WO2013180128A1 - 4-[4-(5-membered aromatic heterocyclic carbonyl ureide)phenyloxy]quinoline derivative - Google Patents

4-[4-(5-membered aromatic heterocyclic carbonyl ureide)phenyloxy]quinoline derivative Download PDF

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WO2013180128A1
WO2013180128A1 PCT/JP2013/064765 JP2013064765W WO2013180128A1 WO 2013180128 A1 WO2013180128 A1 WO 2013180128A1 JP 2013064765 W JP2013064765 W JP 2013064765W WO 2013180128 A1 WO2013180128 A1 WO 2013180128A1
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compound
mmol
esi
nmr
phenyloxy
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Japanese (ja)
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諒平 川井
真麻 山内
磨 佐久
啓 中川
昌祥 名小路
和生 久保
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協和発酵キリン株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention provides colony stimulating factor-1 receptor [Colony Stimulating Factor 1 Receptor (CSF-1R)] and / or tropomyosin-related kinase A [Tropomyosin-related kinase A (TrkA)] inhibitory activity 4- [4- ( The present invention relates to a 5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof.
  • CSF-1R Colony Stimulating Factor 1 Receptor
  • TrkA Tropomyosin-related kinase A
  • CSF-1R [also called M-CSFR (Macrophage colony-stimulating factor receptor) or Fms] is a type of receptor tyrosine kinase and its ligand, macrophage colony-stimulating factor [Macrophage colony-stimulating factor (M-CSFR ), Or CSF-1 (also called Colony Stimulating Factor 1)] or IL-34 binding. Activation of CSF-1R induces differentiation, proliferation, survival and migration of mononuclear cells and macrophage cells.
  • M-CSFR Macrophage colony-stimulating factor receptor
  • Fms Fms
  • CSF-1R Activation of CSF-1R is known as an essential signal that promotes the differentiation of osteoclast precursor cells into mature osteoclasts.
  • osteoclasts Because osteoclasts are not induced to induce osteoclast (Nature, 345, 442-444 (1990)), and by administering active M-CSF to this mouse, Acknowledged and reported to cure marble bone disease [Journal Experience Medicine (J. Exp. Med.), 173, 269-272 (1991)].
  • CSF-1R signal inhibition of CSF-1R is caused by bone lesions caused by multiple myeloma, bone lesions caused by solid cancer bone metastasis, rheumatoid arthritis, osteoporosis, Behcet's disease , Thought to be useful for the treatment of diseases such as osteoarthritis [Expert Opin. The Therapies Targets, Vol. 15, No. 2, pp. 169-181 ( 2011)].
  • anti-M-CSF antibody and anti-CSF-1R antibody inhibit osteoclast differentiation activation and improve bone destruction in a mouse arthritis model [The Journal of Clinical Investigation (J Clin.
  • CSF-1R or M-CSF and activation of CSF-1R may cause prostate cancer, lung cancer, kidney cancer, pancreatic cancer, breast cancer, uterine cancer, myelodysplastic syndrome, acute myeloid leukemia, chronic myelogenous Recognized in leukemia and the like [Expert ⁇ Opin. Ther. Patent, 21, No.2, pp.147-165 (2011)], PLX3397, a CSF-1R inhibitor Is a breast cancer transplantation model, due to the inhibition of migration of Tumor-associated macrophages (TAM) [Nature. Cancer Rev. 4, Vol. 1, No. 1, pp. 71-78 (2004)] It shows the potentiation of anticancer activity by paclitaxel [Cancer Discovery, Vol. 1, No. 1, pp. 54-67 (2011)].
  • TAM Tumor-associated macrophages
  • CSF-1R inhibitors are, for example, bone lesions caused by multiple myeloma, bone lesions caused by solid cancer bone metastases, rheumatoid arthritis, osteoporosis, Behcet's disease, osteoarthritis, prostate cancer, lung cancer, It is considered useful as a therapeutic and / or prophylactic agent for renal cancer, pancreatic cancer, breast cancer, uterine cancer, myelodysplastic syndrome, acute myeloid leukemia, chronic myelogenous leukemia and the like.
  • Trk The tropomyosin-related kinase (Trk) family is a receptor tyrosine kinase, mainly TrkA activated by nerve growth factor (NGF), mainly brain-derived growth factor [Brain -derived neurotrophic factor (BFNF)], or neurotrophin-4 ⁇ also called neurotrophin-4 (NT-4), or neurotrophin-5 [neurotrophin-5 (NT-5)] ⁇ , And TrkC activated mainly by neurotrophin-3 (NT-3) [Phil. Trans. R. Soc B), 361, 1545-1564 (2006)].
  • NGF nerve growth factor
  • BFNF brain-derived growth factor
  • NT-4 neurotrophin-4
  • TrkC activated mainly by neurotrophin-3 (NT-3) [Phil. Trans. R. Soc B), 361, 1545-1564 (2006)].
  • TrkA knockout mice exhibit a unique phenotype of loss of pain, and TrkA gene mutations are the cause of congenital analgesia (Nat. Genet., 13, 485-488) (1996)], pain is induced by administering NGF to normal animals and humans [European Journal of Neuroscience (Eur. J. Neurosci.), 6, 1903-1912 (1994) Year), Neurology, 48, 501-505 (1997)].
  • anti-NGF antibody is a rat arthritis model [Pain, 116, 8-16 (2005)], cancer bone metastasis model [Journal of Pain (J. (Pain), 12, No. 6, 698-711 (2011), Pain, Vol. 152, No. 11, 2564-2574 (2011)], etc., to suppress pain and reduce pain in patients with knee osteoarthritis etc. [The New England Journal of Medicine (N. Engl. J. Med.), 363, 16, 1521-1531 (2010)]. Furthermore, the TrkA inhibitor ARRY-470 has an analgesic effect in a cancer bone metastasis model [Molecular Pain, 6:87 (2010)].
  • the TrkA inhibitor is considered useful as a therapeutic and / or preventive agent for pain such as inflammatory such as rheumatoid arthritis or osteoarthritis and cancerous such as cancer bone metastasis.
  • pain such as inflammatory such as rheumatoid arthritis or osteoarthritis
  • cancerous such as cancer bone metastasis.
  • compounds that inhibit CSF-1R and TrkA simultaneously suppress symptoms such as bone destruction and pain due to cancer bone metastasis, bone destruction and pain such as rheumatoid arthritis patients and osteoarthritis, etc. It is preferable because it is expected.
  • vascular endothelial growth factor receptor 2 [vascular endothelial growth factor receptor-2 (VEGFR-2)] and hepatocyte growth factor receptor [hepatocyte growth factor receptor (HGFR)] are known.
  • VEGFR-2 vascular endothelial growth factor receptor-2
  • HGFR hepatocyte growth factor receptor
  • Anti-VEGF neutralizing antibody and VEGFR-2 inhibitor show antitumor activity against renal cancer, liver cancer, colon cancer, non-vesicular lung cancer, etc. [Nature Review Cancer, Vol. 8, 579 -591, 2008, Nature Review Drug Discovery, Vol. 6, pp. 734-745 (2007), also induces side effects such as increased blood pressure. [Briten de Cancer] (Bull. Cancer), 92, S29-36 (2005)], and administration of VEGF-neutralizing antibody inhibits renal capillary growth and causes renal damage [The New England Journal of ⁇ Medicine (N. Engl. J. Med.), 358, 1129-1136 (2008)].
  • anti-HGF antibody which is an antibody against hepatocyte growth factor (HGF), which is a ligand of HGFR
  • HGFR inhibitor show antitumor activity against renal cancer, liver cancer, prostate cancer, non-vesicular lung cancer, etc.
  • HGF hepatocyte growth factor
  • HGFR knockout mice have similar phenomena to the pathogenesis of fulminant hepatitis such as hepatic regeneration failure [Proceedings of the National Academy of Sciences (PNAS), 101, 4477- 4482 (2004)].
  • VEGFR-2 and HGFR inhibitory activities are lower than the CSF-1R and TrkA inhibitory activities.
  • Kinase inhibitors containing a quinoline derivative having an acylurea or acylthiourea structure at the 4-position are known (Patent Documents 1 to 8, Non-Patent Documents 1 and 2).
  • kinase inhibitors containing a quinoline derivative having a 5-membered aromatic heterocyclic urea structure at the 4-position are also known (Patent Documents 9 to 11, Non-Patent Document 3).
  • An object of the present invention is to provide a 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative having CSF-1R and / or TrkA inhibitory activity, or a pharmaceutically acceptable salt thereof, etc. There is to do.
  • R 1A and R 2A are the same or different and each represents hydroxy, optionally substituted lower alkoxy or optionally substituted aliphatic heterocyclic oxy, and R 3A represents R 4A represents a lower alkoxy, and R 4A may have a substituent (the substituent represents the same or different 1 to 3 substituents selected from the group consisting of the following substituents A1) 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof represented by: Substituent A1: An optionally substituted lower alkyl [the substituent is lower alkoxy, and —NR 5 R 6 (R 5 and R 6 are the same or different and each represents a hydrogen atom or lower alkyl] Selected from the group consisting of: halogen, cycloalkyl optionally substituted with lower alkyl, lower alkoxy and aliphatic heterocyclic groups.
  • R 1 and R 2 are the same or different and each represents an optionally substituted lower alkoxy
  • R 3 represents a lower alkoxy
  • R 4 represents a substituent (the substituent is Represents a 5-membered aromatic heterocyclic group which may have the same or different 1 to 3 substituents selected from the group consisting of the group A]; 5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof:
  • Substituent A optionally substituted lower alkyl [the substituent is lower alkoxy, and —NR 5 R 6 (R 5 and R 6 are the same or different and each represents a hydrogen atom or lower alkyl] And cycloalkyl optionally substituted with halogen and lower alkyl.
  • An effective amount of the 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (10) A method for treating and / or preventing a disease involving a colony stimulating factor-1 receptor or tropomyosin-related kinase A, comprising a step of administering.
  • the present invention has CSF-1R and / or TrkA inhibitory activity, cancer bone metastasis, rheumatoid arthritis, osteoporosis, Behcet's disease, osteoarthritis, prostate cancer, lung cancer, kidney cancer, pancreatic cancer, breast cancer, uterus 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivatives useful for the treatment and / or prevention of cancer, myelodysplastic syndrome, acute myeloid leukemia, chronic myeloid leukemia, etc. Acceptable salts and the like are provided.
  • lower alkyl and lower alkyl in lower alkoxy include linear or branched alkyl having 1 to 10 carbon atoms, and more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -Butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
  • cycloalkyl examples include cycloalkyl having 3 to 8 carbon atoms, and more specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • 5-membered aromatic heterocyclic group examples include a 5-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • Examples include furyl, thienyl, pyrrolyl, imidazolyl, 2-oxoimidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl and the like.
  • Examples of the aliphatic heterocyclic group and the aliphatic heterocyclic moiety in the aliphatic heterocyclic oxy include, for example, a 5-membered or 6-membered monocyclic group including at least one atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom.
  • Halogen means each atom of fluorine, chlorine, bromine and iodine.
  • substituent in the lower alkoxy which may have a substituent are the same or different, for example, those having 1 to 3 substituents, Halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, C 3-8 cycloalkyl, C 6-14 aryl, aliphatic heterocyclic group, aromatic heterocyclic group, optionally substituted C 1 -10 alkoxy (substituents in the substituted C 1-10 alkoxy are the same or different and include, for example, halogen, hydroxy and the like having 1 to 3 substituents), C 3-8 cycloalkoxy, C 6-14 aryl Oxy, C 7-16 aralkyloxy, C 2-11 alkanoyloxy, C 7-15 aroyloxy, C 1-10 alkylsulfanyl, —NR X R Y (wherein R X and R Y are the
  • Examples of the substituent in the aliphatic heterocyclic oxy which may have a substituent are the same or different, for example, those having 1 to 3 substituents, Oxo, halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl,
  • Examples of the substituent in the optionally substituted C 1-10 alkyl (the substituted C 1-10 alkyl, same or different, such substituted Numbers 1 to 3, halogen, amino, hydroxy, cyano, carboxy, C 3-8 cycloalkyl, C 1-10 alkoxy, C 1-10 alkoxycarbonyl, C 2-11 alkanoyloxy, carbamoyl, C 1-10 alkyl Carbamoyl, di-C 1-10 alkylcarbamoyl, etc.), C 3-8 cycloalkyl, C 6-14 aryl, aliphatic heterocyclic group, aromatic heterocyclic group, C 1-10 alkoxy, C 3-8 Cycloalkoxy,
  • C 1-10 alkyl as shown here and C 1-10 alkoxy, C 1-10 alkylsulfanyl, C 2-11 alkanoyl, C 2-11 alkanoyloxy, C 1-10 alkoxycarbonyl, C 1-10 alkylcarbamoyl and
  • Examples of the C 1-10 alkyl moiety of diC 1-10 alkylcarbamoyl include the groups exemplified in the above-mentioned lower alkyl.
  • the two C 1-10 alkyl moieties in the diC 1-10 alkylcarbamoyl may be the same or different.
  • the C 3-8 cycloalkyl and C 3-8 cycloalkyl moiety cycloalkoxy e.g., the groups listed illustrative of the cycloalkyl are exemplified.
  • Examples of the aryl moiety of C 6-14 aryl and C 6-14 aryloxy, C 7-15 aroyl, C 7-15 aroyloxy and C 6-14 aryloxycarbonyl include aryl having 6 to 14 carbon atoms. More specifically, phenyl, naphthyl, azulenyl, anthryl and the like can be mentioned.
  • Examples of the aryl moiety of C 7-16 aralkyloxy, C 7-16 aralkyl and C 7-16 aralkyloxycarbonyl include the groups exemplified in the above examples of C 6-14 aryl and aryl moiety. Examples thereof include C 1-10 alkylene, and more specifically, a group in which one hydrogen atom is removed from the groups exemplified in the lower alkyl.
  • an aliphatic heterocyclic group the group quoted by the illustration of the said aliphatic heterocyclic group is illustrated, for example.
  • the aromatic heterocyclic group include a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring.
  • Examples thereof include condensed bicyclic or tricyclic condensed ring aromatic heterocyclic groups containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically, furyl, thienyl, pyrrolyl, etc.
  • Pharmaceutically acceptable salts of compounds (I) and (IA) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like.
  • examples of the pharmaceutically acceptable acid addition salt of compound (I) include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, oxalate, and maleate.
  • Organic acid salts such as acid salts, fumarate salts, citrate salts, benzoate salts, methanesulfonate salts, and the like.
  • pharmaceutically acceptable metal salts include alkali salts such as sodium salts and potassium salts.
  • Examples thereof include alkaline earth metal salts such as metal salts, magnesium salts, and calcium salts, aluminum salts, and zinc salts.
  • Examples of pharmaceutically acceptable ammonium salts include salts such as ammonium and tetramethylammonium.
  • Examples of the pharmaceutically acceptable organic amine addition salt include addition salts such as morpholine and piperidine.
  • Examples of the pharmaceutically acceptable amino acid addition salt include lysine and glycine. Emissions, phenylalanine, aspartic acid, addition salts of glutamic acid and the like.
  • Diseases involving CSF-1R include, for example, bone lesions caused by multiple myeloma, bone lesions caused by solid cancer bone metastases, rheumatoid arthritis, osteoporosis, Behcet's disease, osteoarthritis, prostate cancer, lung cancer, kidney cancer Pancreatic cancer, breast cancer, uterine cancer, myelodysplastic syndrome, acute myeloid leukemia, chronic myelogenous leukemia and the like.
  • diseases involving TrkA include inflammatory such as rheumatoid arthritis or osteoarthritis, and pain such as cancerous such as cancer bone metastasis.
  • Examples of the diseases involving CSF-1R and TrkA include bone destruction and pain due to cancer bone metastasis, bone destruction and pain such as rheumatoid arthritis patients and osteoarthritis, and the like.
  • production methods of compounds (I) and (IA) will be described.
  • introduction of a protective group commonly used in organic synthetic chemistry and Removal methods e.g., Protective Groups in Organic Synthesis, third edition, written by TW Greene, John Wiley & Sons Inc. (1999), etc.
  • the method can be used to produce the target compound. Further, the order of reaction steps such as introduction of substituents can be changed as necessary.
  • Process 1 Compound (IV) is obtained by reacting Compound (II) in a solvent, preferably in the presence of 1 to 100 equivalents of a base, at a temperature between ⁇ 10 ° C. and the boiling point of the solvent used for 5 minutes to 72 hours, Preferably, it can be produced by reacting with 1 to 100 equivalents of compound (III).
  • Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, diisopropylethylamine, triethylamine, sodium hydroxide, potassium hydroxide, sodium hydride, pyridine, 2,6-lutidine, N, N-dimethylaminopyridine and the like. These can be used alone or in admixture.
  • solvent examples include chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane (DME), N, N-dimethylformamide (DMF), N, N-dimethylacetamide ( DMA), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), toluene, xylene, chlorobenzene and the like, and these can be used alone or in combination.
  • Compound (II) is, for example, WO 97/017329, JP-A-11-158149, WO00 / 43366, WO01 / 47890, WO02 / 088110, WO03 / 000660, WO03 / 033472, WO2004 / 018430, WO2004 / 039782, US5773449A, J. It can be produced according to the method described in Med. Chem., 2005, 48 (5), 1359-1366, or their modifications.
  • Compound (III) can be obtained, for example, as a commercially available product or by a known method [for example, Comprehensive Organic Transformations, second edition, by RC Larock, John Wiley. -And Sons, Inc.
  • Process 2 Compound (V) is obtained by adding Compound (IV) in a solvent in the presence of 0.1 to 100% by weight of metal catalyst, preferably in the presence of 0.1 to 50% by weight of metal catalyst, at ⁇ 10 ° C. with respect to Compound (IV).
  • a temperature between 20 ° C. and the boiling point of the solvent used preferably at a temperature between 20 ° C. and the boiling point of the solvent used, in a hydrogen atmosphere under normal pressure or pressure, or from 1 equivalent to a large excess of suitable hydrogen It can be produced by treating for 5 minutes to 72 hours in the presence of a source. At this time, 0.01 to 30 equivalents of an appropriate acid can be added to promote the reaction.
  • Examples of the solvent include ethanol, methanol, ethyl acetate, diethyl ether, THF, water, acetonitrile, DMF, DMA and the like, and these can be used alone or in combination.
  • Examples of the metal catalyst include palladium carbon, palladium alumina, palladium hydroxide, palladium hydroxide carbon, palladium chloride, and Wilkinson catalyst.
  • the hydrogen source examples include formic acid, ammonium formate, sodium formate, and the like.
  • Examples of the acid include hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and the like.
  • the compound (V) is a compound (IV) in a solvent at a temperature between ⁇ 10 ° C. and the boiling point of the solvent used, preferably at a temperature between 20 ° C. and the boiling point of the solvent used. It can also be produced by treating with a reducing agent of preferably 1 to 10 equivalents relative to compound (IV) for 72 hours.
  • Process 3 Compound (V) is obtained by reacting Compound (II) in a solvent, preferably in the presence of 1 to 10 equivalents of a base with respect to Compound (II), at a temperature between ⁇ 10 ° C. and the boiling point of the solvent used for 5 minutes. It can also be produced by reacting with compound (VI) for ⁇ 72 hours, preferably 1 to 10 equivalents. At this time, 0.01 to 30 equivalents of an appropriate additive may be added.
  • Examples of the solvent include DMF, DMA, NMP, DMSO, chloroform, acetone, methyl ethyl ketone, water and the like, and these can be used alone or in combination.
  • Examples of the base include sodium hydroxide, potassium hydroxide, sodium hydride and the like.
  • Examples of the additive include tetrabutylammonium bromide.
  • Compound (VI) can be obtained, for example, as a commercially available product or by a known method [for example, Comprehensive Organic Transformations, second edition, by RC Larock, John Wiley. And And Wis & Sons Inc. (1999) etc.] or a method according to them.
  • Process 4 Compound (X) is obtained by reacting Compound (V) in a solvent, preferably in the presence of 1 to 100 equivalents of a base, at a temperature between ⁇ 10 ° C. and the boiling point of the solvent used for 5 minutes to 72 hours, Preferably 1 to 100 equivalents of compound (VII) are reacted, preferably 1 to 100 equivalents of compound (VIII) are added, and at a temperature between ⁇ 10 ° C. and the boiling point of the solvent used for 5 minutes to It can be produced by reacting for 72 hours.
  • Examples of the base include potassium carbonate, sodium carbonate, diisopropylethylamine, triethylamine, sodium hydroxide, potassium hydroxide, pyridine, 2,6-lutidine, N, N-dimethylaminopyridine, and the like alone or It can be used by mixing.
  • Examples of the solvent include chloroform, dichloromethane, 1,2-dichloroethane, diethyl ether, THF, dioxane, DMF, DMA, NMP, DMSO, toluene, xylene, chlorotoluene and the like, and these can be used alone or in combination. Can be used.
  • Compound (VII) can be obtained, for example, as a commercial product.
  • Compound (VIII) can be obtained, for example, as a commercial product.
  • compound (X) is obtained by reacting compound (V) in a solvent, preferably in the presence of 1 to 100 equivalents of a base, at a temperature between ⁇ 10 ° C. and the boiling point of the solvent used for 5 minutes to 72 minutes. It can also be produced by reacting with compound (IX) for 1 hour, preferably 1 to 100 equivalents.
  • Examples of the base include potassium carbonate, sodium carbonate, sodium hydroxide, diisopropylethylamine, triethylamine, pyridine, 2,6-lutidine and the like, and these can be used alone or in combination.
  • Examples of the solvent include chloroform, dichloromethane, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, DMSO, pyridine, and the like. Or it can mix and use.
  • Compound (IX) can be obtained, for example, as a commercial product.
  • Process 5 Compound (I) is obtained by reacting Compound (X) in a solvent, preferably in the presence of 1 to 100 equivalents of a base, at a temperature between ⁇ 10 ° C. and the boiling point of the solvent used for 5 minutes to 72 hours, Preferably, it can be produced by reacting with 1 to 100 equivalents of compound (VII).
  • Examples of the base include potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, diisopropylethylamine, triethylamine, sodium hydride, pyridine, 2,6-lutidine, N, N-dimethylaminopyridine, and the like.
  • Examples of the solvent include dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, chlorobenzene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, DMSO, pyridine, and the like. These may be used alone or in combination.
  • Compound (XI) can be obtained, for example, as a commercially available product, or can be produced by the following production method A. Manufacturing method A
  • Compound (XI) is obtained from Compound (XII) by a known method [for example, Comprehensive Organic Transformations, second edition, by RC Larock, John Wiley. John Wiley & Sons Inc. (1999), "5th edition Experimental Chemistry Course Organic Synthesis IV", p.119-154, Maruzen (2001), etc.] or methods according to them Can be synthesized.
  • Compound (XII) can be obtained, for example, as a commercial product or by a known method [for example, Comprehensive Organic Transformations, 2nd Edition, by R. C. Larock, John ⁇ Wiley & Sons Inc. (1999), New Hen Heterocyclic Compound Basics, Akihiro Yamanaka, Satoshi Hino, Masako Nakagawa, Nao Sakamoto, Kodansha Scientific (2004) , New Edition Heterocyclic Compound Application, Yasuhiro Yamanaka, Satoshi Hino, Masako Nakagawa, Takao Sakamoto, Kodansha Scientific (2004), New Edition Heterocyclic Compound Development, Yasuo Sakamoto, Yasuaki Sugaya, Kodansha (2010), etc. ] Or a method according to them, respectively.
  • a known method for example, Comprehensive Organic Transformations, 2nd Edition, by R. C. Larock, John ⁇ Wiley & Sons Inc. (1999), New Hen Heterocyclic Compound Basic
  • Compound (XII) can also be synthesized by the following method.
  • oxazole carboxylic acid can be obtained as a commercial product, for example, 1) J. Org. Chem. 1973, 38 (20), 3571-3575, 2) J. Hetrocyclic Chem., 1998, 35, 859-863, 3) Bioorg. Med. Chem. Lett., 2005, 15, 1075-1078, 4) Tetrahedron, 2004, 60 (18), 3967-3978 etc.
  • Thiazolecarboxylic acid can be obtained as a commercial product, for example, 1) Organic Synthesis, Coll. Vol 6, 1988, p620, 2) Tetrahedron, 2004, 60 (18), 3967-3978, 3) WO2007125061, etc.
  • the pyrazole carboxylic acid can be obtained as a commercial product, for example, 1) Tetrahedron. Lett., 2009, 50, 696-699, 2) J. Med. Chem. 1973, 16 (12), 1346-1354, etc. Can be produced by the method described in 1. above.
  • Isoxazole carboxylic acid can be obtained as a commercial product, for example, 1) Tetrahedron, 2006, 62, 4430-4434, 2) Tetrahedron Lett., 1993, 34 (47), 7509-7512, 3) J. Heterocyclic Chem., 1991, 28, 453-457 and the like.
  • Imidazolecarboxylic acid can be obtained as a commercial product, for example, 1) J. Org.
  • Triazole carboxylic acid can be obtained commercially, or can be produced, for example, by the method described in Synthetic Communication, 2004, 34 (2), 369-376 or the like.
  • Compound (IA) is a method for producing the above compound (I) and known methods (for example, Comprehensive Organic Transformations 2nd edition, RC Larock, Vch It can be produced by combining the method described in Verlagsgesellschaft Mbh (1999). Conversion of the functional group contained in R 1 , R 2 , R 3 or R 4 in compound (I) and R 1A , R 2A , R 3A or R 4A in compound (IA) can be carried out by a known method [for example, The method described in Hensive Organic Transformations 2nd edition, RC Larock, Vch Verlagsgesellschaft Mbh (1999), etc.] or in accordance with them.
  • the intermediates and target compounds in the above production methods are isolated and purified by separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. be able to.
  • the intermediate can be subjected to the next reaction without any particular purification.
  • Some of the compounds (I) and (IA) may have stereoisomers such as geometric isomers and optical isomers, tautomers and the like, but the present invention includes all of them. Includes possible isomers and mixtures thereof.
  • Some or all of the atoms in the compounds (I) and (IA) may be replaced with the corresponding isotope atoms, respectively, and the present invention also includes compounds replaced with these isotope atoms.
  • some or all of the hydrogen atoms in the compounds (I) and (IA) may be hydrogen atoms having an atomic weight of 2 (deuterium atoms).
  • a compound in which part or all of each atom in compounds (I) and (IA) is replaced with the corresponding isotope atom is produced by a method similar to the above production method using a commercially available building block. be able to.
  • a compound in which some or all of the hydrogen atoms in the compounds (I) and (IA) are replaced with deuterium atoms is, for example, 1) deuterium peroxide and deuterating carboxylic acid under basic conditions. Hydrogenation method (see US Pat. No. 3,849,458), 2) Deuteration of alcohol, carboxylic acid, etc. using iridium complex as catalyst and heavy water as deuterium source [Journal of American Chemical Society (J. Am. Chem. Soc.), Vol. 124, no. 10, 2092 (2002)], 3) A method of deuterating fatty acids using palladium carbon as a catalyst and using only deuterium gas as a deuterium source [LIPIDS, Vol. 9, No.
  • Metals such as platinum, palladium, rhodium, ruthenium, and iridium are used as catalysts, and heavy water or heavy water and deuterium gas are used as a deuterium source for acrylic acid, methyl acrylate, methacrylic acid. Deuteration of acids, methyl methacrylate, etc. (see Japanese Patent Publication No. 5-19536, Japanese Patent Laid-Open Nos. 61-277648 and 61-275241), 5) Palladium, nickel, copper or sub- It can also be synthesized by using a catalyst such as copper chromate, deuterating acrylic acid, methyl methacrylate, etc. using heavy water as a deuterium source (see JP-A 63-198638). it can.
  • the compounds (I) and (IA) may be purified as they are when they are obtained in the salt form.
  • (I) and (IA) can be isolated or purified by dissolving or suspending them in a suitable solvent and adding an acid or base to form a salt.
  • compounds (I) and (IA), and pharmaceutically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention. Is done.
  • Test Example 1 Measurement of Human CSF-1R Phosphorylation Inhibitory Activity Assay buffer [100 mmol / L 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), 10 mmol / L chloride on a 384-well polypropylene plate CSF-1R (Fms, 08-155, Carna Biosciences) diluted with magnesium, 0.003 vol% Brij-35, 0.004 vol% Tween20 and 1 mmol / L dithiothreitol, pH 7.5], fluorescently labeled substrate (FL -Peptide 30, 760430, Caliper Life Sciences), adenosine triphosphate [Adenosine triphosphate (ATP)] and a test substance dissolved in DMSO were added and reacted at room temperature for 60 minutes at a total volume of 25 ⁇ L.
  • HEPES (2-hydroxyethyl) -1-piperazineethanesulfonic acid
  • the final concentrations of CSF-1R, fluorescently labeled substrate, ATP and DMSO were 0.8 nmol / L, 1.0 ⁇ mol / L, 300 ⁇ mol / L and 1 vol%, respectively.
  • 45 ⁇ L of termination buffer [100 mmol / L HEPES, 15 mmol / L ethylenediaminetetraacetic acid (EDTA), 0.022 vol% Brij-35, 0.17 vol% Coating Reagent 3 and 7.2 vol% DMSO, pH 7.5] was added to the plate. The enzyme reaction was stopped by adding.
  • CSF-1R phosphorylation inhibition rate at each concentration was obtained by changing the concentration of the test substance in several stages, and based on these, the CSF-1R phosphorylation 50% inhibition concentration (IC 50 ) of the test substance was calculated. .
  • IC 50 CSF-1R phosphorylation 50% inhibition concentration
  • Test Example 2 Measurement of human TrkA phosphorylation inhibitory activity
  • assay buffer [100 mmol / L 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), 10 mmol / L magnesium chloride, TrkA (TrkA, 08-186, Carna Biosciences) diluted with 0.003 vol% Brij-35, 0.004 vol% Tween20 and 1 mmol / L dithiothreitol, pH 7.5], fluorescent labeling substrate (FL-Peptide 30, 760430, Caliper Life Sciences), a test substance dissolved in ATP and DMSO was added, and the whole was reacted at 25 ⁇ L at room temperature for 60 minutes.
  • assay buffer [100 mmol / L 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), 10 mmol / L magnesium chloride, TrkA (TrkA, 08-186, Car
  • TrkA The final concentrations of TrkA, fluorescently labeled substrate, ATP, and DMSO were 2 nmol / L, 1.0 ⁇ mol / L, 75 ⁇ mol / L, and 1 vol%, respectively.
  • 45 ml of termination buffer [100 mmol / L HEPES, 15 mmol / L ethylenediaminetetraacetic acid (EDTA), 0.022 vol% Brij-35, 0.17 vol% Coating Reagent 3 and 7.2 vol% DMSO, pH 7.5] was added to the plate. ⁇ L was added to stop the enzyme reaction.
  • the fluorescence intensity of the fluorescently labeled substrate and the phosphorylated fluorescently labeled substrate was measured.
  • the conversion rate was calculated.
  • the TrkA phosphorylation inhibition rate was calculated by the following formula 3.
  • the concentration of the test substance was changed in several stages, the inhibition rate of TrkA phosphorylation at each concentration was determined, and the TrkA phosphorylation 50% inhibition concentration (IC 50 ) of the test substance was calculated based on them.
  • IC 50 TrkA phosphorylation 50% inhibition concentration
  • Test Example 3 Measurement of human VEGFR-2 phosphorylation inhibitory activity
  • a 384-well polypropylene plate 1 vol% of 3-((3-colamidopropyl) dimethylammonio) -2-hydroxy-1-propanesulfonate (CHAPSO, 07958-41, Nacalai Tesque) assay buffer (100 mmol / L 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), 10 mmol / L magnesium chloride, 0.003 vol% Brij-35, 0.004 VEGFR-2 (KDR, 08-191, Carna Biosciences) diluted with vol% Tween20 and 1 mmol / L dithiothreitol, pH 7.5], fluorescently labeled substrate (FL-Peptide 22, 760366, Caliper Life Sciences) ), A test substance dissolved in ATP and DMSO was added, and the mixture was reacted at 28 ° C.
  • the fluorescence intensity of the fluorescently labeled substrate and the phosphorylated fluorescently labeled substrate was measured.
  • the conversion rate was calculated. Based on the obtained conversion rate, the VEGFR-2 phosphorylation inhibition rate was determined by the following formula 4.
  • Test Example 4 Measurement of human HGFR phosphorylation inhibitory activity
  • assay buffer [100 mmol / L 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), 10 mmol / L magnesium chloride, HGFR (Met, 08-151, Carna Biosciences) diluted with 0.003 vol% Brij-35, 0.004 vol% Tween20 and 1 mmol / L dithiothreitol, pH 7.5]
  • fluorescently labeled substrate FL-Peptide 2, 760346, Caliper Life Sciences
  • HGFR fluorescently labeled substrate
  • ATP phosphatidylcholine
  • DMSO phosphatidylcholine
  • 45 ⁇ L of termination buffer [100 mmol / L HEPES, 15 mmol / L ethylenediaminetetraacetic acid (EDTA), 0.022 vol% Brij-35, 0.17 vol% Coating Reagent 3 and 7.2 vol% DMSO, pH 7.5] was added to the plate. The enzyme reaction was stopped by adding.
  • HGFR phosphorylation inhibition rate at 1 ⁇ mol / L of the test substance was calculated.
  • compounds 1-4, 6-7, 9-13, 15-22, 24-42, 44-45, 48-52, 54, 55, 58-61, 63, 66-77 and 79-85 are Shows a phosphorylation inhibition rate of less than 50%, and compounds 23, 47, 53, 56, 57, 62, 64 and 78 show 50-60% inhibition at the above concentrations, and further compounds 5, 8, 43 and 46 showed an inhibition rate of 61-70% at the above concentrations.
  • compounds (I) and (IA) showed phosphorylation inhibitory activity selectively on CSF-1R and TrkA compared to VEGFR-2 and HGFR. Therefore, compounds (I) and (IA), and pharmaceutically acceptable salts thereof, inhibit CSF-1R and / or TrkA and cause cancer bone metastasis, rheumatoid arthritis, osteoporosis, Behcet's disease, deformability It is considered useful as a therapeutic and / or prophylactic agent for arthropathy, prostate cancer, lung cancer, kidney cancer, pancreatic cancer, breast cancer, uterine cancer, myelodysplastic syndrome, acute myeloid leukemia, chronic myelogenous leukemia and the like.
  • compositions (I) and (IA), or pharmaceutically acceptable salts thereof can be administered alone as they are, but it is usually desirable to provide them as various pharmaceutical preparations. These pharmaceutical preparations are used for animals or humans.
  • the pharmaceutical preparation according to the present invention contains the compounds (I) and (IA) as active ingredients, or pharmaceutically acceptable salts thereof alone or as a mixture with any other active ingredient for treatment. can do.
  • These pharmaceutical preparations are well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmaceutically acceptable carriers (e.g., diluents, solvents, excipients, etc.). Manufactured by any method.
  • oral or parenteral such as intravenous administration.
  • examples of the dosage form include tablets and injections.
  • tablets suitable for oral administration can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like.
  • an injection suitable for parenteral administration can be produced using a diluent or a solvent such as a salt solution, a glucose solution or a mixed solution of a saline solution and a glucose solution.
  • a diluent or a solvent such as a salt solution, a glucose solution or a mixed solution of a saline solution and a glucose solution.
  • the dosage and frequency of administration of compounds (I) and (IA), or pharmaceutically acceptable salts thereof vary depending on the dosage form, patient age, body weight, nature or severity of symptoms to be treated, etc.
  • oral administration it is administered once or several times a day in the range of 0.01 to 1000 mg, preferably 0.05 to 100 mg per adult.
  • parenteral administration such as intravenous administration
  • 0.001 to 1000 mg, preferably 0.01 to 100 mg per adult is administered once to several times a day.
  • the dose and the number of doses vary depending on the various conditions described above.
  • N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -5-methyl-1H-imidazole-4-carboxamide (Compound 51) According to Example 3, compound A2 (200 mg, 0.447 mmol), compound B73 (137 mg, 0.536 mmol), and 60% sodium hydride (21.0 mg, 0.894 mmol) to N- [4- (6,7 -Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -4-methyl-1- ⁇ [2- (trimethylsilyl) ethoxy] methyl ⁇ -1H-imidazole-5-carboxamide was obtained followed by THF (2.24 mL ), Tetrabutylammonium fluoride (1.0 mol / L THF solution, 3.13 mL) was added, and the mixture was stirred under reflux for 18 hours.
  • Reference example 1 4- (6,7-dimethoxyquinolin-4-yloxy) -2-methoxyaniline (Compound A1) To DMSO (100 mL), 60% sodium hydride (1.44 g, 1.74 mmol) and 4-amino-3-methoxyphenol (2.88 g, 20.7 mmol) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. Chem. 2005, 48, 1359-1366 4-Chloro-6,7-dimethoxyquinoline (4.63 g, 20.7 mmol) obtained according to the method described in the method was added, and the mixture was further stirred at 100 ° C. for 5 hours. The mixture was cooled to room temperature, water was added, and the mixture was extracted with chloroform.
  • Reference example 3 7- (Benzyloxy) -4- (3-fluoro-4-nitrophenoxy) -6-methoxyquinoline (Compound A3) 7- (Benzyloxy) -4-chloro-6-methoxyquinoline (9.00 g, 30 mmol) obtained according to the production method 8 of WO2000043366 was dissolved in chlorobenzene (60 mL), and 3-fluoro-4-nitrophenol (5.66 g, 36.1 mmol) was added, and the mixture was stirred at 120 ° C. for 21 hours.
  • Reference example 4 7- (Benzyloxy) -6-methoxy-4- (3-methoxy-4-nitrophenoxy) quinoline (Compound A4)
  • THF 35 mL
  • sodium methoxide-methanol solution 2.91 mL, 14.3 mmol
  • a saturated aqueous ammonium chloride solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered.
  • Reference Example 12 Process 1 Methyl 3-hydroxy-2- (1-methylcyclopropanecarboxamide) butanoate (Compound B21) According to Step 1 of Reference Example 11, L-threonine methyl ester / hydrochloride (1.00 g, 5.90 mmol), 1-methylcyclopropanecarboxylic acid (649 mg, 6.49 mmol), triethylamine (0.904 mL, 6.49 mmol), Compound B21 (1.31 g, 100%) was obtained from EDCI (1.24 g, 6.49 mmol) and HOBt (993 mg, 6.49 mmol).
  • Reference Example 16 Process 1 Methyl 4-bromo-5-cyclopropylisoxazole-3-carboxylate (Compound B40) In accordance with Step 1 of Reference Example 15, methyl 5-cyclopropylisoxazole-3-carboxylate (650 mg, 3.9 mmol), and NBS (3.5 g, 20 mmol) were converted to compound B40 (850 mg, 88%). Obtained. 1 H-NMR (CDCl 3 ) ⁇ : 3.98 (s, 3H), 2.18-2.12 (m, 1H), 1.21-1.19 (m, 4H).
  • Reference Example 25 Process 1 6-Methoxy-4- (3-methoxy-4-nitrophenoxy) -7- (2-methoxyethoxy) quinoline (Compound A12) According to Step 1 of Reference Example 6, compound A5 (1.3 g, 3.9 mmol), 1-bromo-2-methoxyethane (0.55 mL, 5.8 mmol), and potassium carbonate (800 mg, 5.8 mmol) were converted into compound A12 ( 1.3 g, 82%).
  • Reference Example 32 Process 1 7-Methoxy-4- (3-methoxy-4-nitrophenoxy) -6- (methoxymethoxy) quinoline (Compound A29) According to Step 1 of Reference Example 6, compound A28 (400 mg, 1.2 mmol), chloromethyl methyl ether (0.11 mL, 1.4 mmol), and 60% sodium hydride (70 mg, 1.8 mmol) were converted to compound A29 (290 mg, 64%).
  • Reference Example 36 Process 1 7-Methoxy-4- (3-methoxy-4-nitrophenoxy) -6- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] quinoline (Compound A43) According to Step 1 of Reference Example 6, compound A28 (1.0 g, 2.9 mmol), 2- (3-bromopropoxy) tetrahydro-2H-pyran (0.99 mL, 5.8 mmol), and potassium carbonate (810 mg, 5.8 mmol) ) To give Compound A43 (1.3 g, 93%).
  • the present invention has CSF-1R and / or TrkA inhibitory activity, cancer bone metastasis, rheumatoid arthritis, osteoporosis, Behcet's disease, osteoarthritis, prostate cancer, lung cancer, kidney cancer, pancreatic cancer, breast cancer, uterus 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivatives useful for the treatment and / or prevention of cancer, myelodysplastic syndrome, acute myeloid leukemia, chronic myeloid leukemia, etc. Salt and the like can be provided.

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Abstract

Provided is a 4-[4-(5-membered aromatic heterocyclic carbonyl ureide)phenyloxy]quinoline derivative represented by formula (IA), which has an inhibitory activity on colony stimulating factor-1 receptor and/or tropomyosin-related kinase A, a pharmaceutically acceptable salt of the derivative, or the like. (In the formula, R1A and R2A may be the same or different and each represents an optionally substituted lower alkoxy group or the like; R3A represents a lower alkoxy group; and R4A represents a 5-membered aromatic heterocyclic group which may have a substituent.)

Description

4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivatives
　本発明は、コロニー刺激因子-1受容体 [Colony Stimulating Factor 1 Receptor(CSF-1R)]および／またはトロポミオシン関連キナーゼA[Tropomyosin-related kinase A(TrkA)]阻害活性を有する4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩等に関する。 The present invention provides colony stimulating factor-1 receptor [Colony Stimulating Factor 1 Receptor (CSF-1R)] and / or tropomyosin-related kinase A [Tropomyosin-related kinase A (TrkA)] inhibitory activity 4- [4- ( The present invention relates to a 5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof.
　CSF-1R[M-CSFR(Macrophage colony-stimulating factor receptor)、またはFmsとも呼ばれる]は、受容体型チロシンキナーゼの一種であり、そのリガンドであるマクロファージコロニー刺激因子[Macrophage colony-stimulating factor(M-CSF)、またはCSF-1(Colony Stimulating Factor 1)とも呼ばれる]やIL-34の結合によって活性化される。CSF-1Rの活性化は、単核球やマクロファージ系細胞の分化、増殖、生存、遊走を誘導する。 CSF-1R [also called M-CSFR (Macrophage colony-stimulating factor receptor) or Fms] is a type of receptor tyrosine kinase and its ligand, macrophage colony-stimulating factor [Macrophage colony-stimulating factor (M-CSFR ), Or CSF-1 (also called Colony Stimulating Factor 1)] or IL-34 binding. Activation of CSF-1R induces differentiation, proliferation, survival and migration of mononuclear cells and macrophage cells.
　CSF-1Rの活性化は破骨細胞前駆体細胞から成熟した破骨細胞への分化を促進する必須のシグナルとして知られ、例えば、M-CSFが産生されないop/opマウスでは、破骨細胞が分化誘導されないため大理石骨病を呈すること[ネーチャー(Nature)、345巻、442-444頁(1990年)]、および、このマウスに活性型M-CSFを投与することで破骨細胞の発現を認め、大理石骨病が治癒すると報告されている[ジャーナル・エクスペリエンス・メディスン(J. Exp. Med.), 173巻, 269-272頁(1991年)]。そのため、CSF-1Rのシグナル阻害は、破骨細胞の活性化が病態の悪化の要因であると考えられる多発性骨髄腫による骨病変、固形癌骨転移による骨病変、関節リウマチ、骨粗鬆症、ベーチェット病、変形性関節症等の疾患の治療等に有用であると考えられる[エキスパート・オピニオン・オン・セラピューティクス・ターゲット(Expert Opin. Ther. Targets)、15巻、2号、169-181頁(2011年)]。また、抗M-CSF抗体、および抗CSF-1R抗体は、マウス関節炎モデルにおいて破骨細胞の分化活性化を抑制するとともに骨破壊を改善し[ザ・ジャーナル・オブ・クリニカル・インベスティゲーション(J. Clin. Invest.)、115巻、12号、3418-3427頁(2005年)]、CSF-1R阻害剤であるKi20227は、コラーゲン誘発関節炎モデル、および癌骨転移モデルにおける骨破壊を改善し[ヨーロピアン・ジャーナル・オブ・イミュノロジー(Eur. J. Immunol.)、38巻、1号、283-289頁(2008年)、モレキュラー・キャンサー・セラピューティックス(Mol. Cancer Ther.)、5巻、11号, 2634-2643頁(2006年)]、ならびにラット骨粗鬆症モデルでの破骨細胞の分化を抑制する(特許文献11)。 Activation of CSF-1R is known as an essential signal that promotes the differentiation of osteoclast precursor cells into mature osteoclasts.For example, in op / op mice that do not produce M-CSF, osteoclasts Because osteoclasts are not induced to induce osteoclast (Nature, 345, 442-444 (1990)), and by administering active M-CSF to this mouse, Acknowledged and reported to cure marble bone disease [Journal Experience Medicine (J. Exp. Med.), 173, 269-272 (1991)]. Therefore, signal inhibition of CSF-1R is caused by bone lesions caused by multiple myeloma, bone lesions caused by solid cancer bone metastasis, rheumatoid arthritis, osteoporosis, Behcet's disease , Thought to be useful for the treatment of diseases such as osteoarthritis [Expert Opin. The Therapies Targets, Vol. 15, No. 2, pp. 169-181 ( 2011)]. In addition, anti-M-CSF antibody and anti-CSF-1R antibody inhibit osteoclast differentiation activation and improve bone destruction in a mouse arthritis model [The Journal of Clinical Investigation (J Clin. Invest.), 115, 12, 3418-3427 (2005)], a CSF-1R inhibitor Ki20227 improves bone destruction in collagen-induced arthritis models and cancer bone metastasis models [ European Journal of Immunology (Eur. J. Immunol.), 38, No.1, pp.283-289 (2008), Molecular Cancer Therapeutics (Mol. Cancer Ther.), Volume 5 No. 11, pp. 2634-2643 (2006)], and suppression of osteoclast differentiation in a rat osteoporosis model (Patent Document 11).
　また、CSF-1RまたはM-CSFの高発現やCSF-1Rの活性化が、前立腺癌、肺癌、腎臓癌、膵臓癌、乳癌、子宮癌、骨髄異形成症候群、急性骨髄性白血病、慢性骨髄性白血病等で認められ[エキスパート・オピニオン・オン・セラピューティクス・パテント(Expert Opin. Ther. Patent)、21巻、2号、147-165頁(2011年)]、CSF-1R阻害剤であるPLX3397は乳癌移植モデルで、癌関連マクロファージ(Tumor-associated macrophage: TAM)[ネーチャー・レビュー・キャンサー(Nat. Rev. Cancer)、4巻、1号、71-78頁(2004年)]の遊走阻害によりパクリタキセルによる抗癌活性の増強作用を示す[キャンサー・ディスカバリー(Cancer Discovery)、1巻、1号、54-67頁(2011)]。 In addition, high expression of CSF-1R or M-CSF and activation of CSF-1R may cause prostate cancer, lung cancer, kidney cancer, pancreatic cancer, breast cancer, uterine cancer, myelodysplastic syndrome, acute myeloid leukemia, chronic myelogenous Recognized in leukemia and the like [Expert 白血病 Opin. Ther. Patent, 21, No.2, pp.147-165 (2011)], PLX3397, a CSF-1R inhibitor Is a breast cancer transplantation model, due to the inhibition of migration of Tumor-associated macrophages (TAM) [Nature. Cancer Rev. 4, Vol. 1, No. 1, pp. 71-78 (2004)] It shows the potentiation of anticancer activity by paclitaxel [Cancer Discovery, Vol. 1, No. 1, pp. 54-67 (2011)].
　以上のことから、CSF-1R阻害剤は、例えば、多発性骨髄腫による骨病変、固形癌骨転移による骨病変、関節リウマチ、骨粗しょう症、ベーチェット病、変形性関節症、前立腺癌、肺癌、腎臓癌、膵臓癌、乳癌、子宮癌、骨髄異形成症候群、急性骨髄性白血病、慢性骨髄性白血病等の治療剤および/または予防剤等として有用と考えられる。
　トロポミオシン関連キナーゼ[Tropomyosin-related kinase(Trk)]ファミリーは、受容体型チロシンキナーゼであり、主に神経成長因子[Nerve Growth Factor(NGF)]により活性化されるTrkA、主に脳由来成長因子[Brain-derived neurotrophic factor(BFNF)]、またはニューロトロフィン-4 {neurotrophin-4(NT-4)、またはニューロトロフィン-5[neurotrophin-5(NT-5)]とも呼ばれる}により活性化されるTrkB、および主にニューロトロフィン-3[neurotrophin-3(NT-3)]により活性化されるTrkCからなる［フィロソフィカル・トランスアクションズ・オブ・ザ・ローヤル・ソサエティーB（Phil. Trans. R. Soc. B）、361巻、1545-1564頁（2006年）］。 From the above, CSF-1R inhibitors are, for example, bone lesions caused by multiple myeloma, bone lesions caused by solid cancer bone metastases, rheumatoid arthritis, osteoporosis, Behcet's disease, osteoarthritis, prostate cancer, lung cancer, It is considered useful as a therapeutic and / or prophylactic agent for renal cancer, pancreatic cancer, breast cancer, uterine cancer, myelodysplastic syndrome, acute myeloid leukemia, chronic myelogenous leukemia and the like.
The tropomyosin-related kinase (Trk) family is a receptor tyrosine kinase, mainly TrkA activated by nerve growth factor (NGF), mainly brain-derived growth factor [Brain -derived neurotrophic factor (BFNF)], or neurotrophin-4 {also called neurotrophin-4 (NT-4), or neurotrophin-5 [neurotrophin-5 (NT-5)]} , And TrkC activated mainly by neurotrophin-3 (NT-3) [Phil. Trans. R. Soc B), 361, 1545-1564 (2006)].
　TrkAのノックアウトマウスは痛覚が失われる特有の表現系を示し、TrkAの遺伝子変異は先天性無痛無汗症の原因であり[ネーチャー・ジェネティックス(Nat. Genet.)、13巻、485-488頁(1996年)]、正常動物やヒトに対しNGFを投与する事により疼痛が惹起される[ヨーロピアン・ジャーナル・オブ・ニューロサイエンス(Eur. J. Neurosci.)、6巻、1903-1912頁(1994年)、ニューロロジー(Neurology)、48巻、501-505頁(1997年)]。 TrkA knockout mice exhibit a unique phenotype of loss of pain, and TrkA gene mutations are the cause of congenital analgesia (Nat. Genet., 13, 485-488) (1996)], pain is induced by administering NGF to normal animals and humans [European Journal of Neuroscience (Eur. J. Neurosci.), 6, 1903-1912 (1994) Year), Neurology, 48, 501-505 (1997)].
　さらに抗NGF抗体は、ラット関節炎モデル[ペイン(Pain)、116巻、8-16頁(2005年)]、癌骨転移モデル[ジャーナル・オブ・ペイン(J. Pain)、12巻、6号、698-711頁(2011年)、ペイン(Pain)、152巻、11号、2564-2574頁(2011)]等のモデル動物で疼痛を抑制し、変形性膝関節症等の患者に疼痛緩和効果を示す[ザ・ニューイングランド・ジャーナル・オブ・メディシン(N. Engl. J. Med.)、363巻、16号、1521-1531頁(2010年)]。さらに、TrkA阻害剤ARRY-470は、癌骨転移モデルにおいて鎮痛効果を示す[モレキュラー・ペイン(Molecular Pain), 6:87(2010年)]。 Furthermore, anti-NGF antibody is a rat arthritis model [Pain, 116, 8-16 (2005)], cancer bone metastasis model [Journal of Pain (J. (Pain), 12, No. 6, 698-711 (2011), Pain, Vol. 152, No. 11, 2564-2574 (2011)], etc., to suppress pain and reduce pain in patients with knee osteoarthritis etc. [The New England Journal of Medicine (N. Engl. J. Med.), 363, 16, 1521-1531 (2010)]. Furthermore, the TrkA inhibitor ARRY-470 has an analgesic effect in a cancer bone metastasis model [Molecular Pain, 6:87 (2010)].
　従って、TrkA阻害剤は、例えば、関節リウマチ、または変形性関節症等の炎症性、および癌骨転移等の癌性等の疼痛治療剤および/または予防剤として有用と考えられる。
　以上のことから、CSF-1RおよびTrkAを阻害する化合物は、例えば、癌骨転移による骨破壊および疼痛等の症状、関節リウマチ患者や変形性関節症等の骨破壊および疼痛等の症状を同時に抑制することが期待されるため好ましい。 Therefore, the TrkA inhibitor is considered useful as a therapeutic and / or preventive agent for pain such as inflammatory such as rheumatoid arthritis or osteoarthritis and cancerous such as cancer bone metastasis.
Based on the above, compounds that inhibit CSF-1R and TrkA simultaneously suppress symptoms such as bone destruction and pain due to cancer bone metastasis, bone destruction and pain such as rheumatoid arthritis patients and osteoarthritis, etc. It is preferable because it is expected.
　ところで、受容体型チロシンキナーゼとして、血管内皮細胞増殖因子受容体2[vascular endothelial growth factor recepter-2(VEGFR-2)]や肝細胞増殖因子受容体[hepatocyte growth factor receptor (HGFR)]が知られている。
　抗VEGF中和抗体やVEGFR-2阻害剤は、腎癌、肝癌、大腸癌、非小胞性肺癌等に対して抗腫瘍活性を示す[ネーチャー・レビュー・キャンサー(Nature Review Cancer)、8巻、579-591頁、2008年、ネーチャー・レビュー・ドラッグ・ディスカバリー(Nature Review Drug Discovery)、6巻、734－745頁、2007年]が、同時に血圧上昇等の副作用も誘発し、[ブリテン・ドゥ・キャンサー(Bull. Cancer)、92巻、S29-36(2005年)]、また、VEGF中和抗体の投与により、腎臓の毛細血管の成長が阻害され腎障害が起きる [ザ・ニューイングランド・ジャーナル・オブ・メディシン(N. Engl. J. Med.)、358巻、1129-1136頁(2008年)]との報告もある。 By the way, as a receptor type tyrosine kinase, vascular endothelial growth factor receptor 2 [vascular endothelial growth factor receptor-2 (VEGFR-2)] and hepatocyte growth factor receptor [hepatocyte growth factor receptor (HGFR)] are known. Yes.
Anti-VEGF neutralizing antibody and VEGFR-2 inhibitor show antitumor activity against renal cancer, liver cancer, colon cancer, non-vesicular lung cancer, etc. [Nature Review Cancer, Vol. 8, 579 -591, 2008, Nature Review Drug Discovery, Vol. 6, pp. 734-745 (2007), also induces side effects such as increased blood pressure. [Briten de Cancer] (Bull. Cancer), 92, S29-36 (2005)], and administration of VEGF-neutralizing antibody inhibits renal capillary growth and causes renal damage [The New England Journal of・ Medicine (N. Engl. J. Med.), 358, 1129-1136 (2008)].
　また、HGFRのリガンドである肝細胞増殖因子(HGF)に対する抗体である抗HGF抗体、およびHGFR阻害剤は、腎癌、肝臓癌、前立腺癌、非小胞肺癌等に対して抗腫瘍活性を示す[ネーチャー・レビュー・ドラッグ・ディスカバリー(Nature Review Drug Discovery)、7巻、504-516頁、2008年、ネーチャー・レビュー・キャンサー(Nature Review Cancer)、12巻、89-103頁、2011年]。その一方で、HGFRのノックアウトマウスは肝再生不全等の劇症肝炎の病態に類似した現象が見られる[プロシーディングス・オブ・ザ・ナショナル・アカデミー・オブ・サイエンシズ(PNAS)、101巻、4477-4482頁(2004年)]。 In addition, anti-HGF antibody, which is an antibody against hepatocyte growth factor (HGF), which is a ligand of HGFR, and HGFR inhibitor show antitumor activity against renal cancer, liver cancer, prostate cancer, non-vesicular lung cancer, etc. [Nature Review Drug Discovery, 7, 504-516, 2008, Nature Review Cancer, 12, 89-103, 2011]. On the other hand, HGFR knockout mice have similar phenomena to the pathogenesis of fulminant hepatitis such as hepatic regeneration failure [Proceedings of the National Academy of Sciences (PNAS), 101, 4477- 4482 (2004)].
　以上のように毒性回避の観点から、CSF-1RおよびTrkA阻害活性に対してVEGFR-2およびHGFR阻害活性は、低い方が好ましい。
　4位にアシルウレアまたはアシルチオウレア構造を有するキノリン誘導体を含むキナーゼ阻害剤が知られている(特許文献1～8、非特許文献1、2)。また、4位に5員環芳香族複素環ウレア構造を有するキノリン誘導体を含むキナーゼ阻害剤も知られている(特許文献9～11、非特許文献3)。 As described above, from the viewpoint of avoiding the toxicity, it is preferable that the VEGFR-2 and HGFR inhibitory activities are lower than the CSF-1R and TrkA inhibitory activities.
Kinase inhibitors containing a quinoline derivative having an acylurea or acylthiourea structure at the 4-position are known (Patent Documents 1 to 8, Non-Patent Documents 1 and 2). In addition, kinase inhibitors containing a quinoline derivative having a 5-membered aromatic heterocyclic urea structure at the 4-position are also known (Patent Documents 9 to 11, Non-Patent Document 3).
国際公開第97/017329号パンフレットInternational Publication No. 97/017329 Pamphlet 国際公開第01/47890号パンフレットInternational Publication No. 01/47890 Pamphlet 国際公開第03/000660号パンフレットWO03 / 000660 pamphlet 国際公開第2005/030140号パンフレットInternational Publication No. 2005/030140 Pamphlet 国際公開第2005/121125号パンフレットInternational Publication No. 2005/121125 Pamphlet 国際公開第2006/104161号パンフレットInternational Publication No. 2006/104161 Pamphlet 国際公開第2006/108059号パンフレットInternational Publication No. 2006/108059 pamphlet 国際公開第2009/125597号パンフレットInternational Publication No. 2009/125597 Pamphlet 国際公開第02/032872号パンフレットInternational Publication No. 02/032872 Pamphlet 国際公開第02/088110号パンフレットInternational Publication No. 02/088110 Pamphlet 国際公開第2003/093238号パンフレットInternational Publication No. 2003/093238 Pamphlet
　本発明の目的は、CSF-1Rおよび／またはTrkA阻害活性を有する4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩等を提供することにある。 An object of the present invention is to provide a 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative having CSF-1R and / or TrkA inhibitory activity, or a pharmaceutically acceptable salt thereof, etc. There is to do.
（1）式(IA) (1) Formula (IA)
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
[式中、R1AおよびR2Aは、同一または異なって、ヒドロキシ、置換基を有していてもよい低級アルコキシまたは置換基を有していてもよい脂肪族複素環オキシを表し、R3Aは低級アルコキシを表し、R4Aは置換基(該置換基は下記置換基A1からなる群から選ばれる同一のまたは異なる1～3個の置換基を表す)を有していてもよい5員環芳香族複素環基を表す]で表される4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩：
置換基A1：置換基を有していてもよい低級アルキル[該置換基は、低級アルコキシ、および-NR5R6(R5およびR6は、同一または異なって、水素原子、または低級アルキルを表す)からなる群から選ばれる］、ハロゲン、低級アルキルで置換されていてもよいシクロアルキル、低級アルコキシおよび脂肪族複素環基。
（2）R1Aがヒドロキシであり、R2Aが置換基を有していてもよい低級アルコキシである（1）記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。
（3）R1Aが置換基を有していてもよい低級アルコキシであり、R2Aがヒドロキシである（1）記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。
（4）R1Aが置換基を有していてもよい脂肪族複素環オキシであり、R2Aが置換基を有していてもよい低級アルコキシである（1）記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。
（5）R3Aがメトキシである（1）から（4）のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。
（6）R4Aにおける5員環芳香族複素環基がイミダゾリル、2-オキソイミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、トリアゾリルまたはチアゾリルである（1）から（5）のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。
（7）式(I) [Wherein, R 1A and R 2A are the same or different and each represents hydroxy, optionally substituted lower alkoxy or optionally substituted aliphatic heterocyclic oxy, and R 3A represents R 4A represents a lower alkoxy, and R 4A may have a substituent (the substituent represents the same or different 1 to 3 substituents selected from the group consisting of the following substituents A1) 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof represented by:
Substituent A1: An optionally substituted lower alkyl [the substituent is lower alkoxy, and —NR 5 R 6 (R 5 and R 6 are the same or different and each represents a hydrogen atom or lower alkyl] Selected from the group consisting of: halogen, cycloalkyl optionally substituted with lower alkyl, lower alkoxy and aliphatic heterocyclic groups.
(2) 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] according to (1), wherein R 1A is hydroxy and R 2A is optionally substituted lower alkoxy A quinoline derivative or a pharmaceutically acceptable salt thereof.
(3) 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] according to (1), wherein R 1A is optionally substituted lower alkoxy, and R 2A is hydroxy A quinoline derivative or a pharmaceutically acceptable salt thereof.
(4) R 1A is an aliphatic heterocyclic oxy which may have a substituent, and R 2A is a lower alkoxy which may have a substituent. 5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof.
(5) The 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable derivative thereof according to any one of (1) to (4), wherein R 3A is methoxy. Salt.
(6) The 4- [4 according to any one of (1) to (5), wherein the 5-membered aromatic heterocyclic group in R 4A is imidazolyl, 2-oxoimidazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl or thiazolyl -(5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof.
(7) Formula (I)
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
[式中、R1およびR2は、同一または異なって、置換基を有していてもよい低級アルコキシを表し、R3は低級アルコキシを表し、R4は置換基(該置換基は下記置換基Aからなる群から選ばれる同一のまたは異なる1～3個の置換基を表す)を有していてもよい5員環芳香族複素環基を表す]で表される4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩:
置換基A：置換基を有していてもよい低級アルキル[該置換基は、低級アルコキシ、および-NR5R6(R5およびR6は、同一または異なって、水素原子、または低級アルキルを表す)からなる群から選ばれる］、ハロゲンおよび低級アルキルで置換されていてもよいシクロアルキル。
（8）R1およびR2が、同一または異なって、低級アルコキシである（7）記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。
（9）R3がメトキシである（7）または（8）記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。
（10）R4における5員環芳香族複素環基がイミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、トリアゾリルまたはチアゾリルである（7）から（9）のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。
（11）（1）から（10）のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩を有効成分として含有する医薬。
（12）（1）から（10）のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩を有効成分として含有するコロニー刺激因子-1受容体および／またはトロポミオシン関連キナーゼA阻害剤。
（13）（1）から（10）のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩を有効成分として含有するコロニー刺激因子-1受容体およびトロポミオシン関連キナーゼAが関与する疾患の治療および／または予防剤。
（14）（1）から（10）のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩を有効成分として含有するコロニー刺激因子-1受容体またはトロポミオシン関連キナーゼAが関与する疾患の治療および／または予防剤。 [Wherein, R 1 and R 2 are the same or different and each represents an optionally substituted lower alkoxy, R 3 represents a lower alkoxy, R 4 represents a substituent (the substituent is Represents a 5-membered aromatic heterocyclic group which may have the same or different 1 to 3 substituents selected from the group consisting of the group A]; 5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof:
Substituent A: optionally substituted lower alkyl [the substituent is lower alkoxy, and —NR 5 R 6 (R 5 and R 6 are the same or different and each represents a hydrogen atom or lower alkyl] And cycloalkyl optionally substituted with halogen and lower alkyl.
(8) The 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable derivative thereof according to (7), wherein R 1 and R 2 are the same or different and are lower alkoxy. Acceptable salt.
(9) The 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof according to (7) or (8), wherein R 3 is methoxy.
(10) The 4- [4- (5-membered ring) according to any one of (7) to (9), wherein the 5-membered aromatic heterocyclic group in R 4 is imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl or thiazolyl Aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof.
(11) The 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (10) as an active ingredient Contains medicines.
(12) The 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (10) as an active ingredient A colony stimulating factor-1 receptor and / or a tropomyosin-related kinase A inhibitor.
(13) The 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (10) as an active ingredient A therapeutic and / or prophylactic agent for a disease involving colony-stimulating factor-1 receptor and tropomyosin-related kinase A.
(14) The 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (10) as an active ingredient A therapeutic and / or prophylactic agent for a disease involving colony-stimulating factor-1 receptor or tropomyosin-related kinase A.
（15）（1）から（10）のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩の有効量を投与する工程を含む、コロニー刺激因子-1受容体および／またはトロポミオシン関連キナーゼAの阻害方法。
（16）（1）から（10）のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩の有効量を投与する工程を含む、コロニー刺激因子-1受容体およびトロポミオシン関連キナーゼAが関与する疾患の治療および／または予防方法。
（17）（1）から（10）のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩の有効量を投与する工程を含む、コロニー刺激因子-1受容体またはトロポミオシン関連キナーゼAが関与する疾患の治療および／または予防方法。
（18）コロニー刺激因子-1受容体および／またはトロポミオシン関連キナーゼA阻害に使用するための、（1）から（10）のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。
（19）コロニー刺激因子-1受容体およびトロポミオシン関連キナーゼAが関与する疾患の治療および／または予防に使用するための、（1）から（10）のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。
（20）コロニー刺激因子-1受容体またはトロポミオシン関連キナーゼAが関与する疾患の治療および／または予防に使用するための、（1）から（10）のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。 (15) An effective amount of the 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (10) A method of inhibiting colony stimulating factor-1 receptor and / or tropomyosin-related kinase A, comprising a step of administering.
(16) An effective amount of the 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (10) A method for treating and / or preventing a disease involving a colony stimulating factor-1 receptor and tropomyosin-related kinase A, comprising a step of administering.
(17) An effective amount of the 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (10) A method for treating and / or preventing a disease involving a colony stimulating factor-1 receptor or tropomyosin-related kinase A, comprising a step of administering.
(18) The 4- [4- (5-membered aromatic heterocycle] according to any one of (1) to (10) for use in colony-stimulating factor-1 receptor and / or tropomyosin-related kinase A inhibition Carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof.
(19) The 4- [4- (4) according to any one of (1) to (10) for use in treatment and / or prevention of a disease involving colony-stimulating factor-1 receptor and tropomyosin-related kinase A 5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof.
(20) 4- [4- (1) described in any one of (1) to (10) for use in treatment and / or prevention of a disease involving colony stimulating factor-1 receptor or tropomyosin-related kinase A 5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof.
　本発明により、CSF-1Rおよび／またはTrkA阻害活性を有し、癌骨転移、関節リウマチ、骨粗しょう症、ベーチェット病、変形性関節症、前立腺癌、肺癌、腎臓癌、膵臓癌、乳癌、子宮癌、骨髄異形成症候群、急性骨髄性白血病、慢性骨髄性白血病等の治療および／または予防に有用な4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩等が提供される。 According to the present invention, it has CSF-1R and / or TrkA inhibitory activity, cancer bone metastasis, rheumatoid arthritis, osteoporosis, Behcet's disease, osteoarthritis, prostate cancer, lung cancer, kidney cancer, pancreatic cancer, breast cancer, uterus 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivatives useful for the treatment and / or prevention of cancer, myelodysplastic syndrome, acute myeloid leukemia, chronic myeloid leukemia, etc. Acceptable salts and the like are provided.
　以下、一般式(I)および(IA)で表される化合物を、それぞれ化合物(I)および(IA)という。他の式番号の化合物についても同様である。
　一般式(I)および(IA)の各基の定義において、
　低級アルキル、および低級アルコキシにおける低級アルキル部分としては、例えば、直鎖または分岐状の炭素数1～10のアルキルが挙げられ、より具体的にはメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、sec-ブチル、tert-ブチル、ペンチル、イソペンチル、ネオペンチル、ヘキシル、ヘプチル、オクチル、ノニル、デシル等が挙げられる。 Hereinafter, the compounds represented by the general formulas (I) and (IA) are referred to as compounds (I) and (IA), respectively. The same applies to the compounds of other formula numbers.
In the definition of each group of general formulas (I) and (IA)
Examples of lower alkyl and lower alkyl in lower alkoxy include linear or branched alkyl having 1 to 10 carbon atoms, and more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -Butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
　シクロアルキルとしては、例えば、炭素数3～8のシクロアルキルが挙げられ、より具体的にはシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル等が挙げられる。
　5員環芳香族複素環基としては、例えば、窒素原子、酸素原子および硫黄原子から選ばれる少なくとも1個の原子を含む5員の単環性芳香族複素環基等が挙げられ、より具体的にはフリル、チエニル、ピロリル、イミダゾリル、2-オキソイミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、トリアゾリル、テトラゾリル等が挙げられる。 Examples of cycloalkyl include cycloalkyl having 3 to 8 carbon atoms, and more specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
Examples of the 5-membered aromatic heterocyclic group include a 5-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples include furyl, thienyl, pyrrolyl, imidazolyl, 2-oxoimidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl and the like.
　脂肪族複素環基、および脂肪族複素環オキシにおける脂肪族複素環部分としては、例えば、窒素原子、酸素原子および硫黄原子から選ばれる少なくとも1個の原子を含む5員または6員の単環性脂肪族複素環基、3～8員の環が縮合した二環または三環性で窒素原子、酸素原子および硫黄原子から選ばれる少なくとも1個の原子を含む縮環性脂肪族複素環基等が挙げられ、より具体的にはアジリジニル、アゼチジニル、ピロリジニル、ピペリジノ、ピペリジニル、アゼパニル、1,2,5,6-テトラヒドロピリジル、イミダゾリジニル、ピラゾリジニル、ピペラジニル、ホモピペラジニル、ピラゾリニル、オキシラニル、オキセタニル、テトラヒドロフラニル、テトラヒドロ-2H-ピラニル、5,6-ジヒドロ-2H-ピラニル、オキサゾリジニル、モルホリノ、モルホリニル、チオキサゾリジニル、チオモルホリニル、2H-オキサゾリル、2H-チオキサゾリル、ジヒドロインドリル、ジヒドロイソインドリル、ジヒドロベンゾフラニル、ベンゾイミダゾリジニル、ジヒドロベンゾオキサゾリル、ジヒドロベンゾチオキサゾリル、ベンゾジオキソリニル、テトラヒドロキノリル、テトラヒドロイソキノリル、ジヒドロ-2H-クロマニル、ジヒドロ-1H-クロマニル、ジヒドロ-2H-チオクロマニル、ジヒドロ-1H-チオクロマニル、テトラヒドロキノキサリニル、テトラヒドロキナゾリニル、ジヒドロベンゾジオキサニル等が挙げられる。 Examples of the aliphatic heterocyclic group and the aliphatic heterocyclic moiety in the aliphatic heterocyclic oxy include, for example, a 5-membered or 6-membered monocyclic group including at least one atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom. An aliphatic heterocyclic group, a bicyclic or tricyclic condensed 3- to 8-membered ring containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, etc. More specifically, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, piperidinyl, azepanyl, 1,2,5,6-tetrahydropyridyl, imidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazinyl, pyrazolinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, 2H-pyranyl, 5,6-dihydro-2H-pyranyl, oxazolidinyl, morpholino, morpholine Thioxazolidinyl, thiomorpholinyl, 2H-oxazolyl, 2H-thioxazolyl, dihydroindolyl, dihydroisoindolyl, dihydrobenzofuranyl, benzimidazolidinyl, dihydrobenzoxazolyl, dihydrobenzothioxazolyl, Benzodioxolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydro-2H-chromanyl, dihydro-1H-chromanyl, dihydro-2H-thiochromanyl, dihydro-1H-thiochromanyl, tetrahydroquinoxalinyl, tetrahydroquinazolinyl, And dihydrobenzodioxanyl.
　ハロゲンは、フッ素、塩素、臭素、ヨウ素の各原子を意味する。
　置換基を有していてもよい低級アルコキシにおける置換基としては、同一または異なって、例えば、置換数1～3の、
ハロゲン、ヒドロキシ、スルファニル、ニトロ、シアノ、カルボキシ、カルバモイル、C3-8シクロアルキル、C6-14アリール、脂肪族複素環基、芳香族複素環基、置換基を有していてもよいC1-10アルコキシ（該置換C1-10アルコキシにおける置換基としては、同一または異なって例えば置換数1～3の、ハロゲン、ヒドロキシ等が挙げられる）、C3-8シクロアルコキシ、C6-14アリールオキシ、C7-16アラルキルオキシ、C2-11アルカノイルオキシ、C7-15アロイルオキシ、C1-10アルキルスルファニル、-NRXRY(式中、RXおよびRYは同一または異なって、水素原子、C1-10アルキル、C3-8シクロアルキル、C6-14アリール、芳香族複素環基、C7-16アラルキル、C2-11アルカノイル、C7-15アロイル、C1-10アルコキシカルボニルまたはC7-16アラルキルオキシカルボニルを表す)、C2-11アルカノイル、C7-15アロイル、C1-10アルコキシカルボニル、C6-14アリールオキシカルボニル、C1-10アルキルカルバモイルおよびジC1-10アルキルカルバモイルからなる群から選ばれる置換基が挙げられる。 Halogen means each atom of fluorine, chlorine, bromine and iodine.
Examples of the substituent in the lower alkoxy which may have a substituent are the same or different, for example, those having 1 to 3 substituents,
Halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, C 3-8 cycloalkyl, C 6-14 aryl, aliphatic heterocyclic group, aromatic heterocyclic group, optionally substituted C 1 -10 alkoxy (substituents in the substituted C 1-10 alkoxy are the same or different and include, for example, halogen, hydroxy and the like having 1 to 3 substituents), C 3-8 cycloalkoxy, C 6-14 aryl Oxy, C 7-16 aralkyloxy, C 2-11 alkanoyloxy, C 7-15 aroyloxy, C 1-10 alkylsulfanyl, —NR X R Y (wherein R X and R Y are the same or different, hydrogen Atom, C 1-10 alkyl, C 3-8 cycloalkyl, C 6-14 aryl, aromatic heterocyclic group, C 7-16 aralkyl, C 2-11 alkanoyl, C 7-15 aroyl, C 1-10 alkoxy Represents carbonyl or C 7-16 aralkyloxycarbonyl Selected from the group consisting of C 2-11 alkanoyl, C 7-15 aroyl, C 1-10 alkoxycarbonyl, C 6-14 aryloxycarbonyl, C 1-10 alkylcarbamoyl and di-C 1-10 alkylcarbamoyl A substituent is mentioned.
　置換基を有していてもよい脂肪族複素環オキシにおける置換基としては、同一または異なって、例えば、置換数1～3の、
オキソ、ハロゲン、ヒドロキシ、スルファニル、ニトロ、シアノ、カルボキシ、カルバモイル、置換基を有していてもよいC1-10アルキル（該置換C1-10アルキルにおける置換基としては、同一または異なって例えば置換数1～3の、ハロゲン、アミノ、ヒドロキシ、シアノ、カルボキシ、C3-8シクロアルキル、C1-10アルコキシ、C1-10アルコキシカルボニル、C2-11アルカノイルオキシ、カルバモイル、C1-10アルキルカルバモイル、ジC1-10アルキルカルバモイル等が挙げられる）、C3-8シクロアルキル、C6-14アリール、脂肪族複素環基、芳香族複素環基、C1-10アルコキシ、C3-8シクロアルコキシ、C6-14アリールオキシ、C7-16アラルキルオキシ、C2-11アルカノイルオキシ、C7-15アロイルオキシ、C1-10アルキルスルファニル、-NRX1RY1（式中、RX1及びRY1は同一または異なって、水素原子、C1-10アルキル、C3-8シクロアルキル、C6-14アリール、芳香族複素環基、C7-16アラルキル、C2-11アルカノイル、C7-15アロイル、C1-10アルコキシカルボニルまたはC7-16アラルキルオキシカルボニル等を表す）、置換基を有していてもよいC2-11アルカノイル（該置換C1-10アルカノイルにおける置換基としては、同一または異なって例えば置換数1～3の、ハロゲン、アミノ、ヒドロキシ、シアノ、カルボキシ、C3-8シクロアルキル、C1-10アルコキシ、C1-10アルコキシカルボニル、C2-11アルカノイルオキシ、カルバモイル、C1-10アルキルカルバモイル、ジC1-10アルキルカルバモイル等が挙げられる）、C7-15アロイル、C1-10アルコキシカルボニル、C6-14アリールオキシカルボニル、C1-10アルキルカルバモイル、ジC1-10アルキルカルバモイルからなる群から選ばれる置換基が挙げられる。 Examples of the substituent in the aliphatic heterocyclic oxy which may have a substituent are the same or different, for example, those having 1 to 3 substituents,
Oxo, halogen, hydroxy, sulfanyl, nitro, cyano, carboxy, carbamoyl, Examples of the substituent in the optionally substituted C 1-10 alkyl (the substituted C 1-10 alkyl, same or different, such substituted Numbers 1 to 3, halogen, amino, hydroxy, cyano, carboxy, C 3-8 cycloalkyl, C 1-10 alkoxy, C 1-10 alkoxycarbonyl, C 2-11 alkanoyloxy, carbamoyl, C 1-10 alkyl Carbamoyl, di-C 1-10 alkylcarbamoyl, etc.), C 3-8 cycloalkyl, C 6-14 aryl, aliphatic heterocyclic group, aromatic heterocyclic group, C 1-10 alkoxy, C 3-8 Cycloalkoxy, C 6-14 aryloxy, C 7-16 aralkyloxy, C 2-11 alkanoyloxy, C 7-15 aroyloxy, C 1-10 alkylsulfanyl, —NR X1 R Y1 (where R X1 and R Y1 is the same One or different, hydrogen atom, C 1-10 alkyl, C 3-8 cycloalkyl, C 6-14 aryl, aromatic heterocyclic group, C 7-16 aralkyl, C 2-11 alkanoyl, C 7-15 aroyl , C 1-10 alkoxycarbonyl or C 7-16 aralkyloxycarbonyl or the like), C 2-11 alkanoyl optionally having a substituent (the substituents in the substituted C 1-10 alkanoyl are the same or Differently, for example, with 1 to 3 substituents, halogen, amino, hydroxy, cyano, carboxy, C 3-8 cycloalkyl, C 1-10 alkoxy, C 1-10 alkoxycarbonyl, C 2-11 alkanoyloxy, carbamoyl, C 1-10 alkylcarbamoyl, di-C 1-10 alkylcarbamoyl, etc.), C 7-15 aroyl, C 1-10 alkoxycarbonyl, C 6-14 aryloxycarbonyl, C 1-10 alkylcarbamoyl, di-C 1 -10 alkyl It includes substituents selected from the group consisting of Rubamoiru.
　ここで示したC1-10アルキルならびにC1-10アルコキシ、C1-10アルキルスルファニル、C2-11アルカノイル、C2-11アルカノイルオキシ、C1-10アルコキシカルボニル、C1-10アルキルカルバモイルおよびジC1-10アルキルカルバモイルのC1-10アルキル部分としては、例えば、前記低級アルキルの例示で挙げた基が例示される。ジC1-10アルキルカルバモイルにおける2つのC1-10アルキル部分は同一でも異なっていてもよい。 C 1-10 alkyl as shown here and C 1-10 alkoxy, C 1-10 alkylsulfanyl, C 2-11 alkanoyl, C 2-11 alkanoyloxy, C 1-10 alkoxycarbonyl, C 1-10 alkylcarbamoyl and Examples of the C 1-10 alkyl moiety of diC 1-10 alkylcarbamoyl include the groups exemplified in the above-mentioned lower alkyl. The two C 1-10 alkyl moieties in the diC 1-10 alkylcarbamoyl may be the same or different.
　C3-8シクロアルキルおよびC3-8シクロアルコキシのシクロアルキル部分としては、例えば、前記シクロアルキルの例示で挙げた基が例示される。
　C6-14アリールならびにC6-14アリールオキシ、C7-15アロイル、C7-15アロイルオキシおよびC6-14アリールオキシカルボニルのアリール部分としては、例えば、炭素数6～14のアリールが挙げられ、より具体的にはフェニル、ナフチル、アズレニル、アントリルなどが挙げられる。 The C 3-8 cycloalkyl and C 3-8 cycloalkyl moiety cycloalkoxy, e.g., the groups listed illustrative of the cycloalkyl are exemplified.
Examples of the aryl moiety of C 6-14 aryl and C 6-14 aryloxy, C 7-15 aroyl, C 7-15 aroyloxy and C 6-14 aryloxycarbonyl include aryl having 6 to 14 carbon atoms. More specifically, phenyl, naphthyl, azulenyl, anthryl and the like can be mentioned.
　C7-16アラルキルオキシ、C7-16アラルキルおよびC7-16アラルキルオキシカルボニルのアリール部分としては、例えば、前記C6-14アリールおよびアリール部分の例示で挙げた基が例示され、アルキレン部分としては、例えば、C1-10のアルキレンが挙げられ、より具体的には前記低級アルキルで例示で挙げた基から水素原子を1つ除いた基が挙げられる。 Examples of the aryl moiety of C 7-16 aralkyloxy, C 7-16 aralkyl and C 7-16 aralkyloxycarbonyl include the groups exemplified in the above examples of C 6-14 aryl and aryl moiety. Examples thereof include C 1-10 alkylene, and more specifically, a group in which one hydrogen atom is removed from the groups exemplified in the lower alkyl.
　脂肪族複素環基としては、例えば、前記脂肪族複素環基の例示で挙げた基が例示される。
　芳香族複素環基としては、例えば、窒素原子、酸素原子および硫黄原子から選ばれる少なくとも1個の原子を含む5員または6員の単環性芳香族複素環基、3～8員の環が縮合した二環または三環性で窒素原子、酸素原子および硫黄原子から選ばれる少なくとも1個の原子を含む縮環性芳香族複素環基等が挙げられ、より具体的にはフリル、チエニル、ピロリル、イミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、オキサジアゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、トリアゾリル、テトラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアジニル、ベンゾフラニル、ベンゾチオフェニル、ベンゾオキサゾリル、ベンゾチアゾリル、イソインドリル、インドリル、インダゾリル、ベンゾイミダゾリル、ベンゾトリアゾリル、オキサゾロピリミジニル、チアゾロピリミジニル、ピロロピリジニル、ピロロピリミジニル、イミダゾピリジニル、プリニル、キノリニル、イソキノリニル、シンノリニル、フタラジニル、キナゾリニル、キノキサリニル、ナフチリジニル等が挙げられる。 As an aliphatic heterocyclic group, the group quoted by the illustration of the said aliphatic heterocyclic group is illustrated, for example.
Examples of the aromatic heterocyclic group include a 5-membered or 6-membered monocyclic aromatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and a 3- to 8-membered ring. Examples thereof include condensed bicyclic or tricyclic condensed ring aromatic heterocyclic groups containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and more specifically, furyl, thienyl, pyrrolyl, etc. , Imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, indolyl, indryl Benzimidazolyl, Nzotoriazoriru, oxazolopyridine pyrimidinyl, thiazolopyrimidinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, imidazopyridinyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and the like.
　ハロゲンは、前記と同義である。
　化合物(I)および(IA)の薬学的に許容される塩は、例えば、薬学的に許容される酸付加塩、金属塩、アンモニウム塩、有機アミン付加塩、アミノ酸付加塩等を包含する。化合物(I)の薬学的に許容される酸付加塩としては、例えば、塩酸塩、臭化水素酸塩、硝酸塩、硫酸塩、リン酸塩等の無機酸塩、酢酸塩、シュウ酸塩、マレイン酸塩、フマル酸塩、クエン酸塩、安息香酸塩、メタンスルホン酸塩等の有機酸塩等が挙げられ、薬学的に許容される金属塩としては、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩、マグネシウム塩、カルシウム塩等のアルカリ土類金属塩、アルミニウム塩、亜鉛塩等が挙げられ、薬学的に許容されるアンモニウム塩としては、例えば、アンモニウム、テトラメチルアンモニウム等の塩が挙げられ、薬学的に許容される有機アミン付加塩としては、例えば、モルホリン、ピペリジン等の付加塩が挙げられ、薬学的に許容されるアミノ酸付加塩としては、例えば、リジン、グリシン、フェニルアラニン、アスパラギン酸、グルタミン酸等の付加塩が挙げられる。 Halogen has the same meaning as described above.
Pharmaceutically acceptable salts of compounds (I) and (IA) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Examples of the pharmaceutically acceptable acid addition salt of compound (I) include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, acetate, oxalate, and maleate. Organic acid salts such as acid salts, fumarate salts, citrate salts, benzoate salts, methanesulfonate salts, and the like. Examples of pharmaceutically acceptable metal salts include alkali salts such as sodium salts and potassium salts. Examples thereof include alkaline earth metal salts such as metal salts, magnesium salts, and calcium salts, aluminum salts, and zinc salts. Examples of pharmaceutically acceptable ammonium salts include salts such as ammonium and tetramethylammonium. Examples of the pharmaceutically acceptable organic amine addition salt include addition salts such as morpholine and piperidine. Examples of the pharmaceutically acceptable amino acid addition salt include lysine and glycine. Emissions, phenylalanine, aspartic acid, addition salts of glutamic acid and the like.
　CSF-1Rが関与する疾患としては、例えば、多発性骨髄腫による骨病変、固形癌骨転移による骨病変、関節リウマチ、骨粗しょう症、ベーチェット病、変形性関節症、前立腺癌、肺癌、腎臓癌、膵臓癌、乳癌、子宮癌、骨髄異形成症候群、急性骨髄性白血病、慢性骨髄性白血病等が挙げられる。
　TrkAが関与する疾患としては、例えば、関節リウマチ、または変形性関節症等の炎症性、および癌骨転移等の癌性等の疼痛等が挙げられる。 Diseases involving CSF-1R include, for example, bone lesions caused by multiple myeloma, bone lesions caused by solid cancer bone metastases, rheumatoid arthritis, osteoporosis, Behcet's disease, osteoarthritis, prostate cancer, lung cancer, kidney cancer Pancreatic cancer, breast cancer, uterine cancer, myelodysplastic syndrome, acute myeloid leukemia, chronic myelogenous leukemia and the like.
Examples of diseases involving TrkA include inflammatory such as rheumatoid arthritis or osteoarthritis, and pain such as cancerous such as cancer bone metastasis.
　CSF-1RおよびTrkAが関与する疾患としては、例えば、癌骨転移による骨破壊および疼痛、関節リウマチ患者や変形性関節症等の骨破壊および疼痛等が挙げられる。
　次に化合物(I)および(IA)の製造法について説明する。
　なお、以下に示す製造法において、定義した基が該製造法の条件下で変化するか、または該製造法を実施するのに不適切な場合、有機合成化学で常用される保護基の導入および除去方法[例えば、プロテクティブ・グループス・イン・オーガニック・シンセシス第3版(Protective Groups in Organic Synthesis, third edition)、グリーン(T. W. Greene)著、John Wiley & Sons Inc.(1999年)等に記載の方法]等を用いることにより、目的化合物を製造することができる。また、必要に応じて置換基導入等の反応工程の順序を変えることもできる。
製造法1 Examples of the diseases involving CSF-1R and TrkA include bone destruction and pain due to cancer bone metastasis, bone destruction and pain such as rheumatoid arthritis patients and osteoarthritis, and the like.
Next, production methods of compounds (I) and (IA) will be described.
In the production method shown below, when the defined group changes under the conditions of the production method or is inappropriate for carrying out the production method, introduction of a protective group commonly used in organic synthetic chemistry and Removal methods [e.g., Protective Groups in Organic Synthesis, third edition, written by TW Greene, John Wiley & Sons Inc. (1999), etc. The method can be used to produce the target compound. Further, the order of reaction steps such as introduction of substituents can be changed as necessary.
Production method 1
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
(式中、R1、R2、R3およびR4は、それぞれ前記と同義であり、RAおよびRBは、同一または異なって、塩素原子、またはトリクロロメチルオキシを表し、RCは、フェニル、1～5個のフッ素で置換されたフェニル、または1もしくは2個のニトロで置換されたフェニルを表す)
工程1
　化合物(IV)は、化合物(II)を、溶媒中、必要により好ましくは1～100当量の塩基の存在下、-10 ℃と用いる溶媒の沸点との間の温度で、5分間～72時間、好ましくは1～100当量の化合物(III)と反応させることにより製造することができる。 (Wherein R 1 , R 2 , R 3 and R 4 are the same as defined above, R A and R B are the same or different and represent a chlorine atom or trichloromethyloxy, and R C is Represents phenyl, phenyl substituted with 1 to 5 fluorines, or phenyl substituted with 1 or 2 nitros)
Process 1
Compound (IV) is obtained by reacting Compound (II) in a solvent, preferably in the presence of 1 to 100 equivalents of a base, at a temperature between −10 ° C. and the boiling point of the solvent used for 5 minutes to 72 hours, Preferably, it can be produced by reacting with 1 to 100 equivalents of compound (III).
　塩基としては、例えば、炭酸カリウム、炭酸ナトリウム、炭酸セシウム、ジイソプロピルエチルアミン、トリエチルアミン、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム、ピリジン、2,6-ルチジン、N,N-ジメチルアミノピリジン等が挙げられ、これらは単独でまたは混合して用いることができる。
　溶媒としては、例えば、クロロホルム、ジクロロメタン、1,2-ジクロロエタン、テトラヒドロフラン(THF)、ジオキサン、1,2-ジメトキシエタン(DME)、N,N-ジメチルホルムアミド(DMF)、N,N-ジメチルアセトアミド(DMA)、N-メチルピロリドン(NMP)、ジメチルスルホキシド(DMSO)、トルエン、キシレン、クロロベンゼン等が挙げられ、これらは単独でまたは混合して用いることができる。 Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, diisopropylethylamine, triethylamine, sodium hydroxide, potassium hydroxide, sodium hydride, pyridine, 2,6-lutidine, N, N-dimethylaminopyridine and the like. These can be used alone or in admixture.
Examples of the solvent include chloroform, dichloromethane, 1,2-dichloroethane, tetrahydrofuran (THF), dioxane, 1,2-dimethoxyethane (DME), N, N-dimethylformamide (DMF), N, N-dimethylacetamide ( DMA), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), toluene, xylene, chlorobenzene and the like, and these can be used alone or in combination.
　化合物(II)は、例えば、WO97/017329、特開平11-158149、WO00/43366、WO01/47890、WO02/088110、WO03/000660、WO03/033472、WO2004/018430、WO2004/039782、US5773449A、J. Med. Chem., 2005, 48(5), 1359-1366に記載の方法、またはそれらに準じて製造することができる。
　化合物(III)は、例えば、市販品として、または公知の方法［例えば、コンプリヘンシブ・オーガニック・トランスフォーメーションズ第二版（Comprehensive Organic Transformations, second edition）、ラロック（R. C. Larock）著、ジョン・ワイリー・アンド・サンズ・インコーポレイテッド（John Wiley & Sons Inc.）（1999年）等］もしくはそれらに準じた方法により、それぞれ得ることができる。
工程2
　化合物(V)は、化合物(IV)を、溶媒中、化合物(IV)に対して0.1～100 重量％の金属触媒存在下、好ましくは、0.1～50重量％の金属触媒存在下、-10 ℃と用いる溶媒の沸点との間の温度で、好ましくは20 ℃と用いる溶媒の沸点との間の温度で、常圧もしくは加圧下の水素雰囲気下で、または1当量～大過剰量の適当な水素源の存在下で、5分間～72時間処理することにより製造することができる。このとき、0.01～30当量の適当な酸を加え、反応を促進させることもできる。 Compound (II) is, for example, WO 97/017329, JP-A-11-158149, WO00 / 43366, WO01 / 47890, WO02 / 088110, WO03 / 000660, WO03 / 033472, WO2004 / 018430, WO2004 / 039782, US5773449A, J. It can be produced according to the method described in Med. Chem., 2005, 48 (5), 1359-1366, or their modifications.
Compound (III) can be obtained, for example, as a commercially available product or by a known method [for example, Comprehensive Organic Transformations, second edition, by RC Larock, John Wiley. -And Sons, Inc. (John Wiley & Sons Inc.) (1999) etc.] or a method according to them.
Process 2
Compound (V) is obtained by adding Compound (IV) in a solvent in the presence of 0.1 to 100% by weight of metal catalyst, preferably in the presence of 0.1 to 50% by weight of metal catalyst, at −10 ° C. with respect to Compound (IV). At a temperature between 20 ° C. and the boiling point of the solvent used, preferably at a temperature between 20 ° C. and the boiling point of the solvent used, in a hydrogen atmosphere under normal pressure or pressure, or from 1 equivalent to a large excess of suitable hydrogen It can be produced by treating for 5 minutes to 72 hours in the presence of a source. At this time, 0.01 to 30 equivalents of an appropriate acid can be added to promote the reaction.
　溶媒としては、例えば、エタノール、メタノール、酢酸エチル、ジエチルエーテル、THF、水、アセトニトリル、DMF、DMA等が挙げられ、これらは単独でまたは混合して用いることができる。
　金属触媒としては、例えば、パラジウムカーボン、パラジウムアルミナ、水酸化パラジウム、水酸化パラジウムカーボン、塩化パラジウム、ウィルキンソン触媒等が挙げられる。 Examples of the solvent include ethanol, methanol, ethyl acetate, diethyl ether, THF, water, acetonitrile, DMF, DMA and the like, and these can be used alone or in combination.
Examples of the metal catalyst include palladium carbon, palladium alumina, palladium hydroxide, palladium hydroxide carbon, palladium chloride, and Wilkinson catalyst.
　水素源としては、例えば、ギ酸、ギ酸アンモニウム、ギ酸ナトリウム等が挙げられる。
　酸としては、例えば、塩酸、硫酸、硝酸、酢酸、トリフルオロ酢酸、トリフルオロメタンスルホン酸等が挙げられる。
　また化合物(V)は、化合物(IV)を、溶媒中、-10 ℃と用いる溶媒の沸点との間の温度で、好ましくは20 ℃と用いる溶媒の沸点との間の温度で、5分間～72時間、化合物(IV)に対して好ましくは1～10当量の還元剤で処理することにより製造することもできる。 Examples of the hydrogen source include formic acid, ammonium formate, sodium formate, and the like.
Examples of the acid include hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and the like.
The compound (V) is a compound (IV) in a solvent at a temperature between −10 ° C. and the boiling point of the solvent used, preferably at a temperature between 20 ° C. and the boiling point of the solvent used. It can also be produced by treating with a reducing agent of preferably 1 to 10 equivalents relative to compound (IV) for 72 hours.
　溶媒としては、例えば、エタノール、メタノール、酢酸エチル、クロロホルム、ジクロロメタン、ジエチルエーテル、THF、水、アセトニトリル、酢酸等が挙げられ、これらは単独でまたは混合して用いることができる。
　還元剤としては、例えば、亜ジチオン酸ナトリウム、スズ、二塩化スズ、鉄、亜鉛、水素化ホウ素ニッケル、水素化アルミニウムリチウム等が挙げられる。
工程3
　化合物(V)は、化合物(II)を、溶媒中、化合物(II)に対して好ましくは1～10当量の塩基存在下、-10 ℃と用いる溶媒の沸点との間の温度で、5分間～72時間、好ましくは1～10当量の化合物(VI)と反応させることで製造することもできる。このとき、0.01～30当量の適当な添加剤を加えてもよい。 Examples of the solvent include ethanol, methanol, ethyl acetate, chloroform, dichloromethane, diethyl ether, THF, water, acetonitrile, acetic acid and the like, and these can be used alone or in combination.
Examples of the reducing agent include sodium dithionite, tin, tin dichloride, iron, zinc, nickel borohydride, lithium aluminum hydride, and the like.
Process 3
Compound (V) is obtained by reacting Compound (II) in a solvent, preferably in the presence of 1 to 10 equivalents of a base with respect to Compound (II), at a temperature between −10 ° C. and the boiling point of the solvent used for 5 minutes. It can also be produced by reacting with compound (VI) for ˜72 hours, preferably 1 to 10 equivalents. At this time, 0.01 to 30 equivalents of an appropriate additive may be added.
　溶媒としては、例えば、DMF、DMA、NMP、DMSO、クロロホルム、アセトン、メチルエチルケトン、水等が挙げられ、これらは単独でまたは混合して用いることができる。
　塩基としては、例えば、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム等が挙げられる。
　添加剤としては、例えば、テトラブチルアンモニウムブロミド等が挙げられる。 Examples of the solvent include DMF, DMA, NMP, DMSO, chloroform, acetone, methyl ethyl ketone, water and the like, and these can be used alone or in combination.
Examples of the base include sodium hydroxide, potassium hydroxide, sodium hydride and the like.
Examples of the additive include tetrabutylammonium bromide.
　化合物(VI)は、例えば、市販品として、または公知の方法［例えば、コンプリヘンシブ・オーガニック・トランスフォーメーションズ第二版（Comprehensive Organic Transformations, second edition）、ラロック（R. C. Larock）著、ジョン・ワイリー・アンド・サンズ・インコーポレイテッド（John Wiley & Sons Inc.）（1999年）等］もしくはそれらに準じた方法により、それぞれ得ることができる。
工程4
　化合物(X)は、化合物(V)を、溶媒中、必要により好ましくは1～100当量の塩基の存在下、-10 ℃と用いる溶媒の沸点との間の温度で、5分間～72時間、好ましくは1～100当量の化合物(VII)を反応させた後、好ましくは1～100当量の化合物(VIII)を加えて、-10 ℃と用いる溶媒の沸点との間の温度で、5分間～72時間反応させることにより製造することができる。 Compound (VI) can be obtained, for example, as a commercially available product or by a known method [for example, Comprehensive Organic Transformations, second edition, by RC Larock, John Wiley. And And Wis & Sons Inc. (1999) etc.] or a method according to them.
Process 4
Compound (X) is obtained by reacting Compound (V) in a solvent, preferably in the presence of 1 to 100 equivalents of a base, at a temperature between −10 ° C. and the boiling point of the solvent used for 5 minutes to 72 hours, Preferably 1 to 100 equivalents of compound (VII) are reacted, preferably 1 to 100 equivalents of compound (VIII) are added, and at a temperature between −10 ° C. and the boiling point of the solvent used for 5 minutes to It can be produced by reacting for 72 hours.
　塩基としては、例えば、炭酸カリウム、炭酸ナトリウム、ジイソプロピルエチルアミン、トリエチルアミン、水酸化ナトリウム、水酸化カリウム、ピリジン、2,6-ルチジン、N,N-ジメチルアミノピリジン等が挙げられ、これらは単独でまたは混合して用いることができる。
　溶媒としては、例えば、クロロホルム、ジクロロメタン、1,2-ジクロロエタン、ジエチルエーテル、THF、ジオキサン、DMF、DMA、NMP、DMSO、トルエン、キシレン、クロロトルエン等が挙げられ、これらは単独でまたは混合して用いることができる。 Examples of the base include potassium carbonate, sodium carbonate, diisopropylethylamine, triethylamine, sodium hydroxide, potassium hydroxide, pyridine, 2,6-lutidine, N, N-dimethylaminopyridine, and the like alone or It can be used by mixing.
Examples of the solvent include chloroform, dichloromethane, 1,2-dichloroethane, diethyl ether, THF, dioxane, DMF, DMA, NMP, DMSO, toluene, xylene, chlorotoluene and the like, and these can be used alone or in combination. Can be used.
　化合物(VII)は、例えば、市販品として得ることができる。
　化合物(VIII)は、例えば、市販品として得ることができる。
　また、化合物(X)は、化合物(V)を、溶媒中、必要により好ましくは1～100当量の塩基の存在下、-10 ℃と用いる溶媒の沸点との間の温度で、5分間～72時間、好ましくは1～100当量の化合物(IX)と反応させることにより製造することもできる。 Compound (VII) can be obtained, for example, as a commercial product.
Compound (VIII) can be obtained, for example, as a commercial product.
In addition, compound (X) is obtained by reacting compound (V) in a solvent, preferably in the presence of 1 to 100 equivalents of a base, at a temperature between −10 ° C. and the boiling point of the solvent used for 5 minutes to 72 minutes. It can also be produced by reacting with compound (IX) for 1 hour, preferably 1 to 100 equivalents.
　塩基としては、例えば、炭酸カリウム、炭酸ナトリウム、水酸化ナトリウム、ジイソプロピルエチルアミン、トリエチルアミン、ピリジン、2,6-ルチジン等が挙げられ、これらは単独でまたは混合して用いることができる。
　溶媒としては、例えば、クロロホルム、ジクロロメタン、1,2-ジクロロエタン、トルエン、酢酸エチル、アセトニトリル、ジエチルエーテル、THF、DME、ジオキサン、DMF、DMA、NMP、DMSO、ピリジン等が挙げられ、これらは単独でまたは混合して用いることができる。 Examples of the base include potassium carbonate, sodium carbonate, sodium hydroxide, diisopropylethylamine, triethylamine, pyridine, 2,6-lutidine and the like, and these can be used alone or in combination.
Examples of the solvent include chloroform, dichloromethane, 1,2-dichloroethane, toluene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, DMSO, pyridine, and the like. Or it can mix and use.
　化合物(IX)は、例えば、市販品として得ることができる。
工程5
　化合物(I)は、化合物(X)を、溶媒中、必要により好ましくは１～100当量の塩基の存在下、-10 ℃と用いる溶媒の沸点との間の温度で、5分間～72時間、好ましくは1～100当量の化合物(VII)と反応させることにより製造することができる。 Compound (IX) can be obtained, for example, as a commercial product.
Process 5
Compound (I) is obtained by reacting Compound (X) in a solvent, preferably in the presence of 1 to 100 equivalents of a base, at a temperature between −10 ° C. and the boiling point of the solvent used for 5 minutes to 72 hours, Preferably, it can be produced by reacting with 1 to 100 equivalents of compound (VII).
　塩基としては、例えば、炭酸カリウム、炭酸ナトリウム、水酸化ナトリウム、水酸化カリウム、ジイソプロピルエチルアミン、トリエチルアミン、水素化ナトリウム、ピリジン、2,6-ルチジン、N,N-ジメチルアミノピリジン等が挙げられ、これらは単独でまたは混合して用いることができる。
　溶媒としては、例えば、ジクロロメタン、クロロホルム、1,2-ジクロロエタン、トルエン、キシレン、クロロベンゼン、酢酸エチル、アセトニトリル、ジエチルエーテル、THF、DME、ジオキサン、DMF、DMA、NMP、DMSO、ピリジン等が挙げられ、これらは単独でまたは混合して用いることができる。 Examples of the base include potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, diisopropylethylamine, triethylamine, sodium hydride, pyridine, 2,6-lutidine, N, N-dimethylaminopyridine, and the like. Can be used alone or in combination.
Examples of the solvent include dichloromethane, chloroform, 1,2-dichloroethane, toluene, xylene, chlorobenzene, ethyl acetate, acetonitrile, diethyl ether, THF, DME, dioxane, DMF, DMA, NMP, DMSO, pyridine, and the like. These may be used alone or in combination.
　化合物(XI)は、例えば、市販品として得ることができるか、または、下記製造法Aにより製造することができる。
製造法A Compound (XI) can be obtained, for example, as a commercially available product, or can be produced by the following production method A.
Manufacturing method A
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
  (式中、R4は前記と同義である)
　化合物(XI)は、化合物(XII)から、公知の方法［例えば、コンプリヘンシブ・オーガニック・トランスフォーメーションズ第二版(Comprehensive Organic Transformations, second edition）、ラロック(R. C. Larock)著、ジョン・ワイリー・アンド・サンズ・インコーポレイテッド（John Wiley & Sons Inc.)(1999年）、「第5版実験化学講座　有機合成IV」、p.119～154、丸善(2001年)等］もしくはそれらに準じた方法により合成することができる。 (Wherein R 4 is as defined above)
Compound (XI) is obtained from Compound (XII) by a known method [for example, Comprehensive Organic Transformations, second edition, by RC Larock, John Wiley. John Wiley & Sons Inc. (1999), "5th edition Experimental Chemistry Course Organic Synthesis IV", p.119-154, Maruzen (2001), etc.] or methods according to them Can be synthesized.
　化合物(XII)は例えば、市販品として、または公知の方法［例えば、コンプリヘンシブ・オーガニック・トランスフォーメーションズ第二版（Comprehensive Organic Transformations, second edition）、ラロック（R. C. Larock）著、ジョン・ワイリー・アンド・サンズ・インコーポレイテッド（John Wiley & Sons Inc.）（1999年）、新編 ヘテロ環化合物 基礎編、山中 宏、日野 亨、中川 昌子、坂本 尚夫 著、講談社サイエンティフィク (2004年)、新編 ヘテロ環化合物 応用編、山中 宏、日野 亨、中川 昌子、坂本 尚夫 著、講談社サイエンティフィク (2004年)、新編 ヘテロ環化合物 展開編、坂本 尚夫、廣谷 功 著、講談社 (2010年) 等］もしくはそれらに準じた方法により、それぞれ得ることができる。 Compound (XII) can be obtained, for example, as a commercial product or by a known method [for example, Comprehensive Organic Transformations, 2nd Edition, by R. C. Larock, John・ Wiley & Sons Inc. (1999), New Hen Heterocyclic Compound Basics, Akihiro Yamanaka, Satoshi Hino, Masako Nakagawa, Nao Sakamoto, Kodansha Scientific (2004) , New Edition Heterocyclic Compound Application, Yasuhiro Yamanaka, Satoshi Hino, Masako Nakagawa, Takao Sakamoto, Kodansha Scientific (2004), New Edition Heterocyclic Compound Development, Yasuo Sakamoto, Yasuaki Sugaya, Kodansha (2010), etc. ] Or a method according to them, respectively.
　また、化合物(XII)は以下のような方法によって合成することもできる。
　化合物(XII)のうちオキサゾールカルボン酸は市販品として得ることができるか、例えば、1) J. Org. Chem.1973, 38(20), 3571-3575、2) J. Hetrocyclic Chem., 1998, 35, 859-863、3) Bioorg. Med. Chem. Lett., 2005, 15, 1075-1078、4) Tetrahedron, 2004, 60(18), 3967-3978等に記載の方法により製造することができる。チアゾールカルボン酸は、市販品として得ることができるか、例えば、1) Organic Synthesis, Coll. Vol 6, 1988, p620、2)Tetrahedron, 2004, 60(18), 3967-3978、3) WO2007125061等に記載の方法等により製造することができる。ピラゾールカルボン酸は、市販品として得ることができるか、例えば、1) Tetrahedron. Lett., 2009, 50, 696-699、2) J. Med. Chem.1973, 16(12), 1346-1354 等に記載の方法等により製造することができる。イソオキサゾールカルボン酸は、市販品として得ることができるか、例えば、1) Tetrahedron, 2006, 62, 4430-4434、2) Tetrahedron Lett., 1993, 34(47), 7509-7512、3) J. Heterocyclic Chem., 1991, 28, 453-457 等に記載の方法により製造することができる。イミダゾールカルボン酸は、市販品として得ることができるか、例えば、1) J. Org. Chem., 1994, 59, 7635-7642、2) Tetrahedron 2004, 60(18), 3967-3977、3) Org. Lett., 2006, 8 (5), 923-926、4) Synthesis, 1988, 767-771、5) J. Am. Chem. Soc. 1957, 79, 4922-4926等に記載の方法等により製造することができる。トリアゾールカルボン酸は、市販として得ることができるか、例えば、Synthetic Communication, 2004, 34(2), 369-376等に記載の方法等により製造することができる。 Compound (XII) can also be synthesized by the following method.
Among the compounds (XII), oxazole carboxylic acid can be obtained as a commercial product, for example, 1) J. Org. Chem. 1973, 38 (20), 3571-3575, 2) J. Hetrocyclic Chem., 1998, 35, 859-863, 3) Bioorg. Med. Chem. Lett., 2005, 15, 1075-1078, 4) Tetrahedron, 2004, 60 (18), 3967-3978 etc. . Thiazolecarboxylic acid can be obtained as a commercial product, for example, 1) Organic Synthesis, Coll. Vol 6, 1988, p620, 2) Tetrahedron, 2004, 60 (18), 3967-3978, 3) WO2007125061, etc. It can be produced by the method described. The pyrazole carboxylic acid can be obtained as a commercial product, for example, 1) Tetrahedron. Lett., 2009, 50, 696-699, 2) J. Med. Chem. 1973, 16 (12), 1346-1354, etc. Can be produced by the method described in 1. above. Isoxazole carboxylic acid can be obtained as a commercial product, for example, 1) Tetrahedron, 2006, 62, 4430-4434, 2) Tetrahedron Lett., 1993, 34 (47), 7509-7512, 3) J. Heterocyclic Chem., 1991, 28, 453-457 and the like. Imidazolecarboxylic acid can be obtained as a commercial product, for example, 1) J. Org. Chem., 1994, 59, 7635-7642, 2) Tetrahedron 2004, 60 (18), 3967-3977, 3) Org Lett., 2006, 8 (5), 923-926, 4) Synthesis, 1988, 767-771, 5) J. Am. Chem. Soc. 1957, 79, 4922-4926 etc. can do. Triazole carboxylic acid can be obtained commercially, or can be produced, for example, by the method described in Synthetic Communication, 2004, 34 (2), 369-376 or the like.
　化合物(IA)は、上記化合物(I)の製造法と、公知の方法[例えば、コンプリヘンシブ・オーガニック・トランスフォーメーションズ 第2版(Comprehensive Organic Transformations 2nd edition)、R. C. ラロック(Larock)著、Vch Verlagsgesellschaft Mbh(1999年)等に記載の方法]を組み合わせることにより製造することができる。
　化合物(I)におけるR1、R2、R3またはR4、および化合物(IA)におけるR1A、R2A、R3AまたはR4Aに含まれる官能基の変換は、公知の方法[例えば、コンプリヘンシブ・オーガニック・トランスフォーメーションズ 第2版(Comprehensive Organic Transformations 2nd edition)、R. C. ラロック(Larock)著、Vch Verlagsgesellschaft Mbh(1999年)等に記載の方法]でまたはそれらに準じて行うこともできる。 Compound (IA) is a method for producing the above compound (I) and known methods (for example, Comprehensive Organic Transformations 2nd edition, RC Larock, Vch It can be produced by combining the method described in Verlagsgesellschaft Mbh (1999).
Conversion of the functional group contained in R 1 , R 2 , R 3 or R 4 in compound (I) and R 1A , R 2A , R 3A or R 4A in compound (IA) can be carried out by a known method [for example, The method described in Hensive Organic Transformations 2nd edition, RC Larock, Vch Verlagsgesellschaft Mbh (1999), etc.] or in accordance with them.
　上記各製造法における中間体および目的化合物は、有機合成化学で常用される分離精製法、例えば、ろ過、抽出、洗浄、乾燥、濃縮、再結晶、各種クロマトグラフィー等に付して単離精製することができる。また、中間体においては特に精製することなく次の反応に供することも可能である。
　化合物(I)および(IA)の中には、幾何異性体、光学異性体等の立体異性体、互変異性体等が存在し得るものもあるが、本発明は、これらを含め、全ての可能な異性体およびそれらの混合物を包含する。 The intermediates and target compounds in the above production methods are isolated and purified by separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. be able to. The intermediate can be subjected to the next reaction without any particular purification.
Some of the compounds (I) and (IA) may have stereoisomers such as geometric isomers and optical isomers, tautomers and the like, but the present invention includes all of them. Includes possible isomers and mixtures thereof.
　化合物(I)および(IA)中の各原子の一部またはすべては、それぞれ対応する同位体原子で置き換わっていてもよく、本発明は、これら同位体原子で置き換わった化合物も包含する。例えば、化合物(I)および(IA)中の水素原子の一部またはすべては、原子量2の水素原子(重水素原子)であってもよい。
　化合物(I)および(IA)中の各原子の一部またはすべてが、それぞれ対応する同位体原子で置き換わった化合物は、市販のビルディングブロックを用いて、上記各製造法と同様な方法で製造することができる。また、化合物(I)および(IA)中の水素原子の一部またはすべてが重水素原子で置き換わった化合物は、例えば、1) 過酸化重水素を用い、塩基性条件下にカルボン酸等を重水素化する方法（米国特許第3849458号明細書参照）、2) イリジウム錯体を触媒として用い、重水を重水素源として用いてアルコール、カルボン酸等を重水素化する方法[ジャーナル・オブ・アメリカン・ケミカル・ソサイアティ(J. Am. Chem. Soc.), Vol．124，No．10，2092（2002）参照]、3) パラジウムカーボンを触媒として用い、重水素源として重水素ガスのみを用いて脂肪酸を重水素化する方法[リピッズ（LIPIDS），Vol．9，No．11, 913（1974）参照]、4) 白金、パラジウム、ロジウム、ルテニウム、イリジウム等の金属を触媒として用い、重水または重水および重水素ガスを重水素源として用いてアクリル酸、アクリル酸メチル、メタクリル酸、メタクリル酸メチル等を重水素化する方法（特公平5－19536号公報、特開昭61－277648号公報および特開昭61－275241号公報参照）、5) パラジウム、ニッケル、銅または亜クロム酸銅等の触媒を用い、重水を重水素源として用いて、アクリル酸、メタクリル酸メチル等を重水素化する方法（特開昭63－198638号公報参照）等を用いて合成することもできる。 Some or all of the atoms in the compounds (I) and (IA) may be replaced with the corresponding isotope atoms, respectively, and the present invention also includes compounds replaced with these isotope atoms. For example, some or all of the hydrogen atoms in the compounds (I) and (IA) may be hydrogen atoms having an atomic weight of 2 (deuterium atoms).
A compound in which part or all of each atom in compounds (I) and (IA) is replaced with the corresponding isotope atom is produced by a method similar to the above production method using a commercially available building block. be able to. A compound in which some or all of the hydrogen atoms in the compounds (I) and (IA) are replaced with deuterium atoms is, for example, 1) deuterium peroxide and deuterating carboxylic acid under basic conditions. Hydrogenation method (see US Pat. No. 3,849,458), 2) Deuteration of alcohol, carboxylic acid, etc. using iridium complex as catalyst and heavy water as deuterium source [Journal of American Chemical Society (J. Am. Chem. Soc.), Vol. 124, no. 10, 2092 (2002)], 3) A method of deuterating fatty acids using palladium carbon as a catalyst and using only deuterium gas as a deuterium source [LIPIDS, Vol. 9, No. 11, 913 (1974)], 4) Metals such as platinum, palladium, rhodium, ruthenium, and iridium are used as catalysts, and heavy water or heavy water and deuterium gas are used as a deuterium source for acrylic acid, methyl acrylate, methacrylic acid. Deuteration of acids, methyl methacrylate, etc. (see Japanese Patent Publication No. 5-19536, Japanese Patent Laid-Open Nos. 61-277648 and 61-275241), 5) Palladium, nickel, copper or sub- It can also be synthesized by using a catalyst such as copper chromate, deuterating acrylic acid, methyl methacrylate, etc. using heavy water as a deuterium source (see JP-A 63-198638). it can.
　化合物(I)および(IA)の塩を取得したいとき、化合物(I)および(IA)が塩の形で得られるときはそのまま精製すればよく、また、遊離の形で得られるときは、化合物(I)および(IA)を適当な溶媒に溶解または懸濁し、酸または塩基を加えることにより塩を形成させて単離、精製すればよい。
　また、化合物(I)および(IA)、ならびにそれらの薬学的に許容される塩は、水または各種溶媒との付加物の形で存在することもあるが、これらの付加物も本発明に包含される。 When it is desired to obtain salts of the compounds (I) and (IA), the compounds (I) and (IA) may be purified as they are when they are obtained in the salt form. (I) and (IA) can be isolated or purified by dissolving or suspending them in a suitable solvent and adding an acid or base to form a salt.
In addition, compounds (I) and (IA), and pharmaceutically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention. Is done.
　本発明によって得られる化合物(I)および(IA)の具体例を表1～7に示す。ただし、本発明の化合物はこれらに限定されるものではない。
　表中、Meはメチルを表し、Etはエチルを表し、iPrはイソプロピルを表し、tBuはtert-ブチルを表す。 Specific examples of the compounds (I) and (IA) obtained by the present invention are shown in Tables 1 to 7. However, the compound of the present invention is not limited to these.
In the table, Me represents methyl, Et represents ethyl, i Pr represents isopropyl, and t Bu represents tert-butyl.
Figure JPOXMLDOC01-appb-T000007
 　　　　　　　　　　　　　　　　　 
 
Figure JPOXMLDOC01-appb-T000007
 　　　　　　　　　　　　　　　　　 
 
Figure JPOXMLDOC01-appb-T000008
 　　　　　　　　　　　　　　　　　 
 
Figure JPOXMLDOC01-appb-T000008
 　　　　　　　　　　　　　　　　　 
 
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
　次に、代表的な化合物(I)および(IA)の薬理作用について試験例により具体的に説明する。
試験例1　ヒトCSF-1Rリン酸化阻害活性の測定
　384ウェルポリプロピレンプレートに、アッセイバッファー[100 mmol/L 4-(2-ヒドロキシエチル)-1-ピペラジンエタンスルホン酸(HEPES)、10 mmol/L 塩化マグネシウム、0.003 vol% Brij-35、0.004 vol% Tween20および1 mmol/L ジチオスレイトール、pH 7.5]にて希釈したCSF-1R (Fms、08-155、カルナバイオサイエンス社)、蛍光標識基質(FL-Peptide 30、760430、Caliper Life Sciences社)、アデノシン三リン酸[adenosine triphosphate(ATP)]およびDMSOに溶解した被験物質を添加して、全量25 μLにて、室温で60分間反応させた。CSF-1R、蛍光標識基質、ATPおよびDMSOの最終濃度は、それぞれ0.8 nmol/L、1.0 μmol/L、300 μmol/Lおよび1 vol%とした。次に、このプレートにターミネーションバッファー[100 mmol/L HEPES、15 mmol/L エチレンジアミン四酢酸(EDTA)、0.022 vol% Brij-35、0.17 vol％ Coating Reagent 3および7.2 vol% DMSO、pH 7.5］を45μL 添加して酵素反応を停止させた。次に、モビリティーシフトアッセイ装置(LabChip EZ Reader II、Caliper Life Sciences社)を用いて、蛍光標識基質およびリン酸化された蛍光標識基質の蛍光強度を測定し、そのピーク値より、以下の式1に基づき、変換率を算出した。 Next, the pharmacological action of representative compounds (I) and (IA) will be specifically described with reference to test examples.
Test Example 1 Measurement of Human CSF-1R Phosphorylation Inhibitory Activity Assay buffer [100 mmol / L 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), 10 mmol / L chloride on a 384-well polypropylene plate CSF-1R (Fms, 08-155, Carna Biosciences) diluted with magnesium, 0.003 vol% Brij-35, 0.004 vol% Tween20 and 1 mmol / L dithiothreitol, pH 7.5], fluorescently labeled substrate (FL -Peptide 30, 760430, Caliper Life Sciences), adenosine triphosphate [Adenosine triphosphate (ATP)] and a test substance dissolved in DMSO were added and reacted at room temperature for 60 minutes at a total volume of 25 μL. The final concentrations of CSF-1R, fluorescently labeled substrate, ATP and DMSO were 0.8 nmol / L, 1.0 μmol / L, 300 μmol / L and 1 vol%, respectively. Next, 45 μL of termination buffer [100 mmol / L HEPES, 15 mmol / L ethylenediaminetetraacetic acid (EDTA), 0.022 vol% Brij-35, 0.17 vol% Coating Reagent 3 and 7.2 vol% DMSO, pH 7.5] was added to the plate. The enzyme reaction was stopped by adding. Next, using a mobility shift assay device (LabChip EZ Reader II, Caliper Life Sciences), the fluorescence intensity of the fluorescently labeled substrate and the phosphorylated fluorescently labeled substrate was measured, and from the peak value, the following formula 1 was obtained. Based on this, the conversion rate was calculated.
Figure JPOXMLDOC01-appb-M000014
Figure JPOXMLDOC01-appb-M000014
　得られた変換率を元に、以下の式2によりCSF-1Rリン酸化阻害率を求めた。 Based on the obtained conversion rate, the inhibition rate of CSF-1R phosphorylation was determined by the following formula 2.
Figure JPOXMLDOC01-appb-M000015
Figure JPOXMLDOC01-appb-M000015
　被験物質の濃度を数段階に変えて、それぞれの濃度におけるCSF-1Rリン酸化阻害率を求め、それらを元にして、被験物質のCSF-1Rリン酸化50％阻害濃度(IC50)を算出した。その結果、化合物1～3、5～10、12～26および28～85は100 nmol/Lより小さなIC50値を示した。また、化合物4、11および27は、100～150 nmol/LのIC50値を示した。
試験例2　ヒトTrkAリン酸化阻害活性の測定
　384ウェルポリプロピレンプレートに、アッセイバッファー[100 mmol/L 4-(2-ヒドロキシエチル)-1-ピペラジンエタンスルホン酸(HEPES)、10 mmol/L 塩化マグネシウム、0.003 vol% Brij-35、0.004 vol% Tween20および1 mmol/L ジチオスレイトール、pH 7.5]にて希釈したTrkA (TrkA、08－186、カルナバイオサイエンス社)、蛍光標識基質(FL-Peptide 30、760430、Caliper Life Sciences社)、ATPおよびDMSOに溶解した被験物質を添加して、全量25 μLにて、室温で60分間反応させた。TrkA、蛍光標識基質、ATPおよびDMSOの最終濃度は、それぞれ2 nmol/L、1.0 μmol/L、75 μmol/Lおよび1 vol%とした。次に、このプレートにターミネーションバッファー[100 mmol/L HEPES、15 mmol/L エチレンジアミン四酢酸(EDTA)、0.022 vol% Brij-35、0.17 vol％ Coating Reagent 3および7.2 vol% DMSO、pH 7.5]を45 μL 添加して酵素反応を停止させた。次に、モビリティーシフトアッセイ装置(LabChip EZ Reader II、Caliper Life Sciences社)を用いて、蛍光標識基質およびリン酸化された蛍光標識基質の蛍光強度を測定し、そのピーク値より、前記式1に基づき、変換率を算出した。得られた変換率を元に、以下の式3によりTrkAリン酸化阻害率を求めた。 CSF-1R phosphorylation inhibition rate at each concentration was obtained by changing the concentration of the test substance in several stages, and based on these, the CSF-1R phosphorylation 50% inhibition concentration (IC 50 ) of the test substance was calculated. . As a result, Compounds 1-3, 5-10, 12-26 and 28-85 showed IC 50 values smaller than 100 nmol / L. Compounds 4, 11 and 27 also showed IC 50 values of 100 to 150 nmol / L.
Test Example 2 Measurement of human TrkA phosphorylation inhibitory activityInto a 384-well polypropylene plate, assay buffer [100 mmol / L 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), 10 mmol / L magnesium chloride, TrkA (TrkA, 08-186, Carna Biosciences) diluted with 0.003 vol% Brij-35, 0.004 vol% Tween20 and 1 mmol / L dithiothreitol, pH 7.5], fluorescent labeling substrate (FL-Peptide 30, 760430, Caliper Life Sciences), a test substance dissolved in ATP and DMSO was added, and the whole was reacted at 25 μL at room temperature for 60 minutes. The final concentrations of TrkA, fluorescently labeled substrate, ATP, and DMSO were 2 nmol / L, 1.0 μmol / L, 75 μmol / L, and 1 vol%, respectively. Next, 45 ml of termination buffer [100 mmol / L HEPES, 15 mmol / L ethylenediaminetetraacetic acid (EDTA), 0.022 vol% Brij-35, 0.17 vol% Coating Reagent 3 and 7.2 vol% DMSO, pH 7.5] was added to the plate. μL was added to stop the enzyme reaction. Next, using a mobility shift assay device (LabChip EZ Reader II, Caliper Life Sciences), the fluorescence intensity of the fluorescently labeled substrate and the phosphorylated fluorescently labeled substrate was measured. The conversion rate was calculated. Based on the obtained conversion rate, the TrkA phosphorylation inhibition rate was calculated by the following formula 3.
Figure JPOXMLDOC01-appb-M000016
Figure JPOXMLDOC01-appb-M000016
　被験物質の濃度を数段階に変えて、それぞれの濃度におけるTrkAリン酸化阻害率を求め、それらを元にして、被験物質のTrkAリン酸化50％阻害濃度(IC50)を算出した。その結果、化合物1～2、4～16、18、21、23、25～40および42～85は100 nmol/Lより小さなIC50値を示した。また、化合物3、17、19、20、22、24および41は、100～250 nmol/LのIC50値を示した。
試験例3　ヒトVEGFR-2リン酸化阻害活性の測定
　384ウェルポリプロピレンプレートに、1 vol% の3-((3-コラミドプロピル)ジメチルアンモニオ)-2-ヒドロキシ-1-プロパンスルホナート(CHAPSO、07958-41、ナカライテスク)を含むアッセイバッファー[100 mmol/L 4-(2-ヒドロキシエチル)-1-ピペラジンエタンスルホン酸(HEPES)、10 mmol/L 塩化マグネシウム、0.003 vol% Brij-35、0.004 vol% Tween20および1 mmol/L ジチオスレイトール、pH 7.5]にて希釈したVEGFR-2(KDR、08-191、カルナバイオサイエンス社)、蛍光標識基質(FL-Peptide 22、760366、Caliper Life Sciences社)、ATPおよびDMSOに溶解した被験物質を添加して、全量25 μLにて、28 ℃で60分間反応させた。VEGFR-2、蛍光標識基質、ATP およびDMSOの最終濃度は、それぞれ0.3 nmol/L、1.5 μmol/L、165 μmol/Lおよび1 vol%とした。次に、このプレートにターミネーションバッファー[100 mmol/L HEPES、15 mmol/L エチレンジアミン四酢酸(EDTA)、0.022 vol% Brij-35、0.17 vol％ Coating Reagent 3および7.2 vol% DMSO、pH 7.5］を45 μL添加して酵素反応を停止させた。次に、モビリティーシフトアッセイ装置(LabChip EZ Reader II、Caliper Life Sciences社)を用いて、蛍光標識基質およびリン酸化された蛍光標識基質の蛍光強度を測定し、そのピーク値より、前記式1に基づき、変換率を算出した。得られた変換率を元に、以下の式4によりVEGFR-2リン酸化阻害率を求めた。 The concentration of the test substance was changed in several stages, the inhibition rate of TrkA phosphorylation at each concentration was determined, and the TrkA phosphorylation 50% inhibition concentration (IC 50 ) of the test substance was calculated based on them. As a result, compounds 1-2, 4-16, 18, 21, 23, 25-40 and 42-85 showed IC 50 values less than 100 nmol / L. In addition, compounds 3, 17, 19, 20, 22, 24 and 41 showed IC 50 values of 100 to 250 nmol / L.
Test Example 3 Measurement of human VEGFR-2 phosphorylation inhibitory activityInto a 384-well polypropylene plate, 1 vol% of 3-((3-colamidopropyl) dimethylammonio) -2-hydroxy-1-propanesulfonate (CHAPSO, 07958-41, Nacalai Tesque) assay buffer (100 mmol / L 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), 10 mmol / L magnesium chloride, 0.003 vol% Brij-35, 0.004 VEGFR-2 (KDR, 08-191, Carna Biosciences) diluted with vol% Tween20 and 1 mmol / L dithiothreitol, pH 7.5], fluorescently labeled substrate (FL-Peptide 22, 760366, Caliper Life Sciences) ), A test substance dissolved in ATP and DMSO was added, and the mixture was reacted at 28 ° C. for 60 minutes in a total volume of 25 μL. The final concentrations of VEGFR-2, fluorescently labeled substrate, ATP and DMSO were 0.3 nmol / L, 1.5 μmol / L, 165 μmol / L and 1 vol%, respectively. Next, 45 ml of termination buffer [100 mmol / L HEPES, 15 mmol / L ethylenediaminetetraacetic acid (EDTA), 0.022 vol% Brij-35, 0.17 vol% Coating Reagent 3 and 7.2 vol% DMSO, pH 7.5] was added to the plate. μL was added to stop the enzyme reaction. Next, using a mobility shift assay device (LabChip EZ Reader II, Caliper Life Sciences), the fluorescence intensity of the fluorescently labeled substrate and the phosphorylated fluorescently labeled substrate was measured. The conversion rate was calculated. Based on the obtained conversion rate, the VEGFR-2 phosphorylation inhibition rate was determined by the following formula 4.
Figure JPOXMLDOC01-appb-M000017
Figure JPOXMLDOC01-appb-M000017
　被験物質の1 μmol/LにおけるVEGFR-2リン酸化阻害率を算出した。その結果、化合物1～85は50%より小さなリン酸化阻害率を示した。
試験例4　ヒトHGFRリン酸化阻害活性の測定
　384ウェルポリプロピレンプレートに、アッセイバッファー[100 mmol/L 4-(2-ヒドロキシエチル)-1-ピペラジンエタンスルホン酸(HEPES)、10 mmol/L 塩化マグネシウム、0.003 vol% Brij-35、0.004 vol% Tween20および1 mmol/L ジチオスレイトール、pH 7.5]にて希釈したHGFR (Met、08-151、カルナバイオサイエンス社)、蛍光標識基質(FL-Peptide 2、760346、Caliper Life Sciences社)、ATPおよびDMSOに溶解した被験物質を添加して、全量25 μLにて、28 ℃で90分間反応させた。HGFR、蛍光標識基質、ATP およびDMSOの最終濃度は、それぞれ2 nmol/L、1.5 μmol/L、79.5 μmol/Lおよび1 vol%とした。次に、このプレートにターミネーションバッファー[100 mmol/L HEPES、15 mmol/L エチレンジアミン四酢酸(EDTA)、0.022 vol% Brij-35、0.17 vol％ Coating Reagent 3および7.2 vol % DMSO、pH 7.5]を45μL 添加して酵素反応を停止させた。次に、モビリティーシフトアッセイ装置(LabChip EZ Reader II、Caliper Life Sciences社)を用いて、蛍光標識基質およびリン酸化された蛍光標識基質の蛍光強度を測定し、そのピーク値より、前記式1に基づき、変換率を算出した。得られた変換率を元に、以下の式5によりHGFRリン酸化阻害率を求めた。 The inhibition rate of VEGFR-2 phosphorylation at 1 μmol / L of the test substance was calculated. As a result, compounds 1 to 85 showed phosphorylation inhibition rate smaller than 50%.
Test Example 4 Measurement of human HGFR phosphorylation inhibitory activityInto a 384-well polypropylene plate, assay buffer [100 mmol / L 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), 10 mmol / L magnesium chloride, HGFR (Met, 08-151, Carna Biosciences) diluted with 0.003 vol% Brij-35, 0.004 vol% Tween20 and 1 mmol / L dithiothreitol, pH 7.5], fluorescently labeled substrate (FL-Peptide 2, 760346, Caliper Life Sciences), a test substance dissolved in ATP and DMSO was added, and the mixture was reacted at 28 ° C. for 90 minutes in a total volume of 25 μL. The final concentrations of HGFR, fluorescently labeled substrate, ATP and DMSO were 2 nmol / L, 1.5 μmol / L, 79.5 μmol / L and 1 vol%, respectively. Next, 45 μL of termination buffer [100 mmol / L HEPES, 15 mmol / L ethylenediaminetetraacetic acid (EDTA), 0.022 vol% Brij-35, 0.17 vol% Coating Reagent 3 and 7.2 vol% DMSO, pH 7.5] was added to the plate. The enzyme reaction was stopped by adding. Next, using a mobility shift assay device (LabChip EZ Reader II, Caliper Life Sciences), the fluorescence intensity of the fluorescently labeled substrate and the phosphorylated fluorescently labeled substrate was measured. The conversion rate was calculated. Based on the obtained conversion rate, the inhibition rate of HGFR phosphorylation was obtained by the following formula 5.
Figure JPOXMLDOC01-appb-M000018
Figure JPOXMLDOC01-appb-M000018
　被験物質の1 μmol/LにおけるHGFRリン酸化阻害率を算出した。その結果、化合物1～4、6～7、9～13、15～22、24～42、44～45、48～52、54、55、58～61、63、66～77および79～85は50%より小さなリン酸化阻害率を示し、化合物23、47、53、56、57、62、64および78は、上記濃度で50～60％の阻害率を示し、さらに化合物5、8、43および46は、上記濃度で61～70％の阻害率を示した。 HGFR phosphorylation inhibition rate at 1 μmol / L of the test substance was calculated. As a result, compounds 1-4, 6-7, 9-13, 15-22, 24-42, 44-45, 48-52, 54, 55, 58-61, 63, 66-77 and 79-85 are Shows a phosphorylation inhibition rate of less than 50%, and compounds 23, 47, 53, 56, 57, 62, 64 and 78 show 50-60% inhibition at the above concentrations, and further compounds 5, 8, 43 and 46 showed an inhibition rate of 61-70% at the above concentrations.
　上記試験結果から化合物(I)および(IA)は、VEGFR-2およびHGFRと比較してCSF-1RおよびTrkA選択的にリン酸化阻害活性を示した。従って、化合物(I)および(IA)、ならびにそれらの薬学的に許容される塩は、CSF-1Rおよび／またはTrkAを阻害し、癌骨転移、関節リウマチ、骨粗しょう症、ベーチェット病、変形性関節症、前立腺癌、肺癌、腎臓癌、膵臓癌、乳癌、子宮癌、骨髄異形成症候群、急性骨髄性白血病、慢性骨髄性白血病等の治療および／または予防剤として有用であると考えられる。 From the above test results, compounds (I) and (IA) showed phosphorylation inhibitory activity selectively on CSF-1R and TrkA compared to VEGFR-2 and HGFR. Therefore, compounds (I) and (IA), and pharmaceutically acceptable salts thereof, inhibit CSF-1R and / or TrkA and cause cancer bone metastasis, rheumatoid arthritis, osteoporosis, Behcet's disease, deformability It is considered useful as a therapeutic and / or prophylactic agent for arthropathy, prostate cancer, lung cancer, kidney cancer, pancreatic cancer, breast cancer, uterine cancer, myelodysplastic syndrome, acute myeloid leukemia, chronic myelogenous leukemia and the like.
　化合物(I)および(IA)、またはそれらの薬学的に許容される塩は、そのまま単独で投与することも可能であるが、通常各種の医薬製剤として提供するのが望ましい。また、それら医薬製剤は、動物または人に使用されるものである。
　本発明に係わる医薬製剤は、活性成分として化合物(I)および(IA)、またはそれらの薬学的に許容される塩を単独で、または任意の他の治療のための有効成分との混合物として含有することができる。また、それら医薬製剤は、活性成分を薬学的に許容される一種またはそれ以上の担体(例えば、希釈剤、溶剤、賦形剤等)と一緒に混合し、製剤学の技術分野においてよく知られている任意の方法により製造される。 Compounds (I) and (IA), or pharmaceutically acceptable salts thereof can be administered alone as they are, but it is usually desirable to provide them as various pharmaceutical preparations. These pharmaceutical preparations are used for animals or humans.
The pharmaceutical preparation according to the present invention contains the compounds (I) and (IA) as active ingredients, or pharmaceutically acceptable salts thereof alone or as a mixture with any other active ingredient for treatment. can do. These pharmaceutical preparations are well known in the technical field of pharmaceutics by mixing the active ingredient with one or more pharmaceutically acceptable carriers (e.g., diluents, solvents, excipients, etc.). Manufactured by any method.
　投与経路としては、治療に際し最も効果的なものを使用するのが望ましく、経口または、例えば、静脈内等の非経口を挙げることができる。
　投与形態としては、例えば、錠剤、注射剤等が挙げられる。
　経口投与に適当な、例えば、錠剤等は、乳糖等の賦形剤、澱粉等の崩壊剤、ステアリン酸マグネシウム等の滑沢剤、ヒドロキシプロピルセルロース等の結合剤等を用いて製造できる。 As an administration route, it is desirable to use one that is most effective in the treatment, and examples thereof include oral or parenteral such as intravenous administration.
Examples of the dosage form include tablets and injections.
For example, tablets suitable for oral administration can be produced using excipients such as lactose, disintegrants such as starch, lubricants such as magnesium stearate, binders such as hydroxypropylcellulose, and the like.
　非経口投与に適当な、例えば、注射剤等は、塩溶液、ブドウ糖溶液または塩水とブドウ糖溶液の混合液等の希釈剤または溶剤等を用いて製造できる。
　化合物(I)および(IA)、またはそれらの薬学的に許容される塩の投与量および投与回数は、投与形態、患者の年齢、体重、治療すべき症状の性質もしくは重篤度等により異なるが、通常経口の場合、成人一人あたり、0.01～1000 mg、好ましくは0.05～100 mgの範囲で、1日1回ないし数回投与する。静脈内投与等の非経口投与の場合、成人一人あたり0.001～1000 mg、好ましくは0.01～100 mgを1日1回ないし数回投与する。しかしながら、これら投与量および投与回数に関しては、前述の種々の条件により変動する。 For example, an injection suitable for parenteral administration can be produced using a diluent or a solvent such as a salt solution, a glucose solution or a mixed solution of a saline solution and a glucose solution.
The dosage and frequency of administration of compounds (I) and (IA), or pharmaceutically acceptable salts thereof vary depending on the dosage form, patient age, body weight, nature or severity of symptoms to be treated, etc. In general, in the case of oral administration, it is administered once or several times a day in the range of 0.01 to 1000 mg, preferably 0.05 to 100 mg per adult. In the case of parenteral administration such as intravenous administration, 0.001 to 1000 mg, preferably 0.01 to 100 mg per adult is administered once to several times a day. However, the dose and the number of doses vary depending on the various conditions described above.
　以下、本発明を実施例および参考例によりさらに具体的に説明するが、本発明の範囲はこれらの実施例に限定されることはない。
　なお、実施例および参考例で用いられるプロトン核磁気共鳴スペクトル(1H NMR)は、270MHzまたは300MHzで測定されたものであり、化合物および測定条件によって交換性プロトンが明瞭には観測されないことがある。なお、シグナルの多重度の表記としては通常用いられるものを用いるが、brとは見かけ上幅広いシグナルであることを表す。 EXAMPLES Hereinafter, although an Example and a reference example demonstrate this invention further more concretely, the scope of the present invention is not limited to these Examples.
Note that proton nuclear magnetic resonance spectra ( 1 H NMR) used in Examples and Reference Examples are those measured at 270 MHz or 300 MHz, and exchangeable protons may not be clearly observed depending on the compound and measurement conditions. . In addition, although what is used normally is used as description of the multiplicity of a signal, br represents that it is an apparent wide signal.
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-2-メチルオキサゾール-4-カルボキサミド (化合物1)
　対応するカルボン酸から常法で得られる2-メチルオキサゾール-4-カルボキサミド (32.4 mg, 0.257 mmol)をDMF (1.29 mL)に溶解し、60％水素化ナトリウム (12.0 mg, 0.308 mmol)を0 ℃で加えて15分間撹拌した。化合物A2 (57.0 mg, 0.128 mmol)を加えて50 ℃で22時間撹拌した。混合物に水を加え析出した固体をろ取し、得られた固体にアセトニトリルを加えてリスラリー精製し、化合物1 (42.0 mg, 68%)を得た。
1H-NMR (CDCl3) δ: 10.84 (s, 1H), 8.89 (s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.27 (s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.83 (dd, J = 8.8, 2.9 Hz, 1H), 6.78 (d, J = 2.9 Hz, 1H), 6.50 (d, J = 5.9 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.94 (s, 3H), 2.54 (s, 3H).
ESI-MS: m/z 479 [M+H]+. N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -2-methyloxazole-4-carboxamide (Compound 1)
2-Methyloxazole-4-carboxamide (32.4 mg, 0.257 mmol) obtained from the corresponding carboxylic acid by a conventional method is dissolved in DMF (1.29 mL), and 60% sodium hydride (12.0 mg, 0.308 mmol) is dissolved at 0 ° C. And stirred for 15 minutes. Compound A2 (57.0 mg, 0.128 mmol) was added and stirred at 50 ° C. for 22 hours. Water was added to the mixture, and the precipitated solid was collected by filtration, and acetonitrile was added to the obtained solid and reslurry purification was performed to obtain Compound 1 (42.0 mg, 68%).
1 H-NMR (CDCl 3 ) δ: 10.84 (s, 1H), 8.89 (s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.27 ( s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.83 (dd, J = 8.8, 2.9 Hz, 1H), 6.78 (d, J = 2.9 Hz, 1H), 6.50 (d, J = 5.9 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.94 (s, 3H), 2.54 (s, 3H).
ESI-MS: m / z 479 [M + H] + .
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-2-メチルチアゾール-4-カルボキサミド (化合物2)
　実施例1に準じて、化合物A2 (66.0 mg, 0.148 mmol)、2-メチルチアゾール-4-カルボキサミド (42.0 mg, 0.295 mmol)、および60％水素化ナトリウム (14.0 mg, 0.354 mmol)から化合物2 (13.1 mg, 18%)を得た。
1H-NMR (CDCl3) δ: 10.92 (s, 1H), 9.38 (s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.19 (s, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 6.83 (dd, J = 8.8, 2.0 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.51 (d, J = 5.9 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.96 (s, 3H).
ESI-MS: m/z 495 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -2-methylthiazole-4-carboxamide (Compound 2)
According to Example 1, compound 2 (66.0 mg, 0.148 mmol), 2-methylthiazole-4-carboxamide (42.0 mg, 0.295 mmol), and 60% sodium hydride (14.0 mg, 0.354 mmol) to compound 2 ( 13.1 mg, 18%) was obtained.
1 H-NMR (CDCl 3 ) δ: 10.92 (s, 1H), 9.38 (s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.19 ( s, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 6.83 (dd, J = 8.8, 2.0 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.51 (d, J = 5.9 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.96 (s, 3H).
ESI-MS: m / z 495 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1-メチル-1H-イミダゾール-4-カルボキサミド (化合物3)
　実施例1に準じて(ただし、溶媒のDMFをTHFに変更した)、化合物A2 (89.0 mg, 0.200 mmol)、対応するカルボン酸から常法で得られる1-メチル-1H-イミダゾール-4-カルボキサミド (50.0 mg, 0.400 mmol)、および60％水素化ナトリウム (19.0 mg, 0.480 mmol)から化合物3 (50.9 mg, 53%)を得た。
1H-NMR (CDCl3) δ: 10.98 (s, 1H), 9.15 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.41 (d, J = 8.9 Hz, 1H), 7.70 (d, J = 1.3 Hz, 1H), 7.58 (s, 1H), 7.45 (d, J = 1.3 Hz, 1H), 7.43 (s, 1H), 6.82 (dd, J = 8.9, 2.5 Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.94 (s, 3H), 3.80 (s, 3H).
ESI-MS: m/z 478 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1-methyl-1H-imidazole-4-carboxamide (Compound 3)
1-methyl-1H-imidazole-4-carboxamide obtained in a conventional manner from the corresponding carboxylic acid according to Example 1 (however, the solvent DMF was changed to THF), compound A2 (89.0 mg, 0.200 mmol) Compound 3 (50.9 mg, 53%) was obtained from (50.0 mg, 0.400 mmol) and 60% sodium hydride (19.0 mg, 0.480 mmol).
1 H-NMR (CDCl 3 ) δ: 10.98 (s, 1H), 9.15 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.41 (d, J = 8.9 Hz, 1H), 7.70 ( d, J = 1.3 Hz, 1H), 7.58 (s, 1H), 7.45 (d, J = 1.3 Hz, 1H), 7.43 (s, 1H), 6.82 (dd, J = 8.9, 2.5 Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.94 (s, 3H), 3.80 (s, 3H ).
ESI-MS: m / z 478 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1-イソプロピル-3-メチル-1H-ピラゾール-5-カルボキサミド (化合物4)
　実施例1に準じて、化合物A2 (643.0 mg, 1.44 mmol)、化合物B3 (219.0 mg, 0.131 mmol)、および60％水素化ナトリウム (105.0 mg, 2.62 mmol)から化合物4 (9.0 mg, 1%)を得た。
1H-NMR (CDCl3) δ: 10.90 (s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 8.41 (d, J = 8.6 Hz, 1H), 8.33 (s, 1H), 7.92 (s, 1H), 7.62 (s, 1H), 6.85 (dd, J = 8.6, 2.6 Hz, 1H), 6.80 (d, J = 2.6 Hz, 1H), 6.68 (d, J = 5.9 Hz, 1H), 6.58 (s, 1H), 5.51-5.41 (m, 1H), 4.14 (s, 3H), 4.10 (s, 3H), 3.99 (s, 3H), 2.32 (s, 3H), 1.52 (d, J = 6.6 Hz, 6H).
ESI-MS: m/z 520 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1-isopropyl-3-methyl-1H-pyrazole-5-carboxamide (Compound 4)
According to Example 1, compound A2 (643.0 mg, 1.44 mmol), compound B3 (219.0 mg, 0.131 mmol), and 60% sodium hydride (105.0 mg, 2.62 mmol) to compound 4 (9.0 mg, 1%) Got.
1 H-NMR (CDCl 3 ) δ: 10.90 (s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 8.41 (d, J = 8.6 Hz, 1H), 8.33 (s, 1H), 7.92 ( s, 1H), 7.62 (s, 1H), 6.85 (dd, J = 8.6, 2.6 Hz, 1H), 6.80 (d, J = 2.6 Hz, 1H), 6.68 (d, J = 5.9 Hz, 1H), 6.58 (s, 1H), 5.51-5.41 (m, 1H), 4.14 (s, 3H), 4.10 (s, 3H), 3.99 (s, 3H), 2.32 (s, 3H), 1.52 (d, J = (6.6 Hz, 6H).
ESI-MS: m / z 520 [M + H] +
1-tert-ブチル-N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-5-[(ジメチルアミノ)メチル]-1H-ピラゾール-3-カルボキサミド (化合物5)
　実施例1に準じて、化合物A2 (17.0 mg, 0.038 mmol)、化合物B9 (17.0 mg, 0.076 mmol)、および60％水素化ナトリウム (3.6 mg, 0.091 mmol)から化合物5 (11.0 mg, 50%)を得た。
1H-NMR (CDCl3) δ: 11.00 (s, 1H), 8.95 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 6.85-6.77 (m, 3H), 6.52 (d, J = 5.3 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.94 (s, 3H), 3.51 (s, 2H), 2.23 (s, 6H), 1.70 (s, 9H).
ESI-MS: m/z 577 [M+H]+ 1-tert-butyl-N- [4- (6,7-dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -5-[(dimethylamino) methyl] -1H-pyrazole-3-carboxamide (compound Five)
According to Example 1, compound A2 (17.0 mg, 0.038 mmol), compound B9 (17.0 mg, 0.076 mmol), and 60% sodium hydride (3.6 mg, 0.091 mmol) to compound 5 (11.0 mg, 50%) Got.
1 H-NMR (CDCl 3 ) δ: 11.00 (s, 1H), 8.95 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.58 ( s, 1H), 7.43 (s, 1H), 6.85-6.77 (m, 3H), 6.52 (d, J = 5.3 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.94 (s , 3H), 3.51 (s, 2H), 2.23 (s, 6H), 1.70 (s, 9H).
ESI-MS: m / z 577 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-5-メチルオキサゾール-4-カルボキサミド (化合物6)
　実施例3に準じて、化合物A2 (168.0 mg, 0.377 mmol)、5-メチルオキサゾール-4-カルボキサミド (95.0 mg, 0.753 mmol)、および60％水素化ナトリウム (36.0 mg, 0.904 mmol)から化合物6 (136.5 mg, 76%)を得た。
1H-NMR (CDCl3) δ: 10.85 (s, 1H), 8.97 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 7.77 (s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.83 (dd, J = 8.8, 2.0 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.51 (d, J = 4.9 Hz, 1H), 4.06 (s, 6H), 3.95 (s, 3H), 2.75 (s, 3H).
ESI-MS: m/z 479 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -5-methyloxazole-4-carboxamide (Compound 6)
According to Example 3, compound A2 (168.0 mg, 0.377 mmol), 5-methyloxazole-4-carboxamide (95.0 mg, 0.753 mmol), and 60% sodium hydride (36.0 mg, 0.904 mmol) to compound 6 ( 136.5 mg, 76%).
1 H-NMR (CDCl 3 ) δ: 10.85 (s, 1H), 8.97 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 7.77 ( s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.83 (dd, J = 8.8, 2.0 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.51 (d, J = 4.9 Hz, 1H), 4.06 (s, 6H), 3.95 (s, 3H), 2.75 (s, 3H).
ESI-MS: m / z 479 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-5-メチルチアゾール-4-カルボキサミド (化合物7)
　実施例3に準じて、化合物A2 (136.0 mg, 0.304 mmol)、5-メチルチアゾール-4-カルボキサミド (86.5 mg, 0.609 mmol)、および60％水素化ナトリウム (29.0 mg, 0.730 mmol)から化合物7 (105.3 mg, 70%)を得た。
1H-NMR (CDCl3) δ: 10.91 (s, 1H), 9.55 (s, 1H), 8.56 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 6.83 (dd, J = 8.8, 2.9 Hz, 1H), 6.78 (d, J = 2.9 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.96 (s, 3H), 2.93 (s, 3H).
ESI-MS: m/z 495 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -5-methylthiazole-4-carboxamide (Compound 7)
According to Example 3, compound A2 (136.0 mg, 0.304 mmol), 5-methylthiazole-4-carboxamide (86.5 mg, 0.609 mmol), and 60% sodium hydride (29.0 mg, 0.730 mmol) to compound 7 ( 105.3 mg, 70%) was obtained.
1 H-NMR (CDCl 3 ) δ: 10.91 (s, 1H), 9.55 (s, 1H), 8.56 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 6.83 (dd, J = 8.8, 2.9 Hz, 1H), 6.78 (d, J = 2.9 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.96 (s, 3H), 2.93 (s, 3H).
ESI-MS: m / z 495 [M + H] +
2-tert-ブチル-N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]オキサゾール-4-カルボキサミド (化合物8)
　実施例3に準じて、化合物A2 (86.0 mg, 0.194 mmol)、J. Org. Chem. 1996, 61(19), 6496-6497.に記載の方法に準じて得られる 2-tert-ブチル-オキサゾール-4-カルボキサミド (65.1 mg, 0.387 mmol)、および60％水素化ナトリウム (19.0 mg, 0.464 mmol)から化合物8 (45.5 mg, 45%)を得た。
1H-NMR (CDCl3) δ: 10.87 (s, 1H), 8.99 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.28 (s, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 6.83 (dd, J = 8.8, 2.9 Hz, 1H), 6.78 (d, J = 2.9 Hz, 1H), 6.51 (d, J = 5.9 Hz, 1H), 4.07 (s, 3H), 4.06 (s, 3H), 3.94 (s, 3H), 1.41 (s, 9H).
ESI-MS: m/z 521 [M+H]+ 2-tert-Butyl-N- [4- (6,7-dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] oxazole-4-carboxamide (Compound 8)
According to Example 3, compound A2 (86.0 mg, 0.194 mmol), 2-tert-butyl-oxazole obtained according to the method described in J. Org. Chem. 1996, 61 (19), 6496-6497. Compound 8 (45.5 mg, 45%) was obtained from -4-carboxamide (65.1 mg, 0.387 mmol) and 60% sodium hydride (19.0 mg, 0.464 mmol).
1 H-NMR (CDCl 3 ) δ: 10.87 (s, 1H), 8.99 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.28 ( s, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 6.83 (dd, J = 8.8, 2.9 Hz, 1H), 6.78 (d, J = 2.9 Hz, 1H), 6.51 (d, J = 5.9 Hz, 1H), 4.07 (s, 3H), 4.06 (s, 3H), 3.94 (s, 3H), 1.41 (s, 9H).
ESI-MS: m / z 521 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-2-メチルチアゾール-5-カルボキサミド (化合物9)
　実施例3に準じて、化合物A2 (656.0 mg, 1.47 mmol)、2-メチルチアゾール-5-カルボキサミド(190.0 mg, 1.33 mmol)、および60％水素化ナトリウム (64.0 mg, 1.60 mmol)から化合物9 (210 mg, 32%)を得た。
1H-NMR (CDCl3) δ: 11.01 (s, 1H), 10.63 (s, 1H), 8.64 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 6.82-6.78 (m, 2H), 6.51 (d, J = 4.9 Hz, 1H), 4.06 (s, 3H), 4.05 (s, 3H), 3.94 (s, 3H), 2.77 (s, 3H).
ESI-MS: m/z 495 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -2-methylthiazole-5-carboxamide (Compound 9)
According to Example 3, compound 9 (656.0 mg, 1.47 mmol), 2-methylthiazole-5-carboxamide (190.0 mg, 1.33 mmol), and 60% sodium hydride (64.0 mg, 1.60 mmol) to compound 9 ( 210 mg, 32%).
1 H-NMR (CDCl 3 ) δ: 11.01 (s, 1H), 10.63 (s, 1H), 8.64 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.37 (d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 6.82-6.78 (m, 2H), 6.51 (d, J = 4.9 Hz, 1H), 4.06 (s, 3H), 4.05 (s , 3H), 3.94 (s, 3H), 2.77 (s, 3H).
ESI-MS: m / z 495 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-2-メチルオキサゾール-5-カルボキサミド (化合物10)
　実施例3に準じて、化合物A2 (857.0 mg, 1.92 mmol)、2-メチルオキサゾール-5-カルボキサミド (220.0 mg, 1.77 mmol)、および60％水素化ナトリウム (84.0 mg, 2.09 mmol)から化合物10 (470 mg, 56%)を得た。
1H-NMR (CDCl3) δ: 10.80 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.44 (s, 1H), 8.34 (d, J = 8.6 Hz, 1H), 7.87 (s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.83 (dd, J = 8.6, 2.6 Hz, 1H), 6.79 (d, J = 2.6 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.95 (s, 3H), 2.61 (s, 3H).
ESI-MS: m/z 479 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -2-methyloxazole-5-carboxamide (Compound 10)
According to Example 3, from compound A2 (857.0 mg, 1.92 mmol), 2-methyloxazole-5-carboxamide (220.0 mg, 1.77 mmol), and 60% sodium hydride (84.0 mg, 2.09 mmol) to compound 10 ( 470 mg, 56%).
1 H-NMR (CDCl 3 ) δ: 10.80 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.44 (s, 1H), 8.34 (d, J = 8.6 Hz, 1H), 7.87 ( s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.83 (dd, J = 8.6, 2.6 Hz, 1H), 6.79 (d, J = 2.6 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.95 (s, 3H), 2.61 (s, 3H).
ESI-MS: m / z 479 [M + H] +
2-tert-ブチル-N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]チアゾール-4-カルボキサミド (化合物11)
　実施例3に準じて、化合物A2 (104.0 mg, 0.233 mmol)、2-tert-ブチル-チアゾール-4-カルボキサミド (85.7 mg, 0.465 mmol)、および60％水素化ナトリウム (22.0 mg, 0.558 mmol)から化合物11 (63.5 mg, 51%)を得た。
1H-NMR (CDCl3) δ: 10.97 (s, 1H), 9.38 (s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.21 (s, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 6.84 (dd, J = 8.8, 2.0 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 6.52 (d, J = 5.9 Hz, 1H), 4.07 (s, 3H), 4.06 (s, 3H), 3.96 (s, 3H), 1.48 (s, 9H).
ESI-MS: m/z 537 [M+H]+ 2-tert-Butyl-N- [4- (6,7-dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] thiazole-4-carboxamide (Compound 11)
According to Example 3, from compound A2 (104.0 mg, 0.233 mmol), 2-tert-butyl-thiazole-4-carboxamide (85.7 mg, 0.465 mmol), and 60% sodium hydride (22.0 mg, 0.558 mmol) Compound 11 (63.5 mg, 51%) was obtained.
1 H-NMR (CDCl 3 ) δ: 10.97 (s, 1H), 9.38 (s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.21 ( s, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 6.84 (dd, J = 8.8, 2.0 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 6.52 (d, J = 5.9 Hz, 1H), 4.07 (s, 3H), 4.06 (s, 3H), 3.96 (s, 3H), 1.48 (s, 9H).
ESI-MS: m / z 537 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-2,4-ジメチルオキサゾール-5-カルボキサミド (化合物12)
　実施例3に準じて、化合物A2 (91.0 mg, 0.204 mmol)、2,4-ジメチルオキサゾール-5-カルボキサミド (57.2 mg, 0.408 mmol)、および60％水素化ナトリウム (20.0 mg, 0.490 mmol)から化合物12 (56.3 mg, 56%)を得た。
1H-NMR (CDCl3) δ: 10.79 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.15 (s, 1H), 7.57 (s, 1H), 7.44 (s, 1H), 6.83 (dd, J = 8.8, 2.0 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 6.51 (d, J = 4.9 Hz, 1H), 4.06 (s, 6H), 3.95 (s, 3H), 2.55 (s, 3H), 2.55 (s, 3H).
ESI-MS: m/z 493 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -2,4-dimethyloxazole-5-carboxamide (Compound 12)
According to Example 3, compound from compound A2 (91.0 mg, 0.204 mmol), 2,4-dimethyloxazole-5-carboxamide (57.2 mg, 0.408 mmol), and 60% sodium hydride (20.0 mg, 0.490 mmol) 12 (56.3 mg, 56%) was obtained.
1 H-NMR (CDCl 3 ) δ: 10.79 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.15 (s, 1H), 7.57 ( s, 1H), 7.44 (s, 1H), 6.83 (dd, J = 8.8, 2.0 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 6.51 (d, J = 4.9 Hz, 1H), 4.06 (s, 6H), 3.95 (s, 3H), 2.55 (s, 3H), 2.55 (s, 3H).
ESI-MS: m / z 493 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-2,4-ジメチルチアゾール-5-カルボキサミド (化合物13)
　実施例3に準じて、化合物A2 (114.0 mg, 0.256 mmol)、2,4-ジメチルチアゾール-5-カルボキサミド (80.0 mg, 0.512 mmol)、および60％水素化ナトリウム (25.0 mg, 0.615 mmol)から化合物13 (101 mg, 78%)を得た。
1H-NMR (CDCl3) δ: 10.89 (s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 8.32 (d, J = 8.8 Hz, 1H), 7.96 (s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.82 (dd, J = 8.8, 2.0 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 6.51 (d, J = 5.9 Hz, 1H), 4.06 (s, 6H), 3.95 (s, 3H), 2.78 (s, 3H), 2.74 (s, 3H).
ESI-MS: m/z 509 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -2,4-dimethylthiazole-5-carboxamide (Compound 13)
According to Example 3, compound from compound A2 (114.0 mg, 0.256 mmol), 2,4-dimethylthiazole-5-carboxamide (80.0 mg, 0.512 mmol), and 60% sodium hydride (25.0 mg, 0.615 mmol) 13 (101 mg, 78%) was obtained.
1 H-NMR (CDCl 3 ) δ: 10.89 (s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 8.32 (d, J = 8.8 Hz, 1H), 7.96 (s, 1H), 7.57 ( s, 1H), 7.43 (s, 1H), 6.82 (dd, J = 8.8, 2.0 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 6.51 (d, J = 5.9 Hz, 1H), 4.06 (s, 6H), 3.95 (s, 3H), 2.78 (s, 3H), 2.74 (s, 3H).
ESI-MS: m / z 509 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-2,5-ジメチルオキサゾール-4-カルボキサミド (化合物14)
　実施例3に準じて、化合物A2 (98.0 mg, 0.219 mmol)、2,5-ジメチルオキサゾール-4-カルボキサミド (61.5 mg, 0.439 mmol)、および60％水素化ナトリウム (21.0 mg, 0.527 mmol)から化合物14 (78.5 mg, 73%)を得た。
1H-NMR (CDCl3) δ: 10.87 (s, 1H), 8.93 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.82 (dd, J = 8.8, 2.6 Hz, 1H), 6.77 (d, J = 2.6 Hz, 1H), 6.51 (d, J = 5.5 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.95 (s, 3H), 2.68 (s, 3H), 2.45 (s, 3H).
ESI-MS: m/z 493 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -2,5-dimethyloxazole-4-carboxamide (Compound 14)
According to Example 3, compound from compound A2 (98.0 mg, 0.219 mmol), 2,5-dimethyloxazole-4-carboxamide (61.5 mg, 0.439 mmol), and 60% sodium hydride (21.0 mg, 0.527 mmol) 14 (78.5 mg, 73%) was obtained.
1 H-NMR (CDCl 3 ) δ: 10.87 (s, 1H), 8.93 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 7.57 ( s, 1H), 7.43 (s, 1H), 6.82 (dd, J = 8.8, 2.6 Hz, 1H), 6.77 (d, J = 2.6 Hz, 1H), 6.51 (d, J = 5.5 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.95 (s, 3H), 2.68 (s, 3H), 2.45 (s, 3H).
ESI-MS: m / z 493 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-4-メチルオキサゾール-5-カルボキサミド (化合物15)
　実施例3に準じて、化合物A2 (177.0 mg, 0.396 mmol)、4-メチルオキサゾール-5-カルボキサミド (100.0 mg, 0.793 mmol)、および60％水素化ナトリウム (35.0 mg, 0.872 mmol)から化合物15 (24.0 mg, 13%)を得た。
1H-NMR (CDCl3) δ: 10.76 (s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.21 (s, 1H), 7.92 (s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.85-6.79 (m, 2H), 6.51 (d, J = 5.9 Hz, 1H), 4.06 (s, 6H), 3.96 (s, 3H), 2.62 (s, 3H).
ESI-MS: m/z 479 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -4-methyloxazole-5-carboxamide (Compound 15)
According to Example 3, from compound A2 (177.0 mg, 0.396 mmol), 4-methyloxazole-5-carboxamide (100.0 mg, 0.793 mmol), and 60% sodium hydride (35.0 mg, 0.872 mmol) to compound 15 ( 24.0 mg, 13%) was obtained.
1 H-NMR (CDCl 3 ) δ: 10.76 (s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 8.21 (s, 1H), 7.92 ( s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.85-6.79 (m, 2H), 6.51 (d, J = 5.9 Hz, 1H), 4.06 (s, 6H), 3.96 (s , 3H), 2.62 (s, 3H).
ESI-MS: m / z 479 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-4-メチルチアゾール-5-カルボキサミド (化合物16)
　実施例3に準じて、化合物A2 (157.0 mg, 0.352 mmol)、4-メチルチアゾール-5-カルボキサミド (100.0 mg, 0.703 mmol)、および60％水素化ナトリウム (34.0 mg, 0.844 mmol)から化合物16 (22.0 mg, 13%)を得た。
1H-NMR (CDCl3) δ: 10.86 (s, 1H), 8.86 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.06 (s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.84-6.79 (m, 2H), 6.51 (d, J = 4.9 Hz, 1H), 4.06 (s, 6H), 3.96 (s, 3H), 2.86 (s, 3H).
ESI-MS: m/z 495 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -4-methylthiazole-5-carboxamide (Compound 16)
According to Example 3, compound A2 (157.0 mg, 0.352 mmol), 4-methylthiazole-5-carboxamide (100.0 mg, 0.703 mmol), and 60% sodium hydride (34.0 mg, 0.844 mmol) to compound 16 ( 22.0 mg, 13%) was obtained.
1 H-NMR (CDCl 3 ) δ: 10.86 (s, 1H), 8.86 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.06 ( s, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.84-6.79 (m, 2H), 6.51 (d, J = 4.9 Hz, 1H), 4.06 (s, 6H), 3.96 (s , 3H), 2.86 (s, 3H).
ESI-MS: m / z 495 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-3,5-ジメチルイソオキサゾール-4-カルボキサミド (化合物17)
　実施例3に準じて、化合物A2 (110 mg, 0.24 mmol)、3,5-ジメチルイソオキサゾール-4-カルボキサミド (68 mg, 0.49 mmol)、および60％水素化ナトリウム (23 mg, 0.59 mmol)から化合物17 (73 mg, 61％)を得た。
1H-NMR (DMSO-d6) δ: 10.90 (s, 1H), 10.84 (s, 1H), 8.49 (d, J= 5.3 Hz, 1H), 8.30 (d, J = 8.9 Hz, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.9, 2.6 Hz, 1H), 6.52 (d, J = 5.3 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.90 (s, 3H), 2.59 (s, 3H), 2.36 (s, 3H).
ESI-MS: m/z 493 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -3,5-dimethylisoxazole-4-carboxamide (Compound 17)
According to Example 3, from compound A2 (110 mg, 0.24 mmol), 3,5-dimethylisoxazole-4-carboxamide (68 mg, 0.49 mmol), and 60% sodium hydride (23 mg, 0.59 mmol) Compound 17 (73 mg, 61%) was obtained.
1 H-NMR (DMSO-d 6 ) δ: 10.90 (s, 1H), 10.84 (s, 1H), 8.49 (d, J = 5.3 Hz, 1H), 8.30 (d, J = 8.9 Hz, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.9, 2.6 Hz, 1H), 6.52 (d, J = 5.3 Hz, 1H ), 3.95 (s, 3H), 3.94 (s, 3H), 3.90 (s, 3H), 2.59 (s, 3H), 2.36 (s, 3H).
ESI-MS: m / z 493 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-3-メチルイソオキサゾール-4-カルボキサミド (化合物18)
　実施例3に準じて、化合物A2 (85 mg, 0.19 mmol)、3-メチルイソオキサゾール-4-カルボキサミド (36 mg, 0.29 mmol)、および60％水素化ナトリウム (18 mg, 0.46 mmol)から化合物18 (44 mg, 49％)を得た。
1H-NMR (DMSO-d6) δ: 11.14 (s, 1H), 10.93 (s, 1H), 9.64 (s, 1H), 8.48 (d, J = 5.3 Hz, 1H), 8.29 (d, J= 8.9 Hz, 1H), 7.52 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.9, 2.6 Hz, 1H), 6.52 (d, J = 5.3 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.91 (s, 3H), 2.46 (s, 3H).
ESI-MS: m/z 479 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -3-methylisoxazole-4-carboxamide (Compound 18)
According to Example 3, compound 18 from compound A2 (85 mg, 0.19 mmol), 3-methylisoxazole-4-carboxamide (36 mg, 0.29 mmol), and 60% sodium hydride (18 mg, 0.46 mmol) (44 mg, 49%) was obtained.
1 H-NMR (DMSO-d 6 ) δ: 11.14 (s, 1H), 10.93 (s, 1H), 9.64 (s, 1H), 8.48 (d, J = 5.3 Hz, 1H), 8.29 (d, J = 8.9 Hz, 1H), 7.52 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.9, 2.6 Hz, 1H), 6.52 (d , J = 5.3 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.91 (s, 3H), 2.46 (s, 3H).
ESI-MS: m / z 479 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-5-メチルイソオキサゾール-3-カルボキサミド (化合物19)
　実施例3に準じて、化合物A2 (97 mg, 0.22 mmol)、5-メチルイソオキサゾール-3-カルボキサミド (41 mg, 0.33 mmol)、および60％水素化ナトリウム (21 mg, 0.52 mmol)から化合物19 (80 mg, 77％)を得た。
1H-NMR (CDCl3) δ: 10.67 (s, 1H), 8.79 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.84 (dd, J = 8.8, 2.6 Hz, 1H), 6.79 (d, J = 2.6 Hz, 1H), 6.56 (s, 1H), 6.51 (d, J = 5.5 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.95 (s, 3H), 2.55 (s, 3H).
ESI-MS: m/z 479 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -5-methylisoxazole-3-carboxamide (Compound 19)
According to Example 3, compound 19 from compound A2 (97 mg, 0.22 mmol), 5-methylisoxazole-3-carboxamide (41 mg, 0.33 mmol), and 60% sodium hydride (21 mg, 0.52 mmol) (80 mg, 77%) was obtained.
1 H-NMR (CDCl 3 ) δ: 10.67 (s, 1H), 8.79 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 7.57 ( s, 1H), 7.43 (s, 1H), 6.84 (dd, J = 8.8, 2.6 Hz, 1H), 6.79 (d, J = 2.6 Hz, 1H), 6.56 (s, 1H), 6.51 (d, J = 5.5 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.95 (s, 3H), 2.55 (s, 3H).
ESI-MS: m / z 479 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1,4-ジメチル-1H-イミダゾール-5-カルボキサミド (化合物20)
　実施例3に準じて、化合物A2 (76.0 mg, 0.171 mmol)、化合物B13 (47.5 mg, 0.341 mmol)、および60％水素化ナトリウム (16.0 mg, 0.410 mmol)から化合物20 (41.2 mg, 49%)を得た。
1H-NMR (CDCl3) δ: 10.85 (s, 1H), 8.51 (d, J = 5.9 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 7.72 (s, 1H), 7.57 (s, 1H), 7.51 (s, 1H), 7.43 (s, 1H), 6.84 (dd, J = 8.8, 2.9 Hz, 1H), 6.79 (d, J = 2.9 Hz, 1H), 6.51 (d, J = 5.9 Hz, 1H), 4.06 (s, 6H), 3.95 (s, 3H), 3.93 (s, 3H), 2.63 (s, 3H).
ESI-MS: m/z 492 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1,4-dimethyl-1H-imidazole-5-carboxamide (Compound 20)
According to Example 3, compound 20 (41.2 mg, 49%) from compound A2 (76.0 mg, 0.171 mmol), compound B13 (47.5 mg, 0.341 mmol), and 60% sodium hydride (16.0 mg, 0.410 mmol) Got.
1 H-NMR (CDCl 3 ) δ: 10.85 (s, 1H), 8.51 (d, J = 5.9 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 7.72 (s, 1H), 7.57 ( s, 1H), 7.51 (s, 1H), 7.43 (s, 1H), 6.84 (dd, J = 8.8, 2.9 Hz, 1H), 6.79 (d, J = 2.9 Hz, 1H), 6.51 (d, J = 5.9 Hz, 1H), 4.06 (s, 6H), 3.95 (s, 3H), 3.93 (s, 3H), 2.63 (s, 3H).
ESI-MS: m / z 492 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1,5-ジメチル-1H-イミダゾール-4-カルボキサミド (化合物21)
　実施例3に準じて、化合物A2 (76.0 mg, 0.171 mmol)、化合物B15 (47.5 mg, 0.341 mmol)、および60％水素化ナトリウム (16.0 mg, 0.410 mmol)から化合物21 (21.7 mg, 26%)を得た。
1H-NMR (CDCl3) δ: 11.01 (s, 1H), 9.25 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 7.38 (s, 1H), 6.82 (dd, J = 8.8, 2.0 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.95 (s, 3H), 3.62 (s, 3H), 2.63 (s, 3H).
ESI-MS: m/z 492 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1,5-dimethyl-1H-imidazole-4-carboxamide (Compound 21)
According to Example 3, compound 21 (21.7 mg, 26%) from compound A2 (76.0 mg, 0.171 mmol), compound B15 (47.5 mg, 0.341 mmol), and 60% sodium hydride (16.0 mg, 0.410 mmol) Got.
1 H-NMR (CDCl 3 ) δ: 11.01 (s, 1H), 9.25 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.58 ( s, 1H), 7.43 (s, 1H), 7.38 (s, 1H), 6.82 (dd, J = 8.8, 2.0 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.95 (s, 3H), 3.62 (s, 3H), 2.63 (s, 3H).
ESI-MS: m / z 492 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]イソオキサゾール-5-カルボキサミド (化合物22)
　実施例3に準じて、化合物A2 (190 mg, 0.42 mmol)、イソオキサゾール-5-カルボキサミド (71 mg, 0.63 mmol)、および60％水素化ナトリウム (40 mg, 1.0 mmol)から化合物22 (160 mg, 80％)を得た。
1H-NMR (DMSO-d6) δ: 11.58 (s, 1H), 10.83 (s, 1H), 8.88 (s, 1H), 8.49 (d, J = 5.9 Hz, 1H), 8.30 (d, J= 8.8 Hz, 1H), 7.58 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.13 (d, J = 2.9 Hz, 1H), 6.90 (dd, J = 8.8, 2.9 Hz, 1H), 6.53 (d, J = 5.9 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.92 (s, 3H).
ESI-MS: m/z 465 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] isoxazole-5-carboxamide (Compound 22)
According to Example 3, compound 22 (160 mg from Compound A2 (190 mg, 0.42 mmol), isoxazole-5-carboxamide (71 mg, 0.63 mmol), and 60% sodium hydride (40 mg, 1.0 mmol). , 80%).
1 H-NMR (DMSO-d 6 ) δ: 11.58 (s, 1H), 10.83 (s, 1H), 8.88 (s, 1H), 8.49 (d, J = 5.9 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.13 (d, J = 2.9 Hz, 1H), 6.90 (dd, J = 8.8, 2.9 Hz , 1H), 6.53 (d, J = 5.9 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.92 (s, 3H).
ESI-MS: m / z 465 [M + H] +
1-tert-ブチル-N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-3-メチル-1H-ピラゾール-5-カルボキサミド (化合物23)
　実施例3に準じて、化合物A2 (82 mg, 0.18 mmol)、1-tert-ブチル-3-メチル-1H-ピラゾール-5-カルボキサミド (50 mg, 0.28 mmol)、および60％水素化ナトリウム (18 mg, 0.44 mmol)から化合物23 (68 mg, 70％)を得た。
1H-NMR (CDCl3) δ: 10.98 (s, 1H), 9.48 (s, 1H), 8.49 (d, J = 5.9 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 7.44 (s, 1H), 6.83-6.80 (m, 2H), 6.65 (s, 1H), 6.49 (d, J = 5.9 Hz, 1H), 4.07 (s, 3H), 4.06 (s, 3H), 3.95 (s, 3H), 2.27 (s, 3H), 1.72 (s, 9H).
ESI-MS: m/z 534 [M+H]+ 1-tert-Butyl-N- [4- (6,7-dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -3-methyl-1H-pyrazole-5-carboxamide (Compound 23)
According to Example 3, compound A2 (82 mg, 0.18 mmol), 1-tert-butyl-3-methyl-1H-pyrazole-5-carboxamide (50 mg, 0.28 mmol), and 60% sodium hydride (18 mg, 0.44 mmol) gave compound 23 (68 mg, 70%).
1 H-NMR (CDCl 3 ) δ: 10.98 (s, 1H), 9.48 (s, 1H), 8.49 (d, J = 5.9 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 7.58 ( s, 1H), 7.44 (s, 1H), 6.83-6.80 (m, 2H), 6.65 (s, 1H), 6.49 (d, J = 5.9 Hz, 1H), 4.07 (s, 3H), 4.06 (s , 3H), 3.95 (s, 3H), 2.27 (s, 3H), 1.72 (s, 9H).
ESI-MS: m / z 534 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1,3-ジメチル-1H-ピラゾール-5-カルボキサミド (化合物24)
　実施例3に準じて、化合物A2 (110 mg, 0.24 mmol)、1,3-ジメチル-1H-ピラゾール-5-カルボキサミド (50 mg, 0.36 mmol)、および60％水素化ナトリウム (23 mg, 0.58 mmol)から化合物24 (97 mg, 82％)を得た。
1H-NMR (DMSO-d6) δ: 10.98 (s, 1H), 10.96 (s, 1H), 8.48 (d, J= 4.9 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.52 (s, 1H), 7.40 (s, 1H), 7.11 (s, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.60 (s, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.05 (s, 3H), 3.95 (s, 3H), 3.91 (s, 3H), 2.19 (s, 3H), 2.13 (s, 3H).
ESI-MS: m/z 492 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1,3-dimethyl-1H-pyrazole-5-carboxamide (Compound 24)
According to Example 3, compound A2 (110 mg, 0.24 mmol), 1,3-dimethyl-1H-pyrazole-5-carboxamide (50 mg, 0.36 mmol), and 60% sodium hydride (23 mg, 0.58 mmol) ) To give Compound 24 (97 mg, 82%).
1 H-NMR (DMSO-d 6 ) δ: 10.98 (s, 1H), 10.96 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.52 (s, 1H), 7.40 (s, 1H), 7.11 (s, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.60 (s, 1H), 6.52 (d, J = 4.9 Hz, 1H ), 4.05 (s, 3H), 3.95 (s, 3H), 3.91 (s, 3H), 2.19 (s, 3H), 2.13 (s, 3H).
ESI-MS: m / z 492 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1-メチル-1H-ピラゾール-5-カルボキサミド(化合物25)
　実施例3に準じて、化合物A2 (120 mg, 0.27 mmol)、1-メチル-1H-ピラゾール-5-カルボキサミド (50 mg, 0.40 mmol)、および60％水素化ナトリウム (26 mg, 0.64 mmol)から化合物25 (87 mg, 68％)を得た。
1H-NMR (DMSO-d6) δ: 11.09 (s, 1H), 10.97 (s, 1H), 8.49 (d, J= 4.9 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.12 (d, J= 2.0 Hz, 1H), 6.89 (dd, J = 8.8, 2.0 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H), 4.13 (s, 3H), 3.95 (s, 3H), 3.95 (s, 3H), 3.92 (s, 3H).
ESI-MS: m/z 478 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1-methyl-1H-pyrazole-5-carboxamide (Compound 25)
According to Example 3, from compound A2 (120 mg, 0.27 mmol), 1-methyl-1H-pyrazole-5-carboxamide (50 mg, 0.40 mmol), and 60% sodium hydride (26 mg, 0.64 mmol) Compound 25 (87 mg, 68%) was obtained.
1 H-NMR (DMSO-d 6 ) δ: 11.09 (s, 1H), 10.97 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 8.8, 2.0 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H), 4.13 (s, 3H), 3.95 (s, 3H), 3.95 (s, 3H), 3.92 (s , 3H).
ESI-MS: m / z 478 [M + H] +
2-シクロプロピル-N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-5-メチルオキサゾール-4-カルボキサミド (化合物26)
　実施例3に準じて、化合物A2 (119.0 mg, 0.267 mmol)、化合物B20 (88.9 mg, 0.535 mmol)、および60％水素化ナトリウム (26.0 mg, 0.642 mmol)から化合物26 (94.3 mg, 68%)を得た。
1H-NMR (CDCl3) δ: 10.86 (s, 1H), 8.92 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.37 (d, J = 8.6 Hz, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.82 (dd, J = 8.6, 2.5 Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 4.06 (s, 6H), 3.94 (s, 3H), 2.65 (s, 3H), 2.06-1.96 (m, 1H), 1.09 (d, J = 6.6 Hz, 4H).
ESI-MS: m/z 519 [M+H]+ 2-Cyclopropyl-N- [4- (6,7-dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -5-methyloxazole-4-carboxamide (Compound 26)
According to Example 3, compound 26 (94.3 mg, 68%) from compound A2 (119.0 mg, 0.267 mmol), compound B20 (88.9 mg, 0.535 mmol), and 60% sodium hydride (26.0 mg, 0.642 mmol) Got.
1 H-NMR (CDCl 3 ) δ: 10.86 (s, 1H), 8.92 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.37 (d, J = 8.6 Hz, 1H), 7.57 ( s, 1H), 7.43 (s, 1H), 6.82 (dd, J = 8.6, 2.5 Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 4.06 (s, 6H), 3.94 (s, 3H), 2.65 (s, 3H), 2.06-1.96 (m, 1H), 1.09 (d, J = 6.6 Hz, 4H).
ESI-MS: m / z 519 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-5-メチル-2-(1-メチルシクロプロピル)オキサゾール-4-カルボキサミド (化合物27)
　実施例3に準じて、化合物A2 (126.0 mg, 0.281 mmol)、化合物B25 (101.0 mg, 0.563 mmol)、および60％水素化ナトリウム (27.0 mg, 0.675 mmol)から化合物27 (75.7 mg, 51%)を得た。
1H-NMR (CDCl3) δ: 10.88 (s, 1H), 9.00 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.83 (dd, J = 8.6, 2.5 Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.95 (s, 3H), 2.65 (s, 3H), 1.50 (s, 3H), 1.26 (dd, J = 7.1, 4.4 Hz, 2H), 0.89 (dd, J = 7.1, 4.4 Hz, 2H).
ESI-MS: m/z 533 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -5-methyl-2- (1-methylcyclopropyl) oxazole-4-carboxamide (Compound 27)
According to Example 3, compound 27 (75.7 mg, 51%) from compound A2 (126.0 mg, 0.281 mmol), compound B25 (101.0 mg, 0.563 mmol), and 60% sodium hydride (27.0 mg, 0.675 mmol) Got.
1 H-NMR (CDCl 3 ) δ: 10.88 (s, 1H), 9.00 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 7.57 ( s, 1H), 7.43 (s, 1H), 6.83 (dd, J = 8.6, 2.5 Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.95 (s, 3H), 2.65 (s, 3H), 1.50 (s, 3H), 1.26 (dd, J = 7.1, 4.4 Hz, 2H), 0.89 (dd, J = 7.1, 4.4 Hz, 2H).
ESI-MS: m / z 533 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1,5-ジメチル-1H-ピラゾール-4-カルボキサミド (化合物28)
　実施例3に準じて、化合物A2 (130 mg, 0.29 mmol)、1,5-ジメチル-1H-ピラゾール-4-カルボキサミド (60 mg, 0.43 mmol）、および60％水素化ナトリウム (28 mg, 0.69 mmol)から化合物28 (110 mg, 78％)を得た。
1H-NMR (DMSO-d6) δ: 11.21 (s, 1H), 10.56 (s, 1H), 8.54 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.30 (d, J= 8.8 Hz, 1H), 7.52 (s, 1H), 7.40 (s, 1H), 7.09 (d, J = 2.0 Hz, 1H), 6.87 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.90 (s, 3H), 3.81 (s, 3H), 2.38 (s, 3H).
ESI-MS: m/z 492 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1,5-dimethyl-1H-pyrazole-4-carboxamide (Compound 28)
According to Example 3, Compound A2 (130 mg, 0.29 mmol), 1,5-dimethyl-1H-pyrazole-4-carboxamide (60 mg, 0.43 mmol), and 60% sodium hydride (28 mg, 0.69 mmol) ) To give compound 28 (110 mg, 78%).
1 H-NMR (DMSO-d 6 ) δ: 11.21 (s, 1H), 10.56 (s, 1H), 8.54 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.52 (s, 1H), 7.40 (s, 1H), 7.09 (d, J = 2.0 Hz, 1H), 6.87 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d , J = 4.9 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.90 (s, 3H), 3.81 (s, 3H), 2.38 (s, 3H).
ESI-MS: m / z 492 [M + H] +
3-tert-ブチル-N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1-メチル-1H-ピラゾール-5-カルボキサミド (化合物29)
　実施例3に準じて、化合物A2 (99mg, 0.22 mmol)、3-tert-ブチル-1-メチル-1H-ピラゾール-5-カルボキサミド (60 mg, 0.33 mmol)、および60％水素化ナトリウム (21 mg, 0.53 mmol)から化合物29 (100 mg, 85％)を得た。
1H-NMR (CDCl3) δ: 11.07 (s, 1H), 9.66 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.33 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 7.44 (s, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.81 (s, 1H), 6.79 (dd, J = 8.8, 2.4 Hz, 1H), 6.51 (d, J = 4.9 Hz, 1H), 4.21 (s, 3H), 4.07 (s, 3H), 4.06 (s, 3H), 3.97 (s, 3H), 1.29 (s, 9H).
ESI-MS: m/z 534 [M+H]+ 3-tert-Butyl-N- [4- (6,7-dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1-methyl-1H-pyrazole-5-carboxamide (Compound 29)
According to Example 3, compound A2 (99 mg, 0.22 mmol), 3-tert-butyl-1-methyl-1H-pyrazole-5-carboxamide (60 mg, 0.33 mmol), and 60% sodium hydride (21 mg , 0.53 mmol) gave compound 29 (100 mg, 85%).
1 H-NMR (CDCl 3 ) δ: 11.07 (s, 1H), 9.66 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.33 (d, J = 8.8 Hz, 1H), 7.58 ( s, 1H), 7.44 (s, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.81 (s, 1H), 6.79 (dd, J = 8.8, 2.4 Hz, 1H), 6.51 (d, J = 4.9 Hz, 1H), 4.21 (s, 3H), 4.07 (s, 3H), 4.06 (s, 3H), 3.97 (s, 3H), 1.29 (s, 9H).
ESI-MS: m / z 534 [M + H] +
4-クロロ-N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-5-メチルイソオキサゾール-3-カルボキサミド (化合物30)
　実施例3に準じて、化合物A2 (100 mg, 0.22 mmol)、4-クロロ-5-メチルイソオキサゾール-3-カルボキサミド (54 mg, 0.34 mmol)、および60％水素化ナトリウム (27 mg, 0.67 mmol)から化合物30 (37 mg, 32％)を得た。
1H-NMR (CDCl3) δ: 10.57 (s, 1H), 8.91 (br s, 1H), 8.50 (d, J= 5.5 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.83 (dd, J = 8.8, 2.6 Hz, 1H), 6.79 (d, J = 2.6 Hz, 1H), 6.52 (d, J= 5.5 Hz, 1H), 4.06 (s, 6H), 3.95 (s, 3H), 2.53 (s, 3H).
ESI-MS: m/z 513(35Cl), 515(37Cl) [M+H]+ 4-Chloro-N- [4- (6,7-dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -5-methylisoxazole-3-carboxamide (Compound 30)
According to Example 3, compound A2 (100 mg, 0.22 mmol), 4-chloro-5-methylisoxazole-3-carboxamide (54 mg, 0.34 mmol), and 60% sodium hydride (27 mg, 0.67 mmol) ) To give Compound 30 (37 mg, 32%).
1 H-NMR (CDCl 3 ) δ: 10.57 (s, 1H), 8.91 (br s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.34 (d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.83 (dd, J = 8.8, 2.6 Hz, 1H), 6.79 (d, J = 2.6 Hz, 1H), 6.52 (d, J = 5.5 Hz, 1H) , 4.06 (s, 6H), 3.95 (s, 3H), 2.53 (s, 3H).
ESI-MS: m / z 513 ( 35 Cl), 515 ( 37 Cl) [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1,2,5-トリメチル-1H-イミダゾール-4-カルボキサミド (化合物31)
　実施例3に準じて、化合物A2 (125.0 mg, 0.281 mmol)、化合物B30 (86.0 mg, 0.561 mmol)、および60％水素化ナトリウム (27.0 mg, 0.674 mmol)から化合物31 (14.4 mg, 10%)を得た。
1H-NMR (CDCl3) δ: 11.03 (s, 1H), 9.24 (s, 1H), 8.49 (d, J = 5.3 Hz, 1H), 8.41 (d, J = 8.6 Hz, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 6.81 (dd, J = 8.6, 2.5 Hz, 1H), 6.76 (d, J = 2.5 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.95 (s, 3H), 3.48 (s, 3H), 2.60 (s, 3H), 2.38 (s, 3H).
ESI-MS: m/z 506 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1,2,5-trimethyl-1H-imidazole-4-carboxamide (Compound 31)
According to Example 3, compound 31 (14.4 mg, 10%) from compound A2 (125.0 mg, 0.281 mmol), compound B30 (86.0 mg, 0.561 mmol), and 60% sodium hydride (27.0 mg, 0.674 mmol) Got.
1 H-NMR (CDCl 3 ) δ: 11.03 (s, 1H), 9.24 (s, 1H), 8.49 (d, J = 5.3 Hz, 1H), 8.41 (d, J = 8.6 Hz, 1H), 7.58 ( s, 1H), 7.43 (s, 1H), 6.81 (dd, J = 8.6, 2.5 Hz, 1H), 6.76 (d, J = 2.5 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.95 (s, 3H), 3.48 (s, 3H), 2.60 (s, 3H), 2.38 (s, 3H).
ESI-MS: m / z 506 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-2-(メトキシメチル)-1,5-ジメチル-1H-イミダゾール-4-カルボキサミド (化合物32)
　実施例3に準じて化合物A2 (91.0 mg, 0.205 mmol)、化合物B35 (75.0 mg, 0.409 mmol)、および60％水素化ナトリウム (20.0 mg, 0.491 mmol)から化合物32 (65.4 mg, 60%)を得た。
1H-NMR (CDCl3) δ: 11.01 (s, 1H), 9.26 (s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 6.82 (dd, J = 8.8, 2.9 Hz, 1H), 6.77 (d, J = 2.9 Hz, 1H), 6.51 (d, J = 5.9 Hz, 1H), 4.51 (s, 2H), 4.06 (s, 3H), 4.06 (s, 3H), 3.95 (s, 3H), 3.61 (s, 3H), 3.38 (s, 3H), 2.62 (s, 3H).
ESI-MS: m/z 536 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -2- (methoxymethyl) -1,5-dimethyl-1H-imidazole-4-carboxamide (Compound 32)
Compound 32 (65.4 mg, 60%) from compound A2 (91.0 mg, 0.205 mmol), compound B35 (75.0 mg, 0.409 mmol), and 60% sodium hydride (20.0 mg, 0.491 mmol) according to Example 3 Obtained.
1 H-NMR (CDCl 3 ) δ: 11.01 (s, 1H), 9.26 (s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.58 ( s, 1H), 7.43 (s, 1H), 6.82 (dd, J = 8.8, 2.9 Hz, 1H), 6.77 (d, J = 2.9 Hz, 1H), 6.51 (d, J = 5.9 Hz, 1H), 4.51 (s, 2H), 4.06 (s, 3H), 4.06 (s, 3H), 3.95 (s, 3H), 3.61 (s, 3H), 3.38 (s, 3H), 2.62 (s, 3H).
ESI-MS: m / z 536 [M + H] +
4-クロロ-N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1-エチル-1H-ピラゾール-3-カルボキサミド (化合物33)
　実施例3に準じて、化合物A2 (230mg, 0.51 mmol)、4-クロロ-1-エチル-1H-ピラゾール-3-カルボキサミド (130 mg, 0.76 mmol)、および60％水素化ナトリウム (48 mg, 1.2 mmol)から化合物33 (200 mg, 75％)を得た。
1H-NMR (DMSO-d6) δ: 10.78 (s, 1H), 10.13 (s, 1H), 8.48 (d, J= 4.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.27 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H), 4.23 (q, J = 7.8 Hz, 2H), 3.95 (s, 3H), 3.95 (s, 3H), 3.92 (s, 3H), 1.44 (t, J = 7.8 Hz, 3H).
ESI-MS: m/z 526(35Cl), 528(37Cl) [M+H]+ 4-Chloro-N- [4- (6,7-dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1-ethyl-1H-pyrazole-3-carboxamide (Compound 33)
According to Example 3, compound A2 (230 mg, 0.51 mmol), 4-chloro-1-ethyl-1H-pyrazole-3-carboxamide (130 mg, 0.76 mmol), and 60% sodium hydride (48 mg, 1.2 mmol) gave compound 33 (200 mg, 75%).
1 H-NMR (DMSO-d 6 ) δ: 10.78 (s, 1H), 10.13 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.27 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 6.53 (d , J = 4.9 Hz, 1H), 4.23 (q, J = 7.8 Hz, 2H), 3.95 (s, 3H), 3.95 (s, 3H), 3.92 (s, 3H), 1.44 (t, J = 7.8 Hz , 3H).
ESI-MS: m / z 526 ( 35 Cl), 528 ( 37 Cl) [M + H] +
4,5-ジクロロ-N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1-エチル-1H-ピラゾール-3-カルボキサミド (化合物34)
　実施例3に準じて、化合物A2 (96 mg, 0.22 mmol)、4,5-ジクロロ-1-エチル-1H-ピラゾール-3-カルボキサミド (67 mg, 0.32 mmol)、および60％水素化ナトリウム (21 mg, 0.52 mmol)から化合物34 (92 mg, 76％)を得た。
1H-NMR (DMSO-d6) δ: 10.73 (s, 1H), 10.43 (s, 1H), 8.48 (d, J= 4.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.12 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H), 4.30 (q, J= 7.3 Hz, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.92 (s, 3H), 1.44 (t, J = 7.3 Hz, 3H).
ESI-MS: m/z 560(35Cl,35Cl), 562(35Cl,37Cl), 564(37Cl,37Cl) [M+H]+  4,5-Dichloro-N- [4- (6,7-dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1-ethyl-1H-pyrazole-3-carboxamide (Compound 34)
According to Example 3, compound A2 (96 mg, 0.22 mmol), 4,5-dichloro-1-ethyl-1H-pyrazole-3-carboxamide (67 mg, 0.32 mmol), and 60% sodium hydride (21 mg, 0.52 mmol) gave compound 34 (92 mg, 76%).
1 H-NMR (DMSO-d 6 ) δ: 10.73 (s, 1H), 10.43 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.12 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H ), 4.30 (q, J = 7.3 Hz, 2H), 3.95 (s, 3H), 3.94 (s, 3H), 3.92 (s, 3H), 1.44 (t, J = 7.3 Hz, 3H).
ESI-MS: m / z 560 ( 35 Cl, 35 Cl), 562 ( 35 Cl, 37 Cl), 564 ( 37 Cl, 37 Cl) [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1-メチル-1H-イミダゾール-2-カルボキサミド (化合物35)
　実施例3に準じて、化合物A2 (178.0 mg, 0.400 mmol)、1-メチル-1H-イミダゾール-2-カルボキサミド (100.0 mg, 0.799 mmol)、および60％水素化ナトリウム (38.0 mg, 0.959 mmol)から化合物35 (146.3 mg, 77%)を得た。
1H-NMR (CDCl3) δ: 10.69 (s, 1H), 9.43 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.39 (d, J = 8.6 Hz, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 7.12 (d, J = 7.9 Hz, 2H), 6.83 (dd, J = 8.6, 2.5 Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 4.12 (s, 3H), 4.06 (s, 6H), 3.95 (s, 3H).
ESI-MS: m/z 478 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1-methyl-1H-imidazole-2-carboxamide (Compound 35)
According to Example 3, from compound A2 (178.0 mg, 0.400 mmol), 1-methyl-1H-imidazole-2-carboxamide (100.0 mg, 0.799 mmol), and 60% sodium hydride (38.0 mg, 0.959 mmol) Compound 35 (146.3 mg, 77%) was obtained.
1 H-NMR (CDCl 3 ) δ: 10.69 (s, 1H), 9.43 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.39 (d, J = 8.6 Hz, 1H), 7.57 ( s, 1H), 7.43 (s, 1H), 7.12 (d, J = 7.9 Hz, 2H), 6.83 (dd, J = 8.6, 2.5 Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 4.12 (s, 3H), 4.06 (s, 6H), 3.95 (s, 3H).
ESI-MS: m / z 478 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1,3-ジメチル-1H-ピラゾール-4-カルボキサミド (化合物36)
　化合物A2 (64 mg, 0.14 mmol)のキシレン (2.0 mL)溶液に、1,3-ジメチル-1H-ピラゾール-4-カルボキサミド (30 mg, 0.22 mmol)を加え、6時間還流した。混合物を室温まで冷却した後、水を加えてクロロホルムで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (メタノール/クロロホルム＝15/95)で精製し、化合物36 (47 mg, 66％)を得た。
1H-NMR (DMSO-d6) δ: 11.20 (s, 1H), 10.55 (s, 1H), 8.54 (s, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.30 (d, J= 8.8 Hz, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.86 (dd, J = 8.8, 2.2 Hz, 1H), 6.52 (d, J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.90 (s, 3H), 3.81 (s, 3H), 2.39 (s, 3H).
ESI-MS: m/z 492 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1,3-dimethyl-1H-pyrazole-4-carboxamide (Compound 36)
1,3-Dimethyl-1H-pyrazole-4-carboxamide (30 mg, 0.22 mmol) was added to a solution of compound A2 (64 mg, 0.14 mmol) in xylene (2.0 mL), and the mixture was refluxed for 6 hours. The mixture was cooled to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol / chloroform = 15/95) to obtain Compound 36 (47 mg, 66%).
1 H-NMR (DMSO-d 6 ) δ: 11.20 (s, 1H), 10.55 (s, 1H), 8.54 (s, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.86 (dd, J = 8.8, 2.2 Hz, 1H), 6.52 (d , J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.90 (s, 3H), 3.81 (s, 3H), 2.39 (s, 3H).
ESI-MS: m / z 492 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-4,5-ジメチルイソオキサゾール-3-カルボキサミド (化合物37)
　実施例3に準じて、化合物A2 (110 mg, 0.25 mmol)、4,5-ジメチルイソオキサゾール-3-カルボキサミド (53 mg, 0.38 mmol)、および60％水素化ナトリウム (24 mg, 0.61 mmol)から化合物37 (89 mg, 72％)を得た。
1H-NMR (DMSO-d6) δ: 11.09 (s, 1H), 10.61 (s, 1H), 8.48 (d, J= 5.1 Hz, 1H), 8.27 (d, J = 8.6 Hz, 1H), 7.52 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.6, 2.4 Hz, 1H), 6.52 (d, J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.91 (s, 3H), 2.42 (s, 3H), 2.10 (s, 3H).
ESI-MS: m/z 493 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -4,5-dimethylisoxazole-3-carboxamide (Compound 37)
According to Example 3, from compound A2 (110 mg, 0.25 mmol), 4,5-dimethylisoxazole-3-carboxamide (53 mg, 0.38 mmol), and 60% sodium hydride (24 mg, 0.61 mmol) Compound 37 (89 mg, 72%) was obtained.
1 H-NMR (DMSO-d 6 ) δ: 11.09 (s, 1H), 10.61 (s, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.27 (d, J = 8.6 Hz, 1H), 7.52 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.6, 2.4 Hz, 1H), 6.52 (d, J = 5.1 Hz, 1H ), 3.95 (s, 3H), 3.94 (s, 3H), 3.91 (s, 3H), 2.42 (s, 3H), 2.10 (s, 3H).
ESI-MS: m / z 493 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1-メチル-1H-イミダゾール-5-カルボキサミド (化合物38)
　実施例3に準じて、化合物A2 (170 mg, 0.37 mmol)、1-メチル-1H-イミダゾール-5-カルボキサミド (70 mg, 0.56 mmol)、および60％水素化ナトリウム (30 mg, 0.75 mmol)から化合物38 (120 mg, 70％)を得た。
1H-NMR (DMSO-d6) δ: 11.01 (s, 1H), 10.93 (s, 1H), 8.48 (d, J= 4.9 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.8, 2.4 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 3.95 (s, 3H), 3.95 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H).
ESI-MS: m/z 478 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1-methyl-1H-imidazole-5-carboxamide (Compound 38)
According to Example 3, from compound A2 (170 mg, 0.37 mmol), 1-methyl-1H-imidazole-5-carboxamide (70 mg, 0.56 mmol), and 60% sodium hydride (30 mg, 0.75 mmol) Compound 38 (120 mg, 70%) was obtained.
1 H-NMR (DMSO-d 6 ) δ: 11.01 (s, 1H), 10.93 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.8, 2.4 Hz , 1H), 6.52 (d, J = 4.9 Hz, 1H), 3.95 (s, 3H), 3.95 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H).
ESI-MS: m / z 478 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1,2-ジメチル-1H-イミダゾール-5-カルボキサミド (化合物39)
　実施例3に準じて、化合物A2 (150 mg, 0.34 mmol)、1,2-ジメチル-1H-イミダゾール-5-カルボキサミド (71 mg, 0.51 mmol)、および60％水素化ナトリウム (27 mg、0.68 mmol)から化合物39 (71 mg, 42％)を得た。
1H-NMR (DMSO-d6) δ: 11.03 (s, 1H), 10.81 (s, 1H), 8.48 (d, J= 4.9 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H), 8.01 (s, 1H), 7.52 (s, 1H), 7.40 (s, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 8.3, 2.4 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.91 (s, 3H), 3.81 (s, 3H) , 2.37 (s, 3H).
ESI-MS: m/z 492 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1,2-dimethyl-1H-imidazole-5-carboxamide (Compound 39)
According to Example 3, compound A2 (150 mg, 0.34 mmol), 1,2-dimethyl-1H-imidazole-5-carboxamide (71 mg, 0.51 mmol), and 60% sodium hydride (27 mg, 0.68 mmol) ) To give Compound 39 (71 mg, 42%).
1 H-NMR (DMSO-d 6 ) δ: 11.03 (s, 1H), 10.81 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H), 8.01 (s, 1H), 7.52 (s, 1H), 7.40 (s, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 8.3, 2.4 Hz, 1H), 6.52 (d , J = 4.9 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.91 (s, 3H), 3.81 (s, 3H), 2.37 (s, 3H).
ESI-MS: m / z 492 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-5-イソプロピル-4-メチルイソオキサゾール-3-カルボキサミド (化合物40)
　実施例3に準じて、化合物A2 (110 mg, 0.24 mmol)、化合物B39 (61 mg, 0.36 mmol)、および60％水素化ナトリウム (23 mg, 0.58 mmol)から化合物40 (90 mg、72％)を得た。
1H-NMR (DMSO-d6) δ: 11.09 (s, 1H), 10.62 (s, 1H), 8.49 (d, J= 4.9 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.52 (s, 1H), 7.40 (s, 1H), 7.12 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.91 (s, 3H), 3.32-3.23 (m, 1H), 2.13 (s, 3H), 1.28 (d, J = 6.8 Hz, 6H).
ESI-MS: m/z 521 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -5-isopropyl-4-methylisoxazole-3-carboxamide (Compound 40)
According to Example 3, compound 40 (90 mg, 72%) from compound A2 (110 mg, 0.24 mmol), compound B39 (61 mg, 0.36 mmol), and 60% sodium hydride (23 mg, 0.58 mmol) Got.
1 H-NMR (DMSO-d 6 ) δ: 11.09 (s, 1H), 10.62 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.52 (s, 1H), 7.40 (s, 1H), 7.12 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H ), 3.95 (s, 3H), 3.94 (s, 3H), 3.91 (s, 3H), 3.32-3.23 (m, 1H), 2.13 (s, 3H), 1.28 (d, J = 6.8 Hz, 6H) .
ESI-MS: m / z 521 [M + H] +
5-シクロプロピル-N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-4-メチルイソオキサゾール-3-カルボキサミド (化合物41)
　実施例3に準じて、化合物A2 (110 mg, 0.24 mmol)、化合物B43 (60 mg, 0.36 mmol)、および60％水素化ナトリウム (23 mg, 0.58 mmol)から化合物41 (110 mg, 90％)を得た。
1H-NMR (DMSO-d6) δ: 11.06 (s, 1H), 10.61 (s, 1H), 8.49 (d, J= 4.9 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.52 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 3.91 (s, 3H), 2.23-2.20 (m, 1H), 2.17 (s, 3H), 1.12-1.11 (m, 2H), 1.01-0.99 (m, 2H).
ESI-MS: m/z 519 [M+H]+ 5-Cyclopropyl-N- [4- (6,7-dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -4-methylisoxazole-3-carboxamide (Compound 41)
According to Example 3, compound 41 (110 mg, 90%) from compound A2 (110 mg, 0.24 mmol), compound B43 (60 mg, 0.36 mmol), and 60% sodium hydride (23 mg, 0.58 mmol) Got.
1 H-NMR (DMSO-d 6 ) δ: 11.06 (s, 1H), 10.61 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.52 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H ), 3.95 (s, 3H), 3.94 (s, 3H), 3.91 (s, 3H), 2.23-2.20 (m, 1H), 2.17 (s, 3H), 1.12-1.11 (m, 2H), 1.01- 0.99 (m, 2H).
ESI-MS: m / z 519 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1-エチル-1H-イミダゾール-5-カルボキサミド (化合物42)
　実施例3に準じて、化合物A2 (140 mg, 0.32 mmol)、化合物B47 (40 mg, 0.29 mmol)、および60％水素化ナトリウム (23 mg, 0.58 mmol)から化合物42 (89 mg, 63％)を得た。
1H-NMR (DMSO-d6) δ: 10.96 (s, 1H), 10.91 (s, 1H), 8.48 (d, J= 5.3 Hz, 1H), 8.29 (d, J = 8.6 Hz, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.10 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.6, 2.6 Hz, 1H), 6.52 (d, J = 5.3 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.95 (s, 3H), 3.95 (s, 3H), 3.91 (s, 3H), 1.36 (t, J= 7.1 Hz, 3H).
ESI-MS: m/z 492 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1-ethyl-1H-imidazole-5-carboxamide (Compound 42)
According to Example 3, compound 42 (89 mg, 63%) from compound A2 (140 mg, 0.32 mmol), compound B47 (40 mg, 0.29 mmol), and 60% sodium hydride (23 mg, 0.58 mmol) Got.
1 H-NMR (DMSO-d 6 ) δ: 10.96 (s, 1H), 10.91 (s, 1H), 8.48 (d, J = 5.3 Hz, 1H), 8.29 (d, J = 8.6 Hz, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.10 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.6, 2.6 Hz , 1H), 6.52 (d, J = 5.3 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.95 (s, 3H), 3.95 (s, 3H), 3.91 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H).
ESI-MS: m / z 492 [M + H] +
5-シクロプロピル-N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1-メチル-1H-イミダゾール-4-カルボキサミド (化合物43)
　実施例36に準じて、化合物A2 (113.0 mg, 0.253 mmol)、および化合物B53 (62.6 mg, 0.379 mmol)から化合物43 (46.6 mg, 36%)を得た。
1H-NMR (CDCl3) δ: 10.98 (s, 1H), 9.35 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 7.34 (s, 1H), 6.81 (dd, J = 8.6, 2.5 Hz, 1H), 6.76 (d, J = 2.5 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 4.06 (s, 3H), 4.05 (s, 3H), 3.94 (s, 3H), 3.73 (s, 3H), 1.85-1.79 (m, 1H), 1.28-1.12 (m, 2H), 1.00-0.88 (m, 2H).
ESI-MS: m/z 518 [M+H]+ 5-Cyclopropyl-N- [4- (6,7-dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1-methyl-1H-imidazole-4-carboxamide (Compound 43)
According to Example 36, Compound 43 (46.6 mg, 36%) was obtained from Compound A2 (113.0 mg, 0.253 mmol) and Compound B53 (62.6 mg, 0.379 mmol).
1 H-NMR (CDCl 3 ) δ: 10.98 (s, 1H), 9.35 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.38 (d, J = 8.6 Hz, 1H), 7.58 ( s, 1H), 7.43 (s, 1H), 7.34 (s, 1H), 6.81 (dd, J = 8.6, 2.5 Hz, 1H), 6.76 (d, J = 2.5 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 4.06 (s, 3H), 4.05 (s, 3H), 3.94 (s, 3H), 3.73 (s, 3H), 1.85-1.79 (m, 1H), 1.28-1.12 (m, 2H), 1.00-0.88 (m, 2H).
ESI-MS: m / z 518 [M + H] +
5-シクロプロピル-N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1-(2-メトキシエチル)-1H-イミダゾール-4-カルボキサミド (化合物44)
　実施例36に準じて、化合物A2 (226.0 mg, 0.507 mmol)、および化合物B56 (159.0 mg, 0.760 mmol)から化合物44 (86.9 mg, 31%)を得た。
1H-NMR (CDCl3) δ: 10.99 (s, 1H), 9.38 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 7.58 (s, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 6.81 (dd, J = 8.9, 2.5 Hz, 1H), 6.76 (d, J = 2.5 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 4.25 (t, J = 4.9 Hz, 2H), 4.06 (s, 3H), 4.05 (s, 3H), 3.94 (s, 3H), 3.68 (t, J = 4.9 Hz, 2H), 3.36 (s, 3H), 1.81-1.76 (m, 1H), 1.24-1.17 (m, 2H), 0.95-0.90 (m, 2H).
ESI-MS: m/z 562 [M+H]+ 5-Cyclopropyl-N- [4- (6,7-dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1- (2-methoxyethyl) -1H-imidazole-4-carboxamide (Compound 44)
According to Example 36, Compound 44 (86.9 mg, 31%) was obtained from Compound A2 (226.0 mg, 0.507 mmol) and Compound B56 (159.0 mg, 0.760 mmol).
1 H-NMR (CDCl 3 ) δ: 10.99 (s, 1H), 9.38 (s, 1H), 8.50 (d, J = 5.3 Hz, 1H), 8.39 (d, J = 8.9 Hz, 1H), 7.58 ( s, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 6.81 (dd, J = 8.9, 2.5 Hz, 1H), 6.76 (d, J = 2.5 Hz, 1H), 6.51 (d, J = 5.3 Hz, 1H), 4.25 (t, J = 4.9 Hz, 2H), 4.06 (s, 3H), 4.05 (s, 3H), 3.94 (s, 3H), 3.68 (t, J = 4.9 Hz, 2H ), 3.36 (s, 3H), 1.81-1.76 (m, 1H), 1.24-1.17 (m, 2H), 0.95-0.90 (m, 2H).
ESI-MS: m / z 562 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1-エチル-2-メチル-1H-イミダゾール-5-カルボキサミド (化合物45)
　実施例3に準じて、化合物A2 (120 mg, 0.27 mmol)、化合物B61 (34 mg, 0.22 mmol)、および60％水素化ナトリウム (18 mg, 0.45 mmol)から化合物45 (57 mg、51％)を得た。
1H-NMR (DMSO-d6) δ: 10.98 (s, 1H), 10.78 (s, 1H), 8.48 (d, J= 5.1 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.03 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.09 (s, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 5.1 Hz, 1H), 4.31 (q, J = 6.7 Hz, 2H), 3.95 (s, 6H), 3.90 (s, 3H), 2.40 (s, 3H), 1.28 (t, J= 6.7 Hz, 3H).
ESI-MS: m/z 506 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1-ethyl-2-methyl-1H-imidazole-5-carboxamide (Compound 45)
According to Example 3, compound 45 (57 mg, 51%) from compound A2 (120 mg, 0.27 mmol), compound B61 (34 mg, 0.22 mmol), and 60% sodium hydride (18 mg, 0.45 mmol) Got.
1 H-NMR (DMSO-d 6 ) δ: 10.98 (s, 1H), 10.78 (s, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.03 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.09 (s, 1H), 6.87 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 5.1 Hz, 1H ), 4.31 (q, J = 6.7 Hz, 2H), 3.95 (s, 6H), 3.90 (s, 3H), 2.40 (s, 3H), 1.28 (t, J = 6.7 Hz, 3H).
ESI-MS: m / z 506 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-5-エチル-1-メチル-1H-イミダゾール-4-カルボキサミド (化合物46)
　実施例36に準じて、化合物A2 (172.0 mg, 0.385 mmol)、および化合物B67 (88.5 mg, 0.578 mmol)から化合物46 (84.7 mg, 44%)を得た。
1H-NMR (CDCl3) δ: 10.97 (s, 1H), 9.26 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 7.34 (s, 1H), 6.81 (dd, J = 8.8, 2.6 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 6.51 (d, J = 5.5 Hz, 1H), 4.06 (s, 3H), 4.05 (s, 3H), 3.95 (s, 3H), 3.65 (s, 3H), 3.10 (q, J = 7.5 Hz, 2H), 1.26 (t, J = 7.5 Hz, 3H).
ESI-MS: m/z 506 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -5-ethyl-1-methyl-1H-imidazole-4-carboxamide (Compound 46)
According to Example 36, Compound 46 (84.7 mg, 44%) was obtained from Compound A2 (172.0 mg, 0.385 mmol) and Compound B67 (88.5 mg, 0.578 mmol).
1 H-NMR (CDCl 3 ) δ: 10.97 (s, 1H), 9.26 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 7.58 ( s, 1H), 7.43 (s, 1H), 7.34 (s, 1H), 6.81 (dd, J = 8.8, 2.6 Hz, 1H), 6.76 (d, J = 2.6 Hz, 1H), 6.51 (d, J = 5.5 Hz, 1H), 4.06 (s, 3H), 4.05 (s, 3H), 3.95 (s, 3H), 3.65 (s, 3H), 3.10 (q, J = 7.5 Hz, 2H), 1.26 (t , J = 7.5 Hz, 3H).
ESI-MS: m / z 506 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-5-エチル-1-(2-メトキシエチル)-1H-イミダゾール-4-カルボキサミド (化合物47)
　実施例36に準じて、化合物A2 (89.0 mg, 0.200 mmol)、および化合物B70 (59.1 mg, 0.300 mmol)から化合物47 (52.2 mg, 48%)を得た。
1H-NMR (CDCl3) δ: 10.97 (s, 1H), 9.28 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 7.48 (s, 1H), 7.43 (s, 1H), 6.81 (dd, J = 8.8, 2.2 Hz, 1H), 6.76 (d, J = 2.2 Hz, 1H), 6.51 (d, J = 5.5 Hz, 1H), 4.09-4.06 (m, 8H), 3.94 (s, 3H), 3.65 (t, J = 5.1 Hz, 2H), 3.36 (s, 3H), 3.09 (q, J = 7.5 Hz, 2H), 1.26 (t, J = 7.5 Hz, 3H).
ESI-MS: m/z 550 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -5-ethyl-1- (2-methoxyethyl) -1H-imidazole-4-carboxamide (Compound 47)
According to Example 36, Compound 47 (52.2 mg, 48%) was obtained from Compound A2 (89.0 mg, 0.200 mmol) and Compound B70 (59.1 mg, 0.300 mmol).
1 H-NMR (CDCl 3 ) δ: 10.97 (s, 1H), 9.28 (s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 7.58 ( s, 1H), 7.48 (s, 1H), 7.43 (s, 1H), 6.81 (dd, J = 8.8, 2.2 Hz, 1H), 6.76 (d, J = 2.2 Hz, 1H), 6.51 (d, J = 5.5 Hz, 1H), 4.09-4.06 (m, 8H), 3.94 (s, 3H), 3.65 (t, J = 5.1 Hz, 2H), 3.36 (s, 3H), 3.09 (q, J = 7.5 Hz , 2H), 1.26 (t, J = 7.5 Hz, 3H).
ESI-MS: m / z 550 [M + H] +
N-{2-メトキシ-4-[6-メトキシ-7-(3-メトキシプロポキシ)キノリン-4-イルオキシ]フェニルカルバモイル}-1-メチル-1H-イミダゾール-5-カルボキサミド (化合物48)
　実施例3に準じて、化合物A8 (150mg, 0.30 mmol)、1-メチル-1H-イミダゾール-5-カルボキサミド (34 mg, 0.27 mmol)、および60％水素化ナトリウム (22 mg, 0.54 mmol)から化合物48 (86 mg, 60%)を得た。
1H-NMR (DMSO-d6) δ: 11.00 (s, 1H), 10.92 (s, 1H), 8.48 (d, J= 4.9 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 7.96 (s, 1H), 7.53 (s, 1H), 7.39 (s, 1H), 7.10 (d, J = 2.9 Hz, 1H), 6.88 (dd, J = 8.8, 2.9 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.20 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H), 3.53 (t, J= 6.3 Hz, 2H), 3.28 (s, 3H), 2.06 (m, 2H).
ESI-MS: m/z 536 [M+H]+ N- {2-methoxy-4- [6-methoxy-7- (3-methoxypropoxy) quinolin-4-yloxy] phenylcarbamoyl} -1-methyl-1H-imidazole-5-carboxamide (Compound 48)
According to Example 3, compound from compound A8 (150 mg, 0.30 mmol), 1-methyl-1H-imidazole-5-carboxamide (34 mg, 0.27 mmol), and 60% sodium hydride (22 mg, 0.54 mmol) 48 (86 mg, 60%) was obtained.
1 H-NMR (DMSO-d 6 ) δ: 11.00 (s, 1H), 10.92 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 7.96 (s, 1H), 7.53 (s, 1H), 7.39 (s, 1H), 7.10 (d, J = 2.9 Hz, 1H), 6.88 (dd, J = 8.8, 2.9 Hz , 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.20 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H), 3.53 (t, J = 6.3 Hz, 2H), 3.28 (s, 3H), 2.06 (m, 2H).
ESI-MS: m / z 536 [M + H] +
N-{2-メトキシ-4-[6-メトキシ-7-(3-メトキシプロポキシ)キノリン-4-イルオキシ]フェニルカルバモイル}-4-メチルチアゾール-5-カルボキサミド (化合物49)
　実施例3に準じて、化合物A8 (100 mg, 0.20 mmol)、4-メチルチアゾール-5-カルボキサミド (34 mg, 0.24 mmol)、および60％水素化ナトリウム (20 mg, 0.48 mmol)から化合物49 (85 mg, 78%)を得た。
1H-NMR (DMSO-d6) δ: 11.05 (s, 1H), 10.92 (s, 1H), 9.21 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.29 (d, J= 8.8 Hz, 1H), 7.53 (s, 1H), 7.39 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.21 (t, J= 6.3 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.53 (t, J = 6.3 Hz, 2H), 3.28 (s, 3H), 2.66 (s, 3H), 2.06 (m, 2H).
ESI-MS: m/z 553 [M+H]+ N- {2-methoxy-4- [6-methoxy-7- (3-methoxypropoxy) quinolin-4-yloxy] phenylcarbamoyl} -4-methylthiazole-5-carboxamide (Compound 49)
According to Example 3, from compound A8 (100 mg, 0.20 mmol), 4-methylthiazole-5-carboxamide (34 mg, 0.24 mmol), and 60% sodium hydride (20 mg, 0.48 mmol) to compound 49 ( 85 mg, 78%).
1 H-NMR (DMSO-d 6 ) δ: 11.05 (s, 1H), 10.92 (s, 1H), 9.21 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.39 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d , J = 4.9 Hz, 1H), 4.21 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.53 (t, J = 6.3 Hz, 2H), 3.28 (s , 3H), 2.66 (s, 3H), 2.06 (m, 2H).
ESI-MS: m / z 553 [M + H] +
N-{2-メトキシ-4-[6-メトキシ-7-(3-メトキシプロポキシ)キノリン-4-イルオキシ]フェニルカルバモイル}-1,5-ジメチル-1H-イミダゾール-4-カルボキサミド (化合物50)
　実施例3に準じて、化合物A8 (150 mg, 0.30 mmol)から、化合物B15 (38 mg, 0.27 mmol)、および60％水素化ナトリウム (22 mg, 0.54 mmol)から化合物50 (38 mg, 26%)を得た。
1H-NMR (DMSO-d6) δ: 10.94 (s, 1H), 9.33 (s, 1H), 8.47 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 7.39 (s, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.87 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.21 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.62 (s, 3H), 3.53 (t, J= 6.3 Hz, 2H), 3.28 (s, 3H), 2.54 (s, 3H), 2.06 (m, 2H).
ESI-MS: m/z 550 [M+H]+ N- {2-methoxy-4- [6-methoxy-7- (3-methoxypropoxy) quinolin-4-yloxy] phenylcarbamoyl} -1,5-dimethyl-1H-imidazole-4-carboxamide (Compound 50)
According to Example 3, from compound A8 (150 mg, 0.30 mmol), compound B15 (38 mg, 0.27 mmol), and 60% sodium hydride (22 mg, 0.54 mmol) to compound 50 (38 mg, 26% )
1 H-NMR (DMSO-d 6 ) δ: 10.94 (s, 1H), 9.33 (s, 1H), 8.47 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 7.39 (s, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.87 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d , J = 4.9 Hz, 1H), 4.21 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.62 (s, 3H), 3.53 (t, J = 6.3 Hz , 2H), 3.28 (s, 3H), 2.54 (s, 3H), 2.06 (m, 2H).
ESI-MS: m / z 550 [M + H] +
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-5-メチル-1H-イミダゾール-4-カルボキサミド (化合物51)
　実施例3に準じて、化合物A2 (200 mg, 0.447 mmol)、化合物B73 (137 mg, 0.536 mmol)、および60％水素化ナトリウム (21.0 mg, 0.894 mmol)からN-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-4-メチル-1-{[2-(トリメチルシリル)エトキシ]メチル}-1H-イミダゾール-5-カルボキサミドを得た後に、THF (2.24 mL)に溶解し、テトラブチルアンモニウムフルオリド (1.0 mol/L THF溶液、3.13 mL)を加えて、還流下で18時間撹拌した。混合物に1 mol/L 塩酸を加えて中和し、析出した固体をろ取し、得られた固体にアセトニトリルを加えてリスラリー精製し、化合物51 (88.5 mg, 2段階41%)を得た。
1H-NMR (DMSO-d6) δ: 11.01 (s, 1H), 9.37 (s, 1H), 8.71 (d, J = 6.3 Hz, 1H), 8.35 (d, J = 8.6 Hz, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.53 (s, 1H), 7.21 (d, J = 2.6 Hz, 1H), 6.97 (dd, J = 8.6, 2.6 Hz, 1H), 6.82 (d, J = 6.3 Hz, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.93 (s, 3H), 2.53 (s, 3H).
ESI-MS: m/z 478 [M+H]+ N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -5-methyl-1H-imidazole-4-carboxamide (Compound 51)
According to Example 3, compound A2 (200 mg, 0.447 mmol), compound B73 (137 mg, 0.536 mmol), and 60% sodium hydride (21.0 mg, 0.894 mmol) to N- [4- (6,7 -Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -4-methyl-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazole-5-carboxamide was obtained followed by THF (2.24 mL ), Tetrabutylammonium fluoride (1.0 mol / L THF solution, 3.13 mL) was added, and the mixture was stirred under reflux for 18 hours. The mixture was neutralized by adding 1 mol / L hydrochloric acid, and the precipitated solid was collected by filtration, and acetonitrile was added to the resulting solid for reslurry purification to obtain Compound 51 (88.5 mg, 2 steps 41%).
1 H-NMR (DMSO-d 6 ) δ: 11.01 (s, 1H), 9.37 (s, 1H), 8.71 (d, J = 6.3 Hz, 1H), 8.35 (d, J = 8.6 Hz, 1H), 7.76 (s, 1H), 7.69 (s, 1H), 7.53 (s, 1H), 7.21 (d, J = 2.6 Hz, 1H), 6.97 (dd, J = 8.6, 2.6 Hz, 1H), 6.82 (d , J = 6.3 Hz, 1H), 4.02 (s, 3H), 4.01 (s, 3H), 3.93 (s, 3H), 2.53 (s, 3H).
ESI-MS: m / z 478 [M + H] +
工程1
N-(2-メトキシ-4-{6-メトキシ-7-[3-(テトラヒドロ-2H-ピラン-2-イルオキシ)プロポキシ]キノリン-4-イルオキシ}フェニルカルバモイル)-1-メチル-1H-イミダゾール-5-カルボキサミド (化合物52-1)
　実施例3に準じて、化合物A11 (170 mg, 0.29 mmol)、1-メチル-1H-イミダゾール-5-カルボキサミド (30 mg, 0.24 mmol)、および60％水素化ナトリウム (19 mg, 0.48 mmol)から化合物52-1 (84 mg, 58%)を得た。
1H-NMR (CDCl3) δ: 11.03 (s, 1H), 10.32 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.15 (s, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 6.88 (dd, J = 8.8, 2.9 Hz, 1H), 6.80 (d, J = 2.9 Hz, 1H), 6.53 (d, J= 4.9 Hz, 1H), 4.65 (t, J = 3.9 Hz, 1H), 4.34 (t, J = 6.3 Hz, 1H), 4.33 (t, J = 6.3 Hz, 1H), 4.04 (s, 3H), 4.00 (s, 3H), 3.98-3.97 (m, 1H), 3.95 (s, 3H), 3.89-3.83 (m, 1H), 3.66-3.64 (m, 1H), 3.52-3.50 (m, 1H), 2.29-2.23 (m, 2H), 1.83-1.81 (m, 1H), 1.73-1.70 (m, 1H), 1.61-1.51 (m, 4H).
ESI-MS: m/z 606 [M+H]+
工程2
N-{4-[7-(3-ヒドロキシプロポキシ)-6-メトキシキノリン-4-イルオキシ]-2-メトキシフェニルカルバモイル}-1-メチル-1H-イミダゾール-5-カルボキサミド (化合物52)
　化合物52-1 (84 mg, 0.14 mmol)を5% 塩化水素-メタノール溶液 (2.0 mL)に溶解し、室温で30分間撹拌した。混合物に飽和重曹水を加えて中和した後、クロロホルムで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた固体にアセトニトリルを加えてリスラリー精製し、化合物52 (65 mg, 91%)を得た。
1H-NMR (DMSO-d6) δ: 11.00 (s, 1H), 10.92 (s, 1H), 8.47 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 7.96 (s, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 7.11 (s, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.60 (t, J = 5.4 Hz, 1H), 4.22 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H), 3.61 (q, J= 5.4 Hz, 2H), 2.00-1.94 (m, 2H).
ESI-MS: m/z 522 [M+H]+ Process 1
N- (2-methoxy-4- {6-methoxy-7- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] quinolin-4-yloxy} phenylcarbamoyl) -1-methyl-1H-imidazole- 5-carboxamide (Compound 52-1)
According to Example 3, from compound A11 (170 mg, 0.29 mmol), 1-methyl-1H-imidazole-5-carboxamide (30 mg, 0.24 mmol), and 60% sodium hydride (19 mg, 0.48 mmol) Compound 52-1 (84 mg, 58%) was obtained.
1 H-NMR (CDCl 3 ) δ: 11.03 (s, 1H), 10.32 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.35 (d, J = 8.8 Hz, 1H), 8.15 ( s, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 6.88 (dd, J = 8.8, 2.9 Hz, 1H), 6.80 (d, J = 2.9 Hz, 1H ), 6.53 (d, J = 4.9 Hz, 1H), 4.65 (t, J = 3.9 Hz, 1H), 4.34 (t, J = 6.3 Hz, 1H), 4.33 (t, J = 6.3 Hz, 1H), 4.04 (s, 3H), 4.00 (s, 3H), 3.98-3.97 (m, 1H), 3.95 (s, 3H), 3.89-3.83 (m, 1H), 3.66-3.64 (m, 1H), 3.52- 3.50 (m, 1H), 2.29-2.23 (m, 2H), 1.83-1.81 (m, 1H), 1.73-1.70 (m, 1H), 1.61-1.51 (m, 4H).
ESI-MS: m / z 606 [M + H] +
Process 2
N- {4- [7- (3-Hydroxypropoxy) -6-methoxyquinolin-4-yloxy] -2-methoxyphenylcarbamoyl} -1-methyl-1H-imidazole-5-carboxamide (Compound 52)
Compound 52-1 (84 mg, 0.14 mmol) was dissolved in 5% hydrogen chloride-methanol solution (2.0 mL) and stirred at room temperature for 30 minutes. The mixture was neutralized by adding saturated aqueous sodium hydrogen carbonate, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, acetonitrile was added to the resulting solid and purified by reslurry to obtain Compound 52 (65 mg, 91%).
1 H-NMR (DMSO-d 6 ) δ: 11.00 (s, 1H), 10.92 (s, 1H), 8.47 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 7.96 (s, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 7.11 (s, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.52 (d , J = 4.9 Hz, 1H), 4.60 (t, J = 5.4 Hz, 1H), 4.22 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.89 (s , 3H), 3.61 (q, J = 5.4 Hz, 2H), 2.00-1.94 (m, 2H).
ESI-MS: m / z 522 [M + H] +
工程1
N-(2-メトキシ-4-{6-メトキシ-7-[3-(テトラヒドロ-2H-ピラン-2-イルオキシ)プロポキシ]キノリン-4-イルオキシ}フェニルカルバモイル)-4-メチルチアゾール-5-カルボキサミド (化合物53-1)
　実施例3に準じて、化合物A11 (190 mg, 0.34 mmol)、4-メチルチアゾール-5-カルボキサミド (40 mg, 0.28 mmol)、および60％水素化ナトリウム (27 mg, 0.68 mmol)から化合物53-1 (110 mg, 60%)を得た。
1H-NMR (CDCl3) δ: 10.95 (s, 1H), 8.85 (s, 1H), 8.78 (br s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.45 (s, 1H), 6.81 (dd, J= 7.8, 2.0 Hz, 1H), 6.80 (d, J= 2.0 Hz, 1H), 6.50 (d, J = 4.9 Hz, 1H), 4.64 (t, J = 3.9 Hz, 1H), 4.33 (t, J = 6.3 Hz, 1H), 4.33 (t, J = 6.3 Hz, 1H), 4.03 (s, 3H), 4.00-3.98 (m, 1H), 3.96 (s, 3H), 3.87-3.85 (m, 1H), 3.67-3.62 (m, 1H), 3.53-3.48 (m, 1H), 2.85 (s, 3H), 2.28-2.22 (m, 2H), 1.85-1.82 (m, 1H), 1.75-1.68 (m, 1H), 1.60-1.52 (m, 4H).
ESI-MS: m/z 623 [M+H]+
工程2
N-{4-[7-(3-ヒドロキシプロポキシ)-6-メトキシキノリン-4-イルオキシ]-2-メトキシフェニルカルバモイル}-4-メチルチアゾール-5-カルボキサミド (化合物53)
　実施例52の工程2に準じて、化合物53-1 (110 mg, 0.17 mmol)、および5％ 塩化水素-メタノール溶液 (2.0 mL)から化合物53 (55 mg, 61%)を得た。
1H-NMR (DMSO-d6) δ: 11.05 (s, 1H), 10.93 (s, 1H), 9.21 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 7.11 (d, J = 2.9 Hz, 1H), 6.88 (dd, J = 8.8, 2.9 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.60 (t, J = 5.4 Hz, 1H), 4.22 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.62 (q, J = 5.4 Hz, 2H), 2.66 (s, 3H), 2.00-1.94 (m, 2H).
ESI-MS: m/z 539 [M+H]+ Process 1
N- (2-methoxy-4- {6-methoxy-7- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] quinolin-4-yloxy} phenylcarbamoyl) -4-methylthiazole-5-carboxamide (Compound 53-1)
According to Example 3, from compound A11 (190 mg, 0.34 mmol), 4-methylthiazole-5-carboxamide (40 mg, 0.28 mmol), and 60% sodium hydride (27 mg, 0.68 mmol) to compound 53- 1 (110 mg, 60%) was obtained.
1 H-NMR (CDCl 3 ) δ: 10.95 (s, 1H), 8.85 (s, 1H), 8.78 (br s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.45 (s, 1H), 6.81 (dd, J = 7.8, 2.0 Hz, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.50 (d, J = 4.9 Hz, 1H), 4.64 (t, J = 3.9 Hz, 1H), 4.33 (t, J = 6.3 Hz, 1H), 4.33 (t, J = 6.3 Hz, 1H), 4.03 (s, 3H) , 4.00-3.98 (m, 1H), 3.96 (s, 3H), 3.87-3.85 (m, 1H), 3.67-3.62 (m, 1H), 3.53-3.48 (m, 1H), 2.85 (s, 3H) , 2.28-2.22 (m, 2H), 1.85-1.82 (m, 1H), 1.75-1.68 (m, 1H), 1.60-1.52 (m, 4H).
ESI-MS: m / z 623 [M + H] +
Process 2
N- {4- [7- (3-Hydroxypropoxy) -6-methoxyquinolin-4-yloxy] -2-methoxyphenylcarbamoyl} -4-methylthiazole-5-carboxamide (Compound 53)
According to Step 2 of Example 52, compound 53 (55 mg, 61%) was obtained from compound 53-1 (110 mg, 0.17 mmol) and 5% hydrogen chloride-methanol solution (2.0 mL).
1 H-NMR (DMSO-d 6 ) δ: 11.05 (s, 1H), 10.93 (s, 1H), 9.21 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 7.11 (d, J = 2.9 Hz, 1H), 6.88 (dd, J = 8.8, 2.9 Hz, 1H), 6.52 (d , J = 4.9 Hz, 1H), 4.60 (t, J = 5.4 Hz, 1H), 4.22 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.62 (q , J = 5.4 Hz, 2H), 2.66 (s, 3H), 2.00-1.94 (m, 2H).
ESI-MS: m / z 539 [M + H] +
工程1
N-(2-メトキシ-4-{6-メトキシ-7-[3-(テトラヒドロ-2H-ピラン-2-イルオキシ)プロポキシ]キノリン-4-イルオキシ}フェニルカルバモイル)-1,5-ジメチル-1H-イミダゾール-4-カルボキサミド (化合物54-1)
　実施例3に準じて、化合物A11 (250 mg, 0.43 mmol)、化合物B15 (50 mg, 0.36 mmol)、および60％水素化ナトリウム (30 mg, 0.72 mmol)から化合物54-1 (94 mg, 42%)を得た。
1H-NMR (CDCl3) δ: 11.01 (s, 1H), 9.24 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 7.37 (s, 1H), 6.82 (dd, J= 8.8, 2.0 Hz, 1H), 6.77 (d, J= 2.0 Hz, 1H), 6.51 (d, J = 4.9 Hz, 1H), 4.64 (t, J = 3.4 Hz, 1H), 4.33 (t, J = 6.3 Hz, 1H), 4.33 (t, J = 6.3 Hz, 1H), 4.03 (s, 3H), 4.00-3.97 (m, 1H), 3.95 (s, 3H), 3.91-3.83 (m, 1H), 3.67-3.63 (m, 1H), 3.61 (s, 3H), 3.53-3.50 (m, 1H), 2.62 (s, 3H), 2.28-2.22 (m, 2H), 1.86-1.78 (m, 1H), 1.75-1.68 (m, 1H), 1.63-1.49 (m, 4H).
ESI-MS: m/z 620 [M+H]+
工程2
N-{4-[7-(3-ヒドロキシプロポキシ)-6-メトキシキノリン-4-イルオキシ]-2-メトキシフェニルカルバモイル}-1,5-ジメチル-1H-イミダゾール-4-カルボキサミド (化合物54)
　実施例52の工程2に準じて、化合物54-1 (94 mg, 0.15 mmol)、および5% 塩化水素-メタノール溶液 (2.0 mL)から化合物54 (37 mg, 46%)を得た。
1H-NMR (DMSO-d6) δ: 10.94 (s, 1H), 9.33 (s, 1H), 8.47 (d, J = 5.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.52 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.87 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d, J = 5.9 Hz, 1H), 4.60 (t, J = 5.4 Hz, 1H), 4.22 (t, J = 5.9 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.63 (s, 3H), 3.61 (q, J = 5.4 Hz, 2H), 2.54 (s, 3H), 2.00-1.94 (m, 2H).
ESI-MS: m/z 536 [M+H]+ Process 1
N- (2-methoxy-4- {6-methoxy-7- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] quinolin-4-yloxy} phenylcarbamoyl) -1,5-dimethyl-1H- Imidazole-4-carboxamide (Compound 54-1)
According to Example 3, from compound A11 (250 mg, 0.43 mmol), compound B15 (50 mg, 0.36 mmol), and 60% sodium hydride (30 mg, 0.72 mmol) to compound 54-1 (94 mg, 42 %).
1 H-NMR (CDCl 3 ) δ: 11.01 (s, 1H), 9.24 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.56 ( s, 1H), 7.45 (s, 1H), 7.37 (s, 1H), 6.82 (dd, J = 8.8, 2.0 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 6.51 (d, J = 4.9 Hz, 1H), 4.64 (t, J = 3.4 Hz, 1H), 4.33 (t, J = 6.3 Hz, 1H), 4.33 (t, J = 6.3 Hz, 1H), 4.03 (s, 3H), 4.00-3.97 (m, 1H), 3.95 (s, 3H), 3.91-3.83 (m, 1H), 3.67-3.63 (m, 1H), 3.61 (s, 3H), 3.53-3.50 (m, 1H), 2.62 (s, 3H), 2.28-2.22 (m, 2H), 1.86-1.78 (m, 1H), 1.75-1.68 (m, 1H), 1.63-1.49 (m, 4H).
ESI-MS: m / z 620 [M + H] +
Process 2
N- {4- [7- (3-Hydroxypropoxy) -6-methoxyquinolin-4-yloxy] -2-methoxyphenylcarbamoyl} -1,5-dimethyl-1H-imidazole-4-carboxamide (Compound 54)
Compound 54 (37 mg, 46%) was obtained from Compound 54-1 (94 mg, 0.15 mmol) and 5% hydrogen chloride-methanol solution (2.0 mL) according to Step 2 of Example 52.
1 H-NMR (DMSO-d 6 ) δ: 10.94 (s, 1H), 9.33 (s, 1H), 8.47 (d, J = 5.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.52 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.87 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d, J = 5.9 Hz, 1H ), 4.60 (t, J = 5.4 Hz, 1H), 4.22 (t, J = 5.9 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.63 (s, 3H), 3.61 (q , J = 5.4 Hz, 2H), 2.54 (s, 3H), 2.00-1.94 (m, 2H).
ESI-MS: m / z 536 [M + H] +
N-{2-メトキシ-4-[6-メトキシ-7-(2-メトキシエトキシ)キノリン-4-イルオキシ]フェニルカルバモイル}-1-メチル-1H-イミダゾール-5-カルボキサミド (化合物55)
　実施例3に準じて、化合物A14 (200 mg, 0.41 mmol)、1-メチル-1H-イミダゾール-5-カルボキサミド (43 mg, 0.34 mmol)、および60％水素化ナトリウム (27 mg, 0.68 mmol)から化合物55 (54 mg, 31%)を得た。
1H-NMR (DMSO-d6) δ: 10.99 (s, 1H), 10.90 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 7.95 (s, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.28 (t, J= 4.4 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H), 3.76 (t, J = 4.4 Hz, 2H), 3.36 (s, 3H).
ESI-MS: m/z 522 [M+H]+ N- {2-methoxy-4- [6-methoxy-7- (2-methoxyethoxy) quinolin-4-yloxy] phenylcarbamoyl} -1-methyl-1H-imidazole-5-carboxamide (Compound 55)
According to Example 3, from compound A14 (200 mg, 0.41 mmol), 1-methyl-1H-imidazole-5-carboxamide (43 mg, 0.34 mmol), and 60% sodium hydride (27 mg, 0.68 mmol) Compound 55 (54 mg, 31%) was obtained.
1 H-NMR (DMSO-d 6 ) δ: 10.99 (s, 1H), 10.90 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 7.95 (s, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz , 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.28 (t, J = 4.4 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H), 3.76 (t, J = 4.4 Hz, 2H), 3.36 (s, 3H).
ESI-MS: m / z 522 [M + H] +
N-{2-メトキシ-4-[6-メトキシ-7-(2-メトキシエトキシ)キノリン-4-イルオキシ]フェニルカルバモイル}-4-メチルチアゾール-5-カルボキサミド (化合物56)
　実施例3に準じて、化合物A14 (150 mg, 0.31 mmol)、4-メチルチアゾール-5-カルボキサミド (36 mg, 0.26 mmol)、および60％水素化ナトリウム (24 mg, 0.61 mmol)から化合物56 (109 mg, 79%)を得た。
1H-NMR (DMSO-d6) δ: 11.04 (s, 1H), 10.92 (s, 1H), 9.21 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.28 (t, J = 4.4 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.76 (t, J= 4.4 Hz, 2H), 3.35 (s, 3H), 2.66 (s, 3H).
ESI-MS: m/z 539 [M+H]+ N- {2-methoxy-4- [6-methoxy-7- (2-methoxyethoxy) quinolin-4-yloxy] phenylcarbamoyl} -4-methylthiazole-5-carboxamide (Compound 56)
According to Example 3, from compound A14 (150 mg, 0.31 mmol), 4-methylthiazole-5-carboxamide (36 mg, 0.26 mmol), and 60% sodium hydride (24 mg, 0.61 mmol) to compound 56 ( 109 mg, 79%).
1 H-NMR (DMSO-d 6 ) δ: 11.04 (s, 1H), 10.92 (s, 1H), 9.21 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.41 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d , J = 4.9 Hz, 1H), 4.28 (t, J = 4.4 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.76 (t, J = 4.4 Hz, 2H), 3.35 (s , 3H), 2.66 (s, 3H).
ESI-MS: m / z 539 [M + H] +
N-{2-メトキシ-4-[6-メトキシ-7-(2-メトキシエトキシ)キノリン-4-イルオキシ]フェニルカルバモイル}-1,5-ジメチル-1H-イミダゾール-4-カルボキサミド (化合物57)
　実施例3に準じて、化合物A14 (250 mg, 0.51 mmol)、化合物B15 (59 mg, 0.43 mmol)、および60％水素化ナトリウム (34 mg, 0.85 mmol)から化合物57 (29 mg, 13%)を得た。
1H-NMR (CDCl3) δ: 11.01 (s, 1H), 9.24 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.56 (s, 1H), 7.43 (s, 1H), 7.37 (s, 1H), 6.82 (dd, J = 8.8, 2.0 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 6.51 (d, J = 4.9 Hz, 1H), 4.35 (t, J = 4.9 Hz, 2H), 4.03 (s, 3H), 3.95 (s, 3H), 3.90 (t, J = 4.9 Hz, 2H), 3.61 (s, 3H), 3.49 (s, 3H), 2.62 (s, 3H).
ESI-MS: m/z 536 [M+H]+ N- {2-methoxy-4- [6-methoxy-7- (2-methoxyethoxy) quinolin-4-yloxy] phenylcarbamoyl} -1,5-dimethyl-1H-imidazole-4-carboxamide (Compound 57)
According to Example 3, compound 57 (29 mg, 13%) from compound A14 (250 mg, 0.51 mmol), compound B15 (59 mg, 0.43 mmol), and 60% sodium hydride (34 mg, 0.85 mmol) Got.
1 H-NMR (CDCl 3 ) δ: 11.01 (s, 1H), 9.24 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.56 ( s, 1H), 7.43 (s, 1H), 7.37 (s, 1H), 6.82 (dd, J = 8.8, 2.0 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 6.51 (d, J = 4.9 Hz, 1H), 4.35 (t, J = 4.9 Hz, 2H), 4.03 (s, 3H), 3.95 (s, 3H), 3.90 (t, J = 4.9 Hz, 2H), 3.61 (s, 3H ), 3.49 (s, 3H), 2.62 (s, 3H).
ESI-MS: m / z 536 [M + H] +
工程1
N-(2-メトキシ-4-{6-メトキシ-7-[2-(テトラヒドロ-2H-ピラン-2-イルオキシ)エトキシ]キノリン-4-イルオキシ}フェニルカルバモイル)-1-メチル-1H-イミダゾール-5-カルボキサミド (化合物58-1)
　実施例3に準じて、化合物A17 (200 mg, 0.36 mmol)、1-メチル-1H-イミダゾール-5-カルボキサミド (41 mg, 0.32 mmol)、および60％水素化ナトリウム (26 mg, 0.65 mmol)から化合物58-1 (130 mg, 70%)を得た。
1H-NMR (DMSO-d6) δ: 11.00 (s, 1H), 10.92 (s, 1H), 8.48 (d, J= 4.9 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 7.96 (s, 1H), 7.54 (s, 1H), 7.43 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.72 (br s, 1H), 4.32 (t, J = 4.4 Hz, 2H), 4.05-4.00 (m, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.90 (s, 3H), 3.86-3.81 (m, 2H), 3.49-3.45 (m, 1H), 1.76-1.64 (m, 2H), 1.52-1.47 (m, 4H).
ESI-MS: m/z 592 [M+H]+
工程2
N-{4-[7-(2-ヒドロキシエトキシ)-6-メトキシキノリン-4-イルオキシ]-2-メトキシフェニルカルバモイル}-1-メチル-1H-イミダゾール-5-カルボキサミド (化合物58)
　実施例52の工程2に準じて、化合物58-1 (130 mg, 0.22 mmol)、および5% 塩化水素-メタノール溶液 (3.0 mL)から化合物58 (69 mg, 62%)を得た。
1H-NMR (DMSO-d6) δ: 10.99 (s, 1H), 10.91 (s, 1H), 8.47 (d, J= 5.1 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 7.95 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.8, 2.6 Hz, 1H), 6.52 (d, J = 5.1 Hz, 1H), 4.94 (t, J = 5.1 Hz, 1H), 4.17 (t, J = 5.1 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H), 3.83 (q, J= 5.1 Hz, 2H).
ESI-MS: m/z 508 [M+H]+ Process 1
N- (2-methoxy-4- {6-methoxy-7- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] quinolin-4-yloxy} phenylcarbamoyl) -1-methyl-1H-imidazole- 5-carboxamide (Compound 58-1)
According to Example 3, from compound A17 (200 mg, 0.36 mmol), 1-methyl-1H-imidazole-5-carboxamide (41 mg, 0.32 mmol), and 60% sodium hydride (26 mg, 0.65 mmol) Compound 58-1 (130 mg, 70%) was obtained.
1 H-NMR (DMSO-d 6 ) δ: 11.00 (s, 1H), 10.92 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.31 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 7.96 (s, 1H), 7.54 (s, 1H), 7.43 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz , 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.72 (br s, 1H), 4.32 (t, J = 4.4 Hz, 2H), 4.05-4.00 (m, 1H), 3.95 (s, 3H ), 3.91 (s, 3H), 3.90 (s, 3H), 3.86-3.81 (m, 2H), 3.49-3.45 (m, 1H), 1.76-1.64 (m, 2H), 1.52-1.47 (m, 4H ).
ESI-MS: m / z 592 [M + H] +
Process 2
N- {4- [7- (2-hydroxyethoxy) -6-methoxyquinolin-4-yloxy] -2-methoxyphenylcarbamoyl} -1-methyl-1H-imidazole-5-carboxamide (Compound 58)
According to step 2 of Example 52, compound 58 (69 mg, 62%) was obtained from compound 58-1 (130 mg, 0.22 mmol) and 5% hydrogen chloride-methanol solution (3.0 mL).
1 H-NMR (DMSO-d 6 ) δ: 10.99 (s, 1H), 10.91 (s, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.12 (s, 1H), 7.95 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.8, 2.6 Hz , 1H), 6.52 (d, J = 5.1 Hz, 1H), 4.94 (t, J = 5.1 Hz, 1H), 4.17 (t, J = 5.1 Hz, 2H), 3.95 (s, 3H), 3.91 (s , 3H), 3.89 (s, 3H), 3.83 (q, J = 5.1 Hz, 2H).
ESI-MS: m / z 508 [M + H] +
工程1
N-(2-メトキシ-4-{6-メトキシ-7-[2-(テトラヒドロ-2H-ピラン-2-イルオキシ)エトキシ]キノリン-4-イルオキシ}フェニルカルバモイル)-4-メチルチアゾール-5-カルボキサミド (化合物59-1)
　実施例3に準じて、化合物A17 (150 mg, 0.27 mmol)、4-メチルチアゾール-5-カルボキサミド(35 mg, 0.24 mmol)、および60％水素化ナトリウム (23 mg, 0.58 mmol)から化合物59-1 (140 mg, 94%)を得た。
1H-NMR (DMSO-d6) δ: 11.05 (s, 1H), 10.93 (s, 1H), 9.21 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.29 (d, J= 8.8 Hz, 1H), 7.53 (s, 1H), 7.43 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.72 (br s, 1H), 4.32 (t, J = 4.9 Hz, 2H), 4.04-4.00 (m, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.86-3.81 (m, 2H), 3.49-3.43 (m, 1H), 2.66 (s, 3H), 1.77-1.63 (m, 2H), 1.51-1.48 (m, 4H).
ESI-MS: m/z 609 [M+H]+
工程2
N-{4-[7-(2-ヒドロキシエトキシ)-6-メトキシキノリン-4-イルオキシ]-2-メトキシフェニルカルバモイル}-4-メチルチアゾール-5-カルボキサミド (化合物59)
　実施例52の工程2に準じて、化合物59-1 (140 mg, 0.23 mmol)、および5% 塩化水素-メタノール溶液 (2.0 mL)から化合物59 (110 mg, 92%)を得た。
1H-NMR (DMSO-d6) δ: 11.05 (s, 1H), 10.93 (s, 1H), 9.20 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.29 (d, J= 8.8 Hz, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.95 (t, J= 4.9 Hz, 1H), 4.17 (t, J = 4.9 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.82 (q, J = 4.9 Hz, 2H), 3.36 (s, 3H).
ESI-MS: m/z 525 [M+H]+ Process 1
N- (2-methoxy-4- {6-methoxy-7- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] quinolin-4-yloxy} phenylcarbamoyl) -4-methylthiazole-5-carboxamide (Compound 59-1)
According to Example 3, from compound A17 (150 mg, 0.27 mmol), 4-methylthiazole-5-carboxamide (35 mg, 0.24 mmol), and 60% sodium hydride (23 mg, 0.58 mmol) to compound 59- 1 (140 mg, 94%) was obtained.
1 H-NMR (DMSO-d 6 ) δ: 11.05 (s, 1H), 10.93 (s, 1H), 9.21 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.43 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d , J = 4.9 Hz, 1H), 4.72 (br s, 1H), 4.32 (t, J = 4.9 Hz, 2H), 4.04-4.00 (m, 1H), 3.95 (s, 3H), 3.91 (s, 3H ), 3.86-3.81 (m, 2H), 3.49-3.43 (m, 1H), 2.66 (s, 3H), 1.77-1.63 (m, 2H), 1.51-1.48 (m, 4H).
ESI-MS: m / z 609 [M + H] +
Process 2
N- {4- [7- (2-hydroxyethoxy) -6-methoxyquinolin-4-yloxy] -2-methoxyphenylcarbamoyl} -4-methylthiazole-5-carboxamide (Compound 59)
According to Step 2 of Example 52, compound 59 (110 mg, 92%) was obtained from compound 59-1 (140 mg, 0.23 mmol) and 5% hydrogen chloride-methanol solution (2.0 mL).
1 H-NMR (DMSO-d 6 ) δ: 11.05 (s, 1H), 10.93 (s, 1H), 9.20 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d , J = 4.9 Hz, 1H), 4.95 (t, J = 4.9 Hz, 1H), 4.17 (t, J = 4.9 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.82 (q , J = 4.9 Hz, 2H), 3.36 (s, 3H).
ESI-MS: m / z 525 [M + H] +
工程1
N-(2-メトキシ-4-{6-メトキシ-7-[2-(テトラヒドロ-2H-ピラン-2-イルオキシ)エトキシ]キノリン-4-イルオキシ}フェニルカルバモイル)-1,5-ジメチル-1H-イミダゾール-4-カルボキサミド (化合物60-1)
　実施例3に準じて、化合物A17 (300 mg, 0.54 mmol)、化合物B15 (68 mg, 0.49 mmol)、および60％水素化ナトリウム (39 mg, 0.97 mmol)から化合物60-1 (100 mg, 34%)を得た。
1H-NMR (CDCl3) δ: 11.01 (s, 1H), 9.24 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 7.37 (s, 1H), 6.82 (dd, J= 8.8, 2.0 Hz, 1H), 6.77 (d, J= 2.0 Hz, 1H), 6.51 (d, J = 4.9 Hz, 1H), 4.77 (t, J = 3.4 Hz, 1H), 4.40 (t, J = 5.4 Hz, 2H), 4.21-4.16 (m, 1H), 4.01 (s, 3H), 4.00-3.96 (m, 3H), 3.95 (s, 3H), 3.61 (s, 3H), 2.62 (s, 3H), 1.89-1.52 (m, 6H).
ESI-MS: m/z 606 [M+H]+
工程2
N-{4-[7-(2-ヒドロキシエトキシ)-6-メトキシキノリン-4-イルオキシ]-2-メトキシフェニルカルバモイル}-1,5-ジメチル-1H-イミダゾール-4-カルボキサミド (化合物60)
　実施例52の工程2に準じて、化合物60-1 (100 mg, 0.17 mmol)、および5％ 塩化水素-メタノール溶液 (2.0 mL)から化合物60 (38 mg, 43%)を得た。
1H-NMR (DMSO-d6) δ: 10.94 (s, 1H), 9.33 (s, 1H), 8.47 (d, J = 5.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.87 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d, J = 5.9 Hz, 1H), 4.96 (t, J = 4.9 Hz, 1H), 4.17 (t, J = 4.9 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.83 (q, J = 4.9 Hz, 2H), 3.62 (s, 3H), 2.54 (s, 3H).
ESI-MS: m/z 522 [M+H]+
  Process 1
N- (2-methoxy-4- {6-methoxy-7- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] quinolin-4-yloxy} phenylcarbamoyl) -1,5-dimethyl-1H- Imidazole-4-carboxamide (Compound 60-1)
According to Example 3, compound A17 (300 mg, 0.54 mmol), compound B15 (68 mg, 0.49 mmol), and 60% sodium hydride (39 mg, 0.97 mmol) to compound 60-1 (100 mg, 34 %).
1 H-NMR (CDCl 3 ) δ: 11.01 (s, 1H), 9.24 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.57 ( s, 1H), 7.46 (s, 1H), 7.37 (s, 1H), 6.82 (dd, J = 8.8, 2.0 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 6.51 (d, J = 4.9 Hz, 1H), 4.77 (t, J = 3.4 Hz, 1H), 4.40 (t, J = 5.4 Hz, 2H), 4.21-4.16 (m, 1H), 4.01 (s, 3H), 4.00-3.96 (m, 3H), 3.95 (s, 3H), 3.61 (s, 3H), 2.62 (s, 3H), 1.89-1.52 (m, 6H).
ESI-MS: m / z 606 [M + H] +
Process 2
N- {4- [7- (2-hydroxyethoxy) -6-methoxyquinolin-4-yloxy] -2-methoxyphenylcarbamoyl} -1,5-dimethyl-1H-imidazole-4-carboxamide (Compound 60)
Compound 60 (38 mg, 43%) was obtained from Compound 60-1 (100 mg, 0.17 mmol) and 5% hydrogen chloride-methanol solution (2.0 mL) according to Step 2 of Example 52.
1 H-NMR (DMSO-d 6 ) δ: 10.94 (s, 1H), 9.33 (s, 1H), 8.47 (d, J = 5.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.87 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d , J = 5.9 Hz, 1H), 4.96 (t, J = 4.9 Hz, 1H), 4.17 (t, J = 4.9 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H), 3.83 (q , J = 4.9 Hz, 2H), 3.62 (s, 3H), 2.54 (s, 3H).
ESI-MS: m / z 522 [M + H] +
以下の化合物は、それぞれに対応する原料化合物を用い、実施例3に準じて合成した。
化合物61（原料化合物として、化合物A2および化合物B79使用）：
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-5-メチル-1-(オキセタン-3-イル)-1H-イミダゾール-4-カルボキサミド
1H-NMR (CDCl3) δ: 10.97 (s, 1H), 9.27 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 6.82 (dd, J = 8.8, 2.9 Hz, 1H), 6.78-6.73 (m, 1H), 6.52 (d, J = 4.9 Hz, 1H), 5.29-5.27 (m, 1H), 5.16 (t, J = 7.3 Hz, 2H), 4.92 (t, J = 7.3 Hz, 2H), 4.06 (s, 3H), 4.04 (s, 3H), 3.95 (s, 3H), 2.60 (s, 3H).
ESI-MS: m/z 534 [M+H]+.
化合物62（原料化合物として、化合物A17および4-メチルチアゾール-5-カルボキサミド使用）：
N-{4-[7-(2-ヒドロキシエトキシ)-6-メトキシキノリン-4-イルオキシ]-2-メトキシフェニルカルバモイル}-2-メチルチアゾール-5-カルボキサミド
1H-NMR (DMSO-d6) δ: 11.32 (s, 1H), 10.96 (s, 1H), 8.69 (s, 1H), 8.47 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.93 (t, J = 4.9 Hz, 1H), 4.17 (t, J = 4.9 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.83 (q, J = 4.9 Hz, 2H), 2.73 (s, 3H).
ESI-MS: m/z 525 [M+H]+ The following compounds were synthesized according to Example 3 using the corresponding raw material compounds.
Compound 61 (using compound A2 and compound B79 as starting compounds):
N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -5-methyl-1- (oxetan-3-yl) -1H-imidazole-4-carboxamide
1 H-NMR (CDCl 3 ) δ: 10.97 (s, 1H), 9.27 (s, 1H), 8.50 (d, J = 4.9 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.84 ( s, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 6.82 (dd, J = 8.8, 2.9 Hz, 1H), 6.78-6.73 (m, 1H), 6.52 (d, J = 4.9 Hz , 1H), 5.29-5.27 (m, 1H), 5.16 (t, J = 7.3 Hz, 2H), 4.92 (t, J = 7.3 Hz, 2H), 4.06 (s, 3H), 4.04 (s, 3H) , 3.95 (s, 3H), 2.60 (s, 3H).
ESI-MS: m / z 534 [M + H] + .
Compound 62 (using compound A17 and 4-methylthiazole-5-carboxamide as a raw material compound):
N- {4- [7- (2-hydroxyethoxy) -6-methoxyquinolin-4-yloxy] -2-methoxyphenylcarbamoyl} -2-methylthiazole-5-carboxamide
1 H-NMR (DMSO-d 6 ) δ: 11.32 (s, 1H), 10.96 (s, 1H), 8.69 (s, 1H), 8.47 (d, J = 4.9 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d , J = 4.9 Hz, 1H), 4.93 (t, J = 4.9 Hz, 1H), 4.17 (t, J = 4.9 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 3.83 (q , J = 4.9 Hz, 2H), 2.73 (s, 3H).
ESI-MS: m / z 525 [M + H] +
化合物63（原料化合物として、化合物A20および1,5-ジメチル-1H-イミダゾール-4-カルボキサミド使用）：
N-[4-(7-ヒドロキシ-6-メトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1,5-ジメチル-1H-イミダゾール-4-カルボキサミド
1H-NMR (DMSO-d6) δ: 10.94 (s, 1H), 10.10 (s, 1H), 9.33 (s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.51 (s, 1H), 7.28 (s, 1H), 7.09 (d, J= 2.2 Hz, 1H), 6.86 (dd, J = 8.8, 2.2 Hz, 1H), 6.45 (d, J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.62 (s, 3H), 2.54 (s, 3H).
ESI-MS: m/z 478 [M+H]+
化合物64（原料化合物として、化合物A23および1,5-ジメチル-1H-イミダゾール-4-カルボキサミド使用）：
N-(4-{7-[2-(ジメチルアミノ)エトキシ]-6-メトキシキノリン-4-イルオキシ}-2-メトキシフェニルカルバモイル)-1,5-ジメチル-1H-イミダゾール-4-カルボキサミド
1H-NMR (DMSO-d6) δ: 10.95 (s, 1H), 9.34 (s, 1H), 8.47 (d, J = 5.4 Hz, 1H), 8.29 (d, J= 8.6 Hz, 1H), 7.78 (s, 1H), 7.52 (s, 1H), 7.42 (s, 1H), 7.10 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.6, 2.5 Hz, 1H), 6.52 (d, J = 5.4 Hz, 1H), 4.23 (t, J = 5.7 Hz, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.62 (s, 3H), 2.72 (t, J= 5.7 Hz, 2H), 2.54 (s, 3H), 2.26 (s, 6H).
ESI-MS: m/z 549 [M+H]+ Compound 63 (using compound A20 and 1,5-dimethyl-1H-imidazole-4-carboxamide as a raw material compound):
N- [4- (7-Hydroxy-6-methoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1,5-dimethyl-1H-imidazole-4-carboxamide
1 H-NMR (DMSO-d 6 ) δ: 10.94 (s, 1H), 10.10 (s, 1H), 9.33 (s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.51 (s, 1H), 7.28 (s, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.86 (dd, J = 8.8, 2.2 Hz , 1H), 6.45 (d, J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.62 (s, 3H), 2.54 (s, 3H).
ESI-MS: m / z 478 [M + H] +
Compound 64 (using compound A23 and 1,5-dimethyl-1H-imidazole-4-carboxamide as a raw material compound):
N- (4- {7- [2- (dimethylamino) ethoxy] -6-methoxyquinolin-4-yloxy} -2-methoxyphenylcarbamoyl) -1,5-dimethyl-1H-imidazole-4-carboxamide
1 H-NMR (DMSO-d 6 ) δ: 10.95 (s, 1H), 9.34 (s, 1H), 8.47 (d, J = 5.4 Hz, 1H), 8.29 (d, J = 8.6 Hz, 1H), 7.78 (s, 1H), 7.52 (s, 1H), 7.42 (s, 1H), 7.10 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.6, 2.5 Hz, 1H), 6.52 (d , J = 5.4 Hz, 1H), 4.23 (t, J = 5.7 Hz, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.62 (s, 3H), 2.72 (t, J = 5.7 Hz , 2H), 2.54 (s, 3H), 2.26 (s, 6H).
ESI-MS: m / z 549 [M + H] +
化合物65（原料化合物として、化合物A26および1,5-ジメチル-1H-イミダゾール-4-カルボキサミド使用）：
N-(2-メトキシ-4-{6-メトキシ-7-[2-(ピロリジン-1-イル)エトキシ]キノリン-4-イルオキシ}フェニルカルバモイル)-1,5-ジメチル-1H-イミダゾール-4-カルボキサミド
1H-NMR (DMSO-d6) δ: 10.95 (s, 1H), 9.34 (s, 1H), 8.47 (d, J = 5.4 Hz, 1H), 8.29 (d, J= 8.8 Hz, 1H), 7.78 (s, 1H), 7.52 (s, 1H), 7.41 (s, 1H), 7.11 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.8, 2.5 Hz, 1H), 6.52 (d, J = 5.4 Hz, 1H), 4.25 (t, J = 6.1 Hz, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.62 (s, 3H), 2.89 (t, J= 6.1 Hz, 2H), 2.58-2.55 (m, 4H), 2.55 (s, 3H), 1.72-1.69 (m, 4H).
ESI-MS: m/z 575 [M+H]+
化合物66（原料化合物として、化合物A31および1,5-ジメチル-1H-イミダゾール-4-カルボキサミド使用）：
N-(2-メトキシ-4-[7-メトキシ-6-(メトキシメトキシ)キノリン-4-イルオキシ]フェニルカルバモイル)-1,5-ジメチル-1H-イミダゾール-4-カルボキサミド
1H-NMR (DMSO-d6) δ: 10.92 (s, 1H), 9.98 (s, 1H), 9.33 (s, 1H), 8.42 (d, J = 5.1 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.47 (s, 1H), 7.37 (s, 1H), 7.07 (d, J= 2.2 Hz, 1H), 6.81 (dd, J = 8.8, 2.2 Hz, 1H), 6.49 (d, J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.62 (s, 3H), 2.54 (s, 3H).
ESI-MS: m/z 478 [M+H]+ Compound 65 (using compound A26 and 1,5-dimethyl-1H-imidazole-4-carboxamide as a raw material compound):
N- (2-methoxy-4- {6-methoxy-7- [2- (pyrrolidin-1-yl) ethoxy] quinolin-4-yloxy} phenylcarbamoyl) -1,5-dimethyl-1H-imidazole-4- Carboxamide
1 H-NMR (DMSO-d 6 ) δ: 10.95 (s, 1H), 9.34 (s, 1H), 8.47 (d, J = 5.4 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.52 (s, 1H), 7.41 (s, 1H), 7.11 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.8, 2.5 Hz, 1H), 6.52 (d , J = 5.4 Hz, 1H), 4.25 (t, J = 6.1 Hz, 2H), 3.94 (s, 3H), 3.92 (s, 3H), 3.62 (s, 3H), 2.89 (t, J = 6.1 Hz , 2H), 2.58-2.55 (m, 4H), 2.55 (s, 3H), 1.72-1.69 (m, 4H).
ESI-MS: m / z 575 [M + H] +
Compound 66 (using compound A31 and 1,5-dimethyl-1H-imidazole-4-carboxamide as a raw material compound):
N- (2-methoxy-4- [7-methoxy-6- (methoxymethoxy) quinolin-4-yloxy] phenylcarbamoyl) -1,5-dimethyl-1H-imidazole-4-carboxamide
1 H-NMR (DMSO-d 6 ) δ: 10.92 (s, 1H), 9.98 (s, 1H), 9.33 (s, 1H), 8.42 (d, J = 5.1 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.47 (s, 1H), 7.37 (s, 1H), 7.07 (d, J = 2.2 Hz, 1H), 6.81 (dd, J = 8.8, 2.2 Hz , 1H), 6.49 (d, J = 5.1 Hz, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 3.62 (s, 3H), 2.54 (s, 3H).
ESI-MS: m / z 478 [M + H] +
化合物67（原料化合物として、化合物A34および1-エチル-1H-イミダゾール-5-カルボキサミド使用）
N-{4-[6-(2,3-ジヒドロキシプロポキシ)-7-メトキシキノリン-4-イルオキシ]-2-メトキシフェニルカルバモイル}-1,5-ジメチル-1H-イミダゾール-4-カルボキサミド
1H-NMR (DMSO-d6) δ: 10.95 (s, 1H), 9.34 (s, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.28 (d, J= 8.8 Hz, 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.2 Hz, 1H), 6.87 (dd, J = 8.8, 2.2 Hz, 1H), 6.52 (d, J = 5.1 Hz, 1H), 5.02 (d, J = 5.1 Hz, 1H), 4.73 (t, J = 5.7 Hz, 1H), 4.19-4.15 (m, 1H), 4.03-4.00 (m, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.90-3.87 (m, 1H), 3.62 (s, 3H), 3.49 (t, J = 5.7 Hz, 2H), 2.54 (s, 3H).
ESI-MS: m/z 552 [M+H]+
化合物68（原料化合物として、化合物A2および5-メチルチアゾール-2-カルボキサミド使用）：
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-5-メチルチアゾール-2-カルボキサミド
1H-NMR (CDCl3) δ: 10.73 (s, 1H), 9.25 (s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.66 (s, 1H), 7.59 (s, 2H), 6.84 (dd, J = 8.8, 2.9 Hz, 1H), 6.79 (d, J = 2.9 Hz, 1H), 6.57 (d, J = 5.9 Hz, 1H), 4.09 (s, 3H), 4.07 (s, 3H), 3.96 (s, 3H), 2.62 (s, 3H).
ESI-MS: m/z 495 [M+H]+. Compound 67 (compound A34 and 1-ethyl-1H-imidazole-5-carboxamide used as starting compounds)
N- {4- [6- (2,3-dihydroxypropoxy) -7-methoxyquinolin-4-yloxy] -2-methoxyphenylcarbamoyl} -1,5-dimethyl-1H-imidazole-4-carboxamide
1 H-NMR (DMSO-d 6 ) δ: 10.95 (s, 1H), 9.34 (s, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.2 Hz, 1H), 6.87 (dd, J = 8.8, 2.2 Hz, 1H), 6.52 (d , J = 5.1 Hz, 1H), 5.02 (d, J = 5.1 Hz, 1H), 4.73 (t, J = 5.7 Hz, 1H), 4.19-4.15 (m, 1H), 4.03-4.00 (m, 1H) , 3.96 (s, 3H), 3.91 (s, 3H), 3.90-3.87 (m, 1H), 3.62 (s, 3H), 3.49 (t, J = 5.7 Hz, 2H), 2.54 (s, 3H).
ESI-MS: m / z 552 [M + H] +
Compound 68 (using compound A2 and 5-methylthiazole-2-carboxamide as a raw material compound):
N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -5-methylthiazole-2-carboxamide
1 H-NMR (CDCl 3 ) δ: 10.73 (s, 1H), 9.25 (s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.66 ( s, 1H), 7.59 (s, 2H), 6.84 (dd, J = 8.8, 2.9 Hz, 1H), 6.79 (d, J = 2.9 Hz, 1H), 6.57 (d, J = 5.9 Hz, 1H), 4.09 (s, 3H), 4.07 (s, 3H), 3.96 (s, 3H), 2.62 (s, 3H).
ESI-MS: m / z 495 [M + H] + .
化合物69（原料化合物として、化合物A2および化合物B82使用）：
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-5-メトキシオキサゾール-2-カルボキサミド
1H-NMR (CDCl3) δ: 10.66 (s, 1H), 8.85 (s, 1H), 8.50 (d, J = 5.4 Hz, 1H), 8.35 (d, J = 8.6 Hz, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 6.83 (dd, J = 8.6, 2.3 Hz, 1H), 6.78 (d, J = 2.3 Hz, 1H), 6.51 (d, J = 5.4 Hz, 1H), 6.38 (s, 1H), 4.06 (s, 9H), 3.93 (s, 3H).
ESI-MS: m/z 495 [M+H]+.
化合物70（原料化合物として、化合物A2および化合物B85使用）：
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1,5-ジメチル-1H-1,2,3-トリアゾール-4-カルボキサミド
1H-NMR (CDCl3) δ: 10.82 (s, 1H), 9.20 (s, 1H), 8.50 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 9.1 Hz, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 6.83 (dd, J = 9.1, 2.5 Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H), 6.52 (d, J = 5.0 Hz, 1H), 4.06 (s, 6H), 4.03 (s, 3H), 3.95 (s, 3H), 2.68 (s, 3H).
ESI-MS: m/z 493 [M+H]+. Compound 69 (using compound A2 and compound B82 as starting compounds):
N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -5-methoxyoxazole-2-carboxamide
1 H-NMR (CDCl 3 ) δ: 10.66 (s, 1H), 8.85 (s, 1H), 8.50 (d, J = 5.4 Hz, 1H), 8.35 (d, J = 8.6 Hz, 1H), 7.57 ( s, 1H), 7.45 (s, 1H), 6.83 (dd, J = 8.6, 2.3 Hz, 1H), 6.78 (d, J = 2.3 Hz, 1H), 6.51 (d, J = 5.4 Hz, 1H), 6.38 (s, 1H), 4.06 (s, 9H), 3.93 (s, 3H).
ESI-MS: m / z 495 [M + H] + .
Compound 70 (using compound A2 and compound B85 as raw compounds):
N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1,5-dimethyl-1H-1,2,3-triazole-4-carboxamide
1 H-NMR (CDCl 3 ) δ: 10.82 (s, 1H), 9.20 (s, 1H), 8.50 (d, J = 5.0 Hz, 1H), 8.39 (d, J = 9.1 Hz, 1H), 7.57 ( s, 1H), 7.45 (s, 1H), 6.83 (dd, J = 9.1, 2.5 Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H), 6.52 (d, J = 5.0 Hz, 1H), 4.06 (s, 6H), 4.03 (s, 3H), 3.95 (s, 3H), 2.68 (s, 3H).
ESI-MS: m / z 493 [M + H] + .
化合物71（原料化合物として、化合物A37および2-メチルチアゾール-5-カルボキサミド使用）
N-(4-{6-[2-(2-ヒドロキシエトキシ)エトキシ]-7-メトキシキノリン-4-イルオキシ}-2-メトキシフェニルカルバモイル)-2-メチルチアゾール-5-カルボキサミド
1H-NMR (CDCl3) δ: 10.94 (s, 1H), 9.17 (s, 1H), 8.51 (d, J = 5.4 Hz, 1H), 8.41 (s, 1H), 8.33 (d, J = 8.6 Hz, 1H), 7.61 (s, 1H), 7.43 (s, 1H), 6.85 (dd, J = 8.6, 2.5 Hz, 1H), 6.79 (d, J = 2.5 Hz, 1H), 6.52 (d, J = 5.4 Hz, 1H), 4.37 (t, J = 4.8 Hz, 2H), 4.04-4.01 (m, 5H), 3.95 (s, 3H), 3.81-3.77 (m, 2H), 3.75-3.72 (m, 2H), 2.79 (s, 3H), 2.57 (br s, 1H).
ESI-MS: m/z 569 [M+H]+.
化合物72（原料化合物として、化合物A2および化合物B88使用）
N-[4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバモイル]-1,3-ジエチル-2-オキソ-2,3-ジヒドロ-1H-イミダゾール-4-カルボキサミド
1H-NMR (CDCl3) δ: 11.02 (s, 1H), 9.53 (s, 1H), 8.51 (d, J = 5.4 Hz, 1H), 8.22 (d, J = 8.6 Hz, 1H), 7.56 (s, 1H), 7.55 (s, 1H), 7.44 (s, 1H), 6.81 (d, J = 2.3 Hz, 1H), 6.79 (dd, J = 8.6, 2.3 Hz, 1H), 6.48 (d, J = 5.4 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 4.06 (s, 6H), 3.96 (s, 3H), 3.72 (q, J = 7.4 Hz, 2H), 1.33-1.26 (m, 6H).
ESI-MS: m/z 536 [M+H]+. Compound 71 (using compound A37 and 2-methylthiazole-5-carboxamide as a raw material compound)
N- (4- {6- [2- (2-hydroxyethoxy) ethoxy] -7-methoxyquinolin-4-yloxy} -2-methoxyphenylcarbamoyl) -2-methylthiazole-5-carboxamide
1 H-NMR (CDCl 3 ) δ: 10.94 (s, 1H), 9.17 (s, 1H), 8.51 (d, J = 5.4 Hz, 1H), 8.41 (s, 1H), 8.33 (d, J = 8.6 Hz, 1H), 7.61 (s, 1H), 7.43 (s, 1H), 6.85 (dd, J = 8.6, 2.5 Hz, 1H), 6.79 (d, J = 2.5 Hz, 1H), 6.52 (d, J = 5.4 Hz, 1H), 4.37 (t, J = 4.8 Hz, 2H), 4.04-4.01 (m, 5H), 3.95 (s, 3H), 3.81-3.77 (m, 2H), 3.75-3.72 (m, 2H), 2.79 (s, 3H), 2.57 (br s, 1H).
ESI-MS: m / z 569 [M + H] + .
Compound 72 (using compound A2 and compound B88 as raw material compounds)
N- [4- (6,7-Dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamoyl] -1,3-diethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide
1 H-NMR (CDCl 3 ) δ: 11.02 (s, 1H), 9.53 (s, 1H), 8.51 (d, J = 5.4 Hz, 1H), 8.22 (d, J = 8.6 Hz, 1H), 7.56 ( s, 1H), 7.55 (s, 1H), 7.44 (s, 1H), 6.81 (d, J = 2.3 Hz, 1H), 6.79 (dd, J = 8.6, 2.3 Hz, 1H), 6.48 (d, J = 5.4 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 4.06 (s, 6H), 3.96 (s, 3H), 3.72 (q, J = 7.4 Hz, 2H), 1.33-1.26 (m , 6H).
ESI-MS: m / z 536 [M + H] + .
化合物73（原料化合物として、化合物A2および2-メチルチアゾール-5-カルボキサミド使用）
N-(2-メトキシ-4-{7-メトキシ-6-[1-(2-メチルアミノ-2-オキソエチル)ピペリジン-4-イルオキシ]キノリン-4-イルオキシ}フェニルカルバモイル)-2-メチルチアゾール-5-カルボキサミド
1H-NMR (DMSO-d6) δ: 11.35 (s, 1H), 10.98 (s, 1H), 8.69 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.56 (s, 1H), 7.41 (s, 1H), 7.10 (d, J = 2.9 Hz, 1H), 6.85 (dd, J = 8.8, 2.9 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H), 4.60-4.55 (m, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 2.91 (s, 2H), 2.73 (s, 3H), 2.73-2.67 (m, 2H), 2.62 (d, J = 4.8 Hz, 3H), 2.36 (t, J = 8.8 Hz, 2H), 2.03-1.98 (m, 2H), 1.84-1.76 (m, 2H).
ESI-MS: m/z 635 [M+H]+
化合物74（原料化合物として、化合物A42および5-メチルオキサゾール-4-カルボキサミド使用）
N-(2-メトキシ-4-{7-メトキシ-6-[1-(2-メチルアミノ-2-オキソエチル)ピペリジン-4-イルオキシ]キノリン-4-イルオキシ}フェニルカルバモイル)-5-メチルオキサゾール-4-カルボキサミド
1H-NMR (DMSO-d6) δ: 10.80 (s, 1H), 9.86 (s, 1H), 8.51 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 7.11 (d, J = 2.9 Hz, 1H), 6.85 (dd, J = 8.8, 2.9 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H), 4.59-4.55 (m, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 2.91 (s, 2H), 2.74-2.69 (m, 2H), 2.67 (s, 3H), 2.62 (d, J = 4.8 Hz, 3H), 2.36 (t, J = 8.8 Hz, 2H), 2.03-1.98 (m, 2H), 1.81-1.78 (m, 2H).
ESI-MS: m/z 619 [M+H]+ Compound 73 (using compound A2 and 2-methylthiazole-5-carboxamide as raw material compounds)
N- (2-methoxy-4- {7-methoxy-6- [1- (2-methylamino-2-oxoethyl) piperidin-4-yloxy] quinolin-4-yloxy} phenylcarbamoyl) -2-methylthiazole- 5-carboxamide
1 H-NMR (DMSO-d 6 ) δ: 11.35 (s, 1H), 10.98 (s, 1H), 8.69 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.56 (s, 1H), 7.41 (s, 1H), 7.10 (d, J = 2.9 Hz, 1H), 6.85 (dd, J = 8.8, 2.9 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H), 4.60-4.55 (m, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 2.91 (s, 2H) , 2.73 (s, 3H), 2.73-2.67 (m, 2H), 2.62 (d, J = 4.8 Hz, 3H), 2.36 (t, J = 8.8 Hz, 2H), 2.03-1.98 (m, 2H), 1.84-1.76 (m, 2H).
ESI-MS: m / z 635 [M + H] +
Compound 74 (compound A42 and 5-methyloxazole-4-carboxamide used as starting compounds)
N- (2-methoxy-4- {7-methoxy-6- [1- (2-methylamino-2-oxoethyl) piperidin-4-yloxy] quinolin-4-yloxy} phenylcarbamoyl) -5-methyloxazole- 4-carboxamide
1 H-NMR (DMSO-d 6 ) δ: 10.80 (s, 1H), 9.86 (s, 1H), 8.51 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 7.11 (d, J = 2.9 Hz, 1H), 6.85 (dd, J = 8.8, 2.9 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H), 4.59-4.55 (m, 1H), 3.95 (s, 3H), 3.91 (s, 3H), 2.91 (s, 2H) , 2.74-2.69 (m, 2H), 2.67 (s, 3H), 2.62 (d, J = 4.8 Hz, 3H), 2.36 (t, J = 8.8 Hz, 2H), 2.03-1.98 (m, 2H), 1.81-1.78 (m, 2H).
ESI-MS: m / z 619 [M + H] +
化合物75（原料化合物として、化合物A42および化合物B47使用）
1-エチル-N-(2-メトキシ-4-{7-メトキシ-6-[1-(2-メチルアミノ-2-オキソエチル)ピペリジン-4-イルオキシ]キノリン-4-イルオキシ}フェニルカルバモイル)-1H-イミダゾール-5-カルボキサミド
1H-NMR (DMSO-d6) δ: 10.96 (s, 1H), 10.92 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.28 (d, J= 8.8 Hz, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.56 (s, 1H), 7.42 (s, 1H), 7.10 (d, J = 2.9 Hz, 1H), 6.85 (dd, J = 8.8, 2.9 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H), 4.60-4.54 (m, 1H), 4.36 (q, J = 6.8 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 2.91 (s, 2H), 2.73-2.68 (m, 2H), 2.62 (d, J = 4.8 Hz, 3H), 2.36 (t, J = 10.2 Hz, 2H), 2.03-2.00 (m, 2H), 1.84-1.76 (m, 2H), 1.36 (t, J = 6.8 Hz, 3H).
ESI-MS: m/z 632 [M+H]+
化合物76（原料化合物として、化合物A42および2-メチルオキサゾール-5-カルボキサミド使用）
N-(2-メトキシ-4-{7-メトキシ-6-[1-(2-メチルアミノ-2-オキソエチル)ピペリジン-4-イルオキシ]キノリン-4-イルオキシ}フェニルカルバモイル)-2-メチルオキサゾール-5-カルボキサミド
1H-NMR (DMSO-d6) δ: 11.24 (s, 1H), 10.93 (s, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.27 (d, J= 8.8 Hz, 1H), 8.19 (s, 1H), 7.71 (d, J= 4.4 Hz, 1H), 7.56 (s, 1H), 7.41 (s, 1H), 7.09 (d, J = 2.6 Hz, 1H), 6.85 (dd, J = 8.8, 2.6 Hz, 1H), 6.52 (d, J = 5.1 Hz, 1H), 4.60-4.54 (m, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 2.91 (s, 2H), 2.72-2.68 (m, 2H), 2.62 (d, J = 4.8 Hz, 3H), 2.54 (s, 3H), 2.40-2.32 (m, 2H), 2.04-1.98 (m, 2H), 1.85-1.76 (m, 2H).
ESI-MS: m/z 619 [M+H]+ Compound 75 (using compound A42 and compound B47 as raw material compounds)
1-ethyl-N- (2-methoxy-4- {7-methoxy-6- [1- (2-methylamino-2-oxoethyl) piperidin-4-yloxy] quinolin-4-yloxy} phenylcarbamoyl) -1H -Imidazole-5-carboxamide
1 H-NMR (DMSO-d 6 ) δ: 10.96 (s, 1H), 10.92 (s, 1H), 8.49 (d, J = 4.9 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.56 (s, 1H), 7.42 (s, 1H), 7.10 (d, J = 2.9 Hz, 1H ), 6.85 (dd, J = 8.8, 2.9 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H), 4.60-4.54 (m, 1H), 4.36 (q, J = 6.8 Hz, 2H), 3.95 (s, 3H), 3.91 (s, 3H), 2.91 (s, 2H), 2.73-2.68 (m, 2H), 2.62 (d, J = 4.8 Hz, 3H), 2.36 (t, J = 10.2 Hz, 2H), 2.03-2.00 (m, 2H), 1.84-1.76 (m, 2H), 1.36 (t, J = 6.8 Hz, 3H).
ESI-MS: m / z 632 [M + H] +
Compound 76 (using compound A42 and 2-methyloxazole-5-carboxamide as raw material compounds)
N- (2-methoxy-4- {7-methoxy-6- [1- (2-methylamino-2-oxoethyl) piperidin-4-yloxy] quinolin-4-yloxy} phenylcarbamoyl) -2-methyloxazole- 5-carboxamide
1 H-NMR (DMSO-d 6 ) δ: 11.24 (s, 1H), 10.93 (s, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.19 (s, 1H), 7.71 (d, J = 4.4 Hz, 1H), 7.56 (s, 1H), 7.41 (s, 1H), 7.09 (d, J = 2.6 Hz, 1H), 6.85 (dd, J = 8.8, 2.6 Hz, 1H), 6.52 (d, J = 5.1 Hz, 1H), 4.60-4.54 (m, 1H), 3.95 (s, 3H), 3.90 (s, 3H), 2.91 (s, 2H) , 2.72-2.68 (m, 2H), 2.62 (d, J = 4.8 Hz, 3H), 2.54 (s, 3H), 2.40-2.32 (m, 2H), 2.04-1.98 (m, 2H), 1.85-1.76 (m, 2H).
ESI-MS: m / z 619 [M + H] +
化合物77（原料化合物として、化合物A45および化合物B47使用）
1-エチル-N-{4-[6-(3-ヒドロキシプロポキシ)-7-メトキシキノリン-4-イルオキシ]-2-メトキシフェニルカルバモイル}-1H-イミダゾール-5-カルボキサミド
1H-NMR (DMSO-d6) δ: 10.96 (s, 1H), 10.92 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.29 (d, J= 8.8 Hz, 1H), 8.13 (s, 1H), 8.04 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 8.8, 2.4 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.59 (t, J = 5.9 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 4.20 (t, J = 6.3 Hz, 2H), 3.95 (s, 3H), 3.90 (s, 3H), 3.61 (q, J = 5.9 Hz, 2H), 1.99-1.93 (m, 2H), 1.36 (t, J= 7.2 Hz, 3H).
ESI-MS: m/z 536 [M+H]+
化合物78（原料化合物として、化合物A32および化合物B47使用）
N-{4-[6-(2,3-ジヒドロキシプロポキシ)-7-メトキシキノリン-4-イルオキシ]-2-メトキシフェニルカルバモイル}-1-エチル-1H-イミダゾール-5-カルボキサミド
1H-NMR (DMSO-d6) δ: 10.97 (s, 1H), 10.92 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.29 (d, J= 8.8 Hz, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 5.02 (d, J = 4.9 Hz, 1H), 4.72 (t, J = 5.4 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 4.18-4.16 (m, 1H), 4.03-4.01 (m, 1H), 3.96 (s, 3H), 3.91-3.88 (m, 1H), 3.91 (s, 3H), 3.49 (t, J = 5.9 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H).
ESI-MS: m/z 552 [M+H]+ Compound 77 (using compound A45 and compound B47 as raw material compounds)
1-ethyl-N- {4- [6- (3-hydroxypropoxy) -7-methoxyquinolin-4-yloxy] -2-methoxyphenylcarbamoyl} -1H-imidazole-5-carboxamide
1 H-NMR (DMSO-d 6 ) δ: 10.96 (s, 1H), 10.92 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.13 (s, 1H), 8.04 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 8.8, 2.4 Hz , 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.59 (t, J = 5.9 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 4.20 (t, J = 6.3 Hz, 2H ), 3.95 (s, 3H), 3.90 (s, 3H), 3.61 (q, J = 5.9 Hz, 2H), 1.99-1.93 (m, 2H), 1.36 (t, J = 7.2 Hz, 3H).
ESI-MS: m / z 536 [M + H] +
Compound 78 (using compound A32 and compound B47 as raw material compounds)
N- {4- [6- (2,3-dihydroxypropoxy) -7-methoxyquinolin-4-yloxy] -2-methoxyphenylcarbamoyl} -1-ethyl-1H-imidazole-5-carboxamide
1 H-NMR (DMSO-d 6 ) δ: 10.97 (s, 1H), 10.92 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz , 1H), 6.52 (d, J = 4.9 Hz, 1H), 5.02 (d, J = 4.9 Hz, 1H), 4.72 (t, J = 5.4 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H ), 4.18-4.16 (m, 1H), 4.03-4.01 (m, 1H), 3.96 (s, 3H), 3.91-3.88 (m, 1H), 3.91 (s, 3H), 3.49 (t, J = 5.9 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H).
ESI-MS: m / z 552 [M + H] +
化合物79（原料化合物として、化合物A34および2-メチルチアゾール-5-カルボキサミド使用）
N-{4-[6-(2,3-ジヒドロキシプロポキシ)-7-メトキシキノリン-4-イルオキシ]-2-メトキシフェニルカルバモイル}-2-メチルチアゾール-5-カルボキサミド
1H-NMR (DMSO-d6) δ: 11.34 (s, 1H), 10.98 (s, 1H), 8.69 (s, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.2 Hz, 1H), 6.88 (dd, J = 8.8, 2.2 Hz, 1H), 6.52 (d, J = 5.1 Hz, 1H), 5.00 (d, J = 5.1 Hz, 1H), 4.71 (t, J = 5.7 Hz, 1H), 4.18-4.15 (m, 1H), 4.03-4.00 (m, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.90-3.86 (m, 1H), 3.49 (t, J = 5.7 Hz, 2H), 2.73 (s, 3H).
ESI-MS: m/z 555 [M+H]+
化合物80（原料化合物として、化合物A42および化合物B47使用）
1,3-ジメチル-N-(2-メトキシ-4-{7-メトキシ-6-[1-(2-メチルアミノ-2-オキソエチル)ピペリジン-4-イルオキシ]キノリン-4-イルオキシ}フェニルカルバモイル)-2-オキソ-2,3-ジヒドロ-1H-イミダゾール-4-カルボキサミド
1H-NMR (DMSO-d6) δ: 10.88 (s, 1H), 10.63 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.26 (d, J= 8.8 Hz, 1H), 8.03 (s, 1H), 7.72 (d, J= 4.9 Hz, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 8.8, 2.4 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.59-4.54 (m, 1H), 4.03 (q, J = 6.8 Hz, 2H), 3.95 (s, 3H), 3.89 (s, 3H), 3.64 (q, J = 6.8 Hz, 2H), 2.91 (s, 2H), 2.72-2.70 (m, 2H), 2.62 (d, J = 4.9 Hz, 3H), 2.36 (t, J= 9.8 Hz, 2H), 2.03-1.98 (m, 2H), 1.81-1.79 (m, 2H), 1.24 (t, J = 6.8 Hz, 3H), 1.16 (t, J = 6.8 Hz, 3H).
ESI-MS: m/z 676 [M+H]+ Compound 79 (compound A34 and 2-methylthiazole-5-carboxamide used as starting compounds)
N- {4- [6- (2,3-dihydroxypropoxy) -7-methoxyquinolin-4-yloxy] -2-methoxyphenylcarbamoyl} -2-methylthiazole-5-carboxamide
1 H-NMR (DMSO-d 6 ) δ: 11.34 (s, 1H), 10.98 (s, 1H), 8.69 (s, 1H), 8.48 (d, J = 5.1 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.2 Hz, 1H), 6.88 (dd, J = 8.8, 2.2 Hz, 1H), 6.52 (d , J = 5.1 Hz, 1H), 5.00 (d, J = 5.1 Hz, 1H), 4.71 (t, J = 5.7 Hz, 1H), 4.18-4.15 (m, 1H), 4.03-4.00 (m, 1H) , 3.96 (s, 3H), 3.91 (s, 3H), 3.90-3.86 (m, 1H), 3.49 (t, J = 5.7 Hz, 2H), 2.73 (s, 3H).
ESI-MS: m / z 555 [M + H] +
Compound 80 (using compound A42 and compound B47 as raw material compounds)
1,3-dimethyl-N- (2-methoxy-4- {7-methoxy-6- [1- (2-methylamino-2-oxoethyl) piperidin-4-yloxy] quinolin-4-yloxy} phenylcarbamoyl) -2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide
1 H-NMR (DMSO-d 6 ) δ: 10.88 (s, 1H), 10.63 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.26 (d, J = 8.8 Hz, 1H), 8.03 (s, 1H), 7.72 (d, J = 4.9 Hz, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.83 (dd, J = 8.8, 2.4 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.59-4.54 (m, 1H), 4.03 (q, J = 6.8 Hz, 2H), 3.95 (s, 3H), 3.89 (s, 3H), 3.64 (q, J = 6.8 Hz, 2H), 2.91 (s, 2H), 2.72-2.70 (m, 2H), 2.62 (d, J = 4.9 Hz, 3H), 2.36 (t, J = 9.8 Hz, 2H), 2.03-1.98 (m, 2H), 1.81-1.79 (m, 2H), 1.24 (t, J = 6.8 Hz, 3H), 1.16 (t, J = 6.8 Hz, 3H).
ESI-MS: m / z 676 [M + H] +
化合物81（原料化合物として、化合物A37および化合物B47使用）
1-エチル-N-(4-{6-[2-(2-ヒドロキシエトキシ)エトキシ]-7-メトキシキノリン-4-イルオキシ}-2-メトキシフェニルカルバモイル)-1H-イミダゾール-5-カルボキサミド
1H-NMR (CDCl3) δ: 10.87 (s, 1H), 8.96 (s, 1H), 8.50 (d, J = 5.4 Hz, 1H), 8.33 (d, J = 8.6 Hz, 1H), 7.91 (s, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 7.42 (s, 1H), 6.85 (dd, J = 8.6, 2.5 Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H), 6.52 (d, J = 5.4 Hz, 1H), 4.45 (q, J = 7.2 Hz, 2H), 4.37 (t, J = 4.5 Hz, 2H), 4.04-4.01 (m, 5H), 3.95 (s, 3H), 3.81-3.77 (br m, 2H), 3.75-3.72 (m, 2H), 2.64 (br s, 1H), 1.51 (t, J = 7.2 Hz, 3H).
ESI-MS: m/z 566 [M+H]+.
化合物82（原料化合物として、化合物A42および化合物B88使用）
N-{4-[6-(2,3-ジヒドロキシプロポキシ)-7-メトキシキノリン-4-イルオキシ]-2-メトキシフェニルカルバモイル}-1,3-ジエチル-2-オキソ-2,3-ジヒドロ-1H-イミダゾール-4-カルボキサミド
1H-NMR (DMSO-d6) δ: 10.89 (s, 1H), 10.63 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.27 (d, J= 8.8 Hz, 1H), 8.04 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.87 (dd, J = 8.8, 2.0 Hz, 1H), 6.51 (d, J = 4.9 Hz, 1H), 5.02 (d, J = 5.9 Hz, 1H), 4.72 (t, J = 5.9 Hz, 1H), 4.18-4.16 (m, 1H), 4.01-3.98 (m, 4H), 3.96 (s, 3H), 3.90 (s, 3H), 3.65 (q, J = 6.8 Hz, 2H), 3.49 (t, J= 5.4 Hz, 2H), 1.24 (t, J = 6.8 Hz, 3H), 1.17 (t, J = 6.8 Hz, 3H).
ESI-MS: m/z 596 [M+H]+ Compound 81 (using compound A37 and compound B47 as raw material compounds)
1-ethyl-N- (4- {6- [2- (2-hydroxyethoxy) ethoxy] -7-methoxyquinolin-4-yloxy} -2-methoxyphenylcarbamoyl) -1H-imidazole-5-carboxamide
1 H-NMR (CDCl 3 ) δ: 10.87 (s, 1H), 8.96 (s, 1H), 8.50 (d, J = 5.4 Hz, 1H), 8.33 (d, J = 8.6 Hz, 1H), 7.91 ( s, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 7.42 (s, 1H), 6.85 (dd, J = 8.6, 2.5 Hz, 1H), 6.78 (d, J = 2.5 Hz, 1H ), 6.52 (d, J = 5.4 Hz, 1H), 4.45 (q, J = 7.2 Hz, 2H), 4.37 (t, J = 4.5 Hz, 2H), 4.04-4.01 (m, 5H), 3.95 (s , 3H), 3.81-3.77 (br m, 2H), 3.75-3.72 (m, 2H), 2.64 (br s, 1H), 1.51 (t, J = 7.2 Hz, 3H).
ESI-MS: m / z 566 [M + H] + .
Compound 82 (using compound A42 and compound B88 as raw compounds)
N- {4- [6- (2,3-dihydroxypropoxy) -7-methoxyquinolin-4-yloxy] -2-methoxyphenylcarbamoyl} -1,3-diethyl-2-oxo-2,3-dihydro- 1H-imidazole-4-carboxamide
1 H-NMR (DMSO-d 6 ) δ: 10.89 (s, 1H), 10.63 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.87 (dd, J = 8.8, 2.0 Hz, 1H), 6.51 (d , J = 4.9 Hz, 1H), 5.02 (d, J = 5.9 Hz, 1H), 4.72 (t, J = 5.9 Hz, 1H), 4.18-4.16 (m, 1H), 4.01-3.98 (m, 4H) , 3.96 (s, 3H), 3.90 (s, 3H), 3.65 (q, J = 6.8 Hz, 2H), 3.49 (t, J = 5.4 Hz, 2H), 1.24 (t, J = 6.8 Hz, 3H) , 1.17 (t, J = 6.8 Hz, 3H).
ESI-MS: m / z 596 [M + H] +
化合物83（原料化合物として、化合物A42および2-メチルチアゾール-5-カルボキサミド使用）
N-{4-[6-(2,3-ジヒドロキシプロポキシ)-7-メトキシキノリン-4-イルオキシ]-2-メトキシフェニルカルバモイル}-2-メチルオキサゾール-5-カルボキサミド
1H-NMR (DMSO-d6) δ: 11.25 (s, 1H), 10.94 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.28 (d, J= 8.8 Hz, 1H), 8.20 (s, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 5.01 (d, J = 4.9 Hz, 1H), 4.72 (t, J = 5.9 Hz, 1H), 4.18-4.15 (m, 1H), 4.03-4.00 (m, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.90-3.89 (m, 1H), 3.49 (t, J = 5.9 Hz, 2H), 2.54 (s, 3H).
ESI-MS: m/z 539 [M+H]+
化合物84（原料化合物として、化合物A42および2-メチルチアゾール-5-カルボキサミド使用）
N-{4-[6-(2,3-ジヒドロキシプロポキシ)-7-メトキシキノリン-4-イルオキシ]-2-メトキシフェニルカルバモイル}-2-メチルオキサゾール-5-カルボキサミド
1H-NMR (DMSO-d6) δ: 10.80 (s, 1H), 9.86 (s, 1H), 8.50 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.12 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.8, 2.6 Hz, 1H), 6.52 (d, J = 5.5 Hz, 1H), 5.00 (d, J = 5.1 Hz, 1H), 4.71 (t, J = 5.7 Hz, 1H), 4.18-4.15 (m, 1H), 4.03-4.00 (m, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.90-3.83 (m, 1H), 3.49 (t, J = 5.7 Hz, 2H), 2.67 (s, 3H).
ESI-MS: m/z 539 [M+H]+ Compound 83 (using compound A42 and 2-methylthiazole-5-carboxamide as a raw material compound)
N- {4- [6- (2,3-dihydroxypropoxy) -7-methoxyquinolin-4-yloxy] -2-methoxyphenylcarbamoyl} -2-methyloxazole-5-carboxamide
1 H-NMR (DMSO-d 6 ) δ: 11.25 (s, 1H), 10.94 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 8.20 (s, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.8, 2.0 Hz, 1H), 6.52 (d , J = 4.9 Hz, 1H), 5.01 (d, J = 4.9 Hz, 1H), 4.72 (t, J = 5.9 Hz, 1H), 4.18-4.15 (m, 1H), 4.03-4.00 (m, 1H) , 3.96 (s, 3H), 3.91 (s, 3H), 3.90-3.89 (m, 1H), 3.49 (t, J = 5.9 Hz, 2H), 2.54 (s, 3H).
ESI-MS: m / z 539 [M + H] +
Compound 84 (using compound A42 and 2-methylthiazole-5-carboxamide as a raw material compound)
N- {4- [6- (2,3-dihydroxypropoxy) -7-methoxyquinolin-4-yloxy] -2-methoxyphenylcarbamoyl} -2-methyloxazole-5-carboxamide
1 H-NMR (DMSO-d 6 ) δ: 10.80 (s, 1H), 9.86 (s, 1H), 8.50 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.12 (d, J = 2.6 Hz, 1H), 6.88 (dd, J = 8.8, 2.6 Hz, 1H), 6.52 (d , J = 5.5 Hz, 1H), 5.00 (d, J = 5.1 Hz, 1H), 4.71 (t, J = 5.7 Hz, 1H), 4.18-4.15 (m, 1H), 4.03-4.00 (m, 1H) , 3.96 (s, 3H), 3.91 (s, 3H), 3.90-3.83 (m, 1H), 3.49 (t, J = 5.7 Hz, 2H), 2.67 (s, 3H).
ESI-MS: m / z 539 [M + H] +
化合物85（原料化合物として、化合物A45および化合物B88使用）
1,3-ジエチル-N-{4-[6-(3-ヒドロキシプロポキシ)-7-メトキシキノリン-4-イルオキシ]-2-メトキシフェニルカルバモイル}-2-オキソ-2,3-ジヒドロ-1H-イミダゾール-4-カルボキサミド
1H-NMR (DMSO-d6) δ: 10.88 (s, 1H), 10.63 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.27 (d, J= 8.8 Hz, 1H), 8.04 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.86 (dd, J = 8.8, 2.0 Hz, 1H), 6.51 (d, J = 4.9 Hz, 1H), 4.59 (t, J = 5.9 Hz, 1H), 4.20 (t, J = 5.4 Hz, 2H), 3.99 (t, J = 4.4 Hz, 2H), 3.95 (s, 3H), 3.89 (s, 3H), 3.65-3.61 (m, 4H), 1.98-1.95 (m, 2H), 1.24 (t, J = 6.8 Hz, 3H), 1.16 (t, J= 6.8 Hz, 3H).
ESI-MS: m/z 580 [M+H]+
  Compound 85 (using compound A45 and compound B88 as raw material compounds)
1,3-diethyl-N- {4- [6- (3-hydroxypropoxy) -7-methoxyquinolin-4-yloxy] -2-methoxyphenylcarbamoyl} -2-oxo-2,3-dihydro-1H- Imidazole-4-carboxamide
1 H-NMR (DMSO-d 6 ) δ: 10.88 (s, 1H), 10.63 (s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 8.27 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 7.53 (s, 1H), 7.40 (s, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.86 (dd, J = 8.8, 2.0 Hz, 1H), 6.51 (d , J = 4.9 Hz, 1H), 4.59 (t, J = 5.9 Hz, 1H), 4.20 (t, J = 5.4 Hz, 2H), 3.99 (t, J = 4.4 Hz, 2H), 3.95 (s, 3H ), 3.89 (s, 3H), 3.65-3.61 (m, 4H), 1.98-1.95 (m, 2H), 1.24 (t, J = 6.8 Hz, 3H), 1.16 (t, J = 6.8 Hz, 3H) .
ESI-MS: m / z 580 [M + H] +
参考例1
4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシアニリン (化合物A1)
　DMSO (100 mL)に60％水素化ナトリウム (1.44 g, 1.74 mmol)、および4-アミノ-3-メトキシフェノール(2.88 g, 20.7 mmol)を順次加え、室温で30分間撹拌した後、J. Med. Chem. 2005, 48, 1359-1366 記載の方法に従って得られる4-クロロ-6,7-ジメトキシキノリン (4.63 g, 20.7 mmol)を加え、さらに100 ℃で5時間撹拌した。混合物を室温まで冷却し、水を加えてクロロホルムで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣にメタノール (50 mL)を加えてリスラリー精製し、化合物A1 (4.18 g, 62%)を固体として得た。
1H-NMR (CDCl3) δ: 8.47 (d, J = 5.5 Hz, 1H), 7.59 (s, 1H), 7.41 (s, 1H), 6.79-6.75 (m, 1H), 6.65 (t, J= 4.9 Hz, 2H), 6.45 (d, J = 5.5 Hz, 1H), 4.06 (s, 3H), 4.05 (s, 3H), 3.84 (s, 3H).
ESI-MS: m/z 327 [M+H]+. Reference example 1
4- (6,7-dimethoxyquinolin-4-yloxy) -2-methoxyaniline (Compound A1)
To DMSO (100 mL), 60% sodium hydride (1.44 g, 1.74 mmol) and 4-amino-3-methoxyphenol (2.88 g, 20.7 mmol) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. Chem. 2005, 48, 1359-1366 4-Chloro-6,7-dimethoxyquinoline (4.63 g, 20.7 mmol) obtained according to the method described in the method was added, and the mixture was further stirred at 100 ° C. for 5 hours. The mixture was cooled to room temperature, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure, methanol (50 mL) was added to the resulting residue, and reslurry purification was performed to obtain Compound A1 (4.18 g, 62%) as a solid.
1 H-NMR (CDCl 3 ) δ: 8.47 (d, J = 5.5 Hz, 1H), 7.59 (s, 1H), 7.41 (s, 1H), 6.79-6.75 (m, 1H), 6.65 (t, J = 4.9 Hz, 2H), 6.45 (d, J = 5.5 Hz, 1H), 4.06 (s, 3H), 4.05 (s, 3H), 3.84 (s, 3H).
ESI-MS: m / z 327 [M + H] + .
参考例2
フェニル 4-(6,7-ジメトキシキノリン-4-イルオキシ)-2-メトキシフェニルカルバマート (化合物A2)
　化合物A1 (3.10 g, 9.49 mmol)を混合溶媒 (120 mL、トルエン/トリエチルアミン＝3/1)に溶解し、トリホスゲン (4.22 g, 14.2 mmol)を加え、100 ℃で15分間撹拌後、フェノール (1.34 g, 14.2 mmol)を加え、混合物を100 ℃で8時間撹拌した。混合物を室温まで冷却後、飽和重曹水を加えて中和し、クロロホルムで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (メタノール/クロロホルム＝5/95)で精製し、化合物A2 (2.78 g, 66%)を得た。
1H-NMR (300 MHz, CDCl3) δ: 8.50 (d, J = 4.9 Hz, 1H), 8.20-8.17 (br m, 1H), 7.57-7.55 (m, 2H), 7.44-7.40 (m, 3H), 7.30-7.23 (m, 3H), 6.83 (dd, J = 8.8, 2.0 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.49 (d, J = 4.9 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.92 (s, 3H).
ESI-MS: m/z 447 [M+H]+. Reference example 2
Phenyl 4- (6,7-dimethoxyquinolin-4-yloxy) -2-methoxyphenylcarbamate (Compound A2)
Compound A1 (3.10 g, 9.49 mmol) was dissolved in a mixed solvent (120 mL, toluene / triethylamine = 3/1), triphosgene (4.22 g, 14.2 mmol) was added, and the mixture was stirred at 100 ° C. for 15 minutes, and then phenol (1.34 g, 14.2 mmol) was added and the mixture was stirred at 100 ° C. for 8 h. The mixture was cooled to room temperature, neutralized with saturated aqueous sodium hydrogen carbonate, extracted with chloroform, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol / chloroform = 5/95) to obtain Compound A2 (2.78 g, 66%).
1 H-NMR (300 MHz, CDCl 3 ) δ: 8.50 (d, J = 4.9 Hz, 1H), 8.20-8.17 (br m, 1H), 7.57-7.55 (m, 2H), 7.44-7.40 (m, 3H), 7.30-7.23 (m, 3H), 6.83 (dd, J = 8.8, 2.0 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.49 (d, J = 4.9 Hz, 1H), 4.06 (s, 3H), 4.06 (s, 3H), 3.92 (s, 3H).
ESI-MS: m / z 447 [M + H] + .
参考例3
7-(ベンジルオキシ)-4-(3-フルオロ-4-ニトロフェノキシ)-6-メトキシキノリン (化合物A3)
　WO2000043366の製造法8に従って得られる7-(ベンジルオキシ)-4-クロロ-6-メトキシキノリン (9.00 g, 30 mmol)をクロロベンゼン(60 mL)に溶解し、3-フルオロ-4-ニトロフェノール (5.66 g, 36.1 mmol)を加え、120 ℃で21時間撹拌した。混合物を室温まで冷却し、クロロホルムで抽出し、有機層を飽和重曹水、および飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣に混合溶媒 (150 mL、ヘキサン/酢酸エチル＝1/1)を加えてリスラリー精製し化合物A3 (10.4 g, 82%)を得た。
1H-NMR (DMSO-d6) δ: 8.63 (d, J = 5.1 Hz, 1H), 8.27 (t, J = 9.0 Hz, 1H), 7.57-7.51 (m, 4H), 7.43-7.36 (m, 4H), 7.22-7.19 (m, 1H), 6.98 (d, J = 5.1 Hz, 1H), 5.32 (s, 2H), 3.89 (s, 3H).
ESI-MS: m/z 447 [M+H]+ Reference example 3
7- (Benzyloxy) -4- (3-fluoro-4-nitrophenoxy) -6-methoxyquinoline (Compound A3)
7- (Benzyloxy) -4-chloro-6-methoxyquinoline (9.00 g, 30 mmol) obtained according to the production method 8 of WO2000043366 was dissolved in chlorobenzene (60 mL), and 3-fluoro-4-nitrophenol (5.66 g, 36.1 mmol) was added, and the mixture was stirred at 120 ° C. for 21 hours. The mixture was cooled to room temperature and extracted with chloroform, and the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the resulting residue was mixed with a mixed solvent (150 mL, hexane / ethyl acetate = 1/1) and reslurried to obtain compound A3 (10.4 g, 82%).
1 H-NMR (DMSO-d 6 ) δ: 8.63 (d, J = 5.1 Hz, 1H), 8.27 (t, J = 9.0 Hz, 1H), 7.57-7.51 (m, 4H), 7.43-7.36 (m , 4H), 7.22-7.19 (m, 1H), 6.98 (d, J = 5.1 Hz, 1H), 5.32 (s, 2H), 3.89 (s, 3H).
ESI-MS: m / z 447 [M + H] +
参考例4
7-(ベンジルオキシ)-6-メトキシ-4-(3-メトキシ-4-ニトロフェノキシ)キノリン (化合物A4)
　化合物A3 (3.00 g, 7.14 mol)のTHF (35 mL)溶液に、28％ナトリウムメトキシド-メタノール溶液 (2.91 mL, 14.3 mmol)を加え、室温で30分間撹拌した。混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、残渣にメタノール (50 mL)を加えてリスラリー精製し、化合物A4 (2.47 g, 80%)を得た。
1H-NMR (DMSO-d6) δ: 8.57 (d, J = 5.1 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.54-7.52 (m, 3H), 7.46-7.41 (m, 4H), 7.33 (d, J = 2.2 Hz, 1H), 6.88 (dd, J = 9.0, 2.4 Hz, 1H), 6.82 (d, J = 5.1 Hz, 1H), 5.32 (s, 2H), 3.94 (s, 3H), 3.92 (s, 3H).
ESI-MS: m/z 343 [M+H]+ Reference example 4
7- (Benzyloxy) -6-methoxy-4- (3-methoxy-4-nitrophenoxy) quinoline (Compound A4)
To a solution of compound A3 (3.00 g, 7.14 mol) in THF (35 mL) was added 28% sodium methoxide-methanol solution (2.91 mL, 14.3 mmol), and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure, methanol (50 mL) was added to the residue, and reslurry purification was performed to obtain Compound A4 (2.47 g, 80%).
1 H-NMR (DMSO-d 6 ) δ: 8.57 (d, J = 5.1 Hz, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.54-7.52 (m, 3H), 7.46-7.41 (m , 4H), 7.33 (d, J = 2.2 Hz, 1H), 6.88 (dd, J = 9.0, 2.4 Hz, 1H), 6.82 (d, J = 5.1 Hz, 1H), 5.32 (s, 2H), 3.94 (s, 3H), 3.92 (s, 3H).
ESI-MS: m / z 343 [M + H] +
参考例5
6-メトキシ-4-(3-メトキシ-4-ニトロフェノキシ)キノリン-7-オール (化合物A5)
　化合物A4 (2.47 g, 5.71 mmol)のトリフルオロ酢酸 (19 mL)溶液に、氷冷下でトリフルオロメタンスルホン酸 (1.0 mL, 11 mmol)を加え、氷冷下で30分間撹拌した。反応混合物を飽和重曹水に滴下して中和し、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、残渣に酢酸エチル(50 mL)を加えてリスラリー精製し、化合物A5 (1.62 g, 83%)を得た。
1H-NMR (DMSO-d6) δ: 10.25 (br s, 1H), 8.52 (d, J= 5.1 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.40 (s, 1H), 7.33 (s, 1H), 7.32 (d, J = 2.6 Hz, 1H), 6.87 (dd, J = 9.0, 2.4 Hz, 1H), 6.76 (d, J = 5.5 Hz, 1H), 3.94 (s, 3H), 3.92 (s, 3H).
ESI-MS: m/z 343 [M+H]+ Reference Example 5
6-Methoxy-4- (3-methoxy-4-nitrophenoxy) quinolin-7-ol (Compound A5)
To a solution of compound A4 (2.47 g, 5.71 mmol) in trifluoroacetic acid (19 mL) was added trifluoromethanesulfonic acid (1.0 mL, 11 mmol) under ice cooling, and the mixture was stirred under ice cooling for 30 minutes. The reaction mixture was neutralized by adding dropwise to saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure, ethyl acetate (50 mL) was added to the residue, and reslurry purification was performed to obtain Compound A5 (1.62 g, 83%).
1 H-NMR (DMSO-d 6 ) δ: 10.25 (br s, 1H), 8.52 (d, J = 5.1 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.40 (s, 1H) , 7.33 (s, 1H), 7.32 (d, J = 2.6 Hz, 1H), 6.87 (dd, J = 9.0, 2.4 Hz, 1H), 6.76 (d, J = 5.5 Hz, 1H), 3.94 (s, 3H), 3.92 (s, 3H).
ESI-MS: m / z 343 [M + H] +
参考例6
工程1
6-メトキシ-4-(3-メトキシ-4-ニトロフェノキシ)-7-(3-メトキシプロポキシ)キノリン (化合物A6)
　化合物A5 (100 mg, 0.29 mmol)のアセトン (2.0 mL)溶液に、1-ブロモ-3-メトキシプロパン (0.039 mL, 0.35 mmol）、および炭酸カリウム (61 mg, 0.44 mmol)を加え、還流下で終夜撹拌した。混合物を室温まで冷却し、水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (クロロホルム/メタノール＝85/15)で精製し、化合物A6 (93 mg, 77%)を得た。
1H-NMR (CDCl3) δ: 8.60 (d, J = 4.9 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.75 (dd, J = 8.8, 2.0 Hz, 1H), 6.69 (d, J = 4.9 Hz, 1H), 4.31 (t, J = 5.9 Hz, 2H), 4.00 (s, 3H), 3.94 (s, 3H), 3.62 (t, J= 5.9 Hz, 2H), 3.38 (s, 3H), 2.21 (m, 2H).
ESI-MS: m/z 415 [M+H]+.
工程2
2-メトキシ-4-[6-メトキシ-7-(3-メトキシプロポキシ)キノリン-4-イルオキシ]アニリン (化合物A7)
　化合物A6 (600 mg, 1.4 mmol)の酢酸エチル (30 mL)溶液を、フロー式水素化反応装置 [H-Cube(登録商標)、ThalesNano社製]を用いて10% Pd/C CatCart (登録商標) (φ4×30mm)を通過させた [full H2 mode、流速; 1.0 mL/min, 温度; 50 ℃]。反応終了後、混合物を減圧下で溶媒留去し、化合物A7 (540 mg, 97%)を得た。
1H-NMR (DMSO-d6) δ: 8.51 (d, J= 5.9 Hz, 1H), 7.56 (s, 1H), 7.40 (s, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.74 (d, J= 7.8 Hz, 1H), 6.63 (dd, J = 7.8, 2.0 Hz, 1H), 6.51 (d, J = 5.9 Hz, 1H), 4.21 (t, J = 6.3 Hz, 2H), 3.96 (s, 3H), 3.76 (s, 3H), 3.53 (t, J = 6.3 Hz, 2H), 3.28 (s, 3H), 2.06 (m, 2H).
ESI-MS: m/z 385 [M+H]+. Reference Example 6
Process 1
6-Methoxy-4- (3-methoxy-4-nitrophenoxy) -7- (3-methoxypropoxy) quinoline (Compound A6)
To a solution of compound A5 (100 mg, 0.29 mmol) in acetone (2.0 mL), 1-bromo-3-methoxypropane (0.039 mL, 0.35 mmol) and potassium carbonate (61 mg, 0.44 mmol) were added and refluxed. Stir overnight. The mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 85/15) to obtain Compound A6 (93 mg, 77%).
1 H-NMR (CDCl 3 ) δ: 8.60 (d, J = 4.9 Hz, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 6.88 ( d, J = 2.0 Hz, 1H), 6.75 (dd, J = 8.8, 2.0 Hz, 1H), 6.69 (d, J = 4.9 Hz, 1H), 4.31 (t, J = 5.9 Hz, 2H), 4.00 ( s, 3H), 3.94 (s, 3H), 3.62 (t, J = 5.9 Hz, 2H), 3.38 (s, 3H), 2.21 (m, 2H).
ESI-MS: m / z 415 [M + H] + .
Process 2
2-Methoxy-4- [6-methoxy-7- (3-methoxypropoxy) quinolin-4-yloxy] aniline (Compound A7)
A solution of Compound A6 (600 mg, 1.4 mmol) in ethyl acetate (30 mL) was added to a 10% Pd / C CatCart (registered trademark) using a flow hydrogenation reactor [H-Cube (registered trademark), manufactured by ThalesNano]. ) (φ4 × 30 mm) [full H2 mode, flow rate; 1.0 mL / min, temperature; 50 ° C.]. After completion of the reaction, the mixture was evaporated under reduced pressure to give compound A7 (540 mg, 97%).
1 H-NMR (DMSO-d 6 ) δ: 8.51 (d, J = 5.9 Hz, 1H), 7.56 (s, 1H), 7.40 (s, 1H), 6.80 (d, J = 2.0 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 6.63 (dd, J = 7.8, 2.0 Hz, 1H), 6.51 (d, J = 5.9 Hz, 1H), 4.21 (t, J = 6.3 Hz, 2H), 3.96 (s, 3H), 3.76 (s, 3H), 3.53 (t, J = 6.3 Hz, 2H), 3.28 (s, 3H), 2.06 (m, 2H).
ESI-MS: m / z 385 [M + H] + .
工程3
フェニル 2-メトキシ-4-[6-メトキシ-7-(3-メトキシプロポキシ)キノリン-4-イルオキシ]フェニルカルバマート (化合物A8)
　化合物A7 (540 mg, 1.4 mmol)のTHF (14 mL)溶液に、クロロギ酸フェニル (0.27 mL, 2.1 mmol）、および炭酸カリウム (390 mg, 2.8 mmol)を加え、室温で30分間撹拌した。混合物に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (クロロホルム/メタノール＝90/10)で精製し、化合物A8 (570 mg, 81%)を得た。
1H-NMR (DMSO-d6) δ: 9.26 (br s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H), 7.43 (t, J = 7.8 Hz, 2H), 7.39 (s, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 2H), 7.06 (d, J = 2.0 Hz, 1H), 6.84 (dd, J = 8.8, 2.0 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H), 4.20 (t, J = 6.3 Hz, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 3.53 (t, J = 6.3 Hz, 2H), 3.28 (s, 3H), 2.05 (m, 2H).
ESI-MS: m/z 505 [M+H]+. Process 3
Phenyl 2-methoxy-4- [6-methoxy-7- (3-methoxypropoxy) quinolin-4-yloxy] phenylcarbamate (Compound A8)
To a solution of compound A7 (540 mg, 1.4 mmol) in THF (14 mL), phenyl chloroformate (0.27 mL, 2.1 mmol) and potassium carbonate (390 mg, 2.8 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 90/10) to obtain Compound A8 (570 mg, 81%).
1 H-NMR (DMSO-d 6 ) δ: 9.26 (br s, 1H), 8.48 (d, J = 4.9 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.51 (s, 1H) , 7.43 (t, J = 7.8 Hz, 2H), 7.39 (s, 1H), 7.25 (t, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 2H), 7.06 (d, J = 2.0 Hz, 1H), 6.84 (dd, J = 8.8, 2.0 Hz, 1H), 6.53 (d, J = 4.9 Hz, 1H), 4.20 (t, J = 6.3 Hz, 2H), 3.94 (s, 3H) , 3.85 (s, 3H), 3.53 (t, J = 6.3 Hz, 2H), 3.28 (s, 3H), 2.05 (m, 2H).
ESI-MS: m / z 505 [M + H] + .
参考例7
工程1
エチル 1-イソプロピル-3-メチル-1H-ピラゾール-5-カルボキシラート (化合物B1)
　2,4-ジオキソ吉草酸エチル (4.44 mL, 31.6 mmol)のエタノール (30.0 mL)溶液に、イソプロピルヒドラジン・塩酸塩 (4.20 g, 37.9 mmol)、および酢酸 (2.17 mL, 37.9 mmol)を加えて室温で4時間撹拌した。混合物を減圧下で溶媒留去し、水、および飽和重曹水を加えて酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (ヘプタン/酢酸エチル＝80/20)で精製し、化合物B1 (530 mg, 9％)を得た。
1H-NMR (CDCl3) δ: 6.58 (s, 1H), 5.49-5.41 (m, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.28 (s, 3H), 1.47 (d, J = 7.0 Hz, 6H), 1.36 (t, J = 7.1 Hz, 3H).
ESI-MS: m/z 197 [M+H]+
工程2
1-イソプロピル-3-メチル-1H-ピラゾール-5-カルボン酸 (化合物B2)
　化合物B1 (530 mg, 2.70 mmol)を混合溶媒 (5.5 mL、エタノール/水＝1/1)に溶解し、水酸化カリウム (758 mg, 13.5 mmol)を加えて60 ℃で2時間撹拌した。混合物を減圧下で溶媒留去し、残渣に2 mol/L塩酸を加えてpH4に調整した後、室温で30分間撹拌した。析出した固体をろ取して化合物B2 (234 mg, 51%)を得た。
1H-NMR (DMSO-d6) δ: 6.13 (s, 1H), 5.87-5.78 (m, 1H), 2.09 (s, 3H), 1.27 (d, J = 6.6 Hz, 6H). Reference Example 7
Process 1
Ethyl 1-isopropyl-3-methyl-1H-pyrazole-5-carboxylate (Compound B1)
To a solution of ethyl 2,4-dioxovalerate (4.44 mL, 31.6 mmol) in ethanol (30.0 mL) was added isopropylhydrazine hydrochloride (4.20 g, 37.9 mmol) and acetic acid (2.17 mL, 37.9 mmol) at room temperature. For 4 hours. The mixture was evaporated under reduced pressure, water and saturated aqueous sodium hydrogen carbonate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 80/20) to obtain Compound B1 (530 mg, 9%).
1 H-NMR (CDCl 3 ) δ: 6.58 (s, 1H), 5.49-5.41 (m, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.28 (s, 3H), 1.47 (d, J = 7.0 Hz, 6H), 1.36 (t, J = 7.1 Hz, 3H).
ESI-MS: m / z 197 [M + H] +
Process 2
1-Isopropyl-3-methyl-1H-pyrazole-5-carboxylic acid (Compound B2)
Compound B1 (530 mg, 2.70 mmol) was dissolved in a mixed solvent (5.5 mL, ethanol / water = 1/1), potassium hydroxide (758 mg, 13.5 mmol) was added, and the mixture was stirred at 60 ° C. for 2 hr. The mixture was evaporated under reduced pressure, 2 mol / L hydrochloric acid was added to the residue to adjust to pH 4, and the mixture was stirred at room temperature for 30 min. The precipitated solid was collected by filtration to obtain Compound B2 (234 mg, 51%).
1 H-NMR (DMSO-d 6 ) δ: 6.13 (s, 1H), 5.87-5.78 (m, 1H), 2.09 (s, 3H), 1.27 (d, J = 6.6 Hz, 6H).
工程3
1-イソプロピル-3-メチル-1H-ピラゾール-5-カルボキサミド (化合物B3)
　化合物B2 (300 mg, 1.784 mmol)のTHF (8.92 mL)懸濁液に、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド・塩酸塩 (EDCI) (513 mg, 2.68 mmol)、および1-ヒドロキシベンゾトリアゾール・1水和物 (HOBt) (410 mg, 2.68 mmol)を加えて室温で22時間撹拌し、28%アンモニア水 (4.50 mL)を加えて室温でさらに30分間撹拌した。混合物に水を加え、クロロホルムで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (ヘプタン/酢酸エチル＝90/10-50/50)で精製し、化合物B3 (219 mg, 73%)を得た。
1H-NMR (CDCl3) δ: 6.28 (s, 1H), 5.71 (br s, 1H), 5.51-5.43 (m, 1H), 2.29 (s, 3H), 1.48 (d, J = 6.6 Hz, 6H).
ESI-MS: m/z 168 [M+H]+ Process 3
1-Isopropyl-3-methyl-1H-pyrazole-5-carboxamide (Compound B3)
To a suspension of compound B2 (300 mg, 1.784 mmol) in THF (8.92 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (513 mg, 2.68 mmol), and 1 -Hydroxybenzotriazole monohydrate (HOBt) (410 mg, 2.68 mmol) was added and stirred at room temperature for 22 hours, 28% aqueous ammonia (4.50 mL) was added, and the mixture was further stirred at room temperature for 30 minutes. Water was added to the mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane / ethyl acetate = 90 / 10-50 / 50) to obtain Compound B3 (219 mg, 73%). .
1 H-NMR (CDCl 3 ) δ: 6.28 (s, 1H), 5.71 (br s, 1H), 5.51-5.43 (m, 1H), 2.29 (s, 3H), 1.48 (d, J = 6.6 Hz, 6H).
ESI-MS: m / z 168 [M + H] +
参考例8
工程1
エチル 1-tert-ブチル-5-メチル-1H-ピラゾール-3-カルボキシラート (化合物B4)
　参考例7の工程１に準じて、2,4-ジオキソ吉草酸エチル (5.0 g, 31.6 mmol)、tert-ブチルヒドラジン・塩酸塩 (4.73 g, 37.9 mmol)、および酢酸 (3.62 mL, 63.2 mmol)から化合物B4 (4.39 g, 66%)を得た。
1H-NMR (CDCl3) δ: 6.55 (s, 1H), 4.36 (q, J = 7.2 Hz, 2H), 2.47 (s, 3H), 1.67 (s, 9H), 1.37 (t, J = 7.2 Hz, 3H).
工程2
エチル 4-ブロモ-5-(ブロモメチル)-1-tert-ブチル-1H-ピラゾール-3-カルボキシラート (化合物B5)
　化合物B4 (560 mg, 2.66 mmol)のジクロロメタン (26.6 mL)溶液に、臭素 (0.306 mL, 5.95 mmol)、および炭酸カリウム (822 mg, 5,95 mmol)を加えて室温で6時間撹拌した。混合物に飽和チオ硫酸ナトリウム水溶液を加え、1 mol/L塩酸を加えてpH6に調整し、分液ロートを用いて有機層を分離し、得られた有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル＝97/3-90/10)で精製し、化合物B5 (440 mg, 45%)を得た。
ESI-MS: m/z 367(79Br,79Br), 369(79Br,81Br), 371(81Br,81Br) [M+H]+ Reference Example 8
Process 1
Ethyl 1-tert-butyl-5-methyl-1H-pyrazole-3-carboxylate (Compound B4)
According to Step 1 of Reference Example 7, ethyl 2,4-dioxovalerate (5.0 g, 31.6 mmol), tert-butylhydrazine hydrochloride (4.73 g, 37.9 mmol), and acetic acid (3.62 mL, 63.2 mmol) Gave Compound B4 (4.39 g, 66%).
1 H-NMR (CDCl 3 ) δ: 6.55 (s, 1H), 4.36 (q, J = 7.2 Hz, 2H), 2.47 (s, 3H), 1.67 (s, 9H), 1.37 (t, J = 7.2 Hz, 3H).
Process 2
Ethyl 4-bromo-5- (bromomethyl) -1-tert-butyl-1H-pyrazole-3-carboxylate (Compound B5)
Bromine (0.306 mL, 5.95 mmol) and potassium carbonate (822 mg, 5,95 mmol) were added to a solution of compound B4 (560 mg, 2.66 mmol) in dichloromethane (26.6 mL), and the mixture was stirred at room temperature for 6 hours. Saturated aqueous sodium thiosulfate solution is added to the mixture, 1 mol / L hydrochloric acid is added to adjust to pH 6, the organic layer is separated using a separatory funnel, and the resulting organic layer is washed with saturated brine, Dry over sodium and filter. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 97 / 3-90 / 10) to give compound B5 (440 mg, 45%). .
ESI-MS: m / z 367 ( 79 Br, 79 Br), 369 ( 79 Br, 81 Br), 371 ( 81 Br, 81 Br) [M + H] +
工程3
エチル 4-ブロモ-1-tert-ブチル-5-[(ジメチルアミノ)メチル]-1H-ピラゾール-3-カルボキシラート (化合物B6)
　化合物B5 (440 mg, 1.20 mmol)のTHF (12.0 mL)溶液に、2 mol/L ジメチルアミン-メタノール溶液 (1.80 mL, 3.60 mmol)を加えて室温で2時間撹拌した。混合物を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (ヘキサン/酢酸エチル＝90/10)で精製し、化合物B6 (333 mg, 84%)を得た。
1H-NMR (CDCl3) δ: 4.41 (q, J = 7.2 Hz, 2H), 3.57 (s, 2H), 2.21 (s, 6H), 1.71 (s, 9H), 1.41 (t, J = 7.2 Hz, 3H).
ESI-MS: m/z 332(79Br), 334(81Br) [M+H]+
工程4
エチル 1-tert-ブチル-5-[(ジメチルアミノ)メチル]-1H-ピラゾール-3-カルボキシラート (化合物B7)
　化合物B6 (333 mg, 1.00 mmol)のエタノール (10.0 mL)溶液に、10％パラジウム炭素 (27 mg)を加えて、水素雰囲気下、50 ℃で終夜撹拌した。混合物をろ過した後、ろ液を減圧下で溶媒留去し、化合物B7 (267 mg, 99%)を得た。
1H-NMR (CDCl3) δ: 7.42 (s, 1H), 4.53 (s, 2H), 4.37 (q, J = 7.3 Hz, 2H), 2.87 (s, 6H), 1.73 (s, 9H), 1.38 (t, J = 7.3 Hz, 3H).
ESI-MS: m/z 254 [M+H]+ Process 3
Ethyl 4-bromo-1-tert-butyl-5-[(dimethylamino) methyl] -1H-pyrazole-3-carboxylate (Compound B6)
To a THF (12.0 mL) solution of Compound B5 (440 mg, 1.20 mmol), 2 mol / L dimethylamine-methanol solution (1.80 mL, 3.60 mmol) was added and stirred at room temperature for 2 hours. The mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 90/10) to give Compound B6 (333 mg, 84%).
1 H-NMR (CDCl 3 ) δ: 4.41 (q, J = 7.2 Hz, 2H), 3.57 (s, 2H), 2.21 (s, 6H), 1.71 (s, 9H), 1.41 (t, J = 7.2 Hz, 3H).
ESI-MS: m / z 332 ( 79 Br), 334 ( 81 Br) [M + H] +
Process 4
Ethyl 1-tert-butyl-5-[(dimethylamino) methyl] -1H-pyrazole-3-carboxylate (Compound B7)
To a solution of compound B6 (333 mg, 1.00 mmol) in ethanol (10.0 mL) was added 10% palladium carbon (27 mg), and the mixture was stirred at 50 ° C. overnight under a hydrogen atmosphere. The mixture was filtered, and the filtrate was evaporated under reduced pressure to give compound B7 (267 mg, 99%).
1 H-NMR (CDCl 3 ) δ: 7.42 (s, 1H), 4.53 (s, 2H), 4.37 (q, J = 7.3 Hz, 2H), 2.87 (s, 6H), 1.73 (s, 9H), 1.38 (t, J = 7.3 Hz, 3H).
ESI-MS: m / z 254 [M + H] +
工程5
1-tert-ブチル-5-[(ジメチルアミノ)メチル]-1H-ピラゾール-3-カルボン酸 (化合物B8)
　参考例7の工程2に準じて、化合物B7 (267 mg, 1.07 mmol)および水酸化カリウム (598 mg, 10.7 mmol)から化合物B8 (205 mg, 83%)を得た。
1H-NMR (DMSO-d6) δ: 10.03 (br s, 1H), 7.16 (s, 1H), 4.70 (s, 2H), 2.86 (s, 6H), 1.61 (s, 9H).
工程6
1-tert-ブチル-5-((ジメチルアミノ)メチル)-1H-ピラゾール-3-カルボキサミド (化合物B9)
　参考例7の工程3に準じて、化合物B8 (50 mg, 0.222 mmol)、EDCI (64 mg, 0.333 mmol)、HOBt (51 mg, 0.333 mmol)、および28%アンモニア水 (0.691 mL)から化合物B9 (17 mg, 34%)を得た。
1H-NMR (CDCl3) δ: 6.76 (br s, 1H), 6.69 (s, 1H), 5.40 (br s, 1H), 3.47 (s, 2H), 2.20 (s, 6H), 1.67 (s, 9H). Process 5
1-tert-Butyl-5-[(dimethylamino) methyl] -1H-pyrazole-3-carboxylic acid (Compound B8)
According to Step 2 of Reference Example 7, compound B8 (205 mg, 83%) was obtained from compound B7 (267 mg, 1.07 mmol) and potassium hydroxide (598 mg, 10.7 mmol).
1 H-NMR (DMSO-d 6 ) δ: 10.03 (br s, 1H), 7.16 (s, 1H), 4.70 (s, 2H), 2.86 (s, 6H), 1.61 (s, 9H).
Process 6
1-tert-Butyl-5-((dimethylamino) methyl) -1H-pyrazole-3-carboxamide (Compound B9)
According to Step 3 of Reference Example 7, compound B8 (50 mg, 0.222 mmol), EDCI (64 mg, 0.333 mmol), HOBt (51 mg, 0.333 mmol), and 28% aqueous ammonia (0.691 mL) were used as compound B9. (17 mg, 34%) was obtained.
1 H-NMR (CDCl 3 ) δ: 6.76 (br s, 1H), 6.69 (s, 1H), 5.40 (br s, 1H), 3.47 (s, 2H), 2.20 (s, 6H), 1.67 (s , 9H).
参考例9
工程1
エチル1,4-ジメチル-1H-イミダゾール-5-カルボキシラート (化合物B10)
エチル1,5-ジメチル-1H-イミダゾール-4-カルボキシラート (化合物B11)
　エチル5-メチル-1H-イミダゾール-4-カルボキシラート (1.50 g, 9.73 mmol)のDMF (30 mL)溶液に、氷冷下、撹拌しながら60%水素化ナトリウム (0.467 g, 11.7 mmol)およびp-トルエンスルホン酸メチル (1.77 mL, 11.7 mmol)を順次加え、室温で3時間撹拌した。混合物に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (メタノール/クロロホルム＝5/95)で精製し、化合物B10 (0.564 g, 35%)、および化合物B11 (0.548 mg, 34 %)を得た。
化合物B10
1H-NMR (CDCl3) δ: 7.38 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.58 (s, 3H), 2.53 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).
ESI-MS: m/z 169 [M+H]+
化合物B11
1H-NMR (CDCl3) δ: 7.41 (s, 1H), 4.33 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 2.48 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H).
ESI-MS: m/z 169 [M+H]+ Reference Example 9
Process 1
Ethyl 1,4-dimethyl-1H-imidazole-5-carboxylate (Compound B10)
Ethyl 1,5-dimethyl-1H-imidazole-4-carboxylate (Compound B11)
To a solution of ethyl 5-methyl-1H-imidazole-4-carboxylate (1.50 g, 9.73 mmol) in DMF (30 mL) under ice-cooling, 60% sodium hydride (0.467 g, 11.7 mmol) and p -Methyl toluene sulfonate (1.77 mL, 11.7 mmol) was sequentially added, and the mixture was stirred at room temperature for 3 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol / chloroform = 5/95) to give compound B10 (0.564 g, 35%), and compound B11 (0.548 mg, 34%).
Compound B10
1 H-NMR (CDCl 3 ) δ: 7.38 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.58 (s, 3H), 2.53 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).
ESI-MS: m / z 169 [M + H] +
Compound B11
1 H-NMR (CDCl 3 ) δ: 7.41 (s, 1H), 4.33 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H), 2.48 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H).
ESI-MS: m / z 169 [M + H] +
工程2
1,4-ジメチル-1H-イミダゾール-5-カルボン酸 (化合物B12)
　参考例7の工程2に準じて、化合物B10 (409 mg, 2.43 mmol)、および水酸化ナトリウム (584 mg, 14.6 mmol)から化合物B12の粗生成物 (400 mg)を得た。
1H-NMR (DMSO-d6) δ: 8.75 (s, 1H), 3.90 (s, 3H), 2.46 (s, 3H).
ESI-MS: m/z 141 [M+H]+
工程3
1,4-ジメチル-1H-イミダゾール-5-カルボキサミド (化合物B13)
　参考例7の工程3に準じて、化合物B12(100 mg)、1,1'-カルボニルジイミダゾール (CDI) (347 mg, 2.14 mmol)、および28%アンモニア水 (0.278 mL)から化合物B13 (61.9 mg, 2段階 62%)を得た。
1H-NMR (DMSO-d6) δ: 7.55 (s, 1H), 7.33-7.22 (br m, 2H), 3.67 (s, 3H), 2.27 (s, 3H).
ESI-MS: m/z 140 [M+H]+ Process 2
1,4-Dimethyl-1H-imidazole-5-carboxylic acid (Compound B12)
According to Step 2 of Reference Example 7, a crude product (400 mg) of compound B12 was obtained from compound B10 (409 mg, 2.43 mmol) and sodium hydroxide (584 mg, 14.6 mmol).
1 H-NMR (DMSO-d 6 ) δ: 8.75 (s, 1H), 3.90 (s, 3H), 2.46 (s, 3H).
ESI-MS: m / z 141 [M + H] +
Process 3
1,4-Dimethyl-1H-imidazole-5-carboxamide (Compound B13)
According to Step 3 of Reference Example 7, compound B12 (100 mg), 1,1′-carbonyldiimidazole (CDI) (347 mg, 2.14 mmol), and 28% aqueous ammonia (0.278 mL) were converted to compound B13 (61.9 mg, 2 steps 62%).
1 H-NMR (DMSO-d 6 ) δ: 7.55 (s, 1H), 7.33-7.22 (br m, 2H), 3.67 (s, 3H), 2.27 (s, 3H).
ESI-MS: m / z 140 [M + H] +
参考例10
工程1
1,5-ジメチル-1H-イミダゾール-4-カルボン酸 (化合物B14)
　参考例7の工程2に準じて、化合物B11 (564 mg, 3.35 mmol)、および水酸化ナトリウム (805 mg, 20.1 mmol)から化合物B14 (300 mg, 64%)を得た。
1H-NMR (DMSO-d6) δ: 8.96 (s, 1H), 3.74 (s, 3H), 2.51 (s, 3H).
ESI-MS: m/z 141 [M+H]+
工程2
1,5-ジメチル-1H-イミダゾール-4-カルボキサミド (化合物B15)
　参考例7の工程3に準じて、化合物B14 (301 mg, 2.15 mmol)、CDI (1.04 g, 6.44 mmol)、および28%アンモニア水 (1.67 mL)から、化合物B15 (149 mg, 50%)を得た。
1H-NMR (DMSO-d6) δ: 7.54 (s, 1H), 7.14 (br s, 1H), 6.90 (br s, 1H), 3.53 (s, 3H), 2.43 (s, 3H).
ESI-MS: m/z 140 [M+H]+ Reference Example 10
Process 1
1,5-Dimethyl-1H-imidazole-4-carboxylic acid (Compound B14)
According to Step 2 of Reference Example 7, compound B14 (300 mg, 64%) was obtained from compound B11 (564 mg, 3.35 mmol) and sodium hydroxide (805 mg, 20.1 mmol).
1 H-NMR (DMSO-d 6 ) δ: 8.96 (s, 1H), 3.74 (s, 3H), 2.51 (s, 3H).
ESI-MS: m / z 141 [M + H] +
Process 2
1,5-Dimethyl-1H-imidazole-4-carboxamide (Compound B15)
According to Step 3 of Reference Example 7, compound B15 (149 mg, 50%) was obtained from compound B14 (301 mg, 2.15 mmol), CDI (1.04 g, 6.44 mmol), and 28% aqueous ammonia (1.67 mL). Obtained.
1 H-NMR (DMSO-d 6 ) δ: 7.54 (s, 1H), 7.14 (br s, 1H), 6.90 (br s, 1H), 3.53 (s, 3H), 2.43 (s, 3H).
ESI-MS: m / z 140 [M + H] +
参考例11
工程1
メチル 2-(シクロプロパンカルボキサミド)-3-ヒドロキシブタノエート (化合物B16) 
　L-トレオニンメチルエステル・塩酸塩 (1.00 g, 5.90 mmol)のジクロロメタン (29.5 mL)溶液に、シクロプロパンカルボン酸 (0.517 mL, 6.49 mmol)、トリエチルアミン (0.904 mL, 6.49 mmol)、EDCI (1.24 g, 6.49 mmol)、およびHOBt (993 mg, 6.49 mmol)を加えて室温で18時間撹拌した。混合物に水、および飽和重曹水を加え、クロロホルムで抽出し、有機層を無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (クロロホルム/メタノール＝90/10)で精製し、化合物B16 (451 mg, 38%)を得た。
1H-NMR (CDCl3) δ: 6.44-6.42 (br m, 1H), 4.64 (dd, J = 8.8, 2.9 Hz, 1H), 4.37-4.31 (m, 1H), 3.78 (s, 3H), 2.08 (br s, 1H), 1.53-1.47 (m, 1H), 1.24 (d, J = 5.9 Hz, 3H), 1.02-0.98 (m, 2H), 0.81-0.80 (m, 2H).
ESI-MS: m/z 202 [M+H]+
工程2
メチル 2-シクロプロピル-5-メチル-4,5-ジヒドロオキサゾール-4-カルボキシラート (化合物B17)
　化合物B16 (210 mg, 1.04 mmol)のジクロロメタン (14.9 mL)溶液に、氷冷下、塩化チオニル (0.609 mL, 8.35 mmol)を加え、氷冷下で8時間撹拌した。混合物に飽和重曹水を加え、クロロホルムで抽出し、有機層を無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、ジアステレオマー混合物である化合物B17 (188 mg, 98%)を得た。
1H-NMR (CDCl3) δ: 4.87-4.79 (m, 1H), 4.74 (d, J = 10.7 Hz, 1H), 3.76 (s, 3H), 1.75-1.68 (m, 1H), 1.24 (d, J = 6.8 Hz, 3H), 1.02-0.98 (m, 2H), 0.91-0.87 (m, 2H).
ESI-MS: m/z 184 [M+H]+ Reference Example 11
Process 1
Methyl 2- (cyclopropanecarboxamide) -3-hydroxybutanoate (Compound B16)
To a solution of L-threonine methyl ester hydrochloride (1.00 g, 5.90 mmol) in dichloromethane (29.5 mL), cyclopropanecarboxylic acid (0.517 mL, 6.49 mmol), triethylamine (0.904 mL, 6.49 mmol), EDCI (1.24 g, 6.49 mmol) and HOBt (993 mg, 6.49 mmol) were added and stirred at room temperature for 18 hours. Water and saturated aqueous sodium hydrogen carbonate were added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 90/10) to obtain Compound B16 (451 mg, 38%).
1 H-NMR (CDCl 3 ) δ: 6.44-6.42 (br m, 1H), 4.64 (dd, J = 8.8, 2.9 Hz, 1H), 4.37-4.31 (m, 1H), 3.78 (s, 3H), 2.08 (br s, 1H), 1.53-1.47 (m, 1H), 1.24 (d, J = 5.9 Hz, 3H), 1.02-0.98 (m, 2H), 0.81-0.80 (m, 2H).
ESI-MS: m / z 202 [M + H] +
Process 2
Methyl 2-cyclopropyl-5-methyl-4,5-dihydrooxazole-4-carboxylate (Compound B17)
To a solution of compound B16 (210 mg, 1.04 mmol) in dichloromethane (14.9 mL) was added thionyl chloride (0.609 mL, 8.35 mmol) under ice cooling, and the mixture was stirred for 8 hours under ice cooling. Saturated aqueous sodium hydrogen carbonate was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give diastereomeric mixture Compound B17 (188 mg, 98%).
1 H-NMR (CDCl 3 ) δ: 4.87-4.79 (m, 1H), 4.74 (d, J = 10.7 Hz, 1H), 3.76 (s, 3H), 1.75-1.68 (m, 1H), 1.24 (d , J = 6.8 Hz, 3H), 1.02-0.98 (m, 2H), 0.91-0.87 (m, 2H).
ESI-MS: m / z 184 [M + H] +
工程3
メチル 2-シクロプロピル-5-メチルオキサゾール-4-カルボキシラート (化合物B18)
　化合物B17 (188 mg, 1.03 mmol)のジクロロメタン (10.3 mL)溶液に、氷冷下、1,8-ジアザビシクロ[5.4.0]-7-ウンデセン (DBU) (0.773 mL, 5.13 mmol)、およびブロモトリクロロメタン (0.504 mL, 5.13 mmol)を加え、室温で2時間撹拌した。混合物を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (ヘプタン/酢酸エチル＝67/33)で精製し、化合物B18 (132 mg, 71%)を得た。
1H-NMR (CDCl3) δ: 3.89 (s, 3H), 2.56 (s, 3H), 2.08-2.01 (m, 1H), 1.12-1.00 (m, 4H).
ESI-MS: m/z 182 [M+H]+
工程4
2-シクロプロピル-5-メチルオキサゾール-4-カルボン酸 (化合物B19)
　参考例7の工程2に準じて、化合物B18 (118 mg, 0.65 mmol)、および水酸化ナトリウム (0.773 mL, 5.13 mmol)から、化合物B19の粗生成物 (105 mg)を得た。粗生成物は精製することなく次の反応に用いた。
ESI-MS: m/z 166 [M-H]- Process 3
Methyl 2-cyclopropyl-5-methyloxazole-4-carboxylate (Compound B18)
To a solution of compound B17 (188 mg, 1.03 mmol) in dichloromethane (10.3 mL), ice-cooled 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) (0.773 mL, 5.13 mmol), and bromotrichloro Methane (0.504 mL, 5.13 mmol) was added and stirred at room temperature for 2 hours. The mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 67/33) to obtain Compound B18 (132 mg, 71%).
1 H-NMR (CDCl 3 ) δ: 3.89 (s, 3H), 2.56 (s, 3H), 2.08-2.01 (m, 1H), 1.12-1.00 (m, 4H).
ESI-MS: m / z 182 [M + H] +
Process 4
2-Cyclopropyl-5-methyloxazole-4-carboxylic acid (Compound B19)
According to Step 2 of Reference Example 7, a crude product of Compound B19 (105 mg) was obtained from Compound B18 (118 mg, 0.65 mmol) and sodium hydroxide (0.773 mL, 5.13 mmol). The crude product was used in the next reaction without purification.
ESI-MS: m / z 166 [MH] -
工程5
2-シクロプロピル-5-メチルオキサゾール-4-カルボキサミド (化合物B20)
　参考例7の工程3に準じて、化合物B19 (105 mg)、1,1'-カルボニルジイミダゾール (304 mg, 1.87 mmol)、および28%アンモニア水 (0.243 mL)から化合物B20 (94.4 mg, 2段階 91%）を得た。
1H-NMR (CDCl3) δ: 6.75 (br s, 1H), 5.40 (br s, 1H), 2.57 (s, 3H), 2.01-1.94 (m, 1H), 1.03-1.02 (m, 4H).
ESI-MS: m/z 167 [M+H]+ Process 5
2-Cyclopropyl-5-methyloxazole-4-carboxamide (Compound B20)
According to Step 3 of Reference Example 7, compound B19 (105 mg), 1,1′-carbonyldiimidazole (304 mg, 1.87 mmol), and 28% aqueous ammonia (0.243 mL) were converted to compound B20 (94.4 mg, 2 Step 91%) was obtained.
1 H-NMR (CDCl 3 ) δ: 6.75 (br s, 1H), 5.40 (br s, 1H), 2.57 (s, 3H), 2.01-1.94 (m, 1H), 1.03-1.02 (m, 4H) .
ESI-MS: m / z 167 [M + H] +
参考例12
工程1
メチル 3-ヒドロキシ-2-(1-メチルシクロプロパンカルボキサミド)ブタノエート (化合物B21)
　参考例11の工程1に準じて、L-トレオニンメチルエステル・塩酸塩 (1.00 g, 5.90 mmol)、1-メチルシクロプロパンカルボン酸 (649 mg, 6.49 mmol)、トリエチルアミン (0.904 mL, 6.49 mmol)、EDCI (1.24 g, 6.49 mmol)、およびHOBt (993 mg, 6.49 mmol)から、化合物B21 (1.31 g, 100%)を得た。
1H-NMR (CDCl3) δ: 6.51 (br s, 1H), 4.61 (dd, J = 8.8, 2.9 Hz, 1H), 4.34 (br s, 1H), 3.78 (s, 3H), 2.26 (s, 1H), 1.40 (s, 3H), 1.25-1.22 (m, 5H), 0.63 (q, J = 3.3 Hz, 2H).
ESI-MS: m/z 216 [M+H]+
工程2
メチル 5-メチル-2-(1-メチルシクロプロピル)-4,5-ジヒドロオキサゾール-4-カルボキシラート (化合物B22)
　参考例11の工程2に準じて、化合物B21 (503 mg, 2.34 mmol)、および塩化チオニル (1.36 mL, 18.7 mmol)から、ジアステレオマー混合物である化合物B22 (437 mg, 95%)を得た。
1H-NMR (CDCl3) δ: 4.85-4.74 (m, 2H), 3.75 (s, 3H), 1.38 (s, 3H), 1.23 (d, J = 6.8 Hz, 3H), 1.18-1.17 (m, 2H), 0.71-0.65 (m, 2H).
ESI-MS: m/z 198 [M+H]+ Reference Example 12
Process 1
Methyl 3-hydroxy-2- (1-methylcyclopropanecarboxamide) butanoate (Compound B21)
According to Step 1 of Reference Example 11, L-threonine methyl ester / hydrochloride (1.00 g, 5.90 mmol), 1-methylcyclopropanecarboxylic acid (649 mg, 6.49 mmol), triethylamine (0.904 mL, 6.49 mmol), Compound B21 (1.31 g, 100%) was obtained from EDCI (1.24 g, 6.49 mmol) and HOBt (993 mg, 6.49 mmol).
1 H-NMR (CDCl 3 ) δ: 6.51 (br s, 1H), 4.61 (dd, J = 8.8, 2.9 Hz, 1H), 4.34 (br s, 1H), 3.78 (s, 3H), 2.26 (s , 1H), 1.40 (s, 3H), 1.25-1.22 (m, 5H), 0.63 (q, J = 3.3 Hz, 2H).
ESI-MS: m / z 216 [M + H] +
Process 2
Methyl 5-methyl-2- (1-methylcyclopropyl) -4,5-dihydrooxazole-4-carboxylate (Compound B22)
According to Step 2 of Reference Example 11, Compound B21 (437 mg, 95%) as a mixture of diastereomers was obtained from Compound B21 (503 mg, 2.34 mmol) and thionyl chloride (1.36 mL, 18.7 mmol). .
1 H-NMR (CDCl 3 ) δ: 4.85-4.74 (m, 2H), 3.75 (s, 3H), 1.38 (s, 3H), 1.23 (d, J = 6.8 Hz, 3H), 1.18-1.17 (m , 2H), 0.71-0.65 (m, 2H).
ESI-MS: m / z 198 [M + H] +
工程3
メチル 5-メチル-2-(1-メチルシクロプロピル)オキサゾール-4-カルボキシラート (化合物B23)
　参考例11の工程3に準じて、化合物B22 (426 mg, 2.16 mmol)、DBU (1.63 mL, 10.8 mmol)、およびブロモトリクロロメタン (1.06 mL, 10.8 mmol)から、化合物B23 (320 mg, 76%)を得た。
1H-NMR (CDCl3) δ: 3.89 (s, 3H), 2.56 (s, 3H), 1.52 (s, 3H), 1.26 (q, J = 3.6 Hz, 2H), 0.83 (q, J = 3.6 Hz, 2H).
ESI-MS: m/z 196 [M+H]+
工程4
5-メチル-2-(1-メチルシクロプロピル)オキサゾール-4-カルボン酸 (化合物B24)
　参考例7の工程2に準じて、化合物B23 (320 mg, 1.53 mmol)、および水酸化ナトリウム (367 mg, 9.18 mmol)から、化合物B24の粗生成物 (281 mg)を得た。粗生成物は、精製することなく次の反応に用いた。
ESI-MS: m/z 180 [M-H]- Process 3
Methyl 5-methyl-2- (1-methylcyclopropyl) oxazole-4-carboxylate (Compound B23)
According to Step 3 of Reference Example 11, from compound B22 (426 mg, 2.16 mmol), DBU (1.63 mL, 10.8 mmol), and bromotrichloromethane (1.06 mL, 10.8 mmol), compound B23 (320 mg, 76% )
1 H-NMR (CDCl 3 ) δ: 3.89 (s, 3H), 2.56 (s, 3H), 1.52 (s, 3H), 1.26 (q, J = 3.6 Hz, 2H), 0.83 (q, J = 3.6 Hz, 2H).
ESI-MS: m / z 196 [M + H] +
Process 4
5-Methyl-2- (1-methylcyclopropyl) oxazole-4-carboxylic acid (Compound B24)
According to Step 2 of Reference Example 7, a crude product (281 mg) of compound B24 was obtained from compound B23 (320 mg, 1.53 mmol) and sodium hydroxide (367 mg, 9.18 mmol). The crude product was used in the next reaction without purification.
ESI-MS: m / z 180 [MH] -
工程5
5-メチル-2-(1-メチルシクロプロピル)オキサゾール-4-カルボキサミド (化合物B25)
　参考例7の工程3に準じて、化合物B24 (281 mg)、1,1'-カルボニルジイミダゾール (304 mg, 1.87 mmol）、および28%アンモニア水 (0.243 mL)から化合物B25 (261 mg, 2段階 94%)を得た。
1H-NMR (CDCl3) δ: 6.81 (br s, 1H), 5.43 (br s, 1H), 2.57 (s, 3H), 1.48 (s, 3H), 1.22 (q, J = 3.6 Hz, 2H), 0.83 (q, J = 3.6 Hz, 2H).
ESI-MS: m/z 181 [M+H]+ Process 5
5-Methyl-2- (1-methylcyclopropyl) oxazole-4-carboxamide (Compound B25)
According to Step 3 of Reference Example 7, compound B24 (281 mg), 1,1′-carbonyldiimidazole (304 mg, 1.87 mmol), and 28% aqueous ammonia (0.243 mL) were converted to compound B25 (261 mg, 2 Step 94%) was obtained.
1 H-NMR (CDCl 3 ) δ: 6.81 (br s, 1H), 5.43 (br s, 1H), 2.57 (s, 3H), 1.48 (s, 3H), 1.22 (q, J = 3.6 Hz, 2H ), 0.83 (q, J = 3.6 Hz, 2H).
ESI-MS: m / z 181 [M + H] +
参考例13
工程1
メチル 2-アセトアミド-3-ヒドロキシブタノエート (化合物B26)
　参考例11の工程1に準じて、L-トレオニンメチルエステル・塩酸塩 (1.00 g, 5.90 mmol）、酢酸 (0.371 mL, 6.49 mmol）、トリエチルアミン (0.904 mL, 6.49 mmol)、EDCI (1.24 g, 6.49 mmol)、およびHOBt (993 mg, 6.49 mmol)から、化合物B26 (898 mg, 87%)を得た。
1H-NMR (CDCl3) δ: 6.53 (d, J = 8.8 Hz, 1H), 4.59 (dd, J = 8.8, 2.9 Hz, 1H), 4.37-4.32 (m, 1H), 3.77 (s, 3H), 2.97 (s, 1H), 2.09 (s, 3H), 1.22 (d, J = 6.8 Hz, 3H).
ESI-MS: m/z 176 [M+H]+
工程2
メチル 2-アセトアミド-3-オキソブタノエート (化合物B27)
　化合物B26 (878 mg, 5.01 mmol)のジクロロメタン (25.1 mL)溶液に、デス-マーチンペルヨージナン (2.34 g, 5.51 mmol)を加え、室温で2時間撹拌した。混合物に飽和重曹水、および飽和チオ硫酸ナトリウム水溶液を加え、クロロホルムで抽出し、有機層を無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (クロロホルム/メタノール＝94/6)で精製し、化合物B27 (438 mg, 51%)を得た。
1H-NMR (CDCl3) δ: 6.64 (br s, 1H), 5.27 (d, J = 5.9 Hz, 1H), 3.83 (s, 3H), 2.40 (s, 3H), 2.08 (s, 3H).
ESI-MS: m/z 174 [M+H]+ Reference Example 13
Process 1
Methyl 2-acetamido-3-hydroxybutanoate (Compound B26)
According to Step 1 of Reference Example 11, L-threonine methyl ester / hydrochloride (1.00 g, 5.90 mmol), acetic acid (0.371 mL, 6.49 mmol), triethylamine (0.904 mL, 6.49 mmol), EDCI (1.24 g, 6.49) mmol) and HOBt (993 mg, 6.49 mmol) gave compound B26 (898 mg, 87%).
1 H-NMR (CDCl 3 ) δ: 6.53 (d, J = 8.8 Hz, 1H), 4.59 (dd, J = 8.8, 2.9 Hz, 1H), 4.37-4.32 (m, 1H), 3.77 (s, 3H ), 2.97 (s, 1H), 2.09 (s, 3H), 1.22 (d, J = 6.8 Hz, 3H).
ESI-MS: m / z 176 [M + H] +
Process 2
Methyl 2-acetamido-3-oxobutanoate (Compound B27)
Dess-Martin periodinane (2.34 g, 5.51 mmol) was added to a solution of compound B26 (878 mg, 5.01 mmol) in dichloromethane (25.1 mL), and the mixture was stirred at room temperature for 2 hours. To the mixture were added saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium thiosulfate solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 94/6) to obtain Compound B27 (438 mg, 51%).
1 H-NMR (CDCl 3 ) δ: 6.64 (br s, 1H), 5.27 (d, J = 5.9 Hz, 1H), 3.83 (s, 3H), 2.40 (s, 3H), 2.08 (s, 3H) .
ESI-MS: m / z 174 [M + H] +
工程3
メチル 1,2,5-トリメチル-1H-イミダゾール-4-カルボキシラート (化合物B28)
　化合物B27 (400 mg, 2.31 mmol)のトルエン (23.1 mL)溶液に、酢酸 (4.23 mL, 73.9 mmol）、およびメチルアミン (2.0 mol/L THF溶液、9.24 mL)を加え、還流下で終夜撹拌した。混合物を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (クロロホルム/メタノール＝95/5)で精製し、粗精製物の化合物B28 (632 mg)を得た。
ESI-MS: m/z 169 [M+H]+
工程4
1,2,5-トリメチル-1H-イミダゾール-4-カルボン酸 (化合物B29)
　参考例7の工程2に準じて、化合物B28 (632 mg)、および水酸化ナトリウム (592 mg, 14.8 mmol)から化合物B29の粗生成物 (436 mg)を得た。粗生成物は精製することなく次の反応に用いた。
ESI-MS: m/z 155 [M+H]+
工程5
1,2,5-トリメチル-1H-イミダゾール-4-カルボキサミド (化合物B30)
　参考例7の工程3に準じて、化合物B29 (128 mg)、1,1'-カルボニルジイミダゾール (405 mg, 2.50 mmol)、および28%アンモニア水 (1.67 mL)から化合物B30 (84.8 mg, 3段階 67%)を得た。
1H-NMR (CDCl3) δ: 6.90 (br s, 1H), 5.17 (br s, 1H), 3.44 (s, 3H), 2.54 (s, 3H), 2.35 (s, 3H).
ESI-MS: m/z 154 [M+H]+ Process 3
Methyl 1,2,5-trimethyl-1H-imidazole-4-carboxylate (Compound B28)
Acetic acid (4.23 mL, 73.9 mmol) and methylamine (2.0 mol / L THF solution, 9.24 mL) were added to a solution of compound B27 (400 mg, 2.31 mmol) in toluene (23.1 mL), and the mixture was stirred overnight under reflux. . The mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 95/5) to obtain a crude product, Compound B28 (632 mg).
ESI-MS: m / z 169 [M + H] +
Process 4
1,2,5-Trimethyl-1H-imidazole-4-carboxylic acid (Compound B29)
According to Step 2 of Reference Example 7, a crude product of Compound B29 (436 mg) was obtained from Compound B28 (632 mg) and sodium hydroxide (592 mg, 14.8 mmol). The crude product was used in the next reaction without purification.
ESI-MS: m / z 155 [M + H] +
Process 5
1,2,5-trimethyl-1H-imidazole-4-carboxamide (Compound B30)
According to Step 3 of Reference Example 7, compound B30 (84.8 mg, 3) was prepared from compound B29 (128 mg), 1,1′-carbonyldiimidazole (405 mg, 2.50 mmol), and 28% aqueous ammonia (1.67 mL). Stage 67%) was obtained.
1 H-NMR (CDCl 3 ) δ: 6.90 (br s, 1H), 5.17 (br s, 1H), 3.44 (s, 3H), 2.54 (s, 3H), 2.35 (s, 3H).
ESI-MS: m / z 154 [M + H] +
参考例14
工程1
メチル 3-ヒドロキシ-2-(2-メトキシアセトアミド)ブタノエート (化合物B31)
　参考例11の工程1に準じて、L-トレオニンメチルエステル・塩酸塩 (1.00 g, 5.90 mmol）、2-メトキシ酢酸 (0.495 ml, 6.49 mmol)、ジイソプロピルエチルアミン (3.09 mL, 17.7 mmol)、およびN,N,N',N'-テトラメチル-O-(7-アザベンゾトリアゾール-1-イル)ウロニウム ヘキサフルオロホスファート (HATU) (2.69 g, 7.08 mmol)から、化合物B31 (1.14 g, 87%)を得た。
1H-NMR (CDCl3) δ: 7.22 (d, J = 8.8 Hz, 1H), 4.64 (dd, J = 8.8, 2.9 Hz, 1H), 4.41-4.38 (m, 1H), 4.03-3.93 (m, 2H), 3.79 (s, 3H), 3.47 (s, 3H), 2.27 (d, J = 4.9 Hz, 1H), 1.24 (d, J = 6.8 Hz, 3H).
ESI-MS: m/z 206 [M+H]+
工程2
メチル 2-(2-メトキシアセトアミド)-3-オキソブタノエート (化合物B32)
　参考例13の工程2に準じて、化合物B31 (500 mg, 2.44 mmol）、およびデス-マーチンペルヨージナン (1.14 g, 2.68 mmol)から、化合物B32 (320 mg, 65%)を得た。
1H-NMR (CDCl3) δ: 7.61 (s, 1H), 5.32 (d, J = 6.8 Hz, 1H), 3.96 (s, 2H), 3.84 (s, 3H), 3.47 (s, 3H), 2.41 (s, 3H).
ESI-MS: m/z 204 [M+H]+ Reference Example 14
Process 1
Methyl 3-hydroxy-2- (2-methoxyacetamido) butanoate (Compound B31)
According to Step 1 of Reference Example 11, L-threonine methyl ester / hydrochloride (1.00 g, 5.90 mmol), 2-methoxyacetic acid (0.495 ml, 6.49 mmol), diisopropylethylamine (3.09 mL, 17.7 mmol), and N , N, N ', N'-Tetramethyl-O- (7-azabenzotriazol-1-yl) uronium hexafluorophosphate (HATU) (2.69 g, 7.08 mmol) to compound B31 (1.14 g, 87% )
1 H-NMR (CDCl 3 ) δ: 7.22 (d, J = 8.8 Hz, 1H), 4.64 (dd, J = 8.8, 2.9 Hz, 1H), 4.41-4.38 (m, 1H), 4.03-3.93 (m , 2H), 3.79 (s, 3H), 3.47 (s, 3H), 2.27 (d, J = 4.9 Hz, 1H), 1.24 (d, J = 6.8 Hz, 3H).
ESI-MS: m / z 206 [M + H] +
Process 2
Methyl 2- (2-methoxyacetamido) -3-oxobutanoate (Compound B32)
Compound B32 (320 mg, 65%) was obtained from Compound B31 (500 mg, 2.44 mmol) and Dess-Martin periodinane (1.14 g, 2.68 mmol) according to Step 2 of Reference Example 13.
1 H-NMR (CDCl 3 ) δ: 7.61 (s, 1H), 5.32 (d, J = 6.8 Hz, 1H), 3.96 (s, 2H), 3.84 (s, 3H), 3.47 (s, 3H), 2.41 (s, 3H).
ESI-MS: m / z 204 [M + H] +
工程3
メチル 2-(メトキシメチル)-1,5-ジメチル-1H-イミダゾール-4-カルボキシラート (化合物B33)
　参考例13の工程3に準じて、化合物B32 (309 mg, 1.52 mmol)、酢酸 (2.79 mL, 48.7 mmol)、およびメチルアミン (2.0 mol/L THF溶液、6.08 mL)から、化合物B33 (223 mg, 74%)を得た。
1H-NMR (CDCl3) δ: 4.56 (s, 2H), 3.88 (s, 3H), 3.59 (s, 3H), 3.33 (s, 3H), 2.54 (s, 3H).
ESI-MS: m/z 199 [M+H]+
工程4
2-(メトキシメチル)-1,5-ジメチル-1H-イミダゾール-4-カルボン酸 (化合物B34)
　参考例7の工程2に準じて、化合物B33 (223 mg, 1.13 mmol)、および水酸化ナトリウム (296 mg, 7.40 mmol)から化合物B34の粗生成物 (218 mg)を得た。得られた粗生成物は、精製することなく次の反応に用いた。
ESI-MS: m/z 185 [M+H]+
工程5
2-(メトキシメチル)-1,5-ジメチル-1H-イミダゾール-4-カルボキサミド (化合物B35)
　参考例7の工程3に準じて、化合物B34の粗生成物 (218 mg)、1,1'-カルボニルジイミダゾール (572 mg, 3.53 mmol)、および28%アンモニア水 (0.915 mL)から化合物B35 (158 mg, 2段階 73%）を得た。
1H-NMR (CDCl3) δ: 6.93 (s, 1H), 5.22 (s, 1H), 4.48 (s, 2H), 3.56 (s, 3H), 3.36 (s, 3H), 2.56 (s, 3H).
ESI-MS: m/z 184 [M+H]+ Process 3
Methyl 2- (methoxymethyl) -1,5-dimethyl-1H-imidazole-4-carboxylate (Compound B33)
According to Step 3 of Reference Example 13, from compound B32 (309 mg, 1.52 mmol), acetic acid (2.79 mL, 48.7 mmol), and methylamine (2.0 mol / L THF solution, 6.08 mL), compound B33 (223 mg , 74%).
1 H-NMR (CDCl 3 ) δ: 4.56 (s, 2H), 3.88 (s, 3H), 3.59 (s, 3H), 3.33 (s, 3H), 2.54 (s, 3H).
ESI-MS: m / z 199 [M + H] +
Process 4
2- (Methoxymethyl) -1,5-dimethyl-1H-imidazole-4-carboxylic acid (Compound B34)
According to Step 2 of Reference Example 7, a crude product of compound B34 (218 mg) was obtained from compound B33 (223 mg, 1.13 mmol) and sodium hydroxide (296 mg, 7.40 mmol). The obtained crude product was used for the next reaction without purification.
ESI-MS: m / z 185 [M + H] +
Process 5
2- (Methoxymethyl) -1,5-dimethyl-1H-imidazole-4-carboxamide (Compound B35)
According to Step 3 of Reference Example 7, compound B35 (218 mg), 1,1′-carbonyldiimidazole (572 mg, 3.53 mmol), and 28% aqueous ammonia (0.915 mL) were combined with compound B35 ( 158 mg, 2 steps 73%).
1 H-NMR (CDCl 3 ) δ: 6.93 (s, 1H), 5.22 (s, 1H), 4.48 (s, 2H), 3.56 (s, 3H), 3.36 (s, 3H), 2.56 (s, 3H ).
ESI-MS: m / z 184 [M + H] +
参考例15
工程1
メチル 4-ブロモ-5-イソプロピルイソオキサゾール-3-カルボキシラート (化合物B36)
　メチル 5-イソプロピルイソオキサゾール-3-カルボキシラート (440 mg, 2.6 mmol)のDMF (4.0 mL)溶液に、N-ブロモスクシンイミド (NBS) (1.8 g, 9.9 mmol)を加え、50 ℃で終夜撹拌した。混合物を室温まで冷却し、チオ硫酸ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (ヘプタン/酢酸エチル＝75/25)で精製し、化合物B36 (470 mg, 58%)を得た。
1H-NMR (CDCl3) δ: 3.99 (s, 3H), 3.33-3.26 (m, 1H), 1.36 (d, J = 6.8 Hz, 6H).
ESI-MS: m/z 248(79Br), 250(81Br) [M+H]+
工程2
メチル 5-イソプロピル-4-メチルイソオキサゾール-3-カルボキシラート (化合物B37)
　化合物B36 (360 mg, 1.5 mmol)のDMF (5.0 mL)溶液に、2,4,6-トリメチルボロキシン (0.61 mL, 4.4 mmol)、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド-ジクロロメタン錯体 (120 mg, 0.15 mmol）、および炭酸カリウム (600 mg, 4.4 mmol)を加え、80 ℃で2時間撹拌した。混合物を室温まで冷却し、水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (ヘプタン/酢酸エチル＝75/25)で精製し、化合物B37 (130 mg, 49%)を得た。
1H-NMR (CDCl3) δ: 3.96 (s, 3H), 3.20-3.10 (m, 1H), 2.16 (s, 3H), 1.33 (t, J = 6.8 Hz, 6H).
ESI-MS: m/z 184 [M+H]+ Reference Example 15
Process 1
Methyl 4-bromo-5-isopropylisoxazole-3-carboxylate (Compound B36)
N-bromosuccinimide (NBS) (1.8 g, 9.9 mmol) was added to a solution of methyl 5-isopropylisoxazole-3-carboxylate (440 mg, 2.6 mmol) in DMF (4.0 mL), and the mixture was stirred at 50 ° C. overnight. . The mixture was cooled to room temperature, an aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 75/25) to obtain Compound B36 (470 mg, 58%).
1 H-NMR (CDCl 3 ) δ: 3.99 (s, 3H), 3.33-3.26 (m, 1H), 1.36 (d, J = 6.8 Hz, 6H).
ESI-MS: m / z 248 ( 79 Br), 250 ( 81 Br) [M + H] +
Process 2
Methyl 5-isopropyl-4-methylisoxazole-3-carboxylate (Compound B37)
To a solution of compound B36 (360 mg, 1.5 mmol) in DMF (5.0 mL), 2,4,6-trimethylboroxine (0.61 mL, 4.4 mmol), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) Dichloride-dichloromethane complex (120 mg, 0.15 mmol) and potassium carbonate (600 mg, 4.4 mmol) were added, and the mixture was stirred at 80 ° C. for 2 hours. The mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (heptane / ethyl acetate = 75/25) to obtain Compound B37 (130 mg, 49%).
1 H-NMR (CDCl 3 ) δ: 3.96 (s, 3H), 3.20-3.10 (m, 1H), 2.16 (s, 3H), 1.33 (t, J = 6.8 Hz, 6H).
ESI-MS: m / z 184 [M + H] +
工程3
5-イソプロピル-4-メチルイソオキサゾール-3-カルボン酸 (化合物B38)
　参考例7の工程2に準じて、化合物B37 (95 mg, 0.52 mmol)、および水酸化ナトリウム (83 mg, 2.1 mmol)から化合物B38 (91 mg, 99%)を得た。
1H-NMR (CD3OD) δ: 3.26-3.19 (m, 1H), 2.15 (s, 3H), 1.31 (d, J = 6.8 Hz, 6H).
工程4
5-イソプロピル-4-メチルイソオキサゾール-3-カルボキサミド (化合物B39)
　化合物B38 (85 mg, 0.50 mmol)のジクロロメタン (3.0 mL)溶液に、氷冷下、塩化オキサリル (0.066 mL, 0.75 mmol)、およびDMF 2滴を加え、室温で2時間撹拌した。混合物を減圧下で溶媒留去し、得られた残渣のジクロロメタン (2.0 mL)溶液に、28％アンモニア水 (2.0 mL)を加え、室温で終夜撹拌した。混合物に水を加え、クロロホルムで抽出し、有機層を無水硫酸マグネシウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (メタノール/クロロホルム＝10/90)で精製し、化合物B39 (61 mg, 72％)を得た。
1H-NMR (CDCl3) δ: 6.81 (br s, 1H), 6.04 (br s, 1H), 3.20-3.09 (m, 1H), 2.19 (s, 3H), 1.32 (d, J = 6.9 Hz, 6H). Process 3
5-Isopropyl-4-methylisoxazole-3-carboxylic acid (Compound B38)
According to Step 2 of Reference Example 7, compound B38 (91 mg, 99%) was obtained from compound B37 (95 mg, 0.52 mmol) and sodium hydroxide (83 mg, 2.1 mmol).
1 H-NMR (CD 3 OD) δ: 3.26-3.19 (m, 1H), 2.15 (s, 3H), 1.31 (d, J = 6.8 Hz, 6H).
Process 4
5-Isopropyl-4-methylisoxazole-3-carboxamide (Compound B39)
To a solution of compound B38 (85 mg, 0.50 mmol) in dichloromethane (3.0 mL) were added oxalyl chloride (0.066 mL, 0.75 mmol) and 2 drops of DMF under ice cooling, and the mixture was stirred at room temperature for 2 hours. The mixture was evaporated under reduced pressure, 28% aqueous ammonia (2.0 mL) was added to a solution of the obtained residue in dichloromethane (2.0 mL), and the mixture was stirred at room temperature overnight. Water was added to the mixture and extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methanol / chloroform = 10/90) to obtain Compound B39 (61 mg, 72%).
1 H-NMR (CDCl 3 ) δ: 6.81 (br s, 1H), 6.04 (br s, 1H), 3.20-3.09 (m, 1H), 2.19 (s, 3H), 1.32 (d, J = 6.9 Hz , 6H).
参考例16
工程1
メチル 4-ブロモ-5-シクロプロピルイソオキサゾール-3-カルボキシラート (化合物B40)
　参考例15の工程1に準じて、メチル 5-シクロプロピルイソオキサゾール-3-カルボキシラート (650 mg, 3.9 mmol)、およびNBS (3.5 g, 20 mmol)から化合物B40 (850 mg, 88%)を得た。
1H-NMR (CDCl3) δ: 3.98 (s, 3H), 2.18-2.12 (m, 1H), 1.21-1.19 (m, 4H).
ESI-MS: m/z 246(79Br), 248(81Br) [M+H]+
工程2
メチル 5-シクロプロピル-4-メチルイソオキサゾール-3-カルボキシラート (化合物B41)
　参考例15の工程2に準じて、化合物B40 (460 mg, 1.9 mmol)、2,4,6-トリメチルボロキシン (0.78 mL, 5.6 mmol)、[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド-ジクロロメタン錯体 (150 mg, 0.19 mmol）、および炭酸カリウム (770 mg, 5.6 mmol)から化合物B41 (160 mg, 47%)を得た。
1H-NMR (CDCl3) δ: 3.95 (s, 3H), 2.21 (s, 3H), 1.98-1.91 (m, 1H), 1.11-1.06 (m, 4H).
ESI-MS: m/z 182 [M+H]+ Reference Example 16
Process 1
Methyl 4-bromo-5-cyclopropylisoxazole-3-carboxylate (Compound B40)
In accordance with Step 1 of Reference Example 15, methyl 5-cyclopropylisoxazole-3-carboxylate (650 mg, 3.9 mmol), and NBS (3.5 g, 20 mmol) were converted to compound B40 (850 mg, 88%). Obtained.
1 H-NMR (CDCl 3 ) δ: 3.98 (s, 3H), 2.18-2.12 (m, 1H), 1.21-1.19 (m, 4H).
ESI-MS: m / z 246 ( 79 Br), 248 ( 81 Br) [M + H] +
Process 2
Methyl 5-cyclopropyl-4-methylisoxazole-3-carboxylate (Compound B41)
According to Step 2 of Reference Example 15, compound B40 (460 mg, 1.9 mmol), 2,4,6-trimethylboroxine (0.78 mL, 5.6 mmol), [1,1′-bis (diphenylphosphino) ferrocene ] Compound B41 (160 mg, 47%) was obtained from palladium (II) dichloride-dichloromethane complex (150 mg, 0.19 mmol) and potassium carbonate (770 mg, 5.6 mmol).
1 H-NMR (CDCl 3 ) δ: 3.95 (s, 3H), 2.21 (s, 3H), 1.98-1.91 (m, 1H), 1.11-1.06 (m, 4H).
ESI-MS: m / z 182 [M + H] +
工程3
5-シクロプロピル-4-メチルイソオキサゾール-3-カルボン酸 (化合物B42)
　参考例7の工程2に準じて、化合物B41 (110 mg, 0.63 mmol)、および水酸化ナトリウム (100 mg, 2.5 mmol)から化合物B42 (110 mg, 99%)を得た。
1H-NMR (CD3OD) δ: 2.19 (s, 3H), 2.10-2.06 (m, 1H), 1.10-1.03 (m, 4H).
工程4
5-シクロプロピル-4-メチルイソオキサゾール-3-カルボキサミド (化合物B43)
　参考例15の工程4に準じて、化合物B42 (100 mg, 0.61 mmol)、塩化オキサリル (0.079 mL, 0.91 mmol)、DMF 2滴および28％アンモニア水 (2.0 mL)から化合物B43 (78 mg, 77％)を得た。
1H-NMR (CDCl3) δ: 6.72 (br s, 1H), 5.82 (br s, 1H), 2.24 (s, 3H), 1.97-1.92 (m, 1H), 1.10-1.04 (m, 4H) Process 3
5-Cyclopropyl-4-methylisoxazole-3-carboxylic acid (Compound B42)
According to Step 2 of Reference Example 7, compound B42 (110 mg, 99%) was obtained from compound B41 (110 mg, 0.63 mmol) and sodium hydroxide (100 mg, 2.5 mmol).
1 H-NMR (CD 3 OD) δ: 2.19 (s, 3H), 2.10-2.06 (m, 1H), 1.10-1.03 (m, 4H).
Process 4
5-Cyclopropyl-4-methylisoxazole-3-carboxamide (Compound B43)
According to Step 4 of Reference Example 15, compound B42 (100 mg, 0.61 mmol), oxalyl chloride (0.079 mL, 0.91 mmol), 2 drops of DMF and 28% aqueous ammonia (2.0 mL) were added to compound B43 (78 mg, 77 %).
1 H-NMR (CDCl 3 ) δ: 6.72 (br s, 1H), 5.82 (br s, 1H), 2.24 (s, 3H), 1.97-1.92 (m, 1H), 1.10-1.04 (m, 4H)
参考例17
工程1
1-エチル-1H-イミダゾール-4,5-ジカルボニトリル (化合物B44)
　1H-イミダゾール-4,5-ジカルボニトリル (2.0 g, 17 mmol)のアセトン (60 mL)溶液に、ヨードエタン (2.7 mL, 34 mmol）、および炭酸カリウム (4.7 g, 34 mmol)を加え、50 ℃で終夜撹拌した。混合物を室温まで冷却し、ろ過し、ろ液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (クロロホルム/メタノール＝90/10)で精製し、化合物B44 (2.5 g, 99%)を得た。
1H-NMR (CDCl3) δ: 7.71 (s, 1H), 4.23 (q, J = 7.3 Hz, 2H), 1.60 (t, J= 7.3 Hz, 3H).
ESI-MS: m/z 145 [M-H]-
工程2
1-エチル-1H-イミダゾール-4,5-ジカルボン酸 (化合物B45)
　化合物B44 (1.0 g, 6.8 mmol)のエタノール (11 mL)溶液に、6 mol/L 水酸化ナトリウム水溶液 (15 mL, 90 mmol)を加え、還流下で5時間撹拌した。混合物を室温まで冷却し、濃硫酸 (7 mL)を加えて中和した後、生じた固体をろ取し、化合物B45 (650 mg, 52%)を得た。
1H-NMR (DMSO-d6) δ: 9.12 (s, 1H), 4.54 (q, J = 7.3 Hz, 2H), 1.38 (t, J= 7.3 Hz, 3H). Reference Example 17
Process 1
1-Ethyl-1H-imidazole-4,5-dicarbonitrile (Compound B44)
To a solution of 1H-imidazole-4,5-dicarbonitrile (2.0 g, 17 mmol) in acetone (60 mL), iodoethane (2.7 mL, 34 mmol) and potassium carbonate (4.7 g, 34 mmol) were added. Stir overnight at ° C. The mixture was cooled to room temperature and filtered, the filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 90/10) to give compound B44 (2.5 g, 99 %).
1 H-NMR (CDCl 3 ) δ: 7.71 (s, 1H), 4.23 (q, J = 7.3 Hz, 2H), 1.60 (t, J = 7.3 Hz, 3H).
ESI-MS: m / z 145 [MH] -
Process 2
1-Ethyl-1H-imidazole-4,5-dicarboxylic acid (Compound B45)
To a solution of compound B44 (1.0 g, 6.8 mmol) in ethanol (11 mL) was added 6 mol / L aqueous sodium hydroxide solution (15 mL, 90 mmol), and the mixture was stirred under reflux for 5 hours. The mixture was cooled to room temperature and neutralized with concentrated sulfuric acid (7 mL), and the resulting solid was collected by filtration to give compound B45 (650 mg, 52%).
1 H-NMR (DMSO-d 6 ) δ: 9.12 (s, 1H), 4.54 (q, J = 7.3 Hz, 2H), 1.38 (t, J = 7.3 Hz, 3H).
工程3
1-エチル-1H-イミダゾール-5-カルボン酸 (化合物B46)
　化合物B45 (220 mg, 1.2 mmol)に無水酢酸 (6 mL)を加えて、100 ℃で1時間撹拌した。混合物を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (クロロホルム/メタノール＝80/20)で精製し、化合物B46 (70 mg, 41%)を得た。
1H-NMR (DMSO-d6) δ: 7.91 (s, 1H), 7.56 (s, 1H), 4.28 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H).
ESI-MS: m/z 141 [M+H]+
工程4
1-エチル-1H-イミダゾール-5-カルボキサミド (化合物B47)
　参考例15の工程4に準じて、化合物B46 (69 mg, 0.49 mmol)、塩化オキサリル (0.065 mL, 0.74 mmol)、DMF 2滴、および28％アンモニア水 (3.0 mL)から化合物B47 (41 mg、60％)を得た。
1H-NMR (DMSO-d6) δ: 7.77 (s, 1H), 7.68 (br s, 1H), 7.57 (s, 1H), 7.14 (br s, 1H), 4.29 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H).
ESI-MS: m/z 140 [M+H]+ Process 3
1-Ethyl-1H-imidazole-5-carboxylic acid (Compound B46)
Acetic anhydride (6 mL) was added to compound B45 (220 mg, 1.2 mmol), and the mixture was stirred at 100 ° C. for 1 hr. The mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 80/20) to obtain Compound B46 (70 mg, 41%).
1 H-NMR (DMSO-d 6 ) δ: 7.91 (s, 1H), 7.56 (s, 1H), 4.28 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H).
ESI-MS: m / z 141 [M + H] +
Process 4
1-Ethyl-1H-imidazole-5-carboxamide (Compound B47)
According to Step 4 of Reference Example 15, compound B46 (69 mg, 0.49 mmol), oxalyl chloride (0.065 mL, 0.74 mmol), 2 drops of DMF, and 28% aqueous ammonia (3.0 mL) were converted to compound B47 (41 mg, 60%).
1 H-NMR (DMSO-d 6 ) δ: 7.77 (s, 1H), 7.68 (br s, 1H), 7.57 (s, 1H), 7.14 (br s, 1H), 4.29 (q, J = 7.1 Hz , 2H), 1.28 (t, J = 7.1 Hz, 3H).
ESI-MS: m / z 140 [M + H] +
参考例18
工程1
エチル 3-シクロプロピル-2-ホルムアミドアクリレート (化合物B48)
　イソシアノ酢酸エチル (1.94 mL, 17.7 mmol)のTHF (35.4 mL)溶液に、氷冷下で60％水素化ナトリウム (849 mg, 21.2 mmol)を加え、氷冷下で5分間撹拌した後、シクロプロパンカルボキシアルデヒド (1.40 mL, 18.6 mmol)を加え、室温で2時間撹拌した。混合物に10％酢酸水溶液を加え、酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (ヘプタン/酢酸エチル＝50/50)で精製し、化合物B48 (1.87 g, 58%)をE/Z混合物として得た。
ESI-MS: m/z 184 [M+H]+
工程2
エチル 3-ブロモ-3-シクロプロピル-2-ホルムアミドアクリレート (化合物B49)
　化合物B48 (1.87 g, 10.2 mmol)の四塩化炭素 (25.5 mL)溶液に、氷冷下、NBS (2.00 g, 11.2 mmol)を加え、室温で1.5時間撹拌した。混合物にトリエチルアミン (1.42 mL, 10.21 mmol)、および飽和重曹水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (ヘプタン/酢酸エチル＝50/50)で精製し、化合物B49 (1.15 g, 43%)をE/Z混合物として得た。
ESI-MS: m/z 262(79Br), 264(81Br) [M+H]+ Reference Example 18
Process 1
Ethyl 3-cyclopropyl-2-formamide acrylate (Compound B48)
To a solution of ethyl isocyanoacetate (1.94 mL, 17.7 mmol) in THF (35.4 mL) was added 60% sodium hydride (849 mg, 21.2 mmol) under ice-cooling, and the mixture was stirred for 5 minutes under ice-cooling. Carboxaldehyde (1.40 mL, 18.6 mmol) was added, and the mixture was stirred at room temperature for 2 hours. A 10% aqueous acetic acid solution was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane / ethyl acetate = 50/50) to obtain compound B48 (1.87 g, 58%) as an E / Z mixture. It was.
ESI-MS: m / z 184 [M + H] +
Process 2
Ethyl 3-bromo-3-cyclopropyl-2-formamide acrylate (Compound B49)
To a carbon tetrachloride (25.5 mL) solution of compound B48 (1.87 g, 10.2 mmol), NBS (2.00 g, 11.2 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. Triethylamine (1.42 mL, 10.21 mmol) and saturated aqueous sodium hydrogen carbonate were added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane / ethyl acetate = 50/50) to obtain compound B49 (1.15 g, 43%) as an E / Z mixture. It was.
ESI-MS: m / z 262 ( 79 Br), 264 ( 81 Br) [M + H] +
工程3
エチル 3-ブロモ-3-シクロプロピル-2-イソシアノアクリレート (化合物B50)
　化合物B49 (1.14 g, 4.35 mmol)のジクロロメタン (14.5 mL)溶液に、トリエチルアミン (1.52 mL, 10.9 mmol)、およびオキシ塩化リン (0.446 mL, 4.78 mmol)を-10 ℃で加え、同温で2時間撹拌した。混合物に飽和重曹水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、化合物B50の粗生成物 (1.30 g)をE/Z混合物として得た。得られた粗生成物は、精製することなく次の反応に用いた。
1H-NMR (CDCl3) δ: 4.32 (q, J = 7.2 Hz, 2H), 3.36-2.37 (m, 1H), 1.41-1.35 (m, 3H), 1.21-1.06 (m, 4H).
工程4
エチル 5-シクロプロピル-1-メチル-1H-イミダゾール-4-カルボキシラート (化合物B51)
　化合物B50 (203 mg)のDMF (4.17 mL)溶液に、メチルアミン (2.0 mol/L THF溶液、0.500 mL)、およびDBU (0.151 mL, 1.00 mmol)を加え、室温で1時間撹拌した。混合物に飽和重曹水を加え、クロロホルムで抽出し、有機層を無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、残渣をシリカゲルカラムクロマトグラフィー (クロロホルム/メタノール＝95/5)で精製し、化合物B51 (85.8 mg, 2段階 53％)を得た。
1H-NMR (CDCl3) δ: 7.36 (s, 1H), 4.36 (q, J = 7.2 Hz, 2H), 3.69 (s, 3H), 1.76-1.73 (m, 1H), 1.40 (t, J = 7.2 Hz, 3H), 1.14-1.09 (m, 2H), 0.83-0.79 (m, 2H).
ESI-MS: m/z 195 [M+H]+ Process 3
Ethyl 3-bromo-3-cyclopropyl-2-isocyanoacrylate (Compound B50)
To a solution of compound B49 (1.14 g, 4.35 mmol) in dichloromethane (14.5 mL), triethylamine (1.52 mL, 10.9 mmol) and phosphorus oxychloride (0.446 mL, 4.78 mmol) were added at −10 ° C., and the same temperature was maintained for 2 hours. Stir. To the mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give a crude product of compound B50 (1.30 g) as an E / Z mixture. The obtained crude product was used for the next reaction without purification.
1 H-NMR (CDCl 3 ) δ: 4.32 (q, J = 7.2 Hz, 2H), 3.36-2.37 (m, 1H), 1.41-1.35 (m, 3H), 1.21-1.06 (m, 4H).
Process 4
Ethyl 5-cyclopropyl-1-methyl-1H-imidazole-4-carboxylate (Compound B51)
Methylamine (2.0 mol / L THF solution, 0.500 mL) and DBU (0.151 mL, 1.00 mmol) were added to a solution of compound B50 (203 mg) in DMF (4.17 mL), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 95/5) to obtain Compound B51 (85.8 mg, 2 steps 53%).
1 H-NMR (CDCl 3 ) δ: 7.36 (s, 1H), 4.36 (q, J = 7.2 Hz, 2H), 3.69 (s, 3H), 1.76-1.73 (m, 1H), 1.40 (t, J = 7.2 Hz, 3H), 1.14-1.09 (m, 2H), 0.83-0.79 (m, 2H).
ESI-MS: m / z 195 [M + H] +
工程5
5-シクロプロピル-1-メチル-1H-イミダゾール-4-カルボン酸 (化合物B52)
　参考例7の工程2に準じて、化合物B51 (195 mg, 1.00 mmol)、および水酸化ナトリウム (201 mg, 5.01 mmol)から化合物B52 (137 mg, 82%)を得た。
1H-NMR (DMSO-d6) δ: 8.40 (s, 1H), 3.74 (s, 3H), 1.91-1.80 (m, 1H), 1.07-1.00 (m, 2H), 0.88-0.82 (m, 2H).
工程6
5-シクロプロピル-1-メチル-1H-イミダゾール-4-カルボキサミド (化合物B53)
　参考例15の工程4に準じて、化合物B52 (133 mg, 0.799 mmol)、塩化オキサリル (0.237 mL, 2.76 mmol)、DMF 2滴、および28%アンモニア水 (1.15 mL)から化合物B53 (64.6 mg, 49%)を得た。
1H-NMR (DMSO-d6) δ: 7.52 (s, 1H), 7.11 (s, 1H), 6.82 (s, 1H), 3.62 (s, 3H), 1.84-1.79 (m, 1H), 0.92-0.88 (m, 4H).
ESI-MS: m/z 166 [M+H]+ Process 5
5-Cyclopropyl-1-methyl-1H-imidazole-4-carboxylic acid (Compound B52)
According to Step 2 of Reference Example 7, compound B52 (137 mg, 82%) was obtained from compound B51 (195 mg, 1.00 mmol) and sodium hydroxide (201 mg, 5.01 mmol).
1 H-NMR (DMSO-d 6 ) δ: 8.40 (s, 1H), 3.74 (s, 3H), 1.91-1.80 (m, 1H), 1.07-1.00 (m, 2H), 0.88-0.82 (m, 2H).
Process 6
5-Cyclopropyl-1-methyl-1H-imidazole-4-carboxamide (Compound B53)
According to Step 4 of Reference Example 15, compound B52 (133 mg, 0.799 mmol), oxalyl chloride (0.237 mL, 2.76 mmol), 2 drops of DMF, and 28% aqueous ammonia (1.15 mL) were converted to compound B53 (64.6 mg, 49%).
1 H-NMR (DMSO-d 6 ) δ: 7.52 (s, 1H), 7.11 (s, 1H), 6.82 (s, 1H), 3.62 (s, 3H), 1.84-1.79 (m, 1H), 0.92 -0.88 (m, 4H).
ESI-MS: m / z 166 [M + H] +
参考例19
工程1
エチル 5-シクロプロピル-1-(2-メトキシエチル)-1H-イミダゾール-4-カルボキシラート (化合物B54)
　参考例18の工程4に準じて、化合物B50 (709 mg)、2-メトキシエチルアミン (0.301 mL, 3.49 mmol)、およびDBU (0.525 mL, 3.49 mmol)から、化合物B54 (270 mg, 2段階 39％)を得た。
1H-NMR (CDCl3) δ: 7.49 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.22 (t, J = 5.3 Hz, 2H), 3.64 (t, J = 5.3 Hz, 2H), 3.33 (s, 3H), 1.77-1.67 (m, 1H), 1.40 (t, J = 7.1 Hz, 3H), 1.15-1.08 (m, 2H), 0.82-0.76 (m, 2H).
ESI-MS: m/z 239 [M+H]+
工程2
5-シクロプロピル-1-(2-メトキシエチル)-1H-イミダゾール-4-カルボン酸 (化合物B55)
　参考例7の工程2に準じて、化合物B54 (270 mg, 1.13 mmol)、および水酸化ナトリウム (227 mg, 5.67 mmol)から化合物B55 (235 mg, 99%)を得た。
1H-NMR (DMSO-d6) δ: 8.00 (s, 1H), 4.27 (t, J = 5.3 Hz, 2H), 3.68 (t, J = 5.3 Hz, 2H), 3.26 (s, 3H), 1.84-1.73 (m, 1H), 1.05-0.98 (m, 2H), 0.82-0.76 (m, 2H). Reference Example 19
Process 1
Ethyl 5-cyclopropyl-1- (2-methoxyethyl) -1H-imidazole-4-carboxylate (Compound B54)
According to Step 4 of Reference Example 18, from compound B50 (709 mg), 2-methoxyethylamine (0.301 mL, 3.49 mmol), and DBU (0.525 mL, 3.49 mmol), compound B54 (270 mg, two steps 39%) )
1 H-NMR (CDCl 3 ) δ: 7.49 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.22 (t, J = 5.3 Hz, 2H), 3.64 (t, J = 5.3 Hz, 2H), 3.33 (s, 3H), 1.77-1.67 (m, 1H), 1.40 (t, J = 7.1 Hz, 3H), 1.15-1.08 (m, 2H), 0.82-0.76 (m, 2H).
ESI-MS: m / z 239 [M + H] +
Process 2
5-Cyclopropyl-1- (2-methoxyethyl) -1H-imidazole-4-carboxylic acid (Compound B55)
According to Step 2 of Reference Example 7, Compound B55 (235 mg, 99%) was obtained from Compound B54 (270 mg, 1.13 mmol) and sodium hydroxide (227 mg, 5.67 mmol).
1 H-NMR (DMSO-d 6 ) δ: 8.00 (s, 1H), 4.27 (t, J = 5.3 Hz, 2H), 3.68 (t, J = 5.3 Hz, 2H), 3.26 (s, 3H), 1.84-1.73 (m, 1H), 1.05-0.98 (m, 2H), 0.82-0.76 (m, 2H).
工程3
5-シクロプロピル-1-(2-メトキシエチル)-1H-イミダゾール-4-カルボキサミド (化合物B56)
　参考例15の工程4に準じて、化合物B55 (229 mg, 1.09 mmol)、塩化オキサリル (0.187 mL, 2.18 mmol)、DMF (2滴)、および28%アンモニア水 (1.56 mL)から化合物B56 (163 mg, 72%)を得た。
1H-NMR (DMSO-d6) δ: 7.54 (s, 1H), 7.13 (s, 1H), 6.83 (s, 1H), 4.19 (t, J = 5.4 Hz, 2H), 3.64 (t, J = 5.4 Hz, 2H), 3.25 (s, 3H), 1.75-1.72 (m, 1H), 0.93-0.85 (m, 4H).
ESI-MS: m/z 210 [M+H]+ Process 3
5-Cyclopropyl-1- (2-methoxyethyl) -1H-imidazole-4-carboxamide (Compound B56)
According to Step 4 of Reference Example 15, compound B55 (229 mg, 1.09 mmol), oxalyl chloride (0.187 mL, 2.18 mmol), DMF (2 drops), and 28% aqueous ammonia (1.56 mL) were converted to compound B56 (163 mg, 72%).
1 H-NMR (DMSO-d 6 ) δ: 7.54 (s, 1H), 7.13 (s, 1H), 6.83 (s, 1H), 4.19 (t, J = 5.4 Hz, 2H), 3.64 (t, J = 5.4 Hz, 2H), 3.25 (s, 3H), 1.75-1.72 (m, 1H), 0.93-0.85 (m, 4H).
ESI-MS: m / z 210 [M + H] +
参考例20
工程1
2-メチル-1H-イミダゾール-4,5-ジカルボニトリル (化合物B57)
　ジアミノマレオニトリル (2.2 g, 20 mmol)のアセトニトリル (70 mL)溶液に、オルト酢酸トリメチル (3.8 mL, 30 mmol)を加え、還流下で5時間撹拌した。混合物を減圧下で溶媒留去し、得られた残渣をキシレン (70 mL)に溶解し、130 ℃で終夜撹拌した。混合物を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー (クロロホルム/メタノール＝90/10)で精製し化合物B57 (2.4 g, 91%)を得た。
1H-NMR (DMSO-d6) δ: 3.32 (br s, 1H), 2.39 (s, 3H).
ESI-MS: m/z 131 [M-H]-
工程2
1-エチル-2-メチル-1H-イミダゾール-4,5-ジカルボニトリル (化合物B58)
　参考例17の工程1に準じて、化合物B57 (1.2 g, 9.1 mmol)、ヨードエタン (1.5 mL, 18 mmol）、および炭酸カリウム(2.5 g, 18 mmol)から化合物B58(1.4 g, 99%)を得た。
1H-NMR (CDCl3) δ: 4.12 (q, J= 7.2 Hz, 2H), 2.50 (s, 3H), 1.48 (t, J= 7.2 Hz, 3H).
ESI-MS: m/z 159 [M-H]- Reference Example 20
Process 1
2-Methyl-1H-imidazole-4,5-dicarbonitrile (Compound B57)
Trimethyl orthoacetate (3.8 mL, 30 mmol) was added to a solution of diaminomaleonitrile (2.2 g, 20 mmol) in acetonitrile (70 mL), and the mixture was stirred under reflux for 5 hours. The mixture was evaporated under reduced pressure, and the resulting residue was dissolved in xylene (70 mL) and stirred at 130 ° C. overnight. The mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 90/10) to obtain Compound B57 (2.4 g, 91%).
1 H-NMR (DMSO-d 6 ) δ: 3.32 (br s, 1H), 2.39 (s, 3H).
ESI-MS: m / z 131 [MH] -
Process 2
1-ethyl-2-methyl-1H-imidazole-4,5-dicarbonitrile (Compound B58)
According to Step 1 of Reference Example 17, Compound B58 (1.4 g, 99%) was converted from Compound B57 (1.2 g, 9.1 mmol), iodoethane (1.5 mL, 18 mmol), and potassium carbonate (2.5 g, 18 mmol). Obtained.
1 H-NMR (CDCl 3 ) δ: 4.12 (q, J = 7.2 Hz, 2H), 2.50 (s, 3H), 1.48 (t, J = 7.2 Hz, 3H).
ESI-MS: m / z 159 [MH] -
工程3
1-エチル-2-メチル-1H-イミダゾール-4,5-ジカルボン酸 (化合物B59)
　参考例17の工程2に準じて、化合物B58 (1.0 g, 6.3 mmol)、および6 mol/L水酸化ナトリウム水溶液 (15 mL, 90 mmol)から化合物B59 (530 mg, 42%)を得た。
1H-NMR (DMSO-d6) δ: 4.51 (q, J= 7.2 Hz, 2H), 2.60 (s, 3H), 1.30 (t, J= 7.2 Hz, 3H).
ESI-MS: m/z 199 [M+H]+
工程4
1-エチル-2-メチル-1H-イミダゾール-5-カルボン酸 (化合物B60)
　参考例17の工程3に準じて、化合物B59 (340 mg, 1.7 mmol)、および無水酢酸 (9 mL)から化合物B60 (130 mg, 49%)を得た。
1H-NMR (DMSO-d6) δ: 7.46 (s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H).
ESI-MS: m/z 155 [M+H]+ Process 3
1-Ethyl-2-methyl-1H-imidazole-4,5-dicarboxylic acid (Compound B59)
According to Step 2 of Reference Example 17, Compound B59 (530 mg, 42%) was obtained from Compound B58 (1.0 g, 6.3 mmol) and 6 mol / L aqueous sodium hydroxide solution (15 mL, 90 mmol).
1 H-NMR (DMSO-d 6 ) δ: 4.51 (q, J = 7.2 Hz, 2H), 2.60 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H).
ESI-MS: m / z 199 [M + H] +
Process 4
1-Ethyl-2-methyl-1H-imidazole-5-carboxylic acid (Compound B60)
According to Step 3 of Reference Example 17, Compound B60 (130 mg, 49%) was obtained from Compound B59 (340 mg, 1.7 mmol) and acetic anhydride (9 mL).
1 H-NMR (DMSO-d 6 ) δ: 7.46 (s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H).
ESI-MS: m / z 155 [M + H] +
工程5
1-エチル-2-メチル-1H-イミダゾール-5-カルボキサミド (化合物B61)
　参考例15の工程4に準じて、化合物B60 (120 mg, 0.80 mmol)、塩化オキサリル (0.11 mL, 1.2 mmol)、DMF 2滴、および28%アンモニア水 (3.0 mL)から化合物B61 (79 mg, 64％)を得た。
1H-NMR (DMSO-d6) δ: 7.57 (br s, 1H), 7.47 (s, 1H), 7.01 (br s, 1H), 4.26 (q, J = 7.0 Hz, 2H), 2.31 (s, 3H), 1.19 (t, J = 7.0 Hz, 3H).
ESI-MS: m/z 154 [M+H]+ Process 5
1-ethyl-2-methyl-1H-imidazole-5-carboxamide (Compound B61)
According to Step 4 of Reference Example 15, compound B60 (120 mg, 0.80 mmol), oxalyl chloride (0.11 mL, 1.2 mmol), 2 drops of DMF, and 28% aqueous ammonia (3.0 mL) were converted to compound B61 (79 mg, 64%).
1 H-NMR (DMSO-d 6 ) δ: 7.57 (br s, 1H), 7.47 (s, 1H), 7.01 (br s, 1H), 4.26 (q, J = 7.0 Hz, 2H), 2.31 (s , 3H), 1.19 (t, J = 7.0 Hz, 3H).
ESI-MS: m / z 154 [M + H] +
参考例21
工程1
エチル 2-ホルムアミドペント-2-エノエート (化合物B62)
　参考例18の工程1に準じて、イソシアノ酢酸エチル (4.85 mL, 44.2 mmol）、60％水素化ナトリウム (2.12 mg, 53.0 mmol)、およびプロピオンアルデヒド (6.34 mL, 88.0 mmol)から化合物B62 (4.01 g, 53%)をE/Z混合物として得た。
ESI-MS: m/z 172 [M+H]+
工程2
エチル 3-ブロモ-2-ホルムアミドペント-2-エノエート (化合物B63)
　参考例18の工程2に準じて、化合物B62 (4.00 g, 23.4 mmol）、およびNBS (4.57 g, 25.7 mmol)から化合物B63 (3.33 g, 57%)をE/Z混合物として得た。
ESI-MS: m/z 250(79Br), 252(81Br) [M+H]+ Reference Example 21
Process 1
Ethyl 2-formamidopent-2-enoate (Compound B62)
According to Step 1 of Reference Example 18, compound B62 (4.01 g) was obtained from ethyl isocyanoacetate (4.85 mL, 44.2 mmol), 60% sodium hydride (2.12 mg, 53.0 mmol), and propionaldehyde (6.34 mL, 88.0 mmol). , 53%) was obtained as an E / Z mixture.
ESI-MS: m / z 172 [M + H] +
Process 2
Ethyl 3-bromo-2-formamidopent-2-enoate (Compound B63)
According to Step 2 of Reference Example 18, Compound B63 (3.33 g, 57%) was obtained as an E / Z mixture from Compound B62 (4.00 g, 23.4 mmol) and NBS (4.57 g, 25.7 mmol).
ESI-MS: m / z 250 ( 79 Br), 252 ( 81 Br) [M + H] +
工程3
エチル 3-ブロモ-2-イソシアノペント-2-エノエート (化合物B64)
　参考例18の工程3に準じて、化合物B63 (3.33 g, 13.3 mmol）、トリエチルアミン (4.64 mL, 33.3 mmol)、およびオキシ塩化リン (1.37 mL, 14.7 mmol)から化合物B64 (889 mg)をE/Z 混合物として得た。得られた粗生成物は、精製することなく次の反応に用いた。
1H-NMR (CDCl3) δ: 4.37-4.28 (m, 2H), 3.22-2.87 (m, 2H), 1.39-1.35 (m, 3H), 1.27-1.21 (m, 3H).
工程4
エチル 5-エチル-1-メチル-1H-イミダゾール-4-カルボキシラート (化合物B65)
　参考例18の工程4に準じて、化合物B64 (444 mg)、メチルアミン (2.0 mol/L THF溶液、1.15 mL)、およびDBU (0.346 mL, 2.30 mmol)から化合物B65 (187 mg, 54％)を得た。
1H-NMR (CDCl3) δ: 7.36 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.61 (s, 3H), 3.00 (q, J = 7.6 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.6 Hz, 3H).
ESI-MS: m/z 183 [M+H]+ Process 3
Ethyl 3-bromo-2-isocyanopent-2-enoate (Compound B64)
In accordance with Step 3 of Reference Example 18, Compound B63 (3.33 g, 13.3 mmol), triethylamine (4.64 mL, 33.3 mmol), and phosphorus oxychloride (1.37 mL, 14.7 mmol) were converted to Compound B64 (889 mg) by E / Obtained as a Z mixture. The obtained crude product was used for the next reaction without purification.
1 H-NMR (CDCl 3 ) δ: 4.37-4.28 (m, 2H), 3.22-2.87 (m, 2H), 1.39-1.35 (m, 3H), 1.27-1.21 (m, 3H).
Process 4
Ethyl 5-ethyl-1-methyl-1H-imidazole-4-carboxylate (Compound B65)
According to Step 4 of Reference Example 18, compound B64 (444 mg), methylamine (2.0 mol / L THF solution, 1.15 mL), and DBU (0.346 mL, 2.30 mmol) to compound B65 (187 mg, 54%) Got.
1 H-NMR (CDCl 3 ) δ: 7.36 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.61 (s, 3H), 3.00 (q, J = 7.6 Hz, 2H), 1.40 ( t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.6 Hz, 3H).
ESI-MS: m / z 183 [M + H] +
工程5
5-エチル-1-メチル-1H-イミダゾール-4-カルボン酸 (化合物B66)
　参考例7の工程2に準じて、化合物B65 (187 mg, 1.03 mmol）、および水酸化ナトリウム (193 mg, 4.83 mmol)から化合物B66の粗生成物 (206 mg)を得た。得られた粗生成物は、精製することなく次の反応に用いた。
ESI-MS: m/z 155 [M+H]+
工程6
5-エチル-1-メチル-1H-イミダゾール-4-カルボキサミド (化合物B67)
　参考例15の工程4に準じて、化合物B66 (158 mg)、塩化オキサリル (0.176 mL, 2.05 mmol)、DMF 2滴、および28％アンモニア水 (1.47 mL)から化合物B67 (88.5 mg, 2段階 56%)を得た。
1H-NMR (DMSO-d6) δ: 7.52 (s, 1H), 7.11 (s, 1H), 6.87 (s, 1H), 3.58 (s, 3H), 2.93 (q, J = 7.6 Hz, 2H), 1.07 (t, J = 7.6 Hz, 3H).
ESI-MS: m/z 154 [M+H]+ Process 5
5-Ethyl-1-methyl-1H-imidazole-4-carboxylic acid (Compound B66)
According to Step 2 of Reference Example 7, a crude product (206 mg) of compound B66 was obtained from compound B65 (187 mg, 1.03 mmol) and sodium hydroxide (193 mg, 4.83 mmol). The obtained crude product was used for the next reaction without purification.
ESI-MS: m / z 155 [M + H] +
Process 6
5-ethyl-1-methyl-1H-imidazole-4-carboxamide (Compound B67)
According to Step 4 of Reference Example 15, compound B66 (158 mg), oxalyl chloride (0.176 mL, 2.05 mmol), 2 drops of DMF, and 28% aqueous ammonia (1.47 mL) were combined with compound B67 (88.5 mg, two steps 56 %).
1 H-NMR (DMSO-d 6 ) δ: 7.52 (s, 1H), 7.11 (s, 1H), 6.87 (s, 1H), 3.58 (s, 3H), 2.93 (q, J = 7.6 Hz, 2H ), 1.07 (t, J = 7.6 Hz, 3H).
ESI-MS: m / z 154 [M + H] +
参考例22
工程1
エチル 5-エチル-1-(2-メトキシエチル)-1H-イミダゾール-4-カルボキシラート (化合物B68)
　参考例18の工程4に準じて、化合物B64 (445 mg)、2-メトキシエチルアミン (0.199 mL, 2.30 mmol)、およびDBU (0.347 mL, 2.30 mmol)から、化合物B68 (351 mg, 81％)を得た。
1H-NMR (CDCl3) δ: 7.48 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.04 (t, J = 5.3 Hz, 2H), 3.61 (t, J = 5.3 Hz, 2H), 3.33 (s, 3H), 2.99 (q, J = 7.5 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.5 Hz, 3H).
ESI-MS: m/z 227 [M+H]+
工程2
5-エチル-1-(2-メトキシエチル)-1H-イミダゾール-4-カルボン酸 (化合物B69)
　参考例7の工程2に準じて、化合物B68 (350 mg, 1.55 mmol）、および水酸化ナトリウム (283 mg, 7.08 mmol)から化合物B69 (147 mg, 48%)を得た。
1H-NMR (DMSO-d6) δ: 7.59 (s, 1H), 4.10 (t, J = 5.1 Hz, 2H), 3.59 (t, J = 5.1 Hz, 2H), 3.24 (s, 3H), 2.89 (q, J = 7.5 Hz, 2H), 1.09 (t, J = 7.5 Hz, 3H).
ESI-MS: m/z 199 [M+H]+ Reference Example 22
Process 1
Ethyl 5-ethyl-1- (2-methoxyethyl) -1H-imidazole-4-carboxylate (Compound B68)
According to Step 4 of Reference Example 18, compound B68 (351 mg, 81%) was obtained from compound B64 (445 mg), 2-methoxyethylamine (0.199 mL, 2.30 mmol), and DBU (0.347 mL, 2.30 mmol). Obtained.
1 H-NMR (CDCl 3 ) δ: 7.48 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.04 (t, J = 5.3 Hz, 2H), 3.61 (t, J = 5.3 Hz, 2H), 3.33 (s, 3H), 2.99 (q, J = 7.5 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.5 Hz, 3H).
ESI-MS: m / z 227 [M + H] +
Process 2
5-ethyl-1- (2-methoxyethyl) -1H-imidazole-4-carboxylic acid (Compound B69)
According to Step 2 of Reference Example 7, compound B69 (147 mg, 48%) was obtained from compound B68 (350 mg, 1.55 mmol) and sodium hydroxide (283 mg, 7.08 mmol).
1 H-NMR (DMSO-d 6 ) δ: 7.59 (s, 1H), 4.10 (t, J = 5.1 Hz, 2H), 3.59 (t, J = 5.1 Hz, 2H), 3.24 (s, 3H), 2.89 (q, J = 7.5 Hz, 2H), 1.09 (t, J = 7.5 Hz, 3H).
ESI-MS: m / z 199 [M + H] +
工程3
5-エチル-1-(2-メトキシエチル)-1H-イミダゾール-4-カルボキサミド (化合物B70)
　参考例15の工程4に準じて、化合物B69 (140 mg, 0.706 mmol)、塩化オキサリル (0.121 mL, 1.41 mmol)、DMF 2滴、および28%アンモニア水 (1.01 mL)から化合物B70 (62.4 mg, 45%)を得た。
1H-NMR (DMSO-d6) δ: 7.54 (s, 1H), 7.13 (s, 1H), 6.89 (s, 1H), 4.08 (t, J = 5.4 Hz, 2H), 3.58 (t, J = 5.4 Hz, 2H), 3.24 (s, 3H), 2.92 (q, J = 7.5 Hz, 2H), 1.08 (t, J = 7.5 Hz, 3H).
ESI-MS: m/z 198 [M+H]+ Process 3
5-ethyl-1- (2-methoxyethyl) -1H-imidazole-4-carboxamide (Compound B70)
According to Step 4 of Reference Example 15, compound B69 (140 mg, 0.706 mmol), oxalyl chloride (0.121 mL, 1.41 mmol), 2 drops of DMF, and 28% aqueous ammonia (1.01 mL) were converted to compound B70 (62.4 mg, 45%).
1 H-NMR (DMSO-d 6 ) δ: 7.54 (s, 1H), 7.13 (s, 1H), 6.89 (s, 1H), 4.08 (t, J = 5.4 Hz, 2H), 3.58 (t, J = 5.4 Hz, 2H), 3.24 (s, 3H), 2.92 (q, J = 7.5 Hz, 2H), 1.08 (t, J = 7.5 Hz, 3H).
ESI-MS: m / z 198 [M + H] +
参考例23
工程1
エチル4-メチル-1-{[2-(トリメチルシリル)エトキシ]メチル}-1H-イミダゾール-5-カルボキシラート (化合物B71)
　エチル 5-メチル-1H-イミダゾール-4-カルボキシラート (2.0 g, 13.0 mmol)のアセトン (25.9 mL)懸濁液に、炭酸カリウム (3.59 g, 25.9 mmol)、および2-(クロロメトキシ)エチルトリメチルシラン (3.45 mL, 19.5 mmol)を加えて、室温で26時間撹拌した。混合物に水を加え、酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、シリカゲルカラムクロマトグラフィー (ヘプタン/酢酸エチル＝60/40-33/67)で精製し、化合物B71 (2.49 g, 67%)を得た。
1H-NMR (CDCl3) δ: 7.62 (s, 1H), 5.62 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 3.54 (t, J = 8.1 Hz, 2H), 2.50 (s, 3H), 1.38 (t, J = 7.1 Hz, 2H), 0.91 (t, J = 8.1 Hz, 3H), -0.02 (s, 9H).
ESI-MS: m/z 285 [M+H]+ Reference Example 23
Process 1
Ethyl 4-methyl-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazole-5-carboxylate (Compound B71)
To a suspension of ethyl 5-methyl-1H-imidazole-4-carboxylate (2.0 g, 13.0 mmol) in acetone (25.9 mL), potassium carbonate (3.59 g, 25.9 mmol), and 2- (chloromethoxy) ethyltrimethyl Silane (3.45 mL, 19.5 mmol) was added, and the mixture was stirred at room temperature for 26 hours. Water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and purified by silica gel column chromatography (heptane / ethyl acetate = 60 / 40-33 / 67) to obtain Compound B71 (2.49 g, 67%).
1 H-NMR (CDCl 3 ) δ: 7.62 (s, 1H), 5.62 (s, 2H), 4.34 (q, J = 7.1 Hz, 2H), 3.54 (t, J = 8.1 Hz, 2H), 2.50 ( s, 3H), 1.38 (t, J = 7.1 Hz, 2H), 0.91 (t, J = 8.1 Hz, 3H), -0.02 (s, 9H).
ESI-MS: m / z 285 [M + H] +
工程2
4-メチル-1-{[2-(トリメチルシリル)エトキシ]メチル}-1H-イミダゾール-5-カルボン酸 (化合物B72）
　参考例7の工程2に準じて、化合物B71 (2.48 g, 8.71 mmol)、および水酸化ナトリウム (1.64 g, 40.9 mmol)から、化合物B72 (2.16 g, 97%)を得た。
1H-NMR (DMSO-d6) δ: 7.88 (s, 1H), 5.58 (s, 2H), 3.45 (t, J = 7.9 Hz, 3H), 2.34 (s, 3H), 0.81 (t, J = 7.9 Hz, 2H), -0.06 (s, 9H).
ESI-MS: m/z 255 [M-H]-
工程3
4-メチル-1-{[2-(トリメチルシリル)エトキシ]メチル}-1H-イミダゾール-5-カルボキサミド (化合物B73)
　参考例7の工程3に準じて、化合物B72 (300 mg, 1.17 mmol）、トリエチルアミン (0.326 mL, 2.34 mmol)、EDCI (336 mg, 1.76 mmol)、HOBt (269 mg, 2.68 mmol)、および28%アンモニア水 (0.911 mL, 23.4 mmol)から、化合物B73 (150 mg, 50%)を得た。
1H-NMR (CDCl3) δ: 7.42 (s, 1H), 5.23 (s, 2H), 3.49 (t, J = 8.2 Hz, 3H), 2.63 (s, 3H), 0.91 (t, J = 8.2 Hz, 2H), -0.01 (s, 9H).
ESI-MS: m/z 256 [M+H]+ Process 2
4-Methyl-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazole-5-carboxylic acid (Compound B72)
According to Step 2 of Reference Example 7, Compound B72 (2.16 g, 97%) was obtained from Compound B71 (2.48 g, 8.71 mmol) and sodium hydroxide (1.64 g, 40.9 mmol).
1 H-NMR (DMSO-d 6 ) δ: 7.88 (s, 1H), 5.58 (s, 2H), 3.45 (t, J = 7.9 Hz, 3H), 2.34 (s, 3H), 0.81 (t, J = 7.9 Hz, 2H), -0.06 (s, 9H).
ESI-MS: m / z 255 [MH] -
Process 3
4-Methyl-1-{[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazole-5-carboxamide (Compound B73)
According to Step 3 of Reference Example 7, compound B72 (300 mg, 1.17 mmol), triethylamine (0.326 mL, 2.34 mmol), EDCI (336 mg, 1.76 mmol), HOBt (269 mg, 2.68 mmol), and 28% Compound B73 (150 mg, 50%) was obtained from aqueous ammonia (0.911 mL, 23.4 mmol).
1 H-NMR (CDCl 3 ) δ: 7.42 (s, 1H), 5.23 (s, 2H), 3.49 (t, J = 8.2 Hz, 3H), 2.63 (s, 3H), 0.91 (t, J = 8.2 Hz, 2H), -0.01 (s, 9H).
ESI-MS: m / z 256 [M + H] +
参考例24
工程1
6-メトキシ-4-(3-メトキシ-4-ニトロフェノキシ)-7-[3-(テトラヒドロ-2H-ピラン-2-イルオキシ)プロポキシ]キノリン (化合物A9)
　参考例6の工程1に準じて、化合物A5 (1.0 g, 3.1 mmol)、2-(3-ブロモプロポキシ)テトラヒドロ-2H-ピラン (0.77 mL, 4.6 mmol）、および炭酸カリウム (630 mg, 4.6 mmol)から化合物A9 (940 mg, 64%)を得た。
1H-NMR (CDCl3) δ: 8.60 (d, J= 4.9 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 6.87 (d, J = 2.9 Hz, 1H), 6.75 (dd, J = 8.8, 2.9 Hz, 1H), 6.68 (d, J = 4.9 Hz, 1H), 4.64 (t, J= 3.4 Hz, 1H), 4.34 (t, J = 6.3 Hz, 1H), 4.33 (t, J = 6.3 Hz, 1H), 3.99 (s, 3H), 3.97-3.96 (m, 1H), 3.94 (s, 3H), 3.89-3.83 (m, 1H), 3.66-3.63 (m, 1H), 3.54-3.49 (m, 1H), 2.28-2.22 (m, 2H), 1.85-1.80 (m, 1H), 1.74-1.70 (m, 1H), 1.55-1.52 (m, 4H).
ESI-MS: m/z 485 [M+H]+
工程2
2-メトキシ-4-{6-メトキシ-7-[3-(テトラヒドロ-2H-ピラン-2-イルオキシ)プロポキシ]キノリン-4-イルオキシ}アニリン (化合物A10)
　参考例6の工程2に準じて、化合物A9 (720 mg, 1.5 mmol)から、フロー式水素化反応装置[H-Cube(登録商標) ThalesNano社製]および10% Pd/C CatCart(登録商標)(φ4×30 mm)を用いて、化合物A10 (610 mg, 91%)を得た。
1H-NMR (CDCl3) δ: 8.45 (d, J= 4.9 Hz, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.66 (s, 1H), 6.65 (d, J = 7.8 Hz, 1H), 6.44 (d, J= 4.9 Hz, 1H), 4.64 (t, J = 3.9 Hz, 1H), 4.34 (t, J = 6.3 Hz, 1H), 4.33 (t, J = 6.3 Hz, 1H), 4.03 (s, 3H), 3.98-3.95 (m, 2H), 3.84 (s, 3H), 3.64-3.62 (m, 2H), 2.28-2.21 (m, 2H), 1.84-1.80 (m, 1H), 1.71-1.68 (m, 1H), 1.54-1.49 (m, 4H).
ESI-MS: m/z 455 [M+H]+ Reference Example 24
Process 1
6-Methoxy-4- (3-methoxy-4-nitrophenoxy) -7- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] quinoline (Compound A9)
According to Step 1 of Reference Example 6, compound A5 (1.0 g, 3.1 mmol), 2- (3-bromopropoxy) tetrahydro-2H-pyran (0.77 mL, 4.6 mmol), and potassium carbonate (630 mg, 4.6 mmol) ) To give Compound A9 (940 mg, 64%).
1 H-NMR (CDCl 3 ) δ: 8.60 (d, J = 4.9 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.48 (s, 1H), 7.36 (s, 1H), 6.87 ( d, J = 2.9 Hz, 1H), 6.75 (dd, J = 8.8, 2.9 Hz, 1H), 6.68 (d, J = 4.9 Hz, 1H), 4.64 (t, J = 3.4 Hz, 1H), 4.34 ( t, J = 6.3 Hz, 1H), 4.33 (t, J = 6.3 Hz, 1H), 3.99 (s, 3H), 3.97-3.96 (m, 1H), 3.94 (s, 3H), 3.89-3.83 (m , 1H), 3.66-3.63 (m, 1H), 3.54-3.49 (m, 1H), 2.28-2.22 (m, 2H), 1.85-1.80 (m, 1H), 1.74-1.70 (m, 1H), 1.55 -1.52 (m, 4H).
ESI-MS: m / z 485 [M + H] +
Process 2
2-Methoxy-4- {6-methoxy-7- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] quinolin-4-yloxy} aniline (Compound A10)
According to Step 2 of Reference Example 6, from compound A9 (720 mg, 1.5 mmol), a flow-type hydrogenation reactor [H-Cube (registered trademark) manufactured by ThalesNano] and 10% Pd / C CatCart (registered trademark) (φ4 × 30 mm) was used to obtain Compound A10 (610 mg, 91%).
1 H-NMR (CDCl 3 ) δ: 8.45 (d, J = 4.9 Hz, 1H), 7.57 (s, 1H), 7.43 (s, 1H), 6.77 (d, J = 7.8 Hz, 1H), 6.66 ( s, 1H), 6.65 (d, J = 7.8 Hz, 1H), 6.44 (d, J = 4.9 Hz, 1H), 4.64 (t, J = 3.9 Hz, 1H), 4.34 (t, J = 6.3 Hz, 1H), 4.33 (t, J = 6.3 Hz, 1H), 4.03 (s, 3H), 3.98-3.95 (m, 2H), 3.84 (s, 3H), 3.64-3.62 (m, 2H), 2.28-2.21 (m, 2H), 1.84-1.80 (m, 1H), 1.71-1.68 (m, 1H), 1.54-1.49 (m, 4H).
ESI-MS: m / z 455 [M + H] +
工程3
フェニル2-メトキシ-4-{6-メトキシ-7-[3-(テトラヒドロ-2H-ピラン-2-イルオキシ)プロポキシ]キノリン-4-イルオキシ}フェニルカルバマート (化合物A11)
　参考例6の工程3に準じて、化合物A10 (600 mg, 1.3 mmol)、クロロギ酸フェニル (0.25 mL, 2.0 mmol）、および炭酸カリウム (370 mg, 2.7 mmol) から化合物A11 (670 mg, 88%)を得た。
1H-NMR (CDCl3) δ: 8.48 (d, J= 5.1 Hz, 1H), 8.18 (d, J = 7.7 Hz, 1H), 7.54 (s, 1H), 7.44 (s, 1H), 7.40-7.37 (m, 2H), 7.23-7.21 (m, 3H), 6.83 (dd, J = 7.7, 2.4 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 6.48 (d, J = 5.1 Hz, 1H), 4.64 (t, J = 3.3 Hz, 1H), 4.33 (t, J = 6.8 Hz, 2H), 4.03 (s, 3H), 3.91 (s, 3H), 3.87-3.82 (m, 2H), 3.66-3.63 (m, 1H), 3.52-3.49 (m, 1H), 2.29-2.21 (m, 2H), 1.84-1.81 (m, 1H), 1.76-1.69 (m, 1H), 1.57-1.53 (m, 4H).
ESI-MS: m/z 575 [M+H]+ Process 3
Phenyl 2-methoxy-4- {6-methoxy-7- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] quinolin-4-yloxy} phenylcarbamate (Compound A11)
According to Step 3 of Reference Example 6, compound A10 (600 mg, 1.3 mmol), phenyl chloroformate (0.25 mL, 2.0 mmol), and potassium carbonate (370 mg, 2.7 mmol) were converted to compound A11 (670 mg, 88% )
1 H-NMR (CDCl 3 ) δ: 8.48 (d, J = 5.1 Hz, 1H), 8.18 (d, J = 7.7 Hz, 1H), 7.54 (s, 1H), 7.44 (s, 1H), 7.40- 7.37 (m, 2H), 7.23-7.21 (m, 3H), 6.83 (dd, J = 7.7, 2.4 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 6.48 (d, J = 5.1 Hz , 1H), 4.64 (t, J = 3.3 Hz, 1H), 4.33 (t, J = 6.8 Hz, 2H), 4.03 (s, 3H), 3.91 (s, 3H), 3.87-3.82 (m, 2H) , 3.66-3.63 (m, 1H), 3.52-3.49 (m, 1H), 2.29-2.21 (m, 2H), 1.84-1.81 (m, 1H), 1.76-1.69 (m, 1H), 1.57-1.53 ( m, 4H).
ESI-MS: m / z 575 [M + H] +
参考例25
工程1
6-メトキシ-4-(3-メトキシ-4-ニトロフェノキシ)-7-(2-メトキシエトキシ)キノリン (化合物A12)
　参考例6の工程1に準じて、化合物A5 (1.3 g, 3.9 mmol)、1-ブロモ-2-メトキシエタン (0.55 mL, 5.8 mmol)、および炭酸カリウム (800 mg, 5.8 mmol)から化合物A12 (1.3 g, 82%)を得た。
1H-NMR (CDCl3) δ: 8.60 (d, J= 5.1 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.46 (s, 1H), 7.37 (s, 1H), 6.88 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 9.0, 2.4 Hz, 1H), 6.68 (d, J = 5.1 Hz, 1H), 4.35 (t, J= 4.8 Hz, 2H), 3.99 (s, 3H), 3.94 (s, 3H), 3.90 (t, J = 4.8 Hz, 2H), 3.49 (s, 3H).
ESI-MS: m/z 401 [M+H]+
工程2
2-メトキシ-4-[6-メトキシ-7-(2-メトキシエトキシ)キノリン-4-イルオキシ]アニリン (化合物A13)
　参考例6の工程2に準じて、化合物A12 (1.2 g, 3.0 mmol)から、フロー式水素化反応装置 [H-Cube(登録商標) ThalesNano社製]および10% Pd/C CatCart (登録商標) (φ4×30 mm)を用いて、化合物A13 (1.0 g, 92%)を得た。
1H-NMR (CDCl3) δ: 8.45 (d, J= 4.9 Hz, 1H), 7.60 (s, 1H), 7.58 (s, 1H), 6.78 (d, J = 7.8 Hz, 1H), 6.66 (d, J= 2.0 Hz, 1H), 6.65 (dd, J = 7.8, 2.0 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.37 (t, J = 4.4 Hz, 2H), 4.03 (s, 3H), 3.90 (t, J= 4.4 Hz, 2H), 3.85 (s, 3H), 3.49 (s, 3H).
ESI-MS: m/z 371 [M+H]+. Reference Example 25
Process 1
6-Methoxy-4- (3-methoxy-4-nitrophenoxy) -7- (2-methoxyethoxy) quinoline (Compound A12)
According to Step 1 of Reference Example 6, compound A5 (1.3 g, 3.9 mmol), 1-bromo-2-methoxyethane (0.55 mL, 5.8 mmol), and potassium carbonate (800 mg, 5.8 mmol) were converted into compound A12 ( 1.3 g, 82%).
1 H-NMR (CDCl 3 ) δ: 8.60 (d, J = 5.1 Hz, 1H), 8.01 (d, J = 9.0 Hz, 1H), 7.46 (s, 1H), 7.37 (s, 1H), 6.88 ( d, J = 2.4 Hz, 1H), 6.75 (dd, J = 9.0, 2.4 Hz, 1H), 6.68 (d, J = 5.1 Hz, 1H), 4.35 (t, J = 4.8 Hz, 2H), 3.99 ( s, 3H), 3.94 (s, 3H), 3.90 (t, J = 4.8 Hz, 2H), 3.49 (s, 3H).
ESI-MS: m / z 401 [M + H] +
Process 2
2-Methoxy-4- [6-methoxy-7- (2-methoxyethoxy) quinolin-4-yloxy] aniline (Compound A13)
According to Step 2 of Reference Example 6, from compound A12 (1.2 g, 3.0 mmol), a flow-type hydrogenation reactor [H-Cube (registered trademark) manufactured by ThalesNano] and 10% Pd / C CatCart (registered trademark) (φ4 × 30 mm) was used to obtain Compound A13 (1.0 g, 92%).
1 H-NMR (CDCl 3 ) δ: 8.45 (d, J = 4.9 Hz, 1H), 7.60 (s, 1H), 7.58 (s, 1H), 6.78 (d, J = 7.8 Hz, 1H), 6.66 ( d, J = 2.0 Hz, 1H), 6.65 (dd, J = 7.8, 2.0 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 4.37 (t, J = 4.4 Hz, 2H), 4.03 ( s, 3H), 3.90 (t, J = 4.4 Hz, 2H), 3.85 (s, 3H), 3.49 (s, 3H).
ESI-MS: m / z 371 [M + H] + .
工程3
フェニル 2-メトキシ-4-[6-メトキシ-7-(2-メトキシエトキシ)キノリン-4-イルオキシ]フェニルカルバマート (化合物A14)
　参考例6の工程3に準じて、化合物A13 (1.0 g, 2.8 mmol)、クロロギ酸フェニル (0.52 mL, 4.1 mmol）、および炭酸カリウム (760 mg, 5.5 mmol) から化合物A14 (1.1 g, 80%)を得た。
1H-NMR (CDCl3) δ: 8.49 (d, J= 4.9 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.55 (s, 1H), 7.42-7.38 (m, 3H), 7.25-7.22 (m, 3H), 6.83 (dd, J = 8.8, 2.0 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.48 (d, J = 4.9 Hz, 1H), 4.34 (t, J = 4.4 Hz, 2H), 4.03 (s, 3H), 3.91 (s, 3H), 3.90 (t, J = 4.4 Hz, 2H). 3.49 (s, 3H).
ESI-MS: m/z 491 [M+H]+. Process 3
Phenyl 2-methoxy-4- [6-methoxy-7- (2-methoxyethoxy) quinolin-4-yloxy] phenylcarbamate (Compound A14)
According to Step 3 of Reference Example 6, compound A14 (1.1 g, 80%) was obtained from compound A13 (1.0 g, 2.8 mmol), phenyl chloroformate (0.52 mL, 4.1 mmol), and potassium carbonate (760 mg, 5.5 mmol). )
1 H-NMR (CDCl 3 ) δ: 8.49 (d, J = 4.9 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.55 (s, 1H), 7.42-7.38 (m, 3H), 7.25-7.22 (m, 3H), 6.83 (dd, J = 8.8, 2.0 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.48 (d, J = 4.9 Hz, 1H), 4.34 (t , J = 4.4 Hz, 2H), 4.03 (s, 3H), 3.91 (s, 3H), 3.90 (t, J = 4.4 Hz, 2H). 3.49 (s, 3H).
ESI-MS: m / z 491 [M + H] + .
参考例26
工程1
6-メトキシ-4-(3-メトキシ-4-ニトロフェノキシ)-7-[2-(テトラヒドロ-2H-ピラン-2-イルオキシ)エトキシ]キノリン (化合物A15)
　参考例6の工程1に準じて、化合物A5 (1.3 g, 3.8 mmol)、2-(2-ブロモエトキシ)テトラヒドロ-2H-ピラン (0.87 mL, 5.8 mmol）、および炭酸カリウム (800 mg, 5.8 mmol)から化合物A15 (1.5 g, 84%)を得た。
1H-NMR (CDCl3) δ: 8.60 (d, J= 5.1 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), 7.37 (s, 1H), 6.87 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 8.8, 2.4 Hz, 1H), 6.68 (d, J = 5.1 Hz, 1H), 4.77 (t, J= 3.5 Hz, 1H), 4.40 (t, J = 5.1 Hz, 2H), 4.22-4.13 (m, 1H), 4.01-3.90 (m, 2H), 3.99 (s, 3H), 3.94 (s, 3H), 3.58-3.51 (m, 1H), 1.89-1.51 (m, 6H).
ESI-MS: m/z 271 [M+H]+. Reference Example 26
Process 1
6-Methoxy-4- (3-methoxy-4-nitrophenoxy) -7- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] quinoline (Compound A15)
According to Step 1 of Reference Example 6, compound A5 (1.3 g, 3.8 mmol), 2- (2-bromoethoxy) tetrahydro-2H-pyran (0.87 mL, 5.8 mmol), and potassium carbonate (800 mg, 5.8 mmol) ) To give Compound A15 (1.5 g, 84%).
1 H-NMR (CDCl 3 ) δ: 8.60 (d, J = 5.1 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), 7.37 (s, 1H), 6.87 ( d, J = 2.4 Hz, 1H), 6.75 (dd, J = 8.8, 2.4 Hz, 1H), 6.68 (d, J = 5.1 Hz, 1H), 4.77 (t, J = 3.5 Hz, 1H), 4.40 ( t, J = 5.1 Hz, 2H), 4.22-4.13 (m, 1H), 4.01-3.90 (m, 2H), 3.99 (s, 3H), 3.94 (s, 3H), 3.58-3.51 (m, 1H) , 1.89-1.51 (m, 6H).
ESI-MS: m / z 271 [M + H] + .
工程2
2-メトキシ-4-{6-メトキシ-7-[2-(テトラヒドロ-2H-ピラン-2-イルオキシ)エトキシ]キノリン-4-イルオキシ}アニリン (化合物A16)
　参考例6の工程2に準じて、化合物A15 (1.3 g, 2.8 mmol)から、フロー式水素化反応装置 [H-Cube(登録商標) ThalesNano社製]および10% Pd/C CatCart (登録商標) (φ4×30 mm)を用いて、化合物A16 (1.2 g, 100%)を得た。
1H-NMR (CDCl3) δ: 8.45 (d, J= 5.9 Hz, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.66 (d, J= 2.0 Hz, 1H), 6.65 (dd, J = 8.8, 2.0 Hz, 1H), 6.48 (d, J = 5.9 Hz, 1H), 4.77 (t, J = 3.4 Hz, 1H), 4.40 (t, J = 4.9 Hz, 2H), 4.19-4.17 (m, 1H), 4.03 (s, 3H), 3.97-3.94 (m, 2H), 3.84 (s, 3H), 3.58-3.52 (m, 1H), 1.91-1.52 (m, 6H).
ESI-MS: m/z 441 [M+H]+.
工程3
フェニル2-メトキシ-4-{6-メトキシ-7-[2-(テトラヒドロ-2H-ピラン-2-イルオキシ)エトキシ]キノリン-4-イルオキシ}フェニルカルバマート (化合物A17)
　参考例6の工程3に準じて、化合物A16 (1.2 g, 2.8 mmol)、クロロギ酸フェニル (0.53 mL, 4.2 mmol）、および炭酸カリウム (770 mg, 5.5 mmol)から化合物A17 (1.4 g, 88%)を得た。
1H-NMR (CDCl3) δ: 8.49 (d, J= 5.9 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.55 (s, 1H), 7.46 (s, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.27-7.22 (m, 3H), 6.83 (dd, J = 8.3, 2.4 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 6.48 (d, J = 5.9 Hz, 1H), 4.77 (t, J = 3.4 Hz, 1H), 4.39 (t, J = 4.9 Hz, 2H), 4.21-4.16 (m, 1H), 4.02 (s, 3H), 4.01-3.93 (m, 2H), 3.92 (s, 3H), 3.56-3.54 (m, 1H), 1.91-1.51 (m, 6H).
ESI-MS: m/z 561 [M+H]+. Process 2
2-Methoxy-4- {6-methoxy-7- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] quinolin-4-yloxy} aniline (Compound A16)
According to Step 2 of Reference Example 6, from compound A15 (1.3 g, 2.8 mmol), a flow-type hydrogenation reactor [H-Cube (registered trademark) manufactured by ThalesNano] and 10% Pd / C CatCart (registered trademark) Compound A16 (1.2 g, 100%) was obtained using (φ4 × 30 mm).
1 H-NMR (CDCl 3 ) δ: 8.45 (d, J = 5.9 Hz, 1H), 7.58 (s, 1H), 7.54 (s, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.66 ( d, J = 2.0 Hz, 1H), 6.65 (dd, J = 8.8, 2.0 Hz, 1H), 6.48 (d, J = 5.9 Hz, 1H), 4.77 (t, J = 3.4 Hz, 1H), 4.40 ( t, J = 4.9 Hz, 2H), 4.19-4.17 (m, 1H), 4.03 (s, 3H), 3.97-3.94 (m, 2H), 3.84 (s, 3H), 3.58-3.52 (m, 1H) , 1.91-1.52 (m, 6H).
ESI-MS: m / z 441 [M + H] + .
Process 3
Phenyl 2-methoxy-4- {6-methoxy-7- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] quinolin-4-yloxy} phenylcarbamate (Compound A17)
According to Step 3 of Reference Example 6, compound A16 (1.2 g, 2.8 mmol), phenyl chloroformate (0.53 mL, 4.2 mmol), and potassium carbonate (770 mg, 5.5 mmol) were converted to compound A17 (1.4 g, 88% )
1 H-NMR (CDCl 3 ) δ: 8.49 (d, J = 5.9 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.55 (s, 1H), 7.46 (s, 1H), 7.42 ( t, J = 7.8 Hz, 2H), 7.27-7.22 (m, 3H), 6.83 (dd, J = 8.3, 2.4 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 6.48 (d, J = 5.9 Hz, 1H), 4.77 (t, J = 3.4 Hz, 1H), 4.39 (t, J = 4.9 Hz, 2H), 4.21-4.16 (m, 1H), 4.02 (s, 3H), 4.01-3.93 (m, 2H), 3.92 (s, 3H), 3.56-3.54 (m, 1H), 1.91-1.51 (m, 6H).
ESI-MS: m / z 561 [M + H] + .
参考例27
工程1
6-メトキシ-4-(3-メトキシ-4-ニトロフェノキシ)-7-(メトキシメトキシ)キノリン(化合物A18)
　参考例6の工程1に準じて、化合物A5(300 mg, 0.88 mmol)、クロロメチルメチルエーテル (0.10 mL, 1.3 mmol）、および炭酸カリウム(240 mg, 1.8 mmol)から化合物A18(130 mg, 38%)を得た。
1H-NMR (CDCl3) δ: 8.62 (d, J = 5.0 Hz, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.79 (s, 1H), 7.41 (s, 1H), 6.88 (d, J= 2.3 Hz, 1H), 6.75 (dd, J = 9.1, 2.3 Hz, 1H), 6.70 (d, J = 5.0 Hz, 1H), 5.43 (s, 2H), 4.02 (s, 3H), 3.95 (s, 3H), 3.57 (s, 3H).
ESI-MS: m/z 387 [M+H]+.
工程2
2-メトキシ-4-[6-メトキシ-7-(メトキシメトキシ)キノリン-4-イルオキシ]アニリン(化合物A19)
　参考例6の工程2に準じて、化合物A18(160 mg, 410 mmol)から化合物A19(160 mg, 100%)を得た。
1H-NMR (CDCl3) δ: 8.48 (d, J = 5.0 Hz, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 6.77 (d, J = 7.7 Hz, 1H), 6.66-6.63 (m, 2H), 6.48 (d, J = 5.0 Hz, 1H), 5.42 (s, 2H), 4.06 (s, 3H), 3.84 (s, 3H), 3.56 (s, 3H).
ESI-MS: m/z 357 [M+H]+. Reference Example 27
Process 1
6-Methoxy-4- (3-methoxy-4-nitrophenoxy) -7- (methoxymethoxy) quinoline (Compound A18)
According to Step 1 of Reference Example 6, compound A18 (130 mg, 38 mmol) was obtained from compound A5 (300 mg, 0.88 mmol), chloromethyl methyl ether (0.10 mL, 1.3 mmol), and potassium carbonate (240 mg, 1.8 mmol). %).
1 H-NMR (CDCl 3 ) δ: 8.62 (d, J = 5.0 Hz, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.79 (s, 1H), 7.41 (s, 1H), 6.88 ( d, J = 2.3 Hz, 1H), 6.75 (dd, J = 9.1, 2.3 Hz, 1H), 6.70 (d, J = 5.0 Hz, 1H), 5.43 (s, 2H), 4.02 (s, 3H), 3.95 (s, 3H), 3.57 (s, 3H).
ESI-MS: m / z 387 [M + H] + .
Process 2
2-Methoxy-4- [6-methoxy-7- (methoxymethoxy) quinolin-4-yloxy] aniline (Compound A19)
According to Step 2 of Reference Example 6, compound A19 (160 mg, 100%) was obtained from compound A18 (160 mg, 410 mmol).
1 H-NMR (CDCl 3 ) δ: 8.48 (d, J = 5.0 Hz, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 6.77 (d, J = 7.7 Hz, 1H), 6.66- 6.63 (m, 2H), 6.48 (d, J = 5.0 Hz, 1H), 5.42 (s, 2H), 4.06 (s, 3H), 3.84 (s, 3H), 3.56 (s, 3H).
ESI-MS: m / z 357 [M + H] + .
工程3
フェニル2-メトキシ-4-[6-メトキシ-7-(メトキシメトキシ)キノリン-4-イルオキシ]フェニルカーバマート(化合物A20)
　参考例6の工程3に準じて、化合物A19(150 mg, 0.41 mmol)、クロロギ酸フェニル(0.078 mL, 0.62 mmol）、および炭酸カリウム(110 mg, 0.82 mmol)から化合物A20(190 mg, 97%)を得た。
1H-NMR (DMSO-d6) δ: 9.27 (br s, 1H), 8.50 (d, J= 5.0 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.55 (s, 1H), 7.44-7.42 (m, 2H), 7.25-7.15 (m, 3H), 7.06 (d, J = 2.3 Hz, 1H), 6.84 (dd, J = 8.6, 2.3 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 6.55 (d, J = 5.0 Hz, 1H), 5.40 (s, 2H), 3.96 (s, 3H), 3.85 (s, 3H), 3.45 (s, 3H).
ESI-MS: m/z 477 [M+H]+. Process 3
Phenyl 2-methoxy-4- [6-methoxy-7- (methoxymethoxy) quinolin-4-yloxy] phenyl carbamate (Compound A20)
According to Step 3 of Reference Example 6, compound A19 (150 mg, 0.41 mmol), phenyl chloroformate (0.078 mL, 0.62 mmol), and potassium carbonate (110 mg, 0.82 mmol) were converted to compound A20 (190 mg, 97% )
1 H-NMR (DMSO-d 6 ) δ: 9.27 (br s, 1H), 8.50 (d, J = 5.0 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.55 (s, 1H) , 7.44-7.42 (m, 2H), 7.25-7.15 (m, 3H), 7.06 (d, J = 2.3 Hz, 1H), 6.84 (dd, J = 8.6, 2.3 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 6.55 (d, J = 5.0 Hz, 1H), 5.40 (s, 2H), 3.96 (s, 3H), 3.85 (s, 3H), 3.45 (s, 3H).
ESI-MS: m / z 477 [M + H] + .
参考例28
工程1
2-[6-メトキシ-4-(3-メトキシ-4-ニトロフェノキシ)キノリン-7-イルオキシ-N,N-ジメチルエタンアミン(化合物A21)
　参考例6の工程1に準じて、化合物A5(300 mg, 0.88 mmol)、2-(ジメチルアミノ)エチルクロリド塩酸塩(140 mg, 0.96 mmol）、および炭酸カリウム(300 mg, 2.2 mmol)から化合物A21(110 mg, 31%)を得た。
1H-NMR (CDCl3) δ: 8.60 (d, J = 4.9 Hz, 1H), 8.02 (d, J = 9.8 Hz, 1H), 7.46 (s, 1H), 7.37 (s, 1H), 6.88 (d, J= 2.9 Hz, 1H), 6.76 (dd, J = 9.8, 2.9 Hz, 1H), 6.68 (d, J = 4.9 Hz, 1H), 4.31 (t, J = 5.9 Hz, 2H), 3.99 (s, 3H), 3.95 (s, 3H), 2.92 (t, J = 5.9 Hz, 2H), 2.41 (s, 6H).
ESI-MS: m/z 414 [M+H]+.
工程2
4-{7-[2-(ジメチルアミノ)エトキシ]-6-メトキシキノリン-4-イルオキシ}-2-メトキシアニリン(化合物A22)
　参考例6の工程2に準じて、化合物A21(110 mg, 0.25 mmol)から化合物A22(97 mg, 100%)を得た。
1H-NMR (DMSO-d6) δ: 8.44 (d, J = 5.4 Hz, 1H), 7.53 (s, 1H), 7.44 (s, 1H), 6.76 (d, J = 2.3 Hz, 1H), 6.72 (d, J= 8.6 Hz, 1H), 6.60 (dd, J = 8.6, 2.3 Hz, 1H), 6.42 (d, J = 5.4 Hz, 1H), 4.34 (t, J = 5.4 Hz, 2H), 3.95 (s, 3H), 3.76 (s, 3H), 2.51 (br s, 2H), 2.50 (s, 6H).
ESI-MS: m/z 384 [M+H]+. Reference Example 28
Process 1
2- [6-Methoxy-4- (3-methoxy-4-nitrophenoxy) quinolin-7-yloxy-N, N-dimethylethanamine (Compound A21)
According to Step 1 of Reference Example 6, compound A5 (300 mg, 0.88 mmol), 2- (dimethylamino) ethyl chloride hydrochloride (140 mg, 0.96 mmol), and potassium carbonate (300 mg, 2.2 mmol) A21 (110 mg, 31%) was obtained.
1 H-NMR (CDCl 3 ) δ: 8.60 (d, J = 4.9 Hz, 1H), 8.02 (d, J = 9.8 Hz, 1H), 7.46 (s, 1H), 7.37 (s, 1H), 6.88 ( d, J = 2.9 Hz, 1H), 6.76 (dd, J = 9.8, 2.9 Hz, 1H), 6.68 (d, J = 4.9 Hz, 1H), 4.31 (t, J = 5.9 Hz, 2H), 3.99 ( s, 3H), 3.95 (s, 3H), 2.92 (t, J = 5.9 Hz, 2H), 2.41 (s, 6H).
ESI-MS: m / z 414 [M + H] + .
Process 2
4- {7- [2- (Dimethylamino) ethoxy] -6-methoxyquinolin-4-yloxy} -2-methoxyaniline (Compound A22)
According to Step 2 of Reference Example 6, compound A22 (97 mg, 100%) was obtained from compound A21 (110 mg, 0.25 mmol).
1 H-NMR (DMSO-d 6 ) δ: 8.44 (d, J = 5.4 Hz, 1H), 7.53 (s, 1H), 7.44 (s, 1H), 6.76 (d, J = 2.3 Hz, 1H), 6.72 (d, J = 8.6 Hz, 1H), 6.60 (dd, J = 8.6, 2.3 Hz, 1H), 6.42 (d, J = 5.4 Hz, 1H), 4.34 (t, J = 5.4 Hz, 2H), 3.95 (s, 3H), 3.76 (s, 3H), 2.51 (br s, 2H), 2.50 (s, 6H).
ESI-MS: m / z 384 [M + H] + .
工程3
フェニル4-{7-[2-(ジメチルアミノ)エトキシ]-6-メトキシキノリン-4-イルオキシ}-2-メトキシフェニルカーバマート(化合物A23)
　参考例6の工程3に準じて、化合物A22(97 mg, 0.25 mmol)、クロロギ酸フェニル(0.048 mL, 0.38 mmol）、および炭酸カリウム(70 mg, 0.51 mmol) から化合物A23(72 mg, 56%)を得た。
1H-NMR (DMSO-d6) δ: 9.28 (br s, 1H), 8.48 (d, J= 5.4 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.51 (s, 1H), 7.45-7.39 (m, 3H), 7.24-7.19 (m, 3H), 7.07 (d, J = 2.7 Hz, 1H), 6.84 (dd, J = 8.6, 2.7 Hz, 1H), 6.52 (d, J = 5.4 Hz, 1H), 4.23 (t, J = 5.9 Hz, 2H), 3.93 (s, 3H), 3.85 (s, 3H), 2.73 (t, J = 5.9 Hz, 2H), 2.26 (s, 6H).
ESI-MS: m/z 504 [M+H]+. Process 3
Phenyl 4- {7- [2- (dimethylamino) ethoxy] -6-methoxyquinolin-4-yloxy} -2-methoxyphenyl carbamate (Compound A23)
According to Step 3 of Reference Example 6, compound A22 (97 mg, 0.25 mmol), phenyl chloroformate (0.048 mL, 0.38 mmol), and potassium carbonate (70 mg, 0.51 mmol) were converted to compound A23 (72 mg, 56% )
1 H-NMR (DMSO-d 6 ) δ: 9.28 (br s, 1H), 8.48 (d, J = 5.4 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.51 (s, 1H) , 7.45-7.39 (m, 3H), 7.24-7.19 (m, 3H), 7.07 (d, J = 2.7 Hz, 1H), 6.84 (dd, J = 8.6, 2.7 Hz, 1H), 6.52 (d, J = 5.4 Hz, 1H), 4.23 (t, J = 5.9 Hz, 2H), 3.93 (s, 3H), 3.85 (s, 3H), 2.73 (t, J = 5.9 Hz, 2H), 2.26 (s, 6H ).
ESI-MS: m / z 504 [M + H] + .
参考例29
工程1
6-メトキシ-4-(3-メトキシ-4-ニトロフェノキシ)-7-[2-(ピロリジン-1-イル)エトキシ]キノリン(化合物A24)
　参考例6の工程1に準じて、化合物A5(300 mg, 0.88 mmol)、1-(2-クロロエチル)ピロリジン塩酸塩(160 mg, 0.96 mmol）、および炭酸カリウム(300 mg, 2.2 mmol)から化合物A24(150 mg, 40%)を得た。
1H-NMR (DMSO-d6) δ: 8.57 (d, J = 5.0 Hz, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.46 (s, 1H), 7.42 (s, 1H), 7.33 (d, J= 2.3 Hz, 1H), 6.88 (dd, J = 9.1, 2.3 Hz, 1H), 6.82 (d, J = 5.0 Hz, 1H), 4.26 (t, J = 5.9 Hz, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 2.90 (t, J = 5.9 Hz, 2H), 2.58 (br s, 4H), 1.72-1.69 (m, 4H).
ESI-MS: m/z 440 [M+H]+.
工程2
2-メトキシ-4-{6-メトキシ-7-[2-(ピロリジン-1-イル)エトキシ]キノリン-4-イルオキシ}アニリン(化合物A25)
　参考例6の工程2に準じて、化合物A24(150 mg, 0.34 mmol)から化合物A25(140 mg, 100%)を得た。
1H-NMR (DMSO-d6) δ: 8.43 (d, J = 5.4 Hz, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 6.76 (d, J = 2.3 Hz, 1H), 6.72 (d, J= 8.2 Hz, 1H), 6.60 (dd, J = 8.2, 2.3 Hz, 1H), 6.41 (d, J = 5.4 Hz, 1H), 4.27 (t, J = 5.2 Hz, 2H), 3.94 (s, 3H), 3.76 (s, 3H), 2.98 (br s, 2H), 2.67 (br s, 4H), 1.74 (br s, 4H).
ESI-MS: m/z 410 [M+H]+.
工程3
フェニル4-{6-エチル-7-[2-(ピロリジン-1-イル)エトキシ]キノリン-4-イルオキシ}-2-メトキシフェニルカーバマート(化合物A26)
　参考例6の工程3に準じて、化合物A25(140 mg, 0.34 mmol)、クロロギ酸フェニル(0.065 mL, 0.51 mmol）、および炭酸カリウム(95mg, 0.68 mmol)から化合物A26(130 mg, 73%)を得た。
1H-NMR (DMSO-d6) δ: 9.28 (br s, 1H), 8.48 (d, J= 5.4 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.51 (s, 1H), 7.45-7.42 (m, 2H), 7.41 (s, 1H), 7.27-7.14 (m, 3H), 7.07 (d, J = 2.5 Hz, 1H), 6.84 (dd, J = 8.6, 2.5 Hz, 1H), 6.52 (d, J = 5.4 Hz, 1H), 4.24 (t, J = 5.7 Hz, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 2.89 (t, J = 5.7 Hz, 2H), 2.57 (br s, 4H), 1.70 (br s, 4H).
ESI-MS: m/z 530 [M+H]+. Reference Example 29
Process 1
6-Methoxy-4- (3-methoxy-4-nitrophenoxy) -7- [2- (pyrrolidin-1-yl) ethoxy] quinoline (Compound A24)
According to Step 1 of Reference Example 6, compound A5 (300 mg, 0.88 mmol), 1- (2-chloroethyl) pyrrolidine hydrochloride (160 mg, 0.96 mmol), and potassium carbonate (300 mg, 2.2 mmol) A24 (150 mg, 40%) was obtained.
1 H-NMR (DMSO-d 6 ) δ: 8.57 (d, J = 5.0 Hz, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.46 (s, 1H), 7.42 (s, 1H), 7.33 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 9.1, 2.3 Hz, 1H), 6.82 (d, J = 5.0 Hz, 1H), 4.26 (t, J = 5.9 Hz, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 2.90 (t, J = 5.9 Hz, 2H), 2.58 (br s, 4H), 1.72-1.69 (m, 4H).
ESI-MS: m / z 440 [M + H] + .
Process 2
2-Methoxy-4- {6-methoxy-7- [2- (pyrrolidin-1-yl) ethoxy] quinolin-4-yloxy} aniline (Compound A25)
According to Step 2 of Reference Example 6, compound A25 (140 mg, 100%) was obtained from compound A24 (150 mg, 0.34 mmol).
1 H-NMR (DMSO-d 6 ) δ: 8.43 (d, J = 5.4 Hz, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 6.76 (d, J = 2.3 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.60 (dd, J = 8.2, 2.3 Hz, 1H), 6.41 (d, J = 5.4 Hz, 1H), 4.27 (t, J = 5.2 Hz, 2H), 3.94 (s, 3H), 3.76 (s, 3H), 2.98 (br s, 2H), 2.67 (br s, 4H), 1.74 (br s, 4H).
ESI-MS: m / z 410 [M + H] + .
Process 3
Phenyl 4- {6-ethyl-7- [2- (pyrrolidin-1-yl) ethoxy] quinolin-4-yloxy} -2-methoxyphenylcarbamate (Compound A26)
According to Step 3 of Reference Example 6, compound A25 (140 mg, 0.34 mmol), phenyl chloroformate (0.065 mL, 0.51 mmol), and potassium carbonate (95 mg, 0.68 mmol) to compound A26 (130 mg, 73%) Got.
1 H-NMR (DMSO-d 6 ) δ: 9.28 (br s, 1H), 8.48 (d, J = 5.4 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.51 (s, 1H) , 7.45-7.42 (m, 2H), 7.41 (s, 1H), 7.27-7.14 (m, 3H), 7.07 (d, J = 2.5 Hz, 1H), 6.84 (dd, J = 8.6, 2.5 Hz, 1H ), 6.52 (d, J = 5.4 Hz, 1H), 4.24 (t, J = 5.7 Hz, 2H), 3.94 (s, 3H), 3.85 (s, 3H), 2.89 (t, J = 5.7 Hz, 2H ), 2.57 (br s, 4H), 1.70 (br s, 4H).
ESI-MS: m / z 530 [M + H] + .
参考例30
6-(ベンジルオキシ)-7-メトキシ-4-(3-メトキシ-4-ニトロフェノキシ)キノリン (化合物A27)
　参考例3に準じて、WO2005/80377記載の方法に従って得られる 6-(ベンジルオキシ)-4-クロロ-7-メトキシキノリン(9.8 g, 33 mmol)、および3-メトキシ-4-ニトロフェノール(10 g, 65 mmol)から化合物A27(12 g, 85%)を得た。
ESI-MS: m/z 433 [M+H]+. Reference Example 30
6- (Benzyloxy) -7-methoxy-4- (3-methoxy-4-nitrophenoxy) quinoline (Compound A27)
According to Reference Example 3, 6- (benzyloxy) -4-chloro-7-methoxyquinoline (9.8 g, 33 mmol) obtained according to the method described in WO2005 / 80377, and 3-methoxy-4-nitrophenol (10 g, 65 mmol) gave compound A27 (12 g, 85%).
ESI-MS: m / z 433 [M + H] + .
参考例31
7-メトキシ-4-(3-メトキシ-4-ニトロフェノキシ)キノリン-6-オール (化合物A28)
　参考例5 に準じて、化合物A27(10 g, 23 mmol)、トリフルオロ酢酸(40 mL)、およびチオアニソール (6.0 mL)から化合物A28(9.0 g, quant.)を得た。
1H-NMR (DMSO-d6) δ: 10.09 (s, 1H), 8.56 (d, J = 4.9 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.43 (s, 1H), 7.33 (s, 1H), 7.28 (d, J = 2.9 Hz, 1H), 6.86 (d, J= 4.9 Hz, 1H), 6.76 (dd, J = 8.8, 2.9 Hz, 1H), 3.97 (s, 3H), 3.94 (s, 3H).
ESI-MS: m/z 343 [M+H]+. Reference Example 31
7-Methoxy-4- (3-methoxy-4-nitrophenoxy) quinolin-6-ol (Compound A28)
According to Reference Example 5, compound A28 (9.0 g, quant.) Was obtained from compound A27 (10 g, 23 mmol), trifluoroacetic acid (40 mL), and thioanisole (6.0 mL).
1 H-NMR (DMSO-d 6 ) δ: 10.09 (s, 1H), 8.56 (d, J = 4.9 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.43 (s, 1H), 7.33 (s, 1H), 7.28 (d, J = 2.9 Hz, 1H), 6.86 (d, J = 4.9 Hz, 1H), 6.76 (dd, J = 8.8, 2.9 Hz, 1H), 3.97 (s, 3H ), 3.94 (s, 3H).
ESI-MS: m / z 343 [M + H] + .
参考例32
工程1
7-メトキシ-4-(3-メトキシ-4-ニトロフェノキシ)-6-(メトキシメトキシ)キノリン(化合物A29)
　参考例6の工程1に準じて、化合物A28(400 mg, 1.2 mmol)、クロロメチルメチルエーテル(0.11 mL, 1.4 mmol）、および60％水素化ナトリウム(70 mg, 1.8 mmol)から化合物A29(290 mg, 64%)を得た。
1H-NMR (CDCl3) δ: 8.62 (d, J = 5.0 Hz, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.75 (s, 1H), 7.49 (s, 1H), 6.90 (d, J= 2.3 Hz, 1H), 6.75 (dd, J = 9.1, 2.3 Hz, 1H), 6.67 (d, J = 5.0 Hz, 1H), 5.39 (s, 2H), 4.06 (s, 3H), 3.95 (s, 3H), 3.55 (s, 3H).
ESI-MS: m/z 387 [M+H]+.
工程2
2-メトキシ-4-[7-メトキシ-6-(メトキシメトキシ)キノリン-4-イルオキシ]アニリン(化合物A30)
　参考例6の工程2に準じて、化合物A29(280 mg, 730 mmol)から化合物A30(250 mg, 96%)を得た。
1H-NMR (DMSO-d6) δ: 8.57 (d, J = 5.4 Hz, 1H), 7.80 (s, 1H), 7.47 (s, 1H), 6.82 (d, J = 2.5 Hz, 1H), 6.75 (d, J= 8.4 Hz, 1H), 6.64 (dd, J = 8.4, 2.5 Hz, 1H), 6.55 (d, J = 5.4 Hz, 1H), 5.40 (s, 2H), 3.99 (s, 3H), 3.77 (s, 3H), 3.45 (s, 3H).
ESI-MS: m/z 357 [M+H]+.
工程3
フェニル2-メトキシ-4-[7-メトキシ-6-(メトキシメトキシ)キノリン-4-イルオキシ]フェニルカーバマート(化合物A31)
　参考例6の工程3に準じて、化合物A30(250 mg, 0.70 mmol)、クロロギ酸フェニル(0.13 mL, 1.0 mmol）、および炭酸カリウム(190 mg, 1.4 mmol) から化合物A31(280 mg, 85%)を得た。
1H-NMR (DMSO-d6) δ: 9.29 (br s, 1H), 8.52 (d, J= 4.9 Hz, 1H), 7.75 (s, 1H), 7.71 (d, J= 8.8 Hz, 1H), 7.44-7.43 (m, 2H), 7.28-7.21 (m, 3H), 7.08 (d, J = 2.9 Hz, 1H), 6.85 (dd, J = 8.8, 2.9 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 5.37 (s, 2H), 3.97 (s, 3H), 3.85 (s, 3H), 3.45 (s, 3H).
ESI-MS: m/z 477 [M+H]+. Reference Example 32
Process 1
7-Methoxy-4- (3-methoxy-4-nitrophenoxy) -6- (methoxymethoxy) quinoline (Compound A29)
According to Step 1 of Reference Example 6, compound A28 (400 mg, 1.2 mmol), chloromethyl methyl ether (0.11 mL, 1.4 mmol), and 60% sodium hydride (70 mg, 1.8 mmol) were converted to compound A29 (290 mg, 64%).
1 H-NMR (CDCl 3 ) δ: 8.62 (d, J = 5.0 Hz, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.75 (s, 1H), 7.49 (s, 1H), 6.90 ( d, J = 2.3 Hz, 1H), 6.75 (dd, J = 9.1, 2.3 Hz, 1H), 6.67 (d, J = 5.0 Hz, 1H), 5.39 (s, 2H), 4.06 (s, 3H), 3.95 (s, 3H), 3.55 (s, 3H).
ESI-MS: m / z 387 [M + H] + .
Process 2
2-Methoxy-4- [7-methoxy-6- (methoxymethoxy) quinolin-4-yloxy] aniline (Compound A30)
According to Step 2 of Reference Example 6, compound A30 (250 mg, 96%) was obtained from compound A29 (280 mg, 730 mmol).
1 H-NMR (DMSO-d 6 ) δ: 8.57 (d, J = 5.4 Hz, 1H), 7.80 (s, 1H), 7.47 (s, 1H), 6.82 (d, J = 2.5 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.64 (dd, J = 8.4, 2.5 Hz, 1H), 6.55 (d, J = 5.4 Hz, 1H), 5.40 (s, 2H), 3.99 (s, 3H ), 3.77 (s, 3H), 3.45 (s, 3H).
ESI-MS: m / z 357 [M + H] + .
Process 3
Phenyl 2-methoxy-4- [7-methoxy-6- (methoxymethoxy) quinolin-4-yloxy] phenyl carbamate (Compound A31)
According to Step 3 of Reference Example 6, compound A30 (250 mg, 0.70 mmol), phenyl chloroformate (0.13 mL, 1.0 mmol), and potassium carbonate (190 mg, 1.4 mmol) were converted to compound A31 (280 mg, 85% )
1 H-NMR (DMSO-d 6 ) δ: 9.29 (br s, 1H), 8.52 (d, J = 4.9 Hz, 1H), 7.75 (s, 1H), 7.71 (d, J = 8.8 Hz, 1H) , 7.44-7.43 (m, 2H), 7.28-7.21 (m, 3H), 7.08 (d, J = 2.9 Hz, 1H), 6.85 (dd, J = 8.8, 2.9 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 6.52 (d, J = 4.9 Hz, 1H), 5.37 (s, 2H), 3.97 (s, 3H), 3.85 (s, 3H), 3.45 (s, 3H).
ESI-MS: m / z 477 [M + H] + .
参考例33
工程1
6-[(2,2-ジメチル-1,3-ジオキソラン-4-イル)メトキシ]-7-メトキシ-4-(3-メトキシ-4-ニトロフェノキシ)キノリン(化合物A32)
　化合物A28(400 mg, 1.2 mmol)のTHF(6.0 mL）溶液に、2,2-ジメチル-1,3-ジオキソラン-4-メタノール(0.22 mL, 1.8 mmol）、およびトリフェニルホスフィン(370 mg, 1.4 mmol)を加え、氷冷撹拌下、40% アゾジカルボン酸ジエチル－トルエン溶液(0.69 mL, 1.8 mmol)を滴下し、室温にて2時間撹拌した。反応混合液に水を加え、水層を酢酸エチルにて抽出し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムにて乾燥し、不溶物をろ別した。ろ液を減圧濃縮することで得られた残留物をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム= 5/95)で精製することにより、化合物A32(500 mg, 94%)を得た。
1H-NMR (CDCl3) δ: 8.61 (d, J = 5.0 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.45 (s, 1H), 7.44 (s, 1H), 6.88 (d, J= 2.3 Hz, 1H), 6.75 (dd, J = 9.1, 2.3 Hz, 1H), 6.68 (d, J = 5.0 Hz, 1H), 4.64-4.58 (m, 1H), 4.25-4.22 (m, 2H), 4.11-4.09 (m, 1H), 4.02 (s, 3H), 4.00-3.97 (m, 1H), 3.95 (s, 3H), 1.48 (s, 3H), 1.41 (s, 3H).
ESI-MS: m/z 457 [M+H]+.
工程2
4-{6-[(2,2-ジメチル-1,3-ジオキソラン-4-イル)メトキシ]-7-メトキシキノリン-4-イルオキシ}-2-メトキシアニリン(化合物A33)
　参考例6の工程2に準じて、合物A32(500 g, 1.1 mmol)から化合物A33(470 mg, 100%)を得た。
1H-NMR (DMSO-d6) δ: 8.75 (d, J = 5.8 Hz, 1H), 7.79 (s, 1H), 7.60 (s, 1H), 6.93 (d, J = 2.5 Hz, 1H), 6.86-6.83 (m, 2H), 6.74 (dd, J = 8.4, 2.5 Hz, 1H), 4.54-4.50 (m, 1H), 4.33-4.30 (m, 1H), 4.25-4.23 (m, 1H), 4.15-4.13 (m, 1H), 4.04 (s, 3H), 3.86-3.81 (m, 1H), 3.79 (s, 3H), 1.38 (s, 3H), 1.33 (s, 3H).
ESI-MS: m/z 427 [M+H]+.
工程3
フェニル4-{6-[(2,2-ジメチル-1,3-ジオキソラン-4-イル)メトキシ]-7-メトキシキノリン-4-イルオキシ}-2-メトキシフェニルカーバマート(化合物A34)
　参考例6の工程3に準じて、化合物A33(470 mg, 1.1 mmol)、クロロギ酸フェニル(0.21 mL, 1.6 mmol）、および炭酸カリウム(300 mg, 2.2 mmol) から化合物A34(490 mg, 83%)を得た。
1H-NMR (DMSO-d6) δ: 9.27 (br s, 1H), 8.50 (d, J= 5.5 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H), 7.45-7.41 (m, 3H), 7.28-7.18 (m, 3H), 7.06 (d, J = 2.4 Hz, 1H), 6.84 (dd, J = 8.8, 2.4 Hz, 1H), 6.54 (d, J = 5.5 Hz, 1H), 4.53-4.48 (m, 1H), 4.20-4.05 (m, 4H), 3.96 (s, 3H), 3.85 (s, 3H), 1.38 (s, 3H), 1.33 (s, 3H).
ESI-MS: m/z 547 [M+H]+. Reference Example 33
Process 1
6-[(2,2-Dimethyl-1,3-dioxolan-4-yl) methoxy] -7-methoxy-4- (3-methoxy-4-nitrophenoxy) quinoline (Compound A32)
To a solution of compound A28 (400 mg, 1.2 mmol) in THF (6.0 mL), 2,2-dimethyl-1,3-dioxolane-4-methanol (0.22 mL, 1.8 mmol) and triphenylphosphine (370 mg, 1.4 40% diethyl azodicarboxylate-toluene solution (0.69 mL, 1.8 mmol) was added dropwise with stirring under ice cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (methanol / chloroform = 5/95) to obtain Compound A32 (500 mg, 94%).
1 H-NMR (CDCl 3 ) δ: 8.61 (d, J = 5.0 Hz, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.45 (s, 1H), 7.44 (s, 1H), 6.88 ( d, J = 2.3 Hz, 1H), 6.75 (dd, J = 9.1, 2.3 Hz, 1H), 6.68 (d, J = 5.0 Hz, 1H), 4.64-4.58 (m, 1H), 4.25-4.22 (m , 2H), 4.11-4.09 (m, 1H), 4.02 (s, 3H), 4.00-3.97 (m, 1H), 3.95 (s, 3H), 1.48 (s, 3H), 1.41 (s, 3H).
ESI-MS: m / z 457 [M + H] + .
Process 2
4- {6-[(2,2-Dimethyl-1,3-dioxolan-4-yl) methoxy] -7-methoxyquinolin-4-yloxy} -2-methoxyaniline (Compound A33)
According to Step 2 of Reference Example 6, compound A33 (470 mg, 100%) was obtained from Compound A32 (500 g, 1.1 mmol).
1 H-NMR (DMSO-d 6 ) δ: 8.75 (d, J = 5.8 Hz, 1H), 7.79 (s, 1H), 7.60 (s, 1H), 6.93 (d, J = 2.5 Hz, 1H), 6.86-6.83 (m, 2H), 6.74 (dd, J = 8.4, 2.5 Hz, 1H), 4.54-4.50 (m, 1H), 4.33-4.30 (m, 1H), 4.25-4.23 (m, 1H), 4.15-4.13 (m, 1H), 4.04 (s, 3H), 3.86-3.81 (m, 1H), 3.79 (s, 3H), 1.38 (s, 3H), 1.33 (s, 3H).
ESI-MS: m / z 427 [M + H] + .
Process 3
Phenyl 4- {6-[(2,2-dimethyl-1,3-dioxolan-4-yl) methoxy] -7-methoxyquinolin-4-yloxy} -2-methoxyphenylcarbamate (Compound A34)
According to Step 3 of Reference Example 6, compound A33 (470 mg, 1.1 mmol), phenyl chloroformate (0.21 mL, 1.6 mmol), and potassium carbonate (300 mg, 2.2 mmol) were converted to compound A34 (490 mg, 83% )
1 H-NMR (DMSO-d 6 ) δ: 9.27 (br s, 1H), 8.50 (d, J = 5.5 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.58 (s, 1H) , 7.45-7.41 (m, 3H), 7.28-7.18 (m, 3H), 7.06 (d, J = 2.4 Hz, 1H), 6.84 (dd, J = 8.8, 2.4 Hz, 1H), 6.54 (d, J = 5.5 Hz, 1H), 4.53-4.48 (m, 1H), 4.20-4.05 (m, 4H), 3.96 (s, 3H), 3.85 (s, 3H), 1.38 (s, 3H), 1.33 (s, 3H).
ESI-MS: m / z 547 [M + H] + .
参考例34
工程1
2-[2-(2-クロロエトキシ)エトキシ]テトラヒドロ-2H-ピラン（化合物A35）
　2-(2-クロロエトキシ)エタノール（2.54 mL, 24.1 mmol）をジクロロメタン（48.2 mL）に溶解し、トシル酸一水和物（229 mg, 1.20 mmol）、3,4-ジヒドロ-2H-ピラン（2.64 mL, 28.9 mmol）を加えて室温で16時間攪拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ヘプタン/酢酸エチル＝88/12）で精製して2-[2-(2-クロロエトキシ)エトキシ]テトラヒドロ-2H-ピラン（2.51 g, 50%）を得た。 Reference Example 34
Process 1
2- [2- (2-Chloroethoxy) ethoxy] tetrahydro-2H-pyran (Compound A35)
2- (2-Chloroethoxy) ethanol (2.54 mL, 24.1 mmol) was dissolved in dichloromethane (48.2 mL) and tosylic acid monohydrate (229 mg, 1.20 mmol), 3,4-dihydro-2H-pyran ( 2.64 mL, 28.9 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane / ethyl acetate = 88/12) to give 2- [2- (2-chloroethoxy) ethoxy] tetrahydro-2H-pyran ( 2.51 g, 50%).
　上記にて得られる2-[2-(2-クロロエトキシ)エトキシ]テトラヒドロ-2H-ピラン（1.78 g, 8.52 mmol）をDMF（35.5 mL）に溶解し、化合物A28（2.43 g, 7.10 mmol）、炭酸セシウム（2.78 g, 8.52 mmol）、ヨウ化ナトリウム（1.28 g, 8.52 mmol）を加えて80℃で16時間攪拌した。混合物に水を加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥した後、減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール＝98/2）で精製して化合物A35（2.42 g, 66%）を得た。
1H-NMR (CDCl3) δ: 8.61 (d, J = 5.0 Hz, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.45 (s, 1H), 7.43 (s, 1H), 6.88 (d, J = 2.3 Hz, 1H), 6.74 (dd, J = 9.1, 2.3 Hz, 1H), 6.69 (d, J = 5.0 Hz, 1H), 4.63-4.62 (m, 1H), 4.32 (t, J = 5.0 Hz, 2H), 4.03 (s, 3H), 4.01-3.96 (m, 2H), 3.95 (s, 3H), 3.92-3.83 (m, 2H), 3.79-3.77 (m, 2H), 3.67-3.62 (m, 1H), 3.51-3.46 (m, 1H), 1.83-1.49 (m, 6H).
ESI-MS: m/z 515 [M+H]+.
工程2
2-メトキシ-4-(7-メトキシ-6-(2-(2-(テトラヒドロ-2H-ピラン-2-イルオキシ)エトキシ)エトキシ)キノリン-4-イルオキシ)アニリン（化合物A36）
　化合物A35（2.32 g, 4.51 mmol）をTHF（11.3 mL）とエタノール（11.3 mL）の混合溶媒に懸濁させ、塩化アンモニウム（1.21 g, 22.6 mmol）、還元鉄（1.26 g, 22.6 mmol）、水（4.51 mL）を加えて70℃で21時間攪拌した。混合物をセライトでろ過し、ろ液に水を加え、酢酸エチルで抽出した後、無水硫酸ナトリウムで乾燥し、減圧下溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール＝97/3）で精製して化合物A36（1.91 g, 88%）を得た。
1H-NMR (CDCl3) δ: 8.46 (d, J = 5.4 Hz, 1H), 7.62 (s, 1H), 7.39 (s, 1H), 6.77 (d, J = 8.6 Hz, 1H), 6.66-6.62 (m, 2H), 6.44 (d, J = 5.4 Hz, 1H), 4.65-4.63 (m, 1H), 4.37 (t, J = 5.0 Hz, 2H), 4.03-4.01 (m, 5H), 3.93-3.87 (m, 2H), 3.84 (s, 3H), 3.81-3.79 (m, 4H), 3.67-3.64 (m, 1H), 3.51-3.46 (m, 1H), 1.84-1.47 (m, 6H).
ESI-MS: m/z 485 [M+H]+.
工程3
フェニル 2-メトキシ-4-(7-メトキシ-6-(2-(2-(テトラヒドロ-2H-ピラン-2-イルオキシ)エトキシ)エトキシ)キノリン-4-イルオキシ)フェニルカルバマート（化合物A37）
　参考例6の工程3に準じて、化合物A36（1.92 g, 3.96 mmol）、クロロギ酸フェニル（0.751 mL, 5.94 mmol）、および炭酸カリウム（1.10 g, 7.93 mmol）から化合物A37（1.77 g, 74%）を得た。
1H-NMR (CDCl3) δ: 8.49 (d, J = 5.0 Hz, 1H), 8.18 (br s, 1H), 7.60 (s, 1H), 7.55 (br s, 1H), 7.44-7.40 (m, 3H), 7.28-7.21 (m, 3H), 6.82 (dd, J = 8.8, 2.5 Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H), 6.48 (d, J = 5.0 Hz, 1H), 4.65-4.63 (m, 1H), 4.37 (t, J = 5.2 Hz, 2H), 4.03-4.01 (m, 5H), 3.93-3.84 (m, 5H), 3.80 (t, J = 5.2 Hz, 2H), 3.68-3.63 (m, 1H), 3.51-3.46 (m, 1H), 1.84-1.77 (m, 1H), 1.74-1.66 (m, 1H), 1.60-1.47 (m, 4H).
ESI-MS: m/z 605 [M+H]+. 2- [2- (2-chloroethoxy) ethoxy] tetrahydro-2H-pyran (1.78 g, 8.52 mmol) obtained above is dissolved in DMF (35.5 mL), compound A28 (2.43 g, 7.10 mmol), Cesium carbonate (2.78 g, 8.52 mmol) and sodium iodide (1.28 g, 8.52 mmol) were added and stirred at 80 ° C. for 16 hours. Water was added to the mixture, extracted with chloroform, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol = 98/2) to give a compound. A35 (2.42 g, 66%) was obtained.
1 H-NMR (CDCl 3 ) δ: 8.61 (d, J = 5.0 Hz, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.45 (s, 1H), 7.43 (s, 1H), 6.88 ( d, J = 2.3 Hz, 1H), 6.74 (dd, J = 9.1, 2.3 Hz, 1H), 6.69 (d, J = 5.0 Hz, 1H), 4.63-4.62 (m, 1H), 4.32 (t, J = 5.0 Hz, 2H), 4.03 (s, 3H), 4.01-3.96 (m, 2H), 3.95 (s, 3H), 3.92-3.83 (m, 2H), 3.79-3.77 (m, 2H), 3.67- 3.62 (m, 1H), 3.51-3.46 (m, 1H), 1.83-1.49 (m, 6H).
ESI-MS: m / z 515 [M + H] + .
Process 2
2-Methoxy-4- (7-methoxy-6- (2- (2- (tetrahydro-2H-pyran-2-yloxy) ethoxy) ethoxy) quinolin-4-yloxy) aniline (Compound A36)
Compound A35 (2.32 g, 4.51 mmol) is suspended in a mixed solvent of THF (11.3 mL) and ethanol (11.3 mL), ammonium chloride (1.21 g, 22.6 mmol), reduced iron (1.26 g, 22.6 mmol), water (4.51 mL) was added and stirred at 70 ° C. for 21 hours. The mixture was filtered through celite, water was added to the filtrate, the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (chloroform / methanol = 97/3) to obtain Compound A36 (1.91 g, 88%).
1 H-NMR (CDCl 3 ) δ: 8.46 (d, J = 5.4 Hz, 1H), 7.62 (s, 1H), 7.39 (s, 1H), 6.77 (d, J = 8.6 Hz, 1H), 6.66- 6.62 (m, 2H), 6.44 (d, J = 5.4 Hz, 1H), 4.65-4.63 (m, 1H), 4.37 (t, J = 5.0 Hz, 2H), 4.03-4.01 (m, 5H), 3.93 -3.87 (m, 2H), 3.84 (s, 3H), 3.81-3.79 (m, 4H), 3.67-3.64 (m, 1H), 3.51-3.46 (m, 1H), 1.84-1.47 (m, 6H) .
ESI-MS: m / z 485 [M + H] + .
Process 3
Phenyl 2-methoxy-4- (7-methoxy-6- (2- (2- (tetrahydro-2H-pyran-2-yloxy) ethoxy) ethoxy) quinolin-4-yloxy) phenylcarbamate (Compound A37)
According to Step 3 of Reference Example 6, compound A36 (1.92 g, 3.96 mmol), phenyl chloroformate (0.751 mL, 5.94 mmol), and potassium carbonate (1.10 g, 7.93 mmol) were converted to compound A37 (1.77 g, 74% )
1 H-NMR (CDCl 3 ) δ: 8.49 (d, J = 5.0 Hz, 1H), 8.18 (br s, 1H), 7.60 (s, 1H), 7.55 (br s, 1H), 7.44-7.40 (m , 3H), 7.28-7.21 (m, 3H), 6.82 (dd, J = 8.8, 2.5 Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H), 6.48 (d, J = 5.0 Hz, 1H) , 4.65-4.63 (m, 1H), 4.37 (t, J = 5.2 Hz, 2H), 4.03-4.01 (m, 5H), 3.93-3.84 (m, 5H), 3.80 (t, J = 5.2 Hz, 2H ), 3.68-3.63 (m, 1H), 3.51-3.46 (m, 1H), 1.84-1.77 (m, 1H), 1.74-1.66 (m, 1H), 1.60-1.47 (m, 4H).
ESI-MS: m / z 605 [M + H] + .
参考例35
工程1
tert-ブチル 4-[7-メトキシ-4-(3-メトキシ-4-ニトロフェノキシ)キノリン-6-イルオキシ]ピペリジン-1-カルボキシレート(化合物A38)
　参考例33の工程1に準じて、化合物A28(400 mg, 1.2 mmol)、1-(tert-ブトキシカルボニル)-4-ヒドロキシピペリジン(350 mg, 1.8 mmol）、トリフェニルホスフィン(370 mg, 1.4 mmol)、および40％アゾジカルボン酸ジエチル-トルエン溶液(0.69 mL, 1.8 mmol)から化合物A38(310 mg, 100%)を得た。
1H-NMR (CDCl3) δ: 8.61 (d, J = 5.0 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.48 (s, 1H), 7.44 (s, 1H), 6.88 (d, J= 2.3 Hz, 1H), 6.75 (dd, J = 8.6, 2.3 Hz, 1H), 6.67 (d, J = 5.0 Hz, 1H), 4.67-4.62 (m, 1H), 4.03 (s, 3H), 3.95 (s, 3H), 3.82-3.76 (m, 2H), 3.37-3.30 (m, 2H), 2.03-1.99 (m, 2H), 1.87-1.81 (m, 2H), 1.47 (s, 9H).
ESI-MS: m/z 526 [M+H]+.
工程2
7-メトキシ-4-(3-メトキシ-4-ニトロフェノキシ)-6-(ピペリジン-4-イルオキシ)キノリン(化合物A39)
　化合物A38(310 mg, 0.58 mmol)の塩化メチレン(3.0 mL）溶液に、トリフルオロ酢酸(0.90 mL, 12 mmol）を加え、室温にて1時間撹拌した。飽和重曹水を加えて中和した後、クロロホルムで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムにて乾燥し、不溶物をろ別した。ろ液を減圧濃縮することで得られた残留物をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム=20/80)で精製することにより、化合物A39(190 mg, 77%)を得た。
1H-NMR (DMSO-d6) δ: 8.60 (d, J = 4.9 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.45 (s, 1H), 7.35 (s, 1H), 7.32 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 4.9 Hz, 1H), 6.78 (dd, J = 8.8, 2.4 Hz, 1H), 4.53-4.46 (m, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 2.94-2.91 (m, 2H), 2.55-2.52 (m, 2H), 1.90-1.86 (m, 2H), 1.51-1.42 (m, 2H).
ESI-MS: m/z 426 [M+H]+.
工程3
2-{4-[7-メトキシ-4-(3-メトキシ-4-ニトロフェノキシ)キノリン-6-イルオキシ]ピペリジン-1-イル}-N-メチルアセトアミド(化合物A40)
　化合物A39 (220 mg, 0.45 mmol)のDMF(2.2 mL）溶液に、N-メチルクロロアセトアミド(58 mg, 0.54 mmol）、および炭酸カリウム(93 mg, 0.67 mmol）を加え、50℃にて3時間撹拌した。反応混合液に水を加え、水層を酢酸エチルにて抽出し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムにて乾燥し、不溶物をろ別した。ろ液を減圧濃縮することで得られた残留物をシリカゲルカラムクロマトグラフィー(メタノール/クロロホルム=15/85)で精製することにより、化合物A40(210 mg, 100%)を得た。
1H-NMR (DMSO-d6) δ: 8.59 (d, J = 4.9 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 4.9 Hz, 1H), 7.46 (s, 1H), 7.41 (s, 1H), 7.32 (d, J= 2.4 Hz, 1H), 6.85 (d, J = 4.9 Hz, 1H), 6.81 (dd, J = 8.8, 2.4 Hz, 1H), 4.54-4.50 (m, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 2.90 (s, 2H), 2.73-2.65 (m, 2H), 2.62 (d, J = 4.9 Hz, 3H), 2.31 (t, J = 9.3 Hz, 2H), 1.96-1.94 (m, 2H), 1.79-1.71 (m, 2H).
ESI-MS: m/z 497 [M+H]+. Reference Example 35
Process 1
tert-Butyl 4- [7-methoxy-4- (3-methoxy-4-nitrophenoxy) quinolin-6-yloxy] piperidine-1-carboxylate (Compound A38)
According to Step 1 of Reference Example 33, compound A28 (400 mg, 1.2 mmol), 1- (tert-butoxycarbonyl) -4-hydroxypiperidine (350 mg, 1.8 mmol), triphenylphosphine (370 mg, 1.4 mmol) ) And 40% diethyl azodicarboxylate-toluene solution (0.69 mL, 1.8 mmol) to give compound A38 (310 mg, 100%).
1 H-NMR (CDCl 3 ) δ: 8.61 (d, J = 5.0 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.48 (s, 1H), 7.44 (s, 1H), 6.88 ( d, J = 2.3 Hz, 1H), 6.75 (dd, J = 8.6, 2.3 Hz, 1H), 6.67 (d, J = 5.0 Hz, 1H), 4.67-4.62 (m, 1H), 4.03 (s, 3H ), 3.95 (s, 3H), 3.82-3.76 (m, 2H), 3.37-3.30 (m, 2H), 2.03-1.99 (m, 2H), 1.87-1.81 (m, 2H), 1.47 (s, 9H ).
ESI-MS: m / z 526 [M + H] + .
Process 2
7-Methoxy-4- (3-methoxy-4-nitrophenoxy) -6- (piperidin-4-yloxy) quinoline (Compound A39)
Trifluoroacetic acid (0.90 mL, 12 mmol) was added to a solution of compound A38 (310 mg, 0.58 mmol) in methylene chloride (3.0 mL), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added for neutralization, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and insolubles were filtered off. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (methanol / chloroform = 20/80) to obtain Compound A39 (190 mg, 77%).
1 H-NMR (DMSO-d 6 ) δ: 8.60 (d, J = 4.9 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.45 (s, 1H), 7.35 (s, 1H), 7.32 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 4.9 Hz, 1H), 6.78 (dd, J = 8.8, 2.4 Hz, 1H), 4.53-4.46 (m, 1H), 3.95 (s , 3H), 3.94 (s, 3H), 2.94-2.91 (m, 2H), 2.55-2.52 (m, 2H), 1.90-1.86 (m, 2H), 1.51-1.42 (m, 2H).
ESI-MS: m / z 426 [M + H] + .
Process 3
2- {4- [7-methoxy-4- (3-methoxy-4-nitrophenoxy) quinolin-6-yloxy] piperidin-1-yl} -N-methylacetamide (Compound A40)
To a solution of compound A39 (220 mg, 0.45 mmol) in DMF (2.2 mL), N-methylchloroacetamide (58 mg, 0.54 mmol) and potassium carbonate (93 mg, 0.67 mmol) were added, and the mixture was stirred at 50 ° C. for 3 hours. Stir. Water was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (methanol / chloroform = 15/85) to obtain Compound A40 (210 mg, 100%).
1 H-NMR (DMSO-d 6 ) δ: 8.59 (d, J = 4.9 Hz, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 4.9 Hz, 1H), 7.46 ( s, 1H), 7.41 (s, 1H), 7.32 (d, J = 2.4 Hz, 1H), 6.85 (d, J = 4.9 Hz, 1H), 6.81 (dd, J = 8.8, 2.4 Hz, 1H), 4.54-4.50 (m, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 2.90 (s, 2H), 2.73-2.65 (m, 2H), 2.62 (d, J = 4.9 Hz, 3H) , 2.31 (t, J = 9.3 Hz, 2H), 1.96-1.94 (m, 2H), 1.79-1.71 (m, 2H).
ESI-MS: m / z 497 [M + H] + .
工程4
2-{4-[4-(4-アミノ-3-メトキシフェノキシ)-7-メトキシキノリン-6-イルオキシ]ピペリジン-1-イル}-N-メチルアセトアミド(化合物A41)
　参考例6の工程2に準じて、化合物A40(220 mg, 0.45 mmol)から化合物A41(210 mg, 100%)を得た。
1H-NMR (DMSO-d6) δ: 8.63 (d, J = 6.2 Hz, 1H), 8.62 (br s, 1H), 7.79 (s, 1H), 7.59 (s, 1H), 6.83 (d, J = 2.6 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.66 (dd, J = 8.4, 2.6 Hz, 1H), 6.63 (d, J = 6.2 Hz, 1H), 4.93 (br s, 1H), 4.00 (s, 3H), 3.93 (br s, 2H), 3.77 (s, 3H), 3.44-3.42 (m, 2H), 3.20 (s, 2H), 2.62 (d, J = 4.8 Hz, 3H), 2.24 (br s, 2H), 1.99 (br s, 2H).
ESI-MS: m/z 467 [M+H]+.
工程5
フェニル 2-メトキシ-4-{7-メトキシ-6-[1-(2-メチルアミノ-2-オキソエチル)ピペリジン-4-イルオキシ]キノリン-4-イルオキシ}フェニルカーバマート(化合物A42)
　参考例6の工程3に準じて、化合物A41(210 mg, 0.45 mmol)、クロロギ酸フェニル(0.085 mL, 0.67 mmol）、および炭酸カリウム(120 mg, 0.90 mmol) から化合物A42(110 mg, 42%)を得た。
1H-NMR (DMSO-d6) δ: 9.33 (br s, 1H), 8.50 (d, J= 5.9 Hz, 1H), 7.72 (d, J = 6.8 Hz, 1H), 7.54 (s, 1H), 7.44-7.42 (m, 3H), 7.27-7.16 (m, 3H), 7.06 (d, J = 2.9 Hz, 1H), 6.80 (dd, J = 8.6, 2.9 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 6.55 (d, J = 5.9 Hz, 1H), 4.58-4.54 (m, 1H), 3.95 (s, 3H), 3.85 (s, 3H), 2.91 (s, 2H), 2.72-2.70 (m, 2H), 2.62 (d, J = 4.5 Hz, 3H), 2.38-2.35 (m, 2H), 2.02-1.99 (m, 2H), 1.85-1.76 (m, 2H).
ESI-MS: m/z 587 [M+H]+. Process 4
2- {4- [4- (4-Amino-3-methoxyphenoxy) -7-methoxyquinolin-6-yloxy] piperidin-1-yl} -N-methylacetamide (Compound A41)
According to Step 2 of Reference Example 6, compound A41 (210 mg, 100%) was obtained from compound A40 (220 mg, 0.45 mmol).
1 H-NMR (DMSO-d 6 ) δ: 8.63 (d, J = 6.2 Hz, 1H), 8.62 (br s, 1H), 7.79 (s, 1H), 7.59 (s, 1H), 6.83 (d, J = 2.6 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.66 (dd, J = 8.4, 2.6 Hz, 1H), 6.63 (d, J = 6.2 Hz, 1H), 4.93 (br s , 1H), 4.00 (s, 3H), 3.93 (br s, 2H), 3.77 (s, 3H), 3.44-3.42 (m, 2H), 3.20 (s, 2H), 2.62 (d, J = 4.8 Hz , 3H), 2.24 (br s, 2H), 1.99 (br s, 2H).
ESI-MS: m / z 467 [M + H] + .
Process 5
Phenyl 2-methoxy-4- {7-methoxy-6- [1- (2-methylamino-2-oxoethyl) piperidin-4-yloxy] quinolin-4-yloxy} phenylcarbamate (Compound A42)
According to Step 3 of Reference Example 6, compound A41 (210 mg, 0.45 mmol), phenyl chloroformate (0.085 mL, 0.67 mmol), and potassium carbonate (120 mg, 0.90 mmol) were converted to compound A42 (110 mg, 42% )
1 H-NMR (DMSO-d 6 ) δ: 9.33 (br s, 1H), 8.50 (d, J = 5.9 Hz, 1H), 7.72 (d, J = 6.8 Hz, 1H), 7.54 (s, 1H) , 7.44-7.42 (m, 3H), 7.27-7.16 (m, 3H), 7.06 (d, J = 2.9 Hz, 1H), 6.80 (dd, J = 8.6, 2.9 Hz, 1H), 6.75 (d, J = 8.6 Hz, 1H), 6.55 (d, J = 5.9 Hz, 1H), 4.58-4.54 (m, 1H), 3.95 (s, 3H), 3.85 (s, 3H), 2.91 (s, 2H), 2.72 -2.70 (m, 2H), 2.62 (d, J = 4.5 Hz, 3H), 2.38-2.35 (m, 2H), 2.02-1.99 (m, 2H), 1.85-1.76 (m, 2H).
ESI-MS: m / z 587 [M + H] + .
参考例36
工程1
7-メトキシ-4-(3-メトキシ-4-ニトロフェノキシ)-6-[3-(テトラヒドロ-2H-ピラン-2-イルオキシ)プロポキシ]キノリン(化合物A43)
　参考例6の工程1に準じて、化合物A28(1.0 g, 2.9 mmol)、2-(3-ブロモプロポキシ)テトラヒドロ-2H-ピラン (0.99 mL, 5.8 mmol）、および炭酸カリウム(810 mg, 5.8 mmol)から化合物A43(1.3 g, 93%)を得た。
1H-NMR (CDCl3) δ: 8.60 (d, J = 5.0 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.45 (s, 1H), 7.41 (s, 1H), 6.88 (d, J= 2.5 Hz, 1H), 6.75 (dd, J = 8.8, 2.5 Hz, 1H), 6.68 (d, J = 5.0 Hz, 1H), 4.61-4.60 (m, 1H), 4.29-4.26 (m, 2H), 4.04 (s, 3H), 3.98-3.98 (m, 1H), 3.96 (s, 3H), 3.88-3.82 (m, 1H), 3.66-3.64 (m, 1H), 3.50-3.47 (m, 1H), 2.25-2.19 (m, 2H), 1.80-1.70 (m, 2H), 1.56-1.48 (m, 4H).
ESI-MS: m/z 485 [M+H]+.
工程2
2-メトキシ-4-{7-メトキシ-6-[3-(テトラヒドロ-2H-ピラン-2-イルオキシ)プロポキシ]キノリン-4-イルオキシ}アニリン(化合物A44)
　参考例6の工程2に準じて、化合物A43(1.2 g, 2.7 mmol)から化合物A44(1.3 g, 100%)を得た。
1H-NMR (DMSO-d6) δ: 8.52 (d, J = 5.4 Hz, 1H), 7.58 (s, 1H), 7.41 (s, 1H), 6.80 (d, J = 2.5 Hz, 1H), 6.74 (d, J= 8.6 Hz, 1H), 6.63 (dd, J = 8.6, 2.5 Hz, 1H), 6.52 (d, J = 5.4 Hz, 1H), 4.58 (t, J = 3.6 Hz, 1H), 4.24 (t, J = 6.6 Hz, 2H), 3.97 (s, 3H), 3.83-3.80 (m, 1H), 3.76 (s, 3H), 3.73-3.71 (m, 1H), 3.56-3.53 (m, 1H), 3.43-3.42 (m, 1H), 2.10-2.04 (m, 2H), 1.75-1.56 (m, 2H), 1.45-1.42 (m, 4H).
ESI-MS: m/z 455 [M+H]+.
工程3
フェニル2-メトキシ-4-{7-メトキシ-6-[3-(テトラヒドロ-2H-ピラン-2-イルオキシ)プロポキシ]キノリン-4-イルオキシ}フェニルカーバマート(化合物A45)
　参考例6の工程3に準じて、化合物A44(1.2 g, 2.7 mmol)、クロロギ酸フェニル(0.52 mL, 4.1 mmol）、および炭酸カリウム(780 mg, 5.5 mmol) から化合物A45(1.4 g, 91%)を得た。
1H-NMR (DMSO-d6) δ: 9.27 (br s, 1H), 8.49 (d, J= 5.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.45-7.42 (m, 2H), 7.40 (s, 1H), 7.25-7.16 (m, 3H), 7.06 (d, J = 2.5 Hz, 1H), 6.83 (dd, J = 8.4, 2.5 Hz, 1H), 6.53 (d, J = 5.4 Hz, 1H), 4.58 (t, J = 3.6 Hz, 1H), 4.22 (t, J = 6.6 Hz, 2H), 3.95 (s, 3H), 3.85 (s, 3H), 3.82-3.80 (m, 1H), 3.76-3.71 (m, 1H), 3.56-3.51 (m, 1H), 3.43-3.39 (m, 1H), 2.09-2.03 (m, 2H), 1.72-1.58 (m, 2H), 1.46-1.38 (m, 4H).
ESI-MS: m/z 575 [M+H]+. Reference Example 36
Process 1
7-Methoxy-4- (3-methoxy-4-nitrophenoxy) -6- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] quinoline (Compound A43)
According to Step 1 of Reference Example 6, compound A28 (1.0 g, 2.9 mmol), 2- (3-bromopropoxy) tetrahydro-2H-pyran (0.99 mL, 5.8 mmol), and potassium carbonate (810 mg, 5.8 mmol) ) To give Compound A43 (1.3 g, 93%).
1 H-NMR (CDCl 3 ) δ: 8.60 (d, J = 5.0 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.45 (s, 1H), 7.41 (s, 1H), 6.88 ( d, J = 2.5 Hz, 1H), 6.75 (dd, J = 8.8, 2.5 Hz, 1H), 6.68 (d, J = 5.0 Hz, 1H), 4.61-4.60 (m, 1H), 4.29-4.26 (m , 2H), 4.04 (s, 3H), 3.98-3.98 (m, 1H), 3.96 (s, 3H), 3.88-3.82 (m, 1H), 3.66-3.64 (m, 1H), 3.50-3.47 (m , 1H), 2.25-2.19 (m, 2H), 1.80-1.70 (m, 2H), 1.56-1.48 (m, 4H).
ESI-MS: m / z 485 [M + H] + .
Process 2
2-Methoxy-4- {7-methoxy-6- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] quinolin-4-yloxy} aniline (Compound A44)
According to Step 2 of Reference Example 6, compound A44 (1.3 g, 100%) was obtained from compound A43 (1.2 g, 2.7 mmol).
1 H-NMR (DMSO-d 6 ) δ: 8.52 (d, J = 5.4 Hz, 1H), 7.58 (s, 1H), 7.41 (s, 1H), 6.80 (d, J = 2.5 Hz, 1H), 6.74 (d, J = 8.6 Hz, 1H), 6.63 (dd, J = 8.6, 2.5 Hz, 1H), 6.52 (d, J = 5.4 Hz, 1H), 4.58 (t, J = 3.6 Hz, 1H), 4.24 (t, J = 6.6 Hz, 2H), 3.97 (s, 3H), 3.83-3.80 (m, 1H), 3.76 (s, 3H), 3.73-3.71 (m, 1H), 3.56-3.53 (m, 1H), 3.43-3.42 (m, 1H), 2.10-2.04 (m, 2H), 1.75-1.56 (m, 2H), 1.45-1.42 (m, 4H).
ESI-MS: m / z 455 [M + H] + .
Process 3
Phenyl 2-methoxy-4- {7-methoxy-6- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] quinolin-4-yloxy} phenyl carbamate (Compound A45)
According to Step 3 of Reference Example 6, compound A44 (1.2 g, 2.7 mmol), phenyl chloroformate (0.52 mL, 4.1 mmol), and potassium carbonate (780 mg, 5.5 mmol) were converted to compound A45 (1.4 g, 91% )
1 H-NMR (DMSO-d 6 ) δ: 9.27 (br s, 1H), 8.49 (d, J = 5.4 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H) , 7.45-7.42 (m, 2H), 7.40 (s, 1H), 7.25-7.16 (m, 3H), 7.06 (d, J = 2.5 Hz, 1H), 6.83 (dd, J = 8.4, 2.5 Hz, 1H ), 6.53 (d, J = 5.4 Hz, 1H), 4.58 (t, J = 3.6 Hz, 1H), 4.22 (t, J = 6.6 Hz, 2H), 3.95 (s, 3H), 3.85 (s, 3H ), 3.82-3.80 (m, 1H), 3.76-3.71 (m, 1H), 3.56-3.51 (m, 1H), 3.43-3.39 (m, 1H), 2.09-2.03 (m, 2H), 1.72-1.58 (m, 2H), 1.46-1.38 (m, 4H).
ESI-MS: m / z 575 [M + H] + .
参考例37
工程1
エチル 2-ホルムアミドブト-2-エノエート（化合物B74）
　参考例18の工程1に準じて、60%水素化ナトリウム（2.12 g. 53.0 mmol）、エチル 2-イソシアノアセテート（4.85 mL, 44.2 mmol）、アセトアルデヒド（4.99 mL, 88.0 mmol）から化合物B74（2.08 g, 30%）をE/Z混合物として得た。
ESI-MS: m/z 158 [M+H]+.
工程2
エチル 3-ブロモ-2-ホルムアミドブト-2-エノエート（化合物B75）
　参考例18の工程2に準じて、化合物B74（4.38 g, 27.9 mmol）、NBS（5.46 g, 30.7 mmol）、トリエチルアミン（3.88 mL, 27.9 mmol）から化合物B75（4.76 g, 72%）をE/Z混合物として得た。
ESI-MS: m/z 236(79Br), 238(81Br) [M+H]+.
工程3
エチル 3-ブロモ-2-イソシアノブト-2-エノエート（化合物B76）
　参考例18の工程3に準じて、化合物B75（4.75 g, 20.1 mmol）、トリエチルアミン（7.01 mL, 50.3 mmol）、オキシ塩化リン（2.06 mL, 22.1 mmol）から化合物B76（2.88 g）の粗生成物を得、生成することなく次の反応に用いた。
1H-NMR (CDCl3)δ: 4.33 (q, J = 7.2 Hz, 2H), 2.70 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H). Reference Example 37
Process 1
Ethyl 2-formamidobut-2-enoate (Compound B74)
According to Step 1 of Reference Example 18, compound B74 (2.08 g) was obtained from 60% sodium hydride (2.12 g. 53.0 mmol), ethyl 2-isocyanoacetate (4.85 mL, 44.2 mmol), and acetaldehyde (4.99 mL, 88.0 mmol). g, 30%) was obtained as an E / Z mixture.
ESI-MS: m / z 158 [M + H] + .
Process 2
Ethyl 3-bromo-2-formamidobut-2-enoate (Compound B75)
According to Step 2 of Reference Example 18, Compound B74 (4.38 g, 27.9 mmol), NBS (5.46 g, 30.7 mmol), Triethylamine (3.88 mL, 27.9 mmol) to Compound B75 (4.76 g, 72%) were E / Obtained as a Z mixture.
ESI-MS: m / z 236 ( 79 Br), 238 ( 81 Br) [M + H] + .
Process 3
Ethyl 3-bromo-2-isocyanobut-2-enoate (Compound B76)
According to Step 3 of Reference Example 18, compound B75 (4.75 g, 20.1 mmol), triethylamine (7.01 mL, 50.3 mmol), phosphorus oxychloride (2.06 mL, 22.1 mmol) to compound B76 (2.88 g) crude product Was used in the next reaction without production.
1 H-NMR (CDCl 3 ) δ: 4.33 (q, J = 7.2 Hz, 2H), 2.70 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H).
工程4
エチル 5-メチル-1-(オキセタン-3-イル)-1H-イミダゾール-4-カルボキシレート（化合物B77）
　参考例18の工程4に準じて、化合物B76（841 mg, 3.86 mmol）、オキセタン-3-アミン（306 mg, 4.19 mmol）、DBU（0.639 mL, 4.24 mmol）から化合物B77（87.9 mg, 2 steps 11%）を得た。
1H-NMR (CDCl3) δ: 7.84 (s, 1H), 5.29-5.22 (m, 1H), 5.12 (t, J = 6.8 Hz, 2H), 4.90 (t, J = 6.8 Hz, 2H), 4.37 (q, J = 7.2 Hz, 2H), 2.50 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H).
ESI-MS: m/z 211 [M+H]+.
工程5
5-メチル-1-(オキセタン-3-イル)-1H-イミダゾール-4-カルボン酸（化合物B78）
　参考例7の工程2に準じて、化合物B77（87.9 mg, 0.418 mmol）、水酸化ナトリウム（106 mg, 2.65 mmol）から化合物B78（93.5 mg）の粗生成物を得、精製することなく次の反応に用いた。
ESI-MS: m/z 183 [M+H]+.
工程6
5-メチル-1-(オキセタン-3-イル)-1H-イミダゾール-4-カルボキサミド（化合物B79）
　参考例7の工程3を参考に、化合物B78（76.0 mg, 0.418 mmol）、トリエチルアミン（0.117 mL, 0.836 mmol）、EDCI(120 mg, 0.627 mmol)、HOBt(96.0 mg, 0.627 mmol)、28%アンモニア水（0.326 mL）から化合物B79（28.8 mg, 2 steps 38%）を得た。
1H-NMR (DMSO-d6) δ: 8.03 (s, 1H), 7.22 (br s, 1H), 6.96 (br s, 1H), 5.40-5.33 (m, 1H), 4.94 (t, J = 6.8 Hz, 2H), 4.84 (t, J = 6.8 Hz, 2H), 2.40 (s, 3H).
ESI-MS: m/z 182 [M+H]+. Process 4
Ethyl 5-methyl-1- (oxetane-3-yl) -1H-imidazole-4-carboxylate (Compound B77)
According to Step 4 of Reference Example 18, compound B76 (841 mg, 3.86 mmol), oxetane-3-amine (306 mg, 4.19 mmol), DBU (0.639 mL, 4.24 mmol) to compound B77 (87.9 mg, 2 steps 11%).
1 H-NMR (CDCl 3 ) δ: 7.84 (s, 1H), 5.29-5.22 (m, 1H), 5.12 (t, J = 6.8 Hz, 2H), 4.90 (t, J = 6.8 Hz, 2H), 4.37 (q, J = 7.2 Hz, 2H), 2.50 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H).
ESI-MS: m / z 211 [M + H] + .
Process 5
5-Methyl-1- (oxetan-3-yl) -1H-imidazole-4-carboxylic acid (Compound B78)
According to Step 2 of Reference Example 7, a crude product of compound B78 (93.5 mg) was obtained from compound B77 (87.9 mg, 0.418 mmol) and sodium hydroxide (106 mg, 2.65 mmol) without purification. Used for reaction.
ESI-MS: m / z 183 [M + H] + .
Process 6
5-Methyl-1- (oxetane-3-yl) -1H-imidazole-4-carboxamide (Compound B79)
With reference to Step 3 of Reference Example 7, compound B78 (76.0 mg, 0.418 mmol), triethylamine (0.117 mL, 0.836 mmol), EDCI (120 mg, 0.627 mmol), HOBt (96.0 mg, 0.627 mmol), 28% ammonia Compound B79 (28.8 mg, 2 steps 38%) was obtained from water (0.326 mL).
1 H-NMR (DMSO-d 6 ) δ: 8.03 (s, 1H), 7.22 (br s, 1H), 6.96 (br s, 1H), 5.40-5.33 (m, 1H), 4.94 (t, J = 6.8 Hz, 2H), 4.84 (t, J = 6.8 Hz, 2H), 2.40 (s, 3H).
ESI-MS: m / z 182 [M + H] + .
参考例38
工程1
メチル 2-(2-メトキシ-2-オキソエチルアミノ)-2-オキソアセテート（化合物B80）
　グリシンメチルエステル塩酸塩（1.00 g, 7.96 mmol）をメタノール（9.71 mL）に溶解し、トリエチルアミン（2.44 mL, 17.5 mmol）、シュウ酸ジメチル（1.04 g, 8.76 mmol）を加え、還流下で5.5時間攪拌した。混合物に水を加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去することにより、化合物B80（863 mg, 62%）を得た。
1H-NMR (CDCl3) δ: 7.56 (br s, 1H), 4.15 (d, J = 5.4 Hz, 2H), 3.93 (s, 3H), 3.80 (s, 3H).
ESI-MS: m/z 176 [M+H]+.
工程2
メチル 5-メトキシオキサゾール-2-カルボキシレート（化合物B81）
　化合物B81（863 mg, 4.93 mmol）をアセトニトリル（13.0 mL）に溶解し、五酸化二リン（3.15 g, 22.2 mmol）を加えて70℃で3時間攪拌した。反応混合液を氷水に投入し、酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、シリカゲルカラムクロマトグラフィー（ヘプタン/酢酸エチル＝60/40）で精製することにより、化合物B81（469 mg, 61%）を得た。
ESI-MS: m/z 158 [M+H]+.
工程3
5-メトキシオキサゾール-2-カルボキサミド（化合物B82）
　化合物B81（469 mg, 2.98 mmol）に28%アンモニア水（10.0 mL）を加えて室温で3時間攪拌した。混合物を減圧下で溶媒留去し、シリカゲルカラムクロマトグラフィー（クロロホルム/メタノール＝90/10）で精製することにより、化合物B82（340 mg, 80%）を得た。
1H-NMR (DMSO-d6) δ: 7.99 (br s, 1H), 7.67 (br s, 1H), 6.53 (s, 1H), 3.95 (s, 3H).
ESI-MS: m/z 143 [M+H]+. Reference Example 38
Process 1
Methyl 2- (2-methoxy-2-oxoethylamino) -2-oxoacetate (Compound B80)
Glycine methyl ester hydrochloride (1.00 g, 7.96 mmol) is dissolved in methanol (9.71 mL), triethylamine (2.44 mL, 17.5 mmol) and dimethyl oxalate (1.04 g, 8.76 mmol) are added, and the mixture is stirred under reflux for 5.5 hours. did. Water was added to the mixture, extracted with chloroform, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure to give compound B80 (863 mg, 62%).
1 H-NMR (CDCl 3 ) δ: 7.56 (br s, 1H), 4.15 (d, J = 5.4 Hz, 2H), 3.93 (s, 3H), 3.80 (s, 3H).
ESI-MS: m / z 176 [M + H] + .
Process 2
Methyl 5-methoxyoxazole-2-carboxylate (Compound B81)
Compound B81 (863 mg, 4.93 mmol) was dissolved in acetonitrile (13.0 mL), diphosphorus pentoxide (3.15 g, 22.2 mmol) was added, and the mixture was stirred at 70 ° C. for 3 hr. The reaction mixture was poured into ice water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and purified by silica gel column chromatography (heptane / ethyl acetate = 60/40) to give compound B81 (469 mg, 61%).
ESI-MS: m / z 158 [M + H] + .
Process 3
5-Methoxyoxazole-2-carboxamide (Compound B82)
28% aqueous ammonia (10.0 mL) was added to compound B81 (469 mg, 2.98 mmol), and the mixture was stirred at room temperature for 3 hr. The mixture was evaporated under reduced pressure, and purified by silica gel column chromatography (chloroform / methanol = 90/10) to give compound B82 (340 mg, 80%).
1 H-NMR (DMSO-d 6 ) δ: 7.99 (br s, 1H), 7.67 (br s, 1H), 6.53 (s, 1H), 3.95 (s, 3H).
ESI-MS: m / z 143 [M + H] + .
参考例39
工程1
エチル 2－ジアゾ-3-オキソブタノエート（化合物B83）
　エチル 3-オキソブタノエート（0.291 mL, 2.31 mmol）をアセトニトリル（11.5 mL）に溶解し、4-アセトアミドベンゼンスルホニルアジド（554 mg, 2.31 mmol）、トリエチルアミン（0.964 mL, 6.92 mmol）を0℃で加えて室温で5時間攪拌した。混合物を減圧下で溶媒留去し、得られた残渣にヘプタン/ジエチルエーテル＝1/1の混合溶媒を加えて攪拌した後、不溶物をろ別した。得られたろ液を減圧下で溶媒留去し、シリカゲルカラムクロマトフラフィー（ヘプタン/酢酸エチル＝85/15）で精製することにより、化合物B83（191 mg, 53%）を得た。
1H-NMR (CDCl3) δ: 4.31 (q, J = 7.1 Hz, 2H), 2.48 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).
ESI-MS: m/z 157 [M+H]+.
工程2
エチル 1,5-ジメチル-1H-1,2,3-トリアゾール-4-カルボキシレート（化合物B84）
　化合物B83（191 mg, 1.22 mmol）に2.0 mmol/LメチルアミンTHF溶液（6.12 mL, 12.2 mmol）、酢酸（0.600 mL, 10.5 mmol）を加え、還流下で42時間攪拌した。混合物に水を加え、酢酸エチルで抽出し、無水硫酸ナトリウムで乾燥した後にろ過した。ろ液を減圧下で溶媒留去することにより、化合物B84（87.5 mg, 42%）を得た。
1H-NMR (CDCl3) δ: 4.43 (q, J = 7.2 Hz, 2H), 4.00 (s, 3H), 2.58 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H).
ESI-MS: m/z 170 [M+H]+.
工程3
1,5-ジメチル-1H-1,2,3-トリアゾール-4-カルボキサミド（化合物B85）
　化合物B84（87.5 mg, 0.517 mmol）を7 mol/Lアンモニアメタノール溶液（1.48 mL）に溶解し、室温で3時間、50℃で3時間攪拌した。混合物を減圧下で溶媒留去し、得られた残渣に28%アンモニア水（2.00 mL）を加えて室温で17時間攪拌した。混合物を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール＝95/5）で精製することにより、化合物B85（41.3 mg, 57%）を得た。
1H-NMR (DMSO-d6) δ: 7.68 (br s, 1H), 7.31 (br s, 1H), 3.94 (s, 3H), 2.49 (s, 3H).
ESI-MS: m/z 141 [M+H]+. Reference Example 39
Process 1
Ethyl 2-diazo-3-oxobutanoate (Compound B83)
Dissolve ethyl 3-oxobutanoate (0.291 mL, 2.31 mmol) in acetonitrile (11.5 mL) and add 4-acetamidobenzenesulfonyl azide (554 mg, 2.31 mmol) and triethylamine (0.964 mL, 6.92 mmol) at 0 ° C. In addition, the mixture was stirred at room temperature for 5 hours. The mixture was evaporated under reduced pressure, a mixed solvent of heptane / diethyl ether = 1/1 was added to the obtained residue, and the mixture was stirred, and insoluble material was filtered off. The obtained filtrate was evaporated under reduced pressure and purified by silica gel column chromatography (heptane / ethyl acetate = 85/15) to give compound B83 (191 mg, 53%).
1 H-NMR (CDCl 3 ) δ: 4.31 (q, J = 7.1 Hz, 2H), 2.48 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).
ESI-MS: m / z 157 [M + H] + .
Process 2
Ethyl 1,5-dimethyl-1H-1,2,3-triazole-4-carboxylate (Compound B84)
To the compound B83 (191 mg, 1.22 mmol) were added 2.0 mmol / L methylamine THF solution (6.12 mL, 12.2 mmol) and acetic acid (0.600 mL, 10.5 mmol), and the mixture was stirred under reflux for 42 hours. Water was added to the mixture, extracted with ethyl acetate, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under reduced pressure to give compound B84 (87.5 mg, 42%).
1 H-NMR (CDCl 3 ) δ: 4.43 (q, J = 7.2 Hz, 2H), 4.00 (s, 3H), 2.58 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H).
ESI-MS: m / z 170 [M + H] + .
Process 3
1,5-dimethyl-1H-1,2,3-triazole-4-carboxamide (Compound B85)
Compound B84 (87.5 mg, 0.517 mmol) was dissolved in a 7 mol / L ammonia methanol solution (1.48 mL), and the mixture was stirred at room temperature for 3 hours and at 50 ° C. for 3 hours. The mixture was evaporated under reduced pressure, 28% aqueous ammonia (2.00 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 17 hr. The mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 95/5) to give Compound B85 (41.3 mg, 57%).
1 H-NMR (DMSO-d 6 ) δ: 7.68 (br s, 1H), 7.31 (br s, 1H), 3.94 (s, 3H), 2.49 (s, 3H).
ESI-MS: m / z 141 [M + H] + .
参考例40 
工程1
2-オキソ-2,3-ジヒドロ-1H-イミダゾール-4-カルボン酸（化合物B86）
　硫酸（38 mL）中にL-酒石酸（15.7 g, 105 mmol）、尿素（5.00 g, 83.0 mmol）を加え、80℃で1時間攪拌した後、反応混合液を氷水（300 mL）に投入して16時間攪拌した。生じた固体をろ取し、水で洗浄した後、50℃で減圧乾燥することにより化合物B86（2.15 g, 20%）を得た。
1H-NMR (CDCl3) δ: 10.54 (br s, 1H), 10.42 (br s, 1H), 7.14-7.13 (m, 1H).
ESI-MS: m/z 127 [M-H]-.
工程2
1,3-ジエチル-2-オキソ-2,3-ジヒドロ-1H-イミダゾール-4-カルボン酸エチル（化合物B87）
　化合物B86（2.06 g, 16.1 mmol）のDMF（42 mL）懸濁液に、炭酸セシウム（36.7 g, 113 mmol）、ヨウ化エチル（7.80 mL, 96.0 mmol）を加えて50℃で24時間攪拌した。混合物に飽和塩化アンモニウム水溶液を加え、クロロホルムで抽出し、無水硫酸ナトリウムで乾燥し、ろ過した。ろ液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール＝98/2）で精製することにより、化合物B87（2.33 g, 68%）を得た。
1H-NMR (CDCl3) δ: 7.08 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.73 (q, J = 7.1 Hz, 2H), 1.36-1.31 (m, 6H), 1.26 (t, J = 7.1 Hz, 3H).
ESI-MS: m/z 213 [M+H]+.
工程3
1,3-ジエチル-2-オキソ-2,3-ジヒドロ-1H-イミダゾール-4-カルボキサミド（化合物B88）
　化合物B87（1.02 g, 4.79 mmol）を28%アンモニア水（40 mL）に懸濁させ、50℃で23時間攪拌した。減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム/メタノール＝100/0, 90/10）で精製することにより、化合物B88（242 mg, 28%）を得た。
1H-NMR (DMSO-d6) δ: 7.33 (s, 1H), 7.24 (br s, 2H), 3.91 (q, J = 7.1 Hz, 2H), 3.58 (q, J = 7.2 Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H).
ESI-MS: m/z 183 [M+H]+. Reference Example 40
Process 1
2-Oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid (Compound B86)
L-tartaric acid (15.7 g, 105 mmol) and urea (5.00 g, 83.0 mmol) were added to sulfuric acid (38 mL), and the mixture was stirred at 80 ° C for 1 hour, and then the reaction mixture was poured into ice water (300 mL). And stirred for 16 hours. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure at 50 ° C. to obtain compound B86 (2.15 g, 20%).
1 H-NMR (CDCl 3 ) δ: 10.54 (br s, 1H), 10.42 (br s, 1H), 7.14-7.13 (m, 1H).
ESI-MS: m / z 127 [MH] - .
Process 2
Ethyl 1,3-diethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylate (Compound B87)
Cesium carbonate (36.7 g, 113 mmol) and ethyl iodide (7.80 mL, 96.0 mmol) were added to a suspension of compound B86 (2.06 g, 16.1 mmol) in DMF (42 mL), and the mixture was stirred at 50 ° C. for 24 hours. . To the mixture was added saturated aqueous ammonium chloride solution, extracted with chloroform, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform / methanol = 98/2) to give compound B87 (2.33 g, 68%).
1 H-NMR (CDCl 3 ) δ: 7.08 (s, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.73 (q, J = 7.1 Hz, 2H), 1.36-1.31 (m, 6H), 1.26 (t, J = 7.1 Hz, 3H).
ESI-MS: m / z 213 [M + H] + .
Process 3
1,3-Diethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide (Compound B88)
Compound B87 (1.02 g, 4.79 mmol) was suspended in 28% aqueous ammonia (40 mL) and stirred at 50 ° C. for 23 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100/0, 90/10) to obtain Compound B88 (242 mg, 28%).
1 H-NMR (DMSO-d 6 ) δ: 7.33 (s, 1H), 7.24 (br s, 2H), 3.91 (q, J = 7.1 Hz, 2H), 3.58 (q, J = 7.2 Hz, 2H) , 1.19 (t, J = 7.2 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H).
ESI-MS: m / z 183 [M + H] + .
　本発明により、CSF-1Rおよび／またはTrkA阻害活性を有し、癌骨転移、関節リウマチ、骨粗しょう症、ベーチェット病、変形性関節症、前立腺癌、肺癌、腎臓癌、膵臓癌、乳癌、子宮癌、骨髄異形成症候群、急性骨髄性白血病、慢性骨髄性白血病等の治療および／または予防に有用な4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩等を提供することができる。 According to the present invention, it has CSF-1R and / or TrkA inhibitory activity, cancer bone metastasis, rheumatoid arthritis, osteoporosis, Behcet's disease, osteoarthritis, prostate cancer, lung cancer, kidney cancer, pancreatic cancer, breast cancer, uterus 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivatives useful for the treatment and / or prevention of cancer, myelodysplastic syndrome, acute myeloid leukemia, chronic myeloid leukemia, etc. Salt and the like can be provided.

Claims (20)

  1. 式(IA)
    Figure JPOXMLDOC01-appb-C000001
     [式中、R1AおよびR2Aは、同一または異なって、ヒドロキシ、置換基を有していてもよい低級アルコキシまたは置換基を有していてもよい脂肪族複素環オキシを表し、R3Aは低級アルコキシを表し、R4Aは置換基(該置換基は下記置換基A1からなる群から選ばれる同一のまたは異なる1～3個の置換基を表す)を有していてもよい5員環芳香族複素環基を表す]で表される4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩：
    置換基A1：置換基を有していてもよい低級アルキル[該置換基は、低級アルコキシ、および-NR5R6(R5およびR6は、同一または異なって、水素原子、または低級アルキルを表す)からなる群から選ばれる］、ハロゲン、低級アルキルで置換されていてもよいシクロアルキル、低級アルコキシおよび脂肪族複素環基。     Formula (IA)
    Figure JPOXMLDOC01-appb-C000001
     [Wherein, R 1A and R 2A are the same or different and each represents hydroxy, optionally substituted lower alkoxy or optionally substituted aliphatic heterocyclic oxy, and R 3A represents R 4A represents a lower alkoxy, and R 4A may have a substituent (the substituent represents the same or different 1 to 3 substituents selected from the group consisting of the following substituents A1) 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof represented by:
    Substituent A1: An optionally substituted lower alkyl [the substituent is lower alkoxy, and —NR 5 R 6 (R 5 and R 6 are the same or different and each represents a hydrogen atom or lower alkyl] Selected from the group consisting of: halogen, cycloalkyl optionally substituted with lower alkyl, lower alkoxy and aliphatic heterocyclic groups.
  2. R1Aがヒドロキシであり、R2Aが置換基を有していてもよい低級アルコキシである請求項1記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。 4. The 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative according to claim 1, wherein R 1A is hydroxy and R 2A is optionally substituted lower alkoxy. Its pharmaceutically acceptable salt.
  3. R1Aが置換基を有していてもよい低級アルコキシであり、R2Aがヒドロキシである請求項1記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。 The 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative according to claim 1, wherein R 1A is optionally substituted lower alkoxy, and R 2A is hydroxy. Its pharmaceutically acceptable salt.
  4. R1Aが置換基を有していてもよい脂肪族複素環オキシであり、R2Aが置換基を有していてもよい低級アルコキシである請求項1記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。 2. The 4- [4- (5-membered ring) according to claim 1, wherein R 1A is an optionally substituted aliphatic heterocyclic oxy, and R 2A is an optionally substituted lower alkoxy. Aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof.
  5. R3Aがメトキシである請求項1から4のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。 The 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 3A is methoxy.
  6. R4Aにおける5員環芳香族複素環基がイミダゾリル、2-オキソイミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、トリアゾリルまたはチアゾリルである請求項1から5のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。 The 4- [4- (5-membered ring) according to any one of claims 1 to 5, wherein the 5-membered aromatic heterocyclic group in R 4A is imidazolyl, 2-oxoimidazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl or thiazolyl. Aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof.
  7. 式(I)
    Figure JPOXMLDOC01-appb-C000002
     [式中、R1およびR2は、同一または異なって、置換基を有していてもよい低級アルコキシを表し、R3は低級アルコキシを表し、R4は置換基(該置換基は下記置換基Aからなる群から選ばれる同一のまたは異なる1～3個の置換基を表す)を有していてもよい5員環芳香族複素環基を表す]で表される4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩:
    置換基A：置換基を有していてもよい低級アルキル[該置換基は、低級アルコキシ、および-NR5R6(R5およびR6は、同一または異なって、水素原子、または低級アルキルを表す)からなる群から選ばれる］、ハロゲンおよび低級アルキルで置換されていてもよいシクロアルキル。     Formula (I)
    Figure JPOXMLDOC01-appb-C000002
     [Wherein, R 1 and R 2 are the same or different and each represents an optionally substituted lower alkoxy, R 3 represents a lower alkoxy, R 4 represents a substituent (the substituent is Represents a 5-membered aromatic heterocyclic group which may have the same or different 1 to 3 substituents selected from the group consisting of the group A]; 5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof:
    Substituent A: optionally substituted lower alkyl [the substituent is lower alkoxy, and —NR 5 R 6 (R 5 and R 6 are the same or different and each represents a hydrogen atom or lower alkyl] And cycloalkyl optionally substituted with halogen and lower alkyl.
  8. R1およびR2が、同一または異なって、低級アルコキシである請求項7記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。 8. The 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable derivative thereof according to claim 7, wherein R 1 and R 2 are the same or different and are lower alkoxy. salt.
  9. R3がメトキシである請求項7または8記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。 9. The 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof according to claim 7 or 8, wherein R 3 is methoxy.
  10. R4における5員環芳香族複素環基がイミダゾリル、ピラゾリル、オキサゾリル、イソオキサゾリル、トリアゾリルまたはチアゾリルである請求項7から9のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。 The 4- [4- (5-membered aromatic heterocyclic carbonyl) according to any one of claims 7 to 9, wherein the 5-membered aromatic heterocyclic group in R 4 is imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl or thiazolyl. (Ureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof.
  11. 請求項1から10のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩を有効成分として含有する医薬。 11. A medicament comprising the 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 as an active ingredient.
  12. 請求項1から10のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩を有効成分として含有するコロニー刺激因子-1受容体および／またはトロポミオシン関連キナーゼA阻害剤。 Colony stimulating factor comprising the 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient according to any one of claims 1 to 10. -1 receptor and / or tropomyosin-related kinase A inhibitor.
  13. 請求項1から10のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩を有効成分として含有するコロニー刺激因子-1受容体およびトロポミオシン関連キナーゼAが関与する疾患の治療および／または予防剤。 Colony stimulating factor comprising the 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient according to any one of claims 1 to 10. A therapeutic and / or prophylactic agent for diseases involving -1 receptor and tropomyosin-related kinase A.
  14. 請求項1から10のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩を有効成分として含有するコロニー刺激因子-1受容体またはトロポミオシン関連キナーゼAが関与する疾患の治療および／または予防剤。 Colony stimulating factor comprising the 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient according to any one of claims 1 to 10. A therapeutic and / or prophylactic agent for diseases involving -1 receptor or tropomyosin-related kinase A.
  15. 請求項1から10のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩の有効量を投与する工程を含む、コロニー刺激因子-1受容体および／またはトロポミオシン関連キナーゼAの阻害方法。 A step of administering an effective amount of the 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10. A method of inhibiting colony stimulating factor-1 receptor and / or tropomyosin-related kinase A.
  16. 請求項1から10のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩の有効量を投与する工程を含む、コロニー刺激因子-1受容体およびトロポミオシン関連キナーゼAが関与する疾患の治療および／または予防方法。 A step of administering an effective amount of the 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10. , A method for treating and / or preventing a disease involving a colony stimulating factor-1 receptor and tropomyosin-related kinase A.
  17. 請求項1から10のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩の有効量を投与する工程を含む、コロニー刺激因子-1受容体またはトロポミオシン関連キナーゼAが関与する疾患の治療および／または予防方法。 A step of administering an effective amount of the 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10. , A method for treating and / or preventing a disease involving colony stimulating factor-1 receptor or tropomyosin-related kinase A.
  18. コロニー刺激因子-1受容体および／またはトロポミオシン関連キナーゼA阻害に使用するための、請求項1から10のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。 The 4- [4- (5-membered aromatic heterocyclic carbonylureido) phenyloxy according to any one of claims 1 to 10, for use in colony stimulating factor-1 receptor and / or tropomyosin-related kinase A inhibition. ] A quinoline derivative or a pharmaceutically acceptable salt thereof.
  19. コロニー刺激因子-1受容体およびトロポミオシン関連キナーゼAが関与する疾患の治療および／または予防に使用するための、請求項1から10のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。 11. The 4- [4- (5-membered aromatic ring] according to any one of claims 1 to 10, for use in the treatment and / or prevention of diseases involving colony stimulating factor-1 receptor and tropomyosin-related kinase A. Heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof.
  20. コロニー刺激因子-1受容体またはトロポミオシン関連キナーゼAが関与する疾患の治療および／または予防に使用するための、請求項1から10のいずれかに記載の4-[4-(5員環芳香族複素環カルボニルウレイド)フェニルオキシ]キノリン誘導体またはその薬学的に許容される塩。
          11. The 4- [4- (5-membered aromatic ring] according to any one of claims 1 to 10, for use in the treatment and / or prevention of diseases involving colony stimulating factor-1 receptor or tropomyosin-related kinase A. Heterocyclic carbonylureido) phenyloxy] quinoline derivative or a pharmaceutically acceptable salt thereof.
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