, the residue 20 mL of water was added, followed by extraction with ethyl acetate 50 mL, washed sequentially with ethyl acetate layers with water and brine, dried (Na 2 SO 4), vacuum Ethyl acetate was distilled off under.
  • Example 17 115 mg (0.247 mmol) of the compound prepared in (17e) was dissolved in 1 mL of methylene chloride, and 1 mL of methanol and 0.24 mL (1.2 mmol) of 5.0 M aqueous sodium hydroxide were added at room temperature. And stirred for 2 hours. After evaporating the solvent under reduced pressure, 10 mL of water was added, and methanol was added until the precipitate was dissolved. After methanol was distilled off under reduced pressure, the precipitate was collected by filtration to obtain 98 mg (yield: 85%) of a white powder of the title compound.
  • Example 17 200 mg (0.470 mmol) of the compound prepared in (17d) was dissolved in 2 mL of methylene chloride, and 0.062 mL (0.71 mmol) of chlorosulfonyl isocyanate was added dropwise at -78 ° C, followed by stirring at the same temperature for 5 minutes. did. Diisopropyl ether was added to the reaction solution, and the precipitated powder was collected by filtration to obtain 300 mg of a white powder. The obtained white powder (300 mg) was dissolved in acetic acid (2 mL) and stirred at room temperature for 30 minutes. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate and extracted twice with chloroform.
  • Example 21 350 mg (0.861 mmol) of the compound prepared in Example 21 (21a) was dissolved in 6 mL of tetrahydrofuran, 3 mL of methanol and 2.2 mL (2.2 mmol) of 1.0 M lithium hydroxide aqueous solution were added, and the mixture was stirred at room temperature for 9 hours. . Under reduced pressure, methanol and tetrahydrofuran were distilled off, 10 mL of water and 0.40 mL (2.4 mmol) of 6.0 M hydrochloric acid were added, and the mixture was extracted with ethyl acetate.
  • test compound dissolved in DMSO was diluted with an assay buffer (QSS Assist STK ELISA Kit (CDK8 / CycC), Carna Bioscience) to obtain a primary dilution of a 4% DMSO concentration.
  • an assay buffer mixture containing 1 ⁇ M substrate (Carna Bioscience), 20 mM MgCl 2 (Carna Bioscience) and 400 ⁇ M ATP (Carna Bioscience) was added.
  • a kinase solution (0.15 ng / ⁇ L of CDK8 / CycC (Carna Bioscience) diluted with an assay buffer for measurement of CDK8 inhibitory activity) was added. After the addition, the mixture was allowed to stand at 20 to 30 ° C. for 30 minutes. After the completion of the reaction, the solution in the well was discarded, and the well was immediately washed four times with 250 ⁇ L of a wash buffer (50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 0.02% Tween-20) per well.
  • a wash buffer 50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 0.02% Tween-20
  • a blocking buffer (assay buffer containing 0.1% BSA) was added to each well, and the mixture was allowed to stand at room temperature for 30 minutes.
  • the solution in the well was discarded, and a primary antibody solution (Carna Bioscience) (100 ⁇ L) was added to each well, and the mixture was allowed to stand at room temperature for 30 minutes.
  • the solution in the well was discarded and immediately washed four times with 250 ⁇ L of wash buffer per well.
  • 100 ⁇ L of an HRP-labeled secondary antibody solution (Carna Bioscience) was added to each well, and allowed to stand at room temperature for 30 minutes. The solution in the well was discarded and immediately washed four times with 250 ⁇ L of wash buffer per well.
  • a coloring reagent (ELISA POD substrate TMB kit (HYPER), Nacalai Tesque) was added to each well, and reacted at room temperature for 5 minutes. After stopping the reaction by adding 100 ⁇ L of a coloring reaction terminator (Nacalai Tesque) to each well, the absorbance (450 nm) was measured with a plate reader.
  • a coloring reagent ELISA POD substrate TMB kit (HYPER), Nacalai Tesque
  • CDK8 inhibition rate at 1 ⁇ M of the test compound was determined using the absorbance of the well without the test compound as a control and the absorbance of the well without the enzyme as a blank.
  • Test Example 2 The following methods were used to evaluate the activity of the example compounds for inhibiting human acute myeloid leukemia MV4; 11 cell proliferation.
  • the cell growth inhibition rate in the test compound ⁇ 1 ⁇ M ⁇ was determined using the absorbance of the well without the test compound as a control and the absorbance of the well without cells inoculated as a blank.
  • Mouse bone marrow-derived mesenchymal cell line ST2 cells (available from RIKEN) in a 96-well plate in ⁇ -MEM medium containing 10% fetal bovine serum (available from GIBCO BRL Cat. No. 12000-022) The cells were seeded at a cell density of 4 ⁇ 10 3 cells / 0.1 mL / well, and cultured at 37 ° C. under 5% CO 2 for 24 hours. Next, the test compound was added to a final concentration of 0.001 to 10 ⁇ M, and DMSO at a final concentration of 0.1% (v / v) was added to the control. After further culturing for 4 days, alkaline phosphatase (ALP) activity was measured by the following method.
  • ALP alkaline phosphatase
  • PBS buffer (KCl 0.2 g / L, KH 2 PO 4 0.2 g / L, Na 2 HPO 4 ⁇ 12H 2 O 2.9 g / L, NaCl 8 g / L) 100
  • 50 ⁇ L / well of a cell lysate (10 mM MgCl 2 , 2% (v / v) Triton X-100) was added, and the mixture was stirred at room temperature for 3 minutes.
  • substrate solution 50 ⁇ L / well of substrate solution (50 mM diethanolamine (Wako Pure Chemical Cat. No.
  • the increase rate (%) of the absorbance of the test compound when the absorbance of the control was set to 100% was calculated, and the degree of differentiation of osteoblasts was evaluated.
  • the compound (I) of the present invention has excellent inhibitory activity against cyclin-dependent kinase (CDK) 8 and high cell growth inhibitory activity on human acute myeloid leukemia ⁇ MV4; 11 cells It has been found that the compound has excellent osteoblast differentiation action and bone density increasing action.
  • CDK cyclin-dependent kinase
  • Example 1 Manufacture of capsule
  • Fine powdered cellulose 10 mg 3) Lactose 19 mg 4) 1 mg of magnesium stearate 40 mg in total 1), 2), 3) and 4) are mixed and filled into a gelatin capsule.
  • Formulation Example 2 Manufacture of tablets
  • the total amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, dried under vacuum, and sized.
  • 14 g of 4) and 1 g of 5) are mixed with the sized powder and tableted with a tableting machine. In this way, 1000 tablets each containing 10 mg of the example compound are obtained.
  • the compound (I) of the present invention has an excellent inhibitory activity on cyclin-dependent kinase (CDK) 8. Therefore, according to the present invention, an excellent CDK8 inhibitor can be provided. Further, according to the present invention, a medicament useful as a preventive and / or therapeutic agent for a disease associated with CDK8, a disease associated with bone metabolism such as osteoporosis, and a cell proliferative disease such as cancer can be provided.
  • This application is based on patent application Nos. 2018-189561 and 2018-206050 filed in Japan, the contents of which are incorporated in full herein.

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Abstract

La présente invention concerne un nouvel inhibiteur de CDK8. La présente invention concerne : un composé représenté par la formule générale (I) (dans laquelle les symboles sont tels que définis dans la description) ou un sel pharmaceutiquement acceptable de celui-ci ; et une composition pharmaceutique contenant ce composé en tant que principe actif. Le composé fourni par la présente invention a une activité inhibitrice de CDK8 ; la présente invention est donc capable de fournir un produit pharmaceutique utile en tant qu'agent prophylactique et thérapeutique pour des maladies associées à CDK8, des maladies liées au métabolisme osseux telles que l'ostéoporose et des maladies prolifératives cellulaires telles que des cancers.
PCT/JP2019/039376 2018-10-04 2019-10-04 Inhibiteur de cdk8 et utilisation associée WO2020071550A1 (fr)

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WO2021133752A1 (fr) * 2019-12-23 2021-07-01 Bristol-Myers Squibb Company Composés hétéroaryle substitués utiles en tant qu'activateurs de lymphocytes t
US11919879B2 (en) 2021-06-16 2024-03-05 Celgene Corporation Carboxylic acid containing azetidinyl compounds for the treatment of neurodegenerative diseases

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WO2021133752A1 (fr) * 2019-12-23 2021-07-01 Bristol-Myers Squibb Company Composés hétéroaryle substitués utiles en tant qu'activateurs de lymphocytes t
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US11919879B2 (en) 2021-06-16 2024-03-05 Celgene Corporation Carboxylic acid containing azetidinyl compounds for the treatment of neurodegenerative diseases

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