WO2016027780A1 - Dérivé de 4-aminopyridine - Google Patents

Dérivé de 4-aminopyridine Download PDF

Info

Publication number
WO2016027780A1
WO2016027780A1 PCT/JP2015/073046 JP2015073046W WO2016027780A1 WO 2016027780 A1 WO2016027780 A1 WO 2016027780A1 JP 2015073046 W JP2015073046 W JP 2015073046W WO 2016027780 A1 WO2016027780 A1 WO 2016027780A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituted
alkyl group
substituent
halogen atoms
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2015/073046
Other languages
English (en)
Japanese (ja)
Inventor
勢津雄 船坂
聡美 岡田
聰 永尾
大橋　功
祐介 中谷
夕輝 唐牛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eisai R&D Management Co Ltd
Original Assignee
Eisai R&D Management Co Ltd
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 Eisai R&D Management Co Ltd filed Critical Eisai R&D Management Co Ltd
Publication of WO2016027780A1 publication Critical patent/WO2016027780A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • 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
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to a 4-aminopyridine derivative having a FGFR inhibitory action or a pharmaceutically acceptable salt thereof and a pharmaceutical use thereof.
  • FGF fibroblast growth factor
  • FGFR FGF receptors
  • FGFR FGF receptors
  • FGFR is composed of three types: an extracellular domain, a transmembrane domain, and an intracellular tyrosine kinase domain. FGF binds to the FGFR extracellular domain to form a receptor dimer.
  • MAPK mitogen-activated protein kinase
  • ERK extracellular signal-regulated kinase
  • PI3K phosphatidylinositol 3-kinase
  • FGF / FGFR signal abnormality is induced by FGF production enhancement, FGFR gene amplification, FGFR overexpression, FGFR fusion protein formation, FGFR mutation, etc. It has been reported that various cancers such as endometrial cancer and prostate cancer are caused (Non-patent Document 1).
  • non-small cell lung cancer, small cell lung cancer, ovarian cancer, sarcoma, colon cancer, melanoma, glioblastoma, astrocytoma, or head and neck cancer as a cancer with FGF / FGFR signal abnormality (non-patent document) 2, 3), thyroid cancer (Non-patent document 4), pancreatic cancer (Non-patent document 5, 6), liver cancer (Non-patent document 7), skin cancer (Non-patent document 8), renal cancer (Non-patent document 9) ), Squamous cell carcinoma of the lung (Non-Patent Documents 10, 11, 12) and the like have been reported.
  • FGF / FGFR signal is a major angiogenesis signal along with VEGF (vascular endothelial growth factor) / KDR (kinase-insert domain-containing receptor) signal, and also cancer stromal cells (fibroblasts).
  • VEGF vascular endothelial growth factor
  • KDR kinase-insert domain-containing receptor
  • an FGFR inhibitor targeting FGF / FGFR signal is expected as an antitumor agent based on a suppressive action on the abnormal signal or angiogenic signal in cancer with abnormal FGF / FGFR signal.
  • selective FGFR inhibitors that are considered to be less susceptible to other signal confronting effects, such as FGFR1, FGFR2 and FGFR3, which are clearly different in structure from the compounds of the present invention.
  • Patent Document 3 discloses a pyrimidine derivative, but does not disclose an inhibitory action on signal abnormality of FGF / FGFR signal.
  • Patent Document 4 discloses a pyridine derivative or a pyrimidine derivative that suppresses angiogenesis induced by VEGF and FGF. However, these documents do not disclose the compounds according to the present invention.
  • the object of the present invention is to provide a new compound having an FGFR inhibitory action or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing them under these circumstances.
  • the present inventors have synthesized a novel 4-aminopyridine derivative (hereinafter referred to as the present compound (I)) represented by the following formula (I).
  • the present compound (I) found an action of suppressing FGF / FGFR signal, and further an action of selectively suppressing FGF / FGFR signal on VEGF / KDR signal, thereby completing the present invention.
  • a compound represented by formula (I) or a pharmaceutically acceptable salt thereof where A represents a single bond, an optionally substituted C 3-8 cycloalkylene group, an optionally substituted divalent C 3-10 nitrogen-containing non-aromatic heterocyclic group, substituted A C 6-10 arylene group which may have a group, or a C 3-5 heteroarylene group which may have a substituent; J represents a C 3-10 nitrogen-containing non-aromatic hetero group which may have 1 to 3 substituents selected from a hydrogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, and a substituent group L.
  • a C 3-10 nitrogen-containing non-aromatic heterocyclic C 1-6 alkyl group which may have 1 to 3 substituents selected from a cyclic group and a substituent group L, and a substituent group L
  • a C 3-10 nitrogen-containing non-aromatic heterocyclic C 1-6 alkoxy group which may have 1 to 3 substituents and 1 to 3 substituents selected from the substituent group L
  • C 3-10 non-aromatic heterocyclic C 3-10 nitrogen-containing non-aromatic heterocyclic group optionally having 1 to 3 substituents selected from substituent group L 3-8 cycloalkyl C 3-10 nitrogen-Motohi aromatic heterocyclic group
  • a substituent selected from substituent group L may have 1 to 3 C -8 cycloalkyl C 3-10 nitrogen-Motohi aromatic heterocyclic C 1-6 alkyl group
  • an optionally C 3-10 nitrogen Motohi have 1 to 3 substituents selected from substituent group L C 3-10 nitrogen-containing non-aromatic heterocyclic
  • Substituent group L may be substituted with a halogen atom, a hydroxyl group, 1 to 5 halogen atoms, or a C 1-6 alkyl group that may be substituted with 1 to 2 hydroxyl groups, and 1 to 3 halogen atoms.
  • R 11 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms, or a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms.
  • R 12 represents a hydrogen atom or a C 1-6 alkyl group which may be substituted with 1 to 3 halogen atoms
  • R 13 is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C 1-6 acyl group, a C 2-6 alkyl group which may be substituted with 1 to 5 halogen atoms, or 1 to 3 halogen atoms.
  • Optionally substituted hydroxy C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms C 1-6 alkoxy C 1-6 alkyl group, optionally substituted with 1 to 3 halogen atoms a C 1-6 alkoxy C 1-6 alkoxy group, one or two are substituted by a hydroxyl group which may be optionally having a C 1-6 alkyl group a C 3-8 cycloalkyl group, have a substituent
  • R 14 and R 15 each independently represent a hydrogen atom, a halogen atom, or a C 1-6 alkyl group.
  • R 14 and R 15 are each a C 1-6 alkyl group, R 14 and R 15 are Together with the carbon atoms to which it is attached may form a C 3-8 cycloalkyl ring, [3] n is 0 to 1, A is an optionally substituted C 6-10 arylene group or an optionally substituted C 3-5 heteroarylene group, G is a single bond or an oxygen atom, Z is -E (R 11 ) (R 12 ) (R 13 ); E is a C 3-10 nitrogen-containing non-aromatic heterocycle, The compound or a pharmaceutically acceptable salt thereof according to [2], wherein R 6 , R 7 , R 8 , R 9 and R 10 are each independently a hydrogen atom or a halogen atom, [4] R 2 is a hydrogen atom or a C 1-6 alkoxy group which may be substituted with 1 to 3 halogen atoms, R 3 is a hydrogen atom or a C 1-6 alkyl group which may be substituted with 1 to 3
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof has an FGFR inhibitory action as shown in activity data in pharmacological test examples described later. Therefore, the compound (I) of the present invention or a pharmaceutically acceptable salt thereof has applicability as a therapeutic agent for gastric cancer.
  • the structural formula of a compound may represent a certain isomer for convenience, but the present invention includes all geometrical isomers that can occur in the structure of the compound, optical isomers based on asymmetric carbon, stereo It includes isomers such as isomers, rotational isomers, tautomers, and isomer mixtures, and is not limited to the description of formulas for convenience, and may be either one isomer or a mixture. Therefore, the compound of the present invention may have an asymmetric carbon atom in the molecule, and an optically active substance and a racemate may exist. However, the present invention is not limited and includes both. However, it is understood that some of the isomers, racemates, and isomer mixtures may be more active than others.
  • Crystalline bodies are also included, and the compounds of the present invention include anhydrides and solvates such as hydrates.
  • the present invention also includes an isotope-labeled compound of the present compound (I) or a pharmaceutically acceptable salt thereof.
  • This is the same as the compound represented by formula (I) except that one or more atoms are replaced by atoms having an atomic mass or mass number different from those normally found in nature. It is.
  • Isotopes that can be incorporated into the compounds of the present invention are, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, bromine and chlorine, 2 H, 3 H, 11 C, 13 C, 14 C, 18 F, 35 S, 123 I, 125 I and the like.
  • Isotopically labeled compounds for example, compounds incorporating radioactive isotopes such as 3 H and / or 14 C, are useful in pharmaceutical and / or substrate tissue distribution assays. 3 H and 14 C are considered useful because of their ease of preparation and detection.
  • the isotopes 11 C and 18 F are considered useful in PET (positron emission tomography), and the isotope 125 I is considered useful in SPECT (single-photon emission computed tomography) and can be useful in brain imaging There is sex. Substitution with heavier isotopes such as 2 H results in certain therapeutic benefits such as increased in vivo half-life due to higher metabolic stability or reduced dosage requirements, and therefore under certain circumstances It is considered useful.
  • Isotope-labeled compounds are uniformly obtained by performing the procedures disclosed in the following schemes and / or examples, using readily available isotope-labeled reagents in place of non-isotopically labeled reagents. Can be prepared.
  • the compound (I) of the present invention can be used as a chemical probe for capturing a target protein of a physiologically active low molecular compound. That is, the compound of the present invention is different from the structural part essential for the expression of the activity of the compound in a portion different from J. Mass Spectrum. Soc. Jpn. Vol. 51, no. 5. It can be converted into affinity chromatography, photoaffinity probe, etc. by introducing a labeling group, a linker, etc. by the method described in 2003, p492-498 or WO2007 / 139149.
  • Examples of the labeling group and linker used for the chemical probe include groups shown in the following groups (1) to (5).
  • Photoaffinity labeling groups for example, benzoyl group, benzophenone group, azide group, carbonyl azide group, diaziridine group, enone group, diazo group, nitro group, etc.
  • chemical affinity groups for example, alpha carbon atom is halogen
  • a protein labeled group such as a ketone group substituted with an atom, a carbamoyl group, an ester group, an alkylthio group, a Michael acceptor such as an ⁇ , ⁇ -unsaturated ketone, an ester, an oxirane group, and the like;
  • (2) -SS-, -O-Si-O-, cleavable linkers such as monosaccharides (glucose group, galactose group, etc.), disaccharides (lactose etc.), and oligopeptides cleavable
  • a probe prepared by introducing a labeling group selected from the group consisting of the above (1) to (5) into the compound of the present invention according to the method described in the above literature, etc. is a new drug discovery target. It can be used as a chemical probe for identifying a labeled protein useful for searching and the like.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • heteroatom means a nitrogen atom, a sulfur atom, or an oxygen atom.
  • C 1-6 alkyl group is a monovalent group derived by removing any one hydrogen atom from an aliphatic hydrocarbon having 1 to 6 carbon atoms.
  • C 2-6 alkyl group means the above alkyl group excluding a methyl group, and specifically includes, for example, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group. , An isobutyl group, a sec-butyl group, a tert-butyl group, and the like, and preferably an ethyl group.
  • C 2-6 alkenyl group means a linear or branched alkenyl group having 1 to 2 carbon atoms and having 2 to 6 carbon atoms. Specific examples include, for example, vinyl group, 1-propenyl group, allyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1,3-pentadienyl group, 1,4-hexadienyl. Group, pentenyl group, hexenyl group and the like. It is a group.
  • C 2-6 alkynyl group means a linear or branched alkynyl group having 2 to 6 carbon atoms having 1 or 2 triple bonds. Examples thereof include ethynyl group, 1-propynyl group, 2-propynyl group, butynyl group, 1,3-pentanediynyl group, 1,4-hexadiynyl group, pentynyl group, hexynyl group and the like.
  • hydroxy C 1-6 alkyl group means a group in which any one hydrogen atom of the C 1-6 alkyl group is substituted with a hydroxyl group.
  • the position substituted with a hydroxyl group is not particularly limited, and specific examples include hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, 3-hydroxypropyl group, 2-hydroxypropyl group, 1-hydroxypropyl. Group, 2-hydroxy-2,2-dimethylethyl group and the like.
  • 2-hydroxyethyl group 2-hydroxypropyl group, 2-hydroxy-2,2-dimethylethyl group, 3-hydroxy-3-methylpropyl group, 3-hydroxy-3,3-dimethylpropyl group, 4 -Hydroxy-3,3-dimethylbutyl group and the like.
  • C 1-6 alkoxy group means a group in which an oxygen atom is bonded to the terminal of the above-defined “C 1-6 alkyl group”.
  • C 1-6 alkoxy C 1-6 alkyl group as used herein, the definitions any one hydrogen atom in the “C 1-6 alkyl group” is the above-defined “C 1 It means a group substituted with “ -6 alkoxy group”, and the substituted position is not limited.
  • a 2-methoxyethyl group and a 2-ethoxyethyl group are preferable.
  • C 1-6 alkoxy C 1-6 alkoxy group as used herein, the definitions any one hydrogen atom in the "C 1-6 alkoxy group” is the above-defined “C 1 It means a group substituted with “ -6 alkoxy group”, and the substituted position is not limited. Specific examples include methoxymethoxy group, ethoxymethoxy group, n-propoxymethoxy group, 2-methoxyethoxy group, 2-ethoxyethoxy group, 3-methoxypropoxy group and the like. 2-methoxyethoxy group, 2-ethoxyethoxy group, and 3-methoxypropoxy group are preferable.
  • C 3-8 cycloalkyl group refers to a derivative derived by removing one hydrogen atom from a monocyclic or bicyclic saturated aliphatic hydrocarbon compound having 3 to 8 carbon atoms. This means a valent group, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. Preferred are a cyclopropyl group and a cyclobutyl group.
  • C 1-6 acyl group means a group consisting of an atomic group obtained by removing an OH group from a carboxyl group of an aliphatic carboxylic acid having 1 to 6 carbon atoms. Examples include formyl group, acetyl group, propionyl group, butyroyl group.
  • C 1-6 alkoxy C 1-6 acyl group means a group in which any one hydrogen atom of the C 1-6 acyl group is substituted with the C 1-6 alkoxy group And the position to be substituted is not limited.
  • C 1-6 acyl C 1-6 alkyl group refers to a group in which any one hydrogen atom of the C 1-6 alkyl group is substituted with the C 1-6 acyl group And the position to be substituted is not limited.
  • “mono- or di-C 1-6 alkylamino group” means a mono-C 1-6 alkylamino group or a di-C 1-6 alkylamino group. This means a group in which one or two hydrogen atoms are substituted with the above-defined “C 1-6 alkyl group”, specifically, for example, methylamino group, ethylamino group, n-propylamino group, isopropylamino Group, n-butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group, n-pentylamino group, isopentylamino group, sec-pentylamino group, neopentylamino group, 1-methylbutyl Amino group, 2-methylbutylamino group, 1,1-dimethylpropylamino group, 1,2-dimethylpropylamino group, n-hexylamino
  • the position substituted with the mono-C 1-6 alkylamino group is not particularly limited.
  • the term “mono- or di-C 1-6 alkylamino C 2-6 alkenyl group” means that any one hydrogen atom of the C 2-6 alkenyl group is the above mono- or di- This means a group substituted with a —C 1-6 alkylamino group, and the substituted position is not limited.
  • the term “mono- or di-C 1-6 alkylamino C 2-6 alkynyl group” means that any one hydrogen atom of the C 2-6 alkynyl group is mono- or di- This means a group substituted with a —C 1-6 alkylamino group, and the substituted position is not limited.
  • the term “mono- or di-C 1-6 alkylaminocarbonyl group” means a group in which a carbonyl group is bonded to the end of the mono- or di-C 1-6 alkylamino group. .
  • “mono- or di-C 1-6 alkylaminocarbonyl C 1-6 alkyl group” means that any one hydrogen atom of the C 1-6 alkyl group is mono- or The di-C 1-6 alkylaminocarbonyl group means a substituted group, and the substituted position is not limited.
  • any one of the hydrogen atoms of the C 1-6 alkyl group, a mono -Or- means a group substituted with a group having an oxygen atom bonded to the terminal of a di-C 1-6 alkylaminocarbonyl group, and the position of substitution is not limited.
  • the “C 3-10 nitrogen-containing non-aromatic heterocyclic group” means that the number of carbon atoms constituting the ring is 3 to 10, and 1 to 2 atoms constituting the ring Means a monovalent non-aromatic heterocyclic group which may further contain 1 to 2 oxygen atoms or sulfur atoms, and may be a bicyclic bridged ring. .
  • C 3-10 non-aromatic heterocyclic group means 3 to 10 carbon atoms constituting the ring, and 1 to 2 nitrogen atoms in the atoms constituting the ring.
  • C 1-6 alkylene group means a divalent group derived by removing any one hydrogen atom from the “C 1-6 alkyl group”. Examples include methylene group, 1,2-ethylene group, 1,1-ethylene group, 1,3-propylene group, tetramethylene group, pentamethylene group, hexamethylene group and the like.
  • C 3-8 cycloalkylene group means a divalent group derived from the above “C 3-8 cycloalkyl group” by further removing any one hydrogen atom.
  • Specific examples include a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, a cyclohexylene group, a cycloheptylene group, a cyclooctylene group, and the like.
  • it is a cyclopropylene group or the like.
  • the “divalent C 3-10 nitrogen-containing non-aromatic heterocyclic group” refers to any hydrogen atom from the above “C 3-10 nitrogen-containing non-aromatic heterocyclic group”. Is a divalent group derived by removing one, and specific examples include azetidinylene, piperidinylene, piperazinylene and the like.
  • C 6-10 arylene group refers to a divalent group derived by removing any two hydrogen atoms in an aromatic hydrocarbon having 6 to 10 carbon atoms. Specific examples include a phenylene group, a naphthylene group, an indenylene group, an azlenylene group, a heptalenylene group, and the like, and a phenylene group is preferable.
  • the “C 3-5 heteroarylene group” means that the number of carbon atoms constituting the ring is 3 to 5 and contains 1 to 2 heteroatoms in the atoms constituting the ring.
  • a divalent group derived by removing any two hydrogen atoms in a heteroaromatic compound specifically, for example, a furylene group, a thienylene group, a pyrrolylene group, an imidazolylene group, a thiazolylene group, a pyrazolylene group Oxazolylene group, isoxazolylene group, isothiazolylene group, furazanylene group, pyridylene group, pyrazinylene group, pyridazinylene group, pyrimidinylene group, and the like, preferably pyridylene group, pyrazolylene group, and thienylene group.
  • C 3-10 nitrogen-containing non-aromatic heterocyclic C 1-6 alkyl group means that any one hydrogen atom of the C 1-6 alkyl group is the above C 3-10 This means a group substituted with a nitrogen-containing non-aromatic heterocyclic group.
  • the position substituted with the C 3-10 nitrogen-containing non-aromatic heterocyclic group is not particularly limited.
  • C 3-10 non-aromatic heterocyclic C 1-6 alkyl group means that any one hydrogen atom of the C 1-6 alkyl group is the C 3-10 non-aromatic group. Means a group substituted with a heterocyclic group, and the position of substitution is not limited.
  • C 3-10 nitrogen-containing non-aromatic heterocyclic C 1-6 alkoxy group means that any one hydrogen atom of the C 1-6 alkoxy group is the above C 3-10 This means a group substituted with a nitrogen-containing non-aromatic heterocyclic group.
  • the position substituted with the C 3-10 nitrogen-containing non-aromatic heterocyclic group is not particularly limited.
  • C 3-10 non-aromatic heterocyclic C 3-10 nitrogen-containing non-aromatic heterocyclic group means any of the above C 3-10 nitrogen-containing non-aromatic heterocyclic groups In which one hydrogen atom is substituted with the C 3-10 non-aromatic heterocyclic group.
  • the position substituted with the C 3-10 non-aromatic heterocyclic group is not particularly limited.
  • C 3-8 cycloalkyl C 3-10 nitrogen-containing non-aromatic heterocyclic group means any one of the above C 3-10 nitrogen-containing non-aromatic heterocyclic groups. It means a group in which a hydrogen atom is substituted with the C 3-8 cycloalkyl group.
  • the position substituted with the C 3-8 cycloalkyl group is not particularly limited.
  • C 3-10 nitrogen-containing non-aromatic heterocyclic C 3-8 cycloalkyl group means that any one hydrogen atom of the C 3-8 cycloalkyl group is the C 3 -10 means a group substituted with a nitrogen-containing non-aromatic heterocyclic group.
  • the position substituted with the C 3-10 non-aromatic heterocyclic group is not particularly limited.
  • C 3-10 nitrogen-containing non-aromatic heterocyclic oxy group means a group in which an oxygen atom is bonded to the terminal of the C 3-10 nitrogen-containing non-aromatic heterocyclic group. To do.
  • the position at which the oxygen atom is bonded is not particularly limited.
  • C 3-10 nitrogen-containing non-aromatic heterocyclic C 2-6 alkenyl group means that any one hydrogen atom of the C 1-6 alkenyl group is the above C 3-10 This means a group substituted with a nitrogen-containing non-aromatic heterocyclic group.
  • the position substituted with the C 3-10 nitrogen-containing non-aromatic heterocyclic group is not particularly limited.
  • the “C 3-10 nitrogen-containing non-aromatic heterocyclic C 2-6 alkynyl group” means that any one hydrogen atom of the C 1-6 alkynyl group is the C 3-10 This means a group substituted with a nitrogen-containing non-aromatic heterocyclic group.
  • the position substituted with the C 3-10 nitrogen-containing non-aromatic heterocyclic group is not particularly limited.
  • C 3-8 cycloalkyl C 1-6 alkyl group means that any one hydrogen atom of the C 1-6 alkyl group is the C 3-8 cycloalkyl. Means a group substituted by a group.
  • the position substituted with the C 3-8 cycloalkyl group is not particularly limited, and specifically, for example, a cyclopropylmethyl group, a cyclopropylethyl group, a cyclobutylmethyl group, a cyclobutylethyl group, a cyclopentylmethyl group, a cyclopentylethyl group Group, cyclohexylmethyl group, cyclohexylethyl group and the like, and cyclopropylmethyl group, cyclobutylmethyl group and the like are preferable.
  • “mono- or di-C 1-6 alkylaminocarbonyloxy C 3-8 cycloalkyl C 1-6 alkyl group” refers to the aforementioned C 3-8 cycloalkyl C 1-6 alkyl group Means a group in which one hydrogen atom is substituted with a group in which an oxygen atom is bonded to the terminal of the mono- or di-C 1-6 alkylaminocarbonyl group, and their substituted positions are limited. Not.
  • C 1-6 alkylcarbamoyl C 1-6 alkyl group refers to the C 1-6 arbitrary one hydrogen atom C 1-6 alkylcarbamoyl group the alkyl group Means a group substituted by
  • the C 1-6 alkylcarbamoyl group means a group in which a hydrogen atom on a nitrogen atom of a carbamoyl group is substituted with a C 1-6 alkyl group.
  • the position substituted with the C 1-6 alkylcarbamoyl group is not particularly limited.
  • substituent means that a specific group may be in a state of having or not having a substituent.
  • the substitution position is not particularly limited.
  • substituent to be substituted include a halogen atom, cyano group, hydroxyl group, amino group, C 1-6 alkyl group, C 1-6 alkoxy group, mono- or di-C 1-6 alkylamino group, C 2-6 Alkenyl groups, C 2-6 alkynyl groups, C 3-8 cycloalkyl groups, C 3-10 non-aromatic heterocyclic C 2-6 acyl groups, C 6-10 aryl groups, C 3-5 heteroaryl groups, etc. Is mentioned.
  • halogen atoms As used herein, “which may be substituted with 1 to 3 halogen atoms” or “which may be substituted with 1 to 5 halogen atoms” means that 1 to 3 halogen atoms are further added to a specific group. This means that a halogen atom or 1 to 5 halogen atoms may be substituted, and the substitution position is not particularly limited. Specific examples of the halogen atom to be substituted include a fluorine atom and a chlorine atom, and a fluorine atom is more preferable.
  • C 1-6 alkyl group a C 2-6 alkyl group, a C 1-6 alkoxy C 1-6 alkoxy group, or a hydroxy C 1-6 alkyl group, which may be substituted with 1 to 3 halogen atoms
  • halogen atoms Each specifically, for example, monofluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, monochloromethyl group Dichloromethyl group, trichloromethyl group, 2-chloroethyl group, 2,2-dichloroethyl group, 2,2,2-trichloroethyl group, 3-fluoropropyl, 2-fluoroethyl group, 2,2-difluoroethyl 2,2,2-trifluoroethyl group, 2-chloroethyl group, 2,2-dichloroethyl group, 2,2,2-
  • the 1-3 is a C 1-6 alkyl group optionally substituted by a halogen atom
  • 2,2,3,3-tetrafluoropropyl group and the like can be mentioned.
  • the “substituent group L” refers to a C 1-6 alkyl group which may be substituted with a halogen atom, a hydroxyl group, 1 to 5 halogen atoms or 1 to 2 hydroxyl groups, 1 to 3 C 1-6 alkoxy group optionally substituted with 1 halogen atom, C 1-6 alkoxy C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, C 1-6 acyl group, mono -Or represents a group consisting of a di-C 1-6 alkylamino group and a cyano group.
  • A represents the above meaning, but is preferably a C 6-10 arylene group or a C 3-5 heteroarylene group, more preferably a phenylene group, a thienylene group, a pyridylene group, or a pyrazolylene group, and more preferably , A phenylene group.
  • R 1 represents the above meaning, and is preferably a hydrogen atom, a halogen atom, or a C 1-6 alkyl group, and more preferably a hydrogen atom.
  • R 2 represents the above meaning, and is preferably a hydrogen atom, a halogen atom, or a C 1-6 alkoxy group, and more preferably a hydrogen atom.
  • R 3 represents the above meaning, preferably a hydrogen atom, a halogen atom, or a C 1-6 alkyl group, and more preferably a hydrogen atom.
  • R 4 is as defined above, preferably a C 1-6 alkyl group, more preferably a methyl group.
  • R 5 represents the above-mentioned meaning, but is preferably a C 2-6 alkyl group which may be substituted with 1 to 3 halogen atoms, or hydroxy C 1- 1 which may be substituted with 1 to 3 halogen atoms.
  • R 1 is a halogen atom, a cyano group, one to three C 1-6 alkyl group optionally substituted by a halogen atom or may be substituted by 1-3 halogen atoms, C 1-6
  • R 5 is preferably a hydrogen atom or a methyl group. However, in the present invention, at least one of R 1 and R 5 is not a hydrogen atom.
  • R 6 , R 7 , R 8 , R 9 , and R 10 are as defined above, preferably a hydrogen atom, a halogen atom, or a C 1-6 alkyl group, and more preferably a hydrogen atom.
  • J represents the above-mentioned meaning, but is preferably the following partial structure (III).
  • N represents the above meaning and is preferably 0 or 1.
  • G represents the above meaning, and is preferably a single bond or an oxygen atom.
  • E represents the above meaning, and specifically, for example, an azetidine ring, a pyrrolidine ring, a piperidine ring, or a piperazine ring.
  • R 11 represents the above meaning, and specifically, for example, hydrogen, fluorine atom, methyl group, ethyl group, trifluoromethyl group, methoxy group and the like are preferable.
  • R 12 represents the above meaning, and specifically, for example, a hydrogen atom, a methyl group, an ethyl group and the like are preferable.
  • R 13 is as defined above, preferably a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C 1-6 acyl group, a C 2-6 alkyl group optionally substituted with 1 to 5 halogen atoms, A hydroxy C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms, an optionally substituted C 3-8 cycloalkyl group, or an optionally substituted C 3 -10 non-aromatic heterocyclic group, specifically, for example, hydrogen atom, fluorine atom, chlorine atom, bromine atom, iodine atom, hydroxyl group, methyl group, ethyl group, n-propyl group, isopropyl group, n -Butyl, isobutyl, sec-butyl, tert-butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-di
  • hydrogen atom, fluorine atom, hydroxyl group, methyl group, ethyl group, n-propyl group isopropyl group, hydroxymethyl group, 2-hydroxyethyl group, 1-hydroxyethyl group, 3-hydroxypropyl group, 2-hydroxy A propyl group, a 1-hydroxypropyl group, a 2-hydroxy-2,2-dimethylethyl group, a cyclopropyl group, a methylazetidinyl group, an acetylazetidinyl group, a pyrrolidinyl group, or a piperidinyl group, more preferably A hydrogen atom, a fluorine atom, a methyl group, an ethyl group, a hydroxyl group, or a 2-hydroxyethyl group.
  • R 14 and R 15 represent the above meanings, preferably each independently a hydrogen atom or a C 1-6 alkyl group, more preferably a hydrogen atom or a methyl group. Also, R 14 and R 15 may be taken together with the carbon atom to which R 14 and R 15 are attached form a C 3-8 cycloalkyl ring, preferably a cyclopropyl ring.
  • the compound in the present invention is 5-((cyclopropylmethyl) (2- (4-((4-hydroxypiperidin-1-yl) methyl) benzamido) pyridin-4-yl) amino) -N-methyl-1H-indole-1-carboxamide; 5-((2-isopropoxyethyl) (2- (4- (1-methylpiperidin-4-yl) benzamido) pyridin-4-yl) amino) -N-methyl-1H-indole-1-carboxamide; 5-((2- (cyclopropanecarboxamido) pyridin-4-yl) (3-hydroxy-3-methylbutyl) amino) -N-methyl-1H-indole-1-carboxamide; 5-((3-hydroxy-3-methylbutyl) (2- (4- (1- (2-hydroxyethyl) piperidin-4-yl) benzamido) pyridin-4-yl) amino) -N-methyl-1H- Indole-1-
  • salts of the compounds according to the present specification include a salt with an inorganic acid, a salt with an organic acid, a salt with an acidic amino acid, and the like, and among them, a pharmaceutically acceptable salt is preferable.
  • the salts of the compounds according to the present invention include pharmaceutically acceptable salt anhydrides and pharmaceutically acceptable salt solvates such as hydrates.
  • the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • the salt with organic acid include, for example, acetic acid and succinic acid.
  • salts with fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and the like are examples of the salt with inorganic acid.
  • salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be formulated by a usual method.
  • the dosage form include oral preparations (tablets, granules, powders, capsules, syrups). Agents), injections (for intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration, etc.), external preparations (transdermal absorption preparations (ointments, patches, etc.), eye drops, nasal drops Suppositories, etc.).
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof if necessary, an excipient, a binder, a disintegrant, a lubricant, a coloring agent.
  • Etc. can be added and tablets, granules, powders, and capsules can be produced by conventional methods. Tablets, granules, powders, capsules and the like may be coated as necessary.
  • excipient for example, lactose, crystalline cellulose and the like, as the binder, for example, hydroxypropyl cellulose and the like, as the disintegrant, for example, croscarmellose sodium and the like, as the lubricant, for example,
  • the colorant include magnesium stearate, titanium oxide, and the like
  • the coating agent include, but are not limited to, hydroxypropylmethylcellulose and the like.
  • an injection for intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration, etc.
  • a pH adjusting agent, a buffering agent, a suspending agent, a solubilizing agent, an antioxidant, a preservative (preservative), an isotonic agent and the like can be added, and an injection can be produced by a conventional method. .
  • it may be freeze-dried to obtain a freeze-dried preparation that is dissolved at the time of use.
  • pH adjusters and buffers include organic acids or inorganic acids and / or pharmaceutically acceptable salts thereof
  • suspending agents include hydroxypropyl cellulose and the like as solubilizers.
  • polysorbate 80 and the like as an antioxidant, for example, ⁇ -tocopherol and the like, as preservatives, for example, methyl paraoxybenzoate, ethyl paraoxybenzoate and the like, and as an isotonic agent, for example , Glucose and the like can be mentioned, but are not limited thereto.
  • These injections can usually contain any amount of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof as long as it shows a medicinal effect that can be used as a pharmaceutical.
  • a base material is added to the compound (I) of the present invention or a pharmaceutically acceptable salt thereof, and if necessary, for example, the above-mentioned preservatives, pH adjusters, For example, transdermal preparations (ointments, patches, etc.), eye drops, nasal drops, suppositories and the like can be produced by adding antioxidants, colorants and the like by conventional methods.
  • the base material to be used for example, various raw materials usually used for pharmaceuticals, quasi drugs, cosmetics and the like can be used.
  • animal and vegetable oils for example, animal and vegetable oils, mineral oils, ester oils, waxes, emulsifiers, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers And raw materials such as minerals, clay minerals and purified water.
  • These external preparations can usually contain any amount of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof as long as it shows a medicinal effect that can be used as a pharmaceutical.
  • the dose of the compound (I) of the present invention or a pharmaceutically acceptable salt thereof varies depending on the degree of symptoms, age, sex, body weight, dosage form / salt type, specific type of disease, etc.
  • the maximum dose of drug that can be administered without causing unacceptable side effects is exceeded, usually for adults, about 30 ⁇ g to 10 g, for example 100 ⁇ g to 5 g, further for example 100 ⁇ g to 1 g, is orally administered per day.
  • About 30 ⁇ g to 1 g, for example, 100 ⁇ g to 500 mg, for example, 100 ⁇ g to 300 mg are administered once or in several divided doses by injection.
  • the production method of the compound (I) of the present invention will be described.
  • the compound (I) of the present invention can be synthesized using ordinary organic synthesis means.
  • the compound (I) is a method shown in the following [Production Method 1] and the like. Can be synthesized.
  • a protecting group for example, as described in Green's PROTECTIVE GROUP IN ORGANIC CHEMISTRY fourth edition, JOHN WILEY & SONS, INC, etc.
  • a known protecting group is appropriately selected and introduced, and a known method is used as appropriate. Can be deprotected.
  • Step 1-1 This step is a step of obtaining compound (I) by reacting compound (2) with compound (3).
  • the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
  • ether solvents such as 1,4-dioxane, 2- Alcohol solvents such as ethoxyethanol, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, halogenated hydrocarbon solvents such as dichloromethane and chloroform, dimethyl sulfoxide or a mixed solvent thereof can be used. .
  • Additives can be added to this reaction, including pyridine hydrochloride, salts such as pyridinium p-toluenesulfonate, acids such as hydrochloric acid, acetic acid and p-toluenesulfonic acid, bases such as triethylamine and pyridine. Can be used.
  • Compound (3) can be used in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to compound (2).
  • the additive can be used in an amount of 0 equivalent or more with respect to the compound (2), preferably 1 to 5 equivalents of pyridine hydrochloride.
  • the reaction temperature is from room temperature to reflux temperature, and the reaction time is from 10 minutes to 24 hours.
  • Step 1-2 This step is a step of obtaining compound (I) by reacting compound (4) with compound (5).
  • the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
  • ether solvents such as tetrahydrofuran, ester solvents such as ethyl acetate, etc.
  • Solvents, nitrile solvents such as acetonitrile
  • aromatic hydrocarbon solvents such as toluene
  • halogenated hydrocarbon solvents such as dichloromethane and chloroform
  • amide solvents such as N, N-dimethylformamide, N-methylpyrrolidinone or the like
  • a mixed solvent or the like can be used.
  • an alkylamine such as triethylamine or N, N-diisopropylethylamine, an aromatic amine such as 4-dimethylaminopyridine, an inorganic base such as potassium carbonate or cesium carbonate can be used as the base, or these bases can be used. They can be used in combination.
  • a condensing agent is further used.
  • Condensing agent O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, 1-ethyl-3- (3-dimethylaminopropyl) ) Carbodiimide hydrochloride and the like can be used, and 1-hydroxybenzotriazole and the like can be added as an additive.
  • Compound (4) can be used in an amount of 1 equivalent or more, preferably 1 to 3 equivalents, relative to compound (5).
  • the base can be used in the amount of 1 to 10 equivalents based on compound (4).
  • 1 equivalent or more can be used with respect to a compound (4).
  • the reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 24 hours.
  • X 3 is a leaving group containing a halogen atom
  • R 16 is a C 2-5 alkyl group which may be substituted with 1 to 3 halogen atoms or 1 hydroxyl group
  • R 17 is a hydrogen atom independently of each other A C 1-4 alkyl group which may be substituted with 1 to 3 halogen atoms.
  • Compound (6) is produced using the method described in [Production Method 1-2] and the subsequent deprotection reaction using the production example in the examples or an intermediate in which the N atom in E is protected. You can also.
  • Compound (7) may be a commercially available product, or can be produced from a commercially available product by a known method.
  • Step 1-3 compound (II) is obtained by reacting compound (6) with compound (7).
  • the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
  • ether solvents such as tetrahydrofuran, ester solvents such as ethyl acetate, etc.
  • Solvents, nitrile solvents such as acetonitrile, aromatic hydrocarbon solvents such as toluene, halogenated hydrocarbon solvents such as dichloromethane and chloroform, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, ethanol, etc.
  • Alcohol solvents or mixed solvents thereof can be used.
  • alkylamines such as triethylamine and N, N-diisopropylethylamine, aromatic amines such as 4-dimethylaminopyridine, inorganic bases such as potassium carbonate and cesium carbonate can be used as the base, or these bases Can be used in combination.
  • a reducing agent such as sodium triacetoxyborohydride can be used as the reducing agent.
  • An acid such as acetic acid can be added as an additive.
  • the alkylating agent or aldehyde compound can be used in an amount of 1 equivalent or more, preferably 1 to 3 equivalents, relative to compound (6).
  • An excessive amount of the epoxy compound can be used.
  • the base, reducing agent, and additive can be used in the amount of 1 to 10 equivalents based on compound (6).
  • the reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 24 hours.
  • Step 1-4 This step is a step of obtaining compound (II) by reacting compound (8) with compound (9).
  • the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
  • ether solvents such as tetrahydrofuran, ester solvents such as ethyl acetate, etc.
  • Solvents such as acetonitrile, aromatic hydrocarbon solvents such as toluene, halogenated hydrocarbon solvents such as dichloromethane and chloroform, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, dimethyl sulfoxide Alternatively, a mixed solvent thereof or the like can be used.
  • an alkylamine such as triethylamine or N, N-diisopropylethylamine can be used as a base.
  • Compound (9) can be used in an amount of 1 equivalent or more based on compound (8), preferably 1 to 3 equivalents.
  • the base can be used in the amount of 0 to 10 equivalents based on compound (8).
  • the reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 24 hours.
  • Step 2 This step is a step of obtaining compound (2) by reacting compound (10) with compound (11).
  • the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
  • an ester solvent such as ethyl acetate, an ether solvent such as tetrahydrofuran, and the like.
  • a solvent, a nitrile solvent such as acetonitrile, a halogen solvent such as dichloromethane, an amide solvent such as N, N-dimethylformamide, N-methylpyrrolidinone, or a mixed solvent thereof can be used.
  • Step 3-1 In this step, compound (3-1) and compound (12) are reacted to obtain compound (3-2).
  • R 5 is a hydrogen atom
  • step 3-1 is not carried out, and compound (3-1) and compound (3-2) are the same.
  • the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
  • ether solvents such as tetrahydrofuran, nitrile solvents such as acetonitrile, etc.
  • halogen solvents such as dichloromethane, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, or a mixed solvent thereof can be used.
  • compound (12) 0.5 to 2 equivalents of compound (12) can be used with respect to compound (3-1), and 1 to 5 equivalents of sodium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine, etc. can be added as a base. They can also be used as a mixture.
  • the reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 24 hours.
  • Compound (3-2) can also be produced by a known method such as reductive amination or amidation followed by reduction.
  • Step 3-2 In this step, compound (3-2) and compound (13) are reacted to obtain compound (3).
  • the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
  • ether solvents such as tetrahydrofuran, N, N-dimethylformamide, etc.
  • An amide solvent such as can be used.
  • 0.5 to 2 equivalents of compound (13) can be used with respect to compound (3-2), and 0.5 to 2 equivalents of sodium hydride or the like can be added as a base.
  • the reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 24 hours.
  • Step 5-1 This step is a step of reacting compound (3), compound (3-1), or compound (3-2) with compound (14) to obtain compound (5-1) or compound (5-2).
  • the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
  • ether solvents such as 1,4-dioxane, 2- Alcohol solvents such as ethoxyethanol, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidinone, halogenated hydrocarbon solvents such as dichloromethane and chloroform, dimethyl sulfoxide or a mixed solvent thereof can be used. .
  • Additives can be added to this reaction, including pyridine hydrochloride, salts such as pyridinium p-toluenesulfonate, acids such as hydrochloric acid, acetic acid and p-toluenesulfonic acid, bases such as triethylamine and pyridine. Can be used.
  • Compound (3), (3-1), or (3-2) can be used in the amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, based on compound (14).
  • the additive can be used in an amount of 0 equivalent or more with respect to the compound (2), preferably 1 to 5 equivalents of pyridine hydrochloride.
  • the reaction temperature is from room temperature to reflux temperature, and the reaction time is from 10 minutes to 24 hours.
  • Step 5-2 This step is a step of obtaining compound (5) or compound (5-3) by reacting compound (5-1) or compound (5-2) with a transfer reaction reagent.
  • the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
  • ether solvents such as 1,4-dioxane, N
  • An amide solvent such as N-dimethylformamide or N-methylpyrrolidinone
  • a halogenated hydrocarbon solvent such as dichloromethane or chloroform
  • a mixed solvent thereof can be used.
  • the transfer reaction reagent used in this reaction include iodobenzene diacetate, and 1 to 10 equivalents can be added.
  • pyridine, water or the like can be used as the additive.
  • the reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 24 hours.
  • Step 5-3 In this step, compound (5-3) and compound (13) are reacted to obtain compound (5).
  • the solvent used in this reaction is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
  • ether solvents such as tetrahydrofuran, N, N-dimethylformamide, etc.
  • An amide solvent such as can be used.
  • 0.5 to 2 equivalents of compound (13) can be used with respect to compound (5-3), and 0.5 to 2 equivalents of sodium hydride or the like can be added as a base.
  • the reaction temperature is from 0 ° C. to reflux temperature, and the reaction time is from 10 minutes to 24 hours.
  • the compound according to the present invention can be produced, for example, by the methods described in the following production examples and examples. However, these are illustrative, and the compound according to the present invention is not limited to the following specific examples in any case.
  • silica gel 60 (Kanto Chemicals) or Presep Silica Gel (WAKO) was used as the silica gel for purification used in silica gel column chromatography.
  • silica gel for purification used in NH silica gel column chromatography is NH silica gel (Fuji Silysia Chemical LTD.) Or Hi-Flash Column Amino (YAMAZENE CORPORATION), NH Silica Gel TLC (Thin Layer Chromatograph).
  • TLC Plates NH (20 cm ⁇ 20 cm, Fuji Silysia Chemical LTD.) Was used.
  • the proton nuclear magnetic resonance spectrum was measured using a Varian Mercury 400, Varian Mercury Plus 400, or Varian INOVA 500, unless otherwise stated, at 400 MHz.
  • the chemical shift of the proton nuclear magnetic resonance spectrum is recorded in ⁇ units (ppm) relative to tetramethylsilane, and the coupling constant is recorded in hertz (Hz).
  • the abbreviations of the division pattern are as follows. s: singlet, d: doublet, t: triplet, q: quartet, quint: quintet, sep: septet, m: multiplet, brs: broad singlet.
  • Example 1 5-((Cyclopropylmethyl) (2- (4-((4-hydroxypiperidin-1-yl) methyl) benzamido) pyridin-4-yl) amino) -N-methyl-1H-indole -1-Carboxamide 5-((Cyclopropylmethyl) amino) -N-methyl-1H-indole-1-carboxamide (60.3 mg, 0.249 mmol) described in Preparation Example 1-2, N- (4-Chloropyridin-2-yl) -4-((4-hydroxypiperidin-1-yl) methyl) benzamide (112.0 mg, 0.324 mmol), pyridine hydrochloride (71.9 mg, 0.623 mmol) Dissolved in 2-ethoxyethanol (0.8 mL).
  • the starting material 5-((cyclopropylmethyl) amino) -N-methyl-1H-indole-1-carboxamide was synthesized by the following method.
  • the starting material N- (4-chloropyridin-2-yl) -4-((4-hydroxypiperidin-1-yl) methyl) benzamide was synthesized by the following method.
  • the aqueous layer was extracted with ethyl acetate, and the organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine.
  • the organic layer was dried over anhydrous magnesium sulfate and filtered. After evaporating the solvent under reduced pressure, tert-butyl methyl ether and n-heptane were added to the obtained residue. The precipitate was filtered and washed with tert-butyl methyl ether and n-heptane to obtain the title compound (12.8 g, 86%).
  • the aqueous layer was extracted with ethyl acetate, and the organic layers were combined and washed with water and saturated brine.
  • the organic layer was dried over anhydrous magnesium sulfate and filtered. After evaporating the solvent under reduced pressure, ethyl acetate was added to the resulting residue. The precipitate was filtered and washed with ethyl acetate to obtain the title compound (910 mg, 74%).
  • the reaction was stirred at room temperature for 1 hour.
  • the reaction solution was concentrated under reduced pressure to remove trifluoroacetic acid.
  • the reaction mixture was cooled to 0 ° C., and a saturated aqueous ammonium chloride solution and ethyl acetate were added to partition.
  • the aqueous layer was extracted 3 times with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate.
  • the target fraction was concentrated under reduced pressure, and liquid separation was performed again to remove residual N, N-dimethylformamide to obtain the title compound (2.25 g, 92%).
  • Example 3 5-((2-Isopropoxyethyl) (2- (4- (1-methylpiperidin-4-yl) benzamido) pyridin-4-yl) amino) -N-methyl-1H-indole- 1-carboxamide 5-((2-Isopropoxyethyl) (2- (4- (piperidin-4-yl) benzamido) pyridin-4-yl) amino) -N-methyl-1H-indole-1- To a solution of carboxamide (816 mg, 1.47 mmol) in tetrahydrofuran (50 mL) was added sodium triacetoxyborohydride (935 mg, 4.41 mmol) and 35% aqueous formaldehyde solution (1.2 mL, 15.3 mmol) at room temperature.
  • the reaction was stirred at room temperature for 4 hours.
  • the reaction mixture was partitioned by adding a saturated aqueous sodium hydrogen carbonate solution and ethyl acetate.
  • the aqueous layer was extracted once with ethyl acetate, and the combined organic layers were dried over anhydrous sodium sulfate.
  • the fraction of interest was concentrated under reduced pressure, suspended in tert-butyl methyl ether (20 mL), and stirred at 75 ° C. for 30 minutes under a nitrogen atmosphere.
  • Example 4 5-((2- (Cyclopropanecarboxamido) pyridin-4-yl) (3-hydroxy-3-methylbutyl) amino) -N-methyl-1H-indole-1-carboxamide 5-((3-hydroxy-3-methylbutyl) amino) -N-methyl-1H-indole-1-carboxamide (100 mg, 0.363 mmol) described in Preparation Example 4-2 and the description in Preparation Example 4-3 A mixture of N- (4-chloropyridin-2-yl) cyclopropanecarboxamide (25 mg, 0.127 mmol), pyridine hydrochloride (40 mg, 0.346 mmol) and 2-ethoxyethanol (0.6 mL) was added under a nitrogen atmosphere.
  • the starting material 5-((3-hydroxy-3-methylbutyl) amino) -N-methyl-1H-indole-1-carboxamide was synthesized by the following method.
  • a mixed solution of lithium aluminum hydride (1.7 g, 44.8 mmol) in dehydrated tetrahydrofuran (60 mL) was heated to 60 ° C., and a dehydrated tetrahydrofuran (40 mL) solution of the crude product was added dropwise over 30 minutes. Further, the mixture was heated and stirred at 70 ° C. for 1 hour in a nitrogen atmosphere. The reaction solution was cooled to 0 ° C., and water (1.6 mL), 5M aqueous sodium hydroxide solution (1.6 mL), and water (1.6 mL) were sequentially added. After stirring for 1 hour, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
  • the starting material N- (4-chloropyridin-2-yl) cyclopropanecarboxamide was synthesized by the following method.
  • Example 5 5-((3-hydroxy-3-methylbutyl) (2- (4- (1- (2-hydroxyethyl) piperidin-4-yl) benzamido) pyridin-4-yl) amino) -N -Methyl-1H-indole-1-carboxamide 5-((3-Hydroxy-3-methylbutyl) amino) -N-methyl-1H-indole-1-carboxamide (230 mg, 0.834 mmol) described in Preparation Example 4-2 and the description in Preparation Example 5-3 N- (4-chloropyridin-2-yl) -4- (1- (2-hydroxyethyl) piperidin-4-yl) benzamide (100 mg, 0.278 mmol), pyridine hydrochloride (96 mg, 0.834 mmol) and A mixture of 2-ethoxyethanol (2 mL) was stirred at 135 ° C.
  • Example 6 6-Chloro-5-((2- (4- (1-ethylpiperidin-4-yl) benzamido) pyridin-4-yl) amino) -N-methyl-1H-indole-1-carboxamide 6-Chloro-N-methyl-5-((2- (4- (piperidin-4-yl) benzamido) pyridin-4-yl) amino) -1H-indole-1-carboxamide described in Preparation Example 6-7 (10.0 mg, 0.02 mmol) was dissolved in tetrahydrofuran (500 ⁇ L) and acetaldehyde (11.1 ⁇ L, 0.20 mmol), acetic acid (6.83 ⁇ L, 0.12 mmol), sodium triacetoxyborohydride ( 25.3 mg, 0.12 mmol) was added.
  • the starting material 6-chloro-N-methyl-5-((2- (4- (piperidin-4-yl) benzamido) pyridin-4-yl) amino) -1H-indole-1-carboxamide was prepared by the following method. Synthesized.
  • the crude product (6.50 g, 25.9 mmol) was dissolved in tetrahydrofuran (60 mL) and triethylamine (140 mL) and then trimethylsilylacetylene (5.48 mL, 38.8 mmol), bis (tri Phenylphosphine) palladium (II) chloride (907 mg, 1.29 mmol) and copper iodide (492 mg, 2.59 mmol) were added, and the mixture was stirred at 70 ° C.
  • reaction mixture was partitioned by adding water.
  • the aqueous layer was extracted 3 times with ethyl acetate, and the combined organic layers were washed with saturated brine. Dry over anhydrous magnesium sulfate and filter.
  • the reaction mixture was filtered through a glass filter lined with anhydrous sodium sulfate, and the filtrate was 5-((2-aminopyridin-4-yl) amino) -6-chloro-N-methyl-1H described in Preparation Example 6-6.
  • Indole-1-carboxamide (32.0 mg, 0.10 mmol), triethylamine (71.0 ⁇ L, 0.51 mmol), 4-dimethylaminopyridine (2.48 mg, 0.02 mmol), tetrahydrofuran (1 mL) and N, N -To a mixture of dimethylformamide (1 mL) at 0 ° C.
  • the reaction mixture was partitioned by adding a methylamine solution.
  • Example compounds of Table 1 to Table 11 were synthesized according to the production methods, production examples and the methods of Examples 1 to 6.
  • Tables 12 to 19 show mass spectra (ESI-MS (m / z)) of the compounds of Examples 1 to 340.
  • ESI-MS mass spectra
  • Tables 12 to 19 show mass spectra (ESI-MS (m / z)) of the compounds of Examples 1 to 340.
  • ESI-MS mass spectra
  • WatersWaterMicromass ZQ 2000, Waters SQ Detector 2, or Thermo Fisher Scientific LCQ was used.
  • measurement was performed using an electrospray method (ESI®; Electrospray® ionization).
  • FGFR1 Kinase Assay measures the inhibitory activity of a test substance on the tyrosine kinase activity of FGFR1 protein.
  • FGFR1 protein (carnabio) diluted to 1 ⁇ g / mL in a flat bottom 96-well white plate (Sumitomo Bakelite MS-896W) with assay buffer (20 mM HEPES-NaOH, 0.01% Triton X-100, 2 mM DTT, 5 mM MgCl 2 ).
  • Kinase detection reagent was added and reacted at room temperature for 40 minutes to perform conversion from ADP to ATP, luciferase / luciferin coupling reaction, and luminescence reaction by ATP.
  • the enzyme activity was evaluated by measuring the amount of luminescence in each well using Envision TM (Perkin Elmer Co., Ltd.).
  • the light emission rate in the presence of the test substance is obtained by setting the light emission amount when the kinase protein is added without adding the test substance as 100% and the light emission amount when the test substance and the kinase protein are not added as 0%. It was.
  • the concentration (IC 50 value) of the test substance required to inhibit the kinase activity by 50% was calculated from this luminescence amount rate, and is shown in Tables 12 to 19.
  • the ATP concentration was evaluated at a final concentration of 6 ⁇ M in protocol a and at a final concentration of 77.5 ⁇ M in protocol b.
  • SNU-16 Growth Inhibition Assay This assay measures the growth inhibitory activity of a test substance in a human gastric cancer cell line with FGFR2 gene amplification.
  • SNU-16 Human gastric cancer cell line SNU-16 (ATCC Number CRL-5974) has been reported to have FGFR2 gene amplification (Cancer Res. 2008.68: 2340-2348).
  • SNU-16 cells were maintained in a 5% CO 2 incubator (37 ° C.) using RPMI-1640 (WAKO 187-02021) medium containing 10% FBS and penicillin / streptomycin (WAKO 168-23191).
  • RPMI-1640 WAKO 187-02021
  • penicillin / streptomycin WAKO 168-23191
  • 150 ⁇ L of SNU-16 cell suspension prepared to 1 ⁇ 10 4 cells / mL using RPMI-1640 medium containing 10% FBS was added. The cells were cultured overnight in a 5% CO 2 incubator (37 ° C.).
  • HUVEC Growth Inhibition Assay This assay measures the inhibitory activity of a test substance on VEGF-induced vascular endothelial cell proliferation.
  • HUVEC Human Umbilical Vein Endothelial Cells
  • HUVEC prepared to 1.5 ⁇ 10 4 cells / mL in EGM-2 medium containing 2% Fetal bovine serum (FBS: Cell Culture Technologies CC3008-504) in each well of a 96-well plate (Becton Dickinson 35-3075) 100 ⁇ l of each cell suspension was added and cultured overnight in a 5% CO 2 incubator (37 ° C.). The next day, test substance diluted in EGM-2 medium containing 2% FBS and VEGF prepared in EGM-2 medium containing 2% FBS to a final concentration of 10 ng / mL (R & D systems 293-VE-010) 50 ⁇ L each was added and cultured in a 5% CO 2 incubator (37 ° C.) for 3 days.
  • FBS Fetal bovine serum
  • Tumor volume (mm 3 ) major axis (mm) ⁇ minor axis (mm) ⁇ minor axis (mm) / 2
  • the groups were divided so that the average values of the tumor volumes were almost equal.
  • the test substance was dissolved in DMSO, Tween 80 was added, a 10-fold concentrated solution was prepared, and stored frozen.
  • the test sample was orally administered once a day for 11 days at a dose volume of 20 mL / kg, and the control solvent was orally administered under the same conditions.
  • the experiment was conducted with 5 animals per group.
  • the weight ratio (RBW) of the last day to the weight of the first day is calculated.
  • the test substance administration group in which the RBW of the test substance administration group / RBW of the control group was 0.9 or more was determined to be a safe administration group.
  • the ratio (T / C) (%) of the tumor volume after test substance administration to the control tumor volume on the last day was calculated and shown in Table 21.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un composé représenté par la formule (I), ou un sel pharmaceutiquement acceptable de celui-ci, agissant comme inhibiteur du récepteur du facteur de croissance des fibroblastes (FGFR). [Dans la formule : A représente un groupe arylène en C6-10 ou analogue qui peut comprendre un substituant; J représente un groupe hétérocyclique non aromatique contenant de l'azote en C3-10 ou analogue qui peut comprendre 1 à 3 substituants choisis dans le groupe L de substituants; R1, R2, et R3 représentent un atome d'hydrogène ou analogue; R4 représente un groupe alkyle en C1-6 qui peut comprendre un substituant; R5 représente un groupe hydroxy alkyle en C1-6 qui peut être substitué par 1 à 3 atomes d'halogène; R6, R7, R8, R9, et R10 représentent chacun indépendamment un atome d'hydrogène ou analogue; et le groupe L de substituants représente un groupe qui comprend des groupes alkyle en C1-6 ou analogues qui peut être substitué par 1 ou 2 groupes hydroxyle].
PCT/JP2015/073046 2014-08-18 2015-08-17 Dérivé de 4-aminopyridine Ceased WO2016027780A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2014166119A JP2017206437A (ja) 2014-08-18 2014-08-18 ４−アミノピリジン誘導体
JP2014-166119 2014-08-18

Publications (1)

Publication Number Publication Date
WO2016027780A1 true WO2016027780A1 (fr) 2016-02-25

Family

ID=55350724

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2015/073046 Ceased WO2016027780A1 (fr) 2014-08-18 2015-08-17 Dérivé de 4-aminopyridine

Country Status (2)

Country Link
JP (1) JP2017206437A (fr)
WO (1) WO2016027780A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023174400A1 (fr) * 2022-03-18 2023-09-21 上海润石医药科技有限公司 Sel de composé hétérocyclique nitrique à six chaînons amino substitué, forme cristalline de celui-ci, procédé de préparation correspondant et utilisation associée
CN117715902A (zh) * 2021-08-31 2024-03-15 卫材R&D管理有限公司 单环吡啶衍生物的制造方法
WO2024151919A1 (fr) * 2023-01-13 2024-07-18 Ifm Due, Inc. Composés et compositions pour traiter des états pathologiques associés à une activité de sting
RU2854499C2 (ru) * 2021-08-31 2026-01-13 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Способ получения моноциклического производного пиридина

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108367000A (zh) 2015-12-17 2018-08-03 卫材R&D管理有限公司 用于乳腺癌的治疗剂

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004020434A1 (fr) * 2002-08-30 2004-03-11 Eisai Co., Ltd. Derives d'azaarene
WO2006030941A1 (fr) * 2004-09-13 2006-03-23 Eisai R & D Management Co., Ltd. Utilisation concomitante d'un compose contenant du sulfonamide et d'un inhibiteur d'angiogenese
WO2007015578A1 (fr) * 2005-08-02 2007-02-08 Eisai R & D Management Co., Ltd. Procédé d’analyse de l’effet d’un inhibiteur de vascularisation
WO2007015569A1 (fr) * 2005-08-01 2007-02-08 Eisai R & D Management Co., Ltd. Procédé de prédiction de l’efficacité d’un inhibiteur de vascularisation
JP2012511535A (ja) * 2008-12-09 2012-05-24 ノバルティス アーゲー Ｖｅｇｆ−ｒ２のピリジルオキシインドール類阻害剤および疾患の処置のためのその使用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004020434A1 (fr) * 2002-08-30 2004-03-11 Eisai Co., Ltd. Derives d'azaarene
WO2006030941A1 (fr) * 2004-09-13 2006-03-23 Eisai R & D Management Co., Ltd. Utilisation concomitante d'un compose contenant du sulfonamide et d'un inhibiteur d'angiogenese
WO2007015569A1 (fr) * 2005-08-01 2007-02-08 Eisai R & D Management Co., Ltd. Procédé de prédiction de l’efficacité d’un inhibiteur de vascularisation
WO2007015578A1 (fr) * 2005-08-02 2007-02-08 Eisai R & D Management Co., Ltd. Procédé d’analyse de l’effet d’un inhibiteur de vascularisation
JP2012511535A (ja) * 2008-12-09 2012-05-24 ノバルティス アーゲー Ｖｅｇｆ−ｒ２のピリジルオキシインドール類阻害剤および疾患の処置のためのその使用

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117715902A (zh) * 2021-08-31 2024-03-15 卫材R&D管理有限公司 单环吡啶衍生物的制造方法
RU2854499C2 (ru) * 2021-08-31 2026-01-13 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Способ получения моноциклического производного пиридина
WO2023174400A1 (fr) * 2022-03-18 2023-09-21 上海润石医药科技有限公司 Sel de composé hétérocyclique nitrique à six chaînons amino substitué, forme cristalline de celui-ci, procédé de préparation correspondant et utilisation associée
WO2024151919A1 (fr) * 2023-01-13 2024-07-18 Ifm Due, Inc. Composés et compositions pour traiter des états pathologiques associés à une activité de sting

Also Published As

Publication number Publication date
JP2017206437A (ja) 2017-11-24

Similar Documents

Publication Publication Date Title
KR102318875B1 (ko) 헤테로아릴 유도체, 이를 제조하는 방법, 및 이를 유효성분으로 포함하는 약학적 조성물
JP6934261B2 (ja) Ｎ−（アザアリール）シクロラクタム−１−カルボキサミド誘導体、その製造方法および応用
TWI672139B (zh) 單環吡啶衍生物
KR101663637B1 (ko) 키나아제 억제제
RU2658821C1 (ru) Соль моноциклического производного пиридина и ее кристалл
JP7034512B2 (ja) キナーゼ阻害剤としてのヘテロアリール化合物
EA007063B1 (ru) ПРОИЗВОДНЫЕ АМИНОБЕНЗАМИДОВ В КАЧЕСТВЕ ИНГИБИТОРОВ ГЛИКОГЕНСИНТАЗА-КИНАЗЫ 3β;
CN102898386A (zh) 喹唑啉衍生物、其制备方法、中间体、组合物及其应用
EA028057B1 (ru) Производные аминопиримидина для применения в качестве модуляторов киназной активности
JP2009534458A (ja) アミノ−エチル−アミノ−アリール（ａｅａａ）化合物およびそれらの使用
KR20200020607A (ko) 이소인돌린-1온 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물
WO2016027780A1 (fr) Dérivé de 4-aminopyridine
KR20210110288A (ko) 치환된 아릴 화합물, 및 이의 제조 방법 및 이의 용도
EP3663285B1 (fr) Dérivé de formylpyridine ayant une activité inhibitrice de fgfr4, son procédé de préparation et son utilisation
US12582654B2 (en) Cyano-substituted pyridine and cyano-substituted pyrimidine compound and preparation method therefor and application thereof
US20240150337A1 (en) Heteroaryl derivative, method for producing same, and pharmaceutical composition comprising same as effective component
KR102472103B1 (ko) 국소 부착 키나아제 저해제로서 신규한 아다만탄 유도체
JP2022551180A (ja) イソクエン酸デヒドロゲナーゼ（ｉｄｈ）阻害剤
TWI820414B (zh) 喹唑啉類化合物、製備方法及其應用
CN103373971A (zh) 作为蛋白激酶抑制剂的脲类化合物
HK1215949B (en) Monocyclic pyridine derivative

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15833478

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15833478

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP