WO2009096435A1 - Condensed heterocyclic derivatives and uses thereof - Google Patents

Condensed heterocyclic derivatives and uses thereof Download PDF

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Publication number
WO2009096435A1
WO2009096435A1 PCT/JP2009/051383 JP2009051383W WO2009096435A1 WO 2009096435 A1 WO2009096435 A1 WO 2009096435A1 JP 2009051383 W JP2009051383 W JP 2009051383W WO 2009096435 A1 WO2009096435 A1 WO 2009096435A1
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alkyl
optionally
mmol
compound
pyridazin
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PCT/JP2009/051383
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French (fr)
Japanese (ja)
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Naoki Miyamoto
Shigemitsu Matsumoto
Shinichi Imamura
Takaharu Hirayama
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Takeda Pharmaceutical Company Limited
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Priority to JP2009551545A priority Critical patent/JPWO2009096435A1/en
Publication of WO2009096435A1 publication Critical patent/WO2009096435A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to fused heterocyclic derivatives and uses thereof, and more particularly to imidazopyridazine derivatives having strong kinase inhibitory activity and useful for cancer prevention and treatment and uses thereof.
  • VEGF Vascular endothelial growth factor
  • VEGFR vascular endothelial growth factor receptor
  • HGF hepatocyte growth factor
  • c-Met vascular endothelial cells
  • HGF hepatocyte growth factor
  • c-Met is highly expressed in various cancers (such as colorectal cancer, stomach cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, etc.), and is clearly involved in the growth and survival of cancer cells.
  • Non-Patent Document 5 a tumor cell invasion / metastasis
  • c-Met inhibition is thought to be effective in preventing cancer invasion / metastasis. .
  • Examples of compounds that inhibit kinases including VEGFR and c-Met include phthalazine derivatives (see, for example, Patent Document 1), pyrrole-substituted 2-indolinone derivatives (see, for example, Patent Document 2), and quinazoline derivatives (for example, Patent Document).
  • Patent Document 4 ⁇ -carboxyaryl-substituted diphenylurea derivatives
  • Patent Document 4 quinoline derivatives and / or quinazoline derivatives
  • Patent Documents 5 7, and 13
  • nitrogen-containing aromatic ring derivatives for example, Patents
  • Patent Document 8 pyrazole-substituted indole derivatives
  • Patent Document 9 pyrrolopyridine and / or pyrrolopyrimidine derivatives
  • imidazopyridazine derivatives see, for example, Patent Document 10
  • imidazopyridine, Triazolopyridine, benzothiazole And / or thiazolopyridine derivatives is known (Patent Document 11 reference) and the like.
  • Patent Document 12 describes imidazopyridazine derivatives as antidiabetic agents.
  • Kinase inhibitors with excellent affinity for kinases, excellent drug efficacy, pharmacokinetics, solubility, interaction with other drugs, safety and stability can be expected to have excellent therapeutic effects. .
  • none of them has been found to be excellent in affinity for kinases and sufficiently satisfactory in terms of drug efficacy, pharmacokinetics, solubility, interaction with other pharmaceuticals, safety and stability. Therefore, development of a compound having excellent kinase inhibitory activity and sufficiently satisfactory as a pharmaceutical is eagerly desired. Accordingly, an object of the present invention is to provide a compound having excellent kinase inhibitory activity, low toxicity and sufficiently satisfactory as a pharmaceutical product.
  • X represents N or CR 1 (R 1 represents a hydrogen atom, a halogen atom or C 1-6 alkyl); Y represents N or CR 2 (R 2 represents a hydrogen atom, a halogen atom or C 1-6 alkyl); R 3 represents a hydrogen atom, a halogen atom or C 1-6 alkyl; R 4 represents a hydrogen atom, a halogen atom or C 1-6 alkyl; R 5 represents a hydrogen atom; R 60 is (1) a C 6-10 arylamino optionally having C 1-6 alkyl, optionally substituted by 1 to 3 halogen atoms, (2) C 7-12 aralkyl-carbonylamino, (3) C 7-12 aralkyloxy, (4) (a) (i ) C 1-6 alkoxy, and (ii) C 1-6 alkyl - which may have a substituent group selected from a carbonyl C 1-6 alkyl, (b) C 6-10 aryl, (c
  • R 5 and R 60 may together form a fused heterocycle;
  • Z represents O or S.
  • the following 4 compounds are excluded.
  • X represents N or CR 1 (R 1 represents a hydrogen atom, a halogen atom or C 1-6 alkyl); Y represents N or CR 2 (R 2 represents a hydrogen atom, a halogen atom or C 1-6 alkyl); R 3 represents a hydrogen atom, a halogen atom or C 1-6 alkyl; R 4 represents a hydrogen atom, a halogen atom or C 1-6 alkyl; R 5 represents a hydrogen atom; R 6 is (1) C 6-10 arylamino optionally having C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms, (2) C 7-12 aralkyl-carbonylamino, (3) C 7-12 aralkyloxy, (4) (a) (i ) C 1-6 alkoxy, and (ii) C 1-6 alkyl - which may have a substituent group selected from a carbonyl C 1-6 alkyl, (b) C 6-10 aryl, (c) o
  • R 5 and R 6 may be taken together to form a fused heterocycle;
  • Z represents O or S.
  • the following 4 compounds are excluded: (1) N- [4-( ⁇ 2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl ⁇ oxy) phenyl] -5-methyl-1-phenyl-1H-pyrazole -3-carboxamide; (2) N- [4-( ⁇ 2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl ⁇ oxy) phenyl] -3-methyl-1-phenyl-1H-pyrazole -5-carboxamide; (3) N- [4-( ⁇ 2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl ⁇ oxy) phenyl] -1,3-dimethyl
  • X is N or CR 1 ′ (R 1 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
  • Y is N or CR 2 ′ (R 2 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
  • R 3 is a hydrogen atom or a halogen atom;
  • R 4 is a hydrogen atom or a halogen atom;
  • R 5 is a hydrogen atom;
  • R 6 is (1) C 6-10 arylamino optionally having C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms, (2) C 7-12 aralkyloxy, (3) (a) C 1-6 alkyl, (b) a C 6-10 aryl optionally having 1
  • the compounds of the present invention have a strong inhibitory effect on kinases such as vascular endothelial growth factor receptor, hepatocyte growth factor receptor, platelet-derived growth factor receptor and the like, and also have a strong anti-angiogenic effect, and thus are clinically useful for cancer Prophylactic / therapeutic agents, cancer growth inhibitors, and cancer invasion / metastasis inhibitors can be provided. Furthermore, the compound of the present invention can provide a clinically useful prophylactic / therapeutic agent in applications other than cancer such as rheumatoid arthritis and diabetic retinopathy. It is also excellent in terms of interaction with pharmaceuticals, safety, and stability.
  • halogen atom represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • C 1-6 alkyl means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl. Indicates.
  • C 6-10 arylamino refers to, for example, phenylamino and naphthylamino.
  • C 7-12 aralkyl-carbonylamino refers to, for example, benzylcarbonylamino, phenethylcarbonylamino, naphthylmethylcarbonylamino.
  • C 7-12 aralkyloxy refers to, for example, benzyloxy, phenethyloxy, naphthylmethyloxy.
  • C 1-6 alkoxy means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy.
  • C 1-6 alkyl-carbonyl means, for example, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, hexyl. Indicates carbonyl.
  • C 6-10 aryl means, for example, phenyl or naphthyl.
  • the “nitrogen-containing 5-membered ring group” contains 1 to 4 nitrogen atoms in addition to carbon atoms as ring-constituting atoms, and further oxygen and sulfur atoms (the sulfur atoms are oxidized).
  • a non-aromatic nitrogen-containing 5-membered cyclic group eg, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl
  • a 5-membered aromatic group which may contain 1 or 2 heteroatoms selected from A nitrogen-containing heterocyclic group (eg, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl);
  • the “5-membered aromatic heterocyclic group” means a hetero atom selected from an oxygen atom, a sulfur atom (the sulfur atom may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring constituent atom.
  • a 5-membered aromatic heterocyclic group containing 1 to 4 atoms eg, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl
  • the “nitrogen-containing 6-membered ring group” contains 1 to 4 nitrogen atoms in addition to carbon atoms as ring-constituting atoms, and further oxygen atoms and sulfur atoms (the sulfur atoms are oxidized).
  • a non-aromatic nitrogen-containing 6-membered cyclic group eg, dihydropyridyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl
  • an aromatic nitrogen-containing 6-membered group which may contain 1 or 2 heteroatoms selected from A cyclic group (eg, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl) is shown.
  • the “oxidized nitrogen-containing 6-membered cyclic group” represented by “optionally oxidized nitrogen-containing 6-membered cyclic group” is a group in which the nitrogen-containing 6-membered cyclic group is oxidized ( Example pyridyl oxide).
  • C 6-10 aryl-carbamoyl-C 1-6 alkyl means, for example, phenylcarbamoylmethyl, 1-methyl-1- (phenylcarbamoyl) ethyl.
  • C 7-12 aralkyl refers to, for example, benzyl, phenethyl, and naphthylmethyl.
  • C 6-10 aryl-carbonyl means, for example, benzoyl or naphthylcarbonyl.
  • C 6-10 aryl-carbonylamino refers to, for example, benzoylamino.
  • C 3-6 cycloalkyl means, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
  • C 1-6 alkylthio refers to methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio.
  • C 1-6 alkoxy-carbonyl means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl Represents hexyloxycarbonyl.
  • the “aromatic heterocyclic group” means a hetero atom selected from an oxygen atom, a sulfur atom (the sulfur atom may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring constituent atom.
  • 5 to 7-membered monocyclic aromatic heterocyclic group containing 1 to 4 eg, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl
  • a group formed by condensation of rings corresponding to a 5- to 7-membered monocyclic aromatic heterocyclic group, or a ring corresponding to a 5- to 7-membered monocyclic aromatic heterocyclic group and a benzene ring are condensed.
  • quinolyl quinolyl
  • the “6-membered heterocycle” formed by R 7 and R 8 together with —NR 7 R 8 is a ring corresponding to the nitrogen-containing 6-membered ring group (eg, piperidine, morpholine). , Thiomorpholine).
  • the “fused heterocycle” formed by R 5 and R 60 or R 5 and R 6 together refers to the ring corresponding to the nitrogen-containing 6-membered ring group and the aromatic heterocyclic group.
  • X represents N or CR 1 (R 1 represents a hydrogen atom, a halogen atom or C 1-6 alkyl).
  • R 1 is preferably a hydrogen atom, a fluorine atom, a chlorine atom or methyl.
  • X is preferably N or CR 1 ′ (R 1 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl).
  • Y represents N or CR 2 (R 2 represents a hydrogen atom, a halogen atom or C 1-6 alkyl).
  • R 2 is preferably a hydrogen atom, a fluorine atom, a chlorine atom or methyl.
  • Y is preferably N or CR 2 ′ (R 2 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl).
  • R 3 represents a hydrogen atom, a halogen atom or C 1-6 alkyl.
  • R 3 is preferably a hydrogen atom or a halogen atom (particularly a fluorine atom).
  • R 4 represents a hydrogen atom, a halogen atom or C 1-6 alkyl.
  • R 4 is preferably a hydrogen atom or a halogen atom (particularly a fluorine atom).
  • R 5 represents a hydrogen atom.
  • R 60 is (1) a C 6-10 arylamino optionally having C 1-6 alkyl, optionally substituted by 1 to 3 halogen atoms, (2) C 7-12 aralkyl-carbonylamino, (3) C 7-12 aralkyloxy, (4) (a) (i ) C 1-6 alkoxy, and (ii) C 1-6 alkyl - which may have a substituent group selected from a carbonyl C 1-6 alkyl, (b) C 6-10 aryl, (c) oxo, (d) hydroxy, and (e) a nitrogen-containing 5-membered cyclic group optionally having 1 to 4 substituents selected from C 1-6 alkoxy, (5) (a) C 1-6 alkyl, (b) a C 6-10 aryl optionally having 1 to 3 halogen atoms or C 1-6 alkyl, (c) oxo, (d) 1 to 3 C 1-6 alkyl optionally having 5 membered aromatic heterocyclic group, and (
  • R 6 is (1) C 6-10 arylamino optionally having C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms, (2) C 7-12 aralkyl-carbonylamino, (3) C 7-12 aralkyloxy, (4) (a) (i ) C 1-6 alkoxy, and (ii) C 1-6 alkyl - which may have a substituent group selected from a carbonyl C 1-6 alkyl, (b) C 6-10 aryl, (c) oxo, (d) hydroxy, and (e) a nitrogen-containing 5-membered cyclic group optionally having 1 to 3 substituents selected from C 1-6 alkoxy, (5) (a) C 1-6 alkyl, (b) C 6-10 aryl optionally having 1 to 3 halogen atoms or C 1-6 alkyl, (c) oxo, (d) a 5-membered aromatic heterocyclic group optionally having 1 to 3 C 1-6 alkyls, and (e)
  • R 6 (1) C 6-10 arylamino (eg, optionally having C 1-6 alkyl (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine)) Phenylamino), (2) C 7-12 aralkyl-carbonylamino (eg, benzylcarbonylamino), (3) C 7-12 aralkyloxy (eg, benzyloxy), (4) (a) (i) C 1-6 alkoxy (eg, methoxy), and (ii) C 1-6 alkyl-carbonyl (eg, acetyl) C 1-6 alkyl (eg, methyl, ethyl), which may have a substituent selected from (b) C 6-10 aryl (eg, phenyl), (c) oxo, (d) hydroxy, and (e) C 1-6 alkoxy (eg, methoxy)
  • a nitrogen-containing 5-membered cyclic group for example,
  • R 6 is (1) phenylamino optionally having trifluoromethyl, (2) benzylcarbonylamino, (3) benzyloxy, (4) (a) C 1-6 alkyl (eg, methyl, ethyl) optionally having a substituent selected from methoxy and acetyl, (b) phenyl, (c) oxo, (d) hydroxy, and (e) a nitrogen-containing 5-membered ring group (eg, pyrazolyl, pyrrolidinyl, dihydropyrazolyl) optionally having 1 to 3 substituents selected from methoxy, (5) (a) methyl or ethyl, (b) phenyl optionally having 1 to 3 fluorine atoms or methyl, (c) oxo, (d) a 5-membered aromatic heterocyclic group (eg, thiazolyl) optionally having 1 to 3 methyl groups, and (e) 1 to
  • a nitrogen-containing 6-membered cyclic group (eg, dihydropyridyl) which may be oxidized, (4) C 6-10 aryl-carbamoyl-C 1-6 alkyl (eg, phenylcarbamoylmethyl, 1-methyl-1- (phenylcarbamoyl) methyl, 1-methyl-1- (phenylcarbamoyl) ethyl), (5) benzyl or (6) Benzoyl, carboxyl or formula —CONR 7 ′ R 8 ′ (Wherein R 7 ′ is (a) C 1-6 alkyl optionally having furyl (eg, methyl, ethyl, propyl, isopropyl, tert-butyl), (b) C 3-6 cycloalkyl (eg, cyclopropyl, cyclopentyl, cyclohexyl) optionally having C 1-6 alkyl (eg, methyl, tert-butyl
  • Z represents O or S.
  • compound (I) include the following: [Compound A]
  • X is N or CR 1 ′ (R 1 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
  • Y is N or CR 2 ′ (R 2 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
  • R 3 is a hydrogen atom or a halogen atom (eg, fluorine atom);
  • R 4 is a hydrogen atom or a halogen atom (eg, fluorine atom);
  • R 5 is a hydrogen atom;
  • R 6 is (1) phenylamino optionally having trifluoromethyl, (2) benzylcarbonylamino, (3) benzyloxy, (4) (a) C 1-6 alkyl (eg, methyl, ethyl) optionally having a substituent selected from methoxy and acetyl, (b) phenyl, (c
  • X is N or CR 1 ′ (R 1 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl); Y is N or CR 2 ′ (R 2 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl); R 3 is a hydrogen atom or a fluorine atom; R 4 is a hydrogen atom or a fluorine atom; R 5 is a hydrogen atom; R 6 is (1) phenylamino optionally having trifluoromethyl, (2) benzyloxy, (3) (a) methyl, (b) phenyl optionally having 1 to 3 fluorine atoms or methyl, (c) oxo, (d) optionally having 1 to 3 methyl groups, a 5-membered aromatic heterocyclic group (eg, thiazolyl), and (e) having 1 to 3 substituents selected from epoxy.
  • R 3 is a hydrogen atom or a fluorine atom
  • a nitrogen-containing 6-membered cyclic group (eg, dihydropyridyl) which may be oxidized, (4) C 6-10 aryl-carbamoyl-C 1-6 alkyl (eg, phenylcarbamoylmethyl, 1-methyl-1- (phenylcarbamoyl) methyl, 1-methyl-1- (phenylcarbamoyl) ethyl), (5) benzyl or (6) (a) benzoyl, (b) Carboxyl, or (c) Formula —CONR 7 ′ R 8 ′ (Wherein R 7 ′ is (a) C 1-6 alkyl optionally having furyl (eg, methyl, ethyl, propyl, isopropyl, tert-butyl), (b) C 3-6 cycloalkyl (eg, cyclopropyl, cyclopentyl, cyclohexyl) optionally having C 1-6 alkyl (eg,
  • X is N or CR 1 ′ (R 1 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl); Y is N or CR 2 ′ (R 2 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl); R 3 is a hydrogen atom or a fluorine atom; R 4 is a hydrogen atom or a fluorine atom; R 5 is a hydrogen atom; R 6 is (1) phenylamino optionally having trifluoromethyl, (2) benzyloxy, (3) (a) methyl or ethyl, (b) phenyl optionally having 1 to 3 fluorine atoms or methyl, (c) oxo, (d) a 5-membered aromatic heterocyclic group (eg, thiazolyl) optionally having 1 to 3 methyl groups, and (e) 1 to 3 substituents selected from epoxy Well, a nitrogen-containing
  • examples of such a salt include a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a basic or acidic amino acid, and the like.
  • examples include salts.
  • the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • Examples include salts with ethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salt with organic acid examples include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene Examples thereof include salts with sulfonic acid, p-toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned. Of these, pharmaceutically acceptable salts are preferred.
  • inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts
  • a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid
  • organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
  • Compound (I) can be obtained, for example, by a method represented by the following reaction formula or a method analogous thereto.
  • the compound in a formula also includes the case where the salt is formed, as such a salt, the thing similar to the salt in the compound (I) illustrated above etc. is used, for example.
  • the compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can be isolated from the reaction mixture according to a conventional method, such as recrystallization, distillation, chromatography, etc. It can be easily purified by separation means.
  • a schematic diagram of the reaction formula is shown below, and each symbol of the compound in the schematic diagram has the same meaning as described above.
  • Halogen atom refers to fluorine, chlorine, bromine and iodine.
  • the “optionally substituted alkylsulfonyl” is substituted with a substituent selected from a halogen atom, an optionally halogenated C 1-6 alkyl (eg, methyl, ethyl, trifluoromethyl) and nitro.
  • C 1-6 alkylsulfonyl eg, methylsulfonyl, ethylsulfonyl, etc. which may be optionally represented.
  • the “optionally substituted alkylsulfonyloxy” is substituted with a substituent selected from a halogen atom, an optionally halogenated C 1-6 alkyl (eg, methyl, ethyl, trifluoromethyl) and nitro.
  • C 1-6 alkylsulfonyloxy eg, methylsulfonyloxy, ethylsulfonyloxy and the like
  • the “optionally substituted arylsulfonyloxy” is substituted with a substituent selected from a halogen atom, an optionally halogenated C 1-6 alkyl (eg, methyl, ethyl, trifluoromethyl) and nitro.
  • C 6-14 arylsulfonyloxy (eg, phenylsulfonyloxy and the like) which may be optionally represented.
  • the “optionally substituted aryloxy” is substituted with a substituent selected from a halogen atom, an optionally halogenated C 1-6 alkyl (eg, methyl, ethyl, trifluoromethyl) and nitro.
  • C 6-14 aryloxy eg, phenyloxy etc.
  • the “optionally substituted alkoxy” is substituted with a substituent selected from a halogen atom, an optionally halogenated C 1-6 alkyl (eg, methyl, ethyl, trifluoromethyl) and nitro.
  • C 1-6 alkoxy eg, methoxy, ethoxy, etc.).
  • L 1 represents a leaving group
  • R 0 represents R 60 or R 6.
  • Other symbols are as defined above.
  • a halogen atom an optionally substituted alkylsulfonyl, an optionally substituted alkylsulfonyloxy, an optionally substituted arylsulfonyloxy and the like are used.
  • Step 1-1 Compound (I) can be produced by reacting compound (II) with compound (III) in the presence of a base.
  • Compound (III) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (II).
  • As the base an inorganic base, an organic base, or the like is used.
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • a solvent is not particularly limited as long as the reaction proceeds.
  • alcohols such as methanol, ethanol, 2-propanol, 2-methyl-2-propanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1
  • Ethers such as 2-dimethoxyethane
  • hydrocarbons such as benzene, toluene, cyclohexane and hexane
  • esters such as ethyl acetate and butyl acetate
  • ketones such as acetone and methyl ethyl ketone
  • N N-dimethylformamide
  • Amides such as N-dimethylacetamide and 1-methyl-2-pyrrolidone
  • halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane
  • reaction time varies depending on the reagent and solvent to be used, it is generally 1 min to 200 hr, preferably 10 min to 100 hr.
  • reaction temperature varies depending on the reagent and solvent to be used, it is generally ⁇ 100 to 250 ° C., preferably ⁇ 78 to 200 ° C.
  • the reaction may be carried out using a microwave reactor.
  • Step 2-1 Compound (V) can be produced by reacting compound (II) with compound (IV) in the presence of a base.
  • Compound (IV) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (II).
  • the base those similar to the base exemplified in Reaction Scheme 1 can be used.
  • the base is used in an amount of 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to compound (II).
  • Step 2-2 Compound (VII) can be produced by reducing the nitro group of compound (V). The reduction of nitro can be carried out according to a method known per se, for example, the method described in the 4th edition Experimental Chemistry Course, Vol. 20, 279-280 or the like, or a method analogous thereto.
  • Step 2-3 Compound (VII) can also be produced by reacting Compound (II) with Compound (VI) in the presence of a base.
  • Compound (VI) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (II).
  • the base those similar to the base exemplified in Reaction Scheme 1 can be used.
  • the base is used in an amount of 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to compound (II).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • the solvent the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • the reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours.
  • Step 2-4 Compound (I-1) can be produced by reacting Compound (VII) with Compound (VIII) in the presence of a condensing agent.
  • Compound (VIII) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (VII).
  • condensing agent examples include 1-ethyl-1- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1,3-dicyclohexylcarbodiimide, diethyl cyanophosphate, diphenylphosphoryl azide, 1,1′-carbonyldiimidazole, benzoate Triazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, O— ( 7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate and the like can be used.
  • condensation accelerator for example, 1-hydroxybenzotriazole, N-hydroxysuccinimide, etc.
  • condensation accelerators are used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (VII).
  • the reaction may proceed more smoothly by adding a base.
  • the base those similar to the base exemplified in Reaction Scheme 1 can be used.
  • the base is used in an amount of 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents, relative to compound (VII). This reaction is advantageously performed using a solvent inert to the reaction.
  • the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • the reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours.
  • the reaction temperature is generally ⁇ 100 to 250 ° C., preferably ⁇ 78 to 200 ° C.
  • Compound (I-1) can also be produced by reacting compound (VII) with compound (IX).
  • Compound (IX) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (VII).
  • the base may be used in an amount of 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents, relative to compound (VII).
  • As the base those similar to the base exemplified in Reaction Scheme 1 can be used.
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • the solvent the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • the reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours.
  • the reaction temperature is generally ⁇ 100 to 250 ° C., preferably ⁇ 78 to 200 ° C.
  • R 6A is (a) C 1-6 alkyl optionally having a 5-membered aromatic heterocyclic group, and (b) C 3-6 optionally having C 1-6 alkyl.
  • Step 3-1 Compound (I-2) can be produced by reacting compound (VII) with a monohalide of compound (X) in an appropriate solvent (eg, N, N-dimethylacetamide, etc.). .
  • the monohalide of compound (X) can be produced by reacting compound (X) with thionyl chloride in the presence of a base (for example, triethylamine) in an appropriate solvent (for example, tetrahydrofuran).
  • Step 3-2 Compound (I-3) can be produced by condensing compound (I-2) and compound (XI) by the same method as in Step 2-4.
  • Step 4-1 Compound (I-4) can be produced by reacting compound (VII) with isocyanate derivative (XII).
  • the isocyanate derivative (XII) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (VII).
  • 0.01 to 10 equivalents, preferably 0.01 to 3 equivalents of a base may be used.
  • the base those similar to the base exemplified in Reaction Scheme 1 can be used. This reaction is advantageously performed using a solvent inert to the reaction.
  • the solvent the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • the reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours.
  • the reaction temperature is generally ⁇ 100 to 250 ° C., preferably ⁇ 78 to 200 ° C.
  • Compound (I) can also be produced by the method shown in Reaction Scheme 5.
  • Compound (I-5) is encompassed in compound (I). (Reaction Formula 5)
  • Step 5-1 Compound (I-5) can be produced by reacting compound (VII) with acyl thiocyanate derivative (XIII).
  • the acyl thiocyanate derivative (XIII) is used in an amount of 0.1 to 10 equivalents, preferably 0.5 to 5 equivalents, relative to compound (VII).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • the solvent the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • the reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours.
  • the reaction temperature is generally ⁇ 100 to 250 ° C., preferably ⁇ 78 to 200 ° C.
  • reaction formula 6 The compound (II) represented by the reaction formulas 1 and 2 can be produced by, for example, the method represented by the following reaction formula or a method analogous thereto. (Reaction Formula 6)
  • Step 6-1 Compound (XVI) can be produced by reacting compound (XIV) with acetylcarbamic acid derivative (XV).
  • the acetylcarbamic acid derivative (XV) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 5 equivalents, relative to compound (XIV).
  • the base may be used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 5 equivalents, relative to compound (XIV).
  • an inorganic base or an organic base is used as the base.
  • Step 6-2 Compound (XVII) can be produced by treating compound (XVI) with a base or acid.
  • the base include sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide and the like.
  • the base is used in an amount of 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents, relative to compound (XVI).
  • the acid examples include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, trifluoroacetic acid and the like.
  • the acid is used in an amount of 0.1 to 20 equivalents, preferably 0.3 to 10 equivalents, relative to compound (XVI).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • the solvent the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • Step 6-3 Compound (II) can be produced by reacting compound (XVII) with compound (XVIII).
  • Compound (XVIII) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (XVII).
  • the base may be used in an amount of 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents, relative to compound (XVII).
  • the base those similar to the base exemplified in Reaction Scheme 1 can be used.
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • the solvent the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • the reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours.
  • the reaction temperature is generally ⁇ 100 to 250 ° C., preferably ⁇ 78 to 200 ° C.
  • Step 7-1 Compound (XXI) can be produced by reacting compound (XIX) with compound (XX).
  • Compound (XX) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (XIX).
  • the base may be used in an amount of 0.01 to 10 equivalents relative to compound (XIX).
  • the base those similar to the base exemplified in Reaction Scheme 1 can be used. This reaction is advantageously performed using a solvent inert to the reaction.
  • Step 7-2 Compound (II) can be produced by reacting compound (XXI) with compound (XIV).
  • Compound (XXI) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 5 equivalents, relative to compound (XIV).
  • the base may be used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 5 equivalents, relative to compound (XIV).
  • an inorganic base or an organic base is used as the base.
  • Undec-7-ene pyridine, 4- (dimethylamino) pyridine, N, N-dimethylaniline and the like. This reaction is advantageously performed using a solvent inert to the reaction.
  • the solvent the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • the reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours.
  • the reaction temperature is generally ⁇ 100 to 250 ° C., preferably ⁇ 78 to 200 ° C.
  • Compound (II) can also be produced by sequentially performing Step 7-1 and Step 7-2 without isolating and purifying Compound (XXI).
  • Step 8-1 Compound (V) can be produced by reacting compound (XXII) with compound (XXIII) in the presence of a base.
  • Compound (XXIII) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (XXII).
  • As the base those similar to the base exemplified in Reaction Scheme 1 can be used.
  • the base is used in the amount of 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to compound (XXII).
  • This reaction is advantageously performed using a solvent inert to the reaction.
  • the solvent the same solvents as those exemplified in Reaction Scheme 1 can be used.
  • the reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours.
  • the reaction temperature is generally ⁇ 100 to 250 ° C., preferably ⁇ 78 to 200 ° C.
  • Reaction Scheme 8 Compound (XXII) represented by Reaction Scheme 8 can be produced, for example, by the method represented by the following Reaction Formula or a method analogous thereto. (Reaction Formula 9)
  • Step 9-1 Compound (XXIV) can be produced by reacting compound (XVII) with sodium methoxide in an appropriate solvent (eg, methanol).
  • Step 9-2 Compound (XXV) can be produced by reacting compound (XXIV) with compound (XVIII) by the same method as in Step 6-3.
  • Step 9-3 Compound (XXII) can be produced by reacting compound (XXV) with sodium ethanethiolate in a suitable solvent (eg, N, N-dimethylformamide and the like).
  • a suitable solvent eg, N, N-dimethylformamide and the like.
  • Step 10-1 Compound (I-6) can be produced by reacting compound (VII) with compound (XXVI) in the same manner as in Step 2-4.
  • Step 10-2 Compound (I-7) can be produced by reacting compound (I-6) with triethyl orthoformate and acetic acid in a suitable solvent (eg, ethanol, tetrahydrofuran, etc.).
  • a suitable solvent eg, ethanol, tetrahydrofuran, etc.
  • a compound within the scope of the present invention can also be produced by applying means known per se to compound (I) to further introduce substituents or convert functional groups.
  • substituent conversion known general methods are used. For example, conversion to carboxy by hydrolysis of ester, conversion to carbamoyl by amidation of carboxy, conversion to hydroxymethyl by reduction of carboxy, reduction of carbonyl or alkyl To alcohol by rehydration, reductive amination of carbonyl, oximation of carbonyl, acylation / urealation / sulfonylation / alkylation of amino, substitution / amination of active halogen with amine, amination by reduction of nitro , Hydroxy alkylation, hydroxy substitution / amination.
  • a protective group is introduced into the reactive substituent in advance by a publicly known means as necessary.
  • the protecting group can be removed by means known per se to produce a compound within the scope of the present invention.
  • the raw material compound or intermediate has an amino group, carboxyl group or hydroxyl group as a substituent, these groups may be protected with a protecting group generally used in peptide chemistry or the like.
  • the target compound can be obtained by removing the protecting group as necessary after the reaction.
  • Examples of the protecting group for amino group include formyl group, C 1-6 alkyl-carbonyl group, C 1-6 alkoxy-carbonyl group, benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), C 7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, Dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like.
  • C 7-10 aralkyl-carbonyl group eg, benzylcarbonyl
  • These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group and a nitro group.
  • the protecting group for the carboxyl group include a C 1-6 alkyl group, a C 7-11 aralkyl group (eg, benzyl), a phenyl group, a trityl group, a substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like.
  • hydroxyl protecting group examples include C 1-6 alkyl group, phenyl group, trityl group, C 7-10 aralkyl group (eg, benzyl), formyl group, C 1-6 alkyl-carbonyl group, benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert- Butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like.
  • C 1-6 alkyl group eg, phenyl group, trityl group, C 7-10 aralkyl group (eg, benzyl), formyl group, C 1-6 alkyl
  • These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a nitro group.
  • substituents selected from a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a nitro group.
  • Examples of the method for removing the protecting group include methods known per se, such as the method described in “Protective Groups in Organic Synthesis”, edited by John Wiley and Sons (1980).
  • the method used or the reduction method is used.
  • Compound (I) can be isolated and purified by known means such as phase transfer, concentration, solvent extraction, fractionation, liquid conversion, crystallization, recrystallization, chromatography and the like.
  • compound (I) When compound (I) is obtained as a free compound, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely when it is obtained as a salt, it is known per se. It can be converted into a free form or other desired salt by the method or a method analogous thereto.
  • Compound (I) may be used as a prodrug.
  • a prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc.
  • a compound in which the amino of the compound (I) is acylated, alkylated or phosphorylated for example, the amino of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, ( 5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); compounds ( Compounds wherein the hydroxyl of I) is acylated, alkylated, phosphorylated, borated (eg, hydroxyl of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, Dimethylaminomethylcarbonylated compounds, etc.
  • prodrug of compound (I) changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163 to 198. There may be.
  • any one of the isomers and a mixture are included in the compound (I).
  • the optical isomer resolved from the racemate is also encompassed in compound (I).
  • Each of these isomers can be obtained as a single product by a known synthesis method or separation method (concentration, solvent extraction, column chromatography, recrystallization, etc.).
  • Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a crystal form mixture. Crystals can be produced by crystallization by applying a crystallization method known per se. Compound (I) may be a co-crystal. Compound (I) may be a solvate (eg, hydrate etc.) or non-solvate (eg non-hydrate etc.), both of which are encompassed in compound (I). The Compounds labeled with isotopes (eg, 2 H, 3 H, 14 C, 35 S, 125 I, etc.) are also encompassed in compound (I). Further, compound (I) may be a deuterium converter.
  • Compound (I) or a prodrug thereof (may be abbreviated as “the compound of the present invention” in the present specification) has, for example, an activity of inhibiting its phosphorylation against the phosphorylation action of a kinase.
  • the kinase includes not only a substance having a phosphorylation action as a whole, but also a substance having a phosphorylation action on its part, and the phosphorylation action of a kinase is a phosphorylation action on self and It includes both effects of phosphorylation on other substances.
  • vascular endothelial growth factor receptor examples include vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), Raf, c-Met and the like.
  • VEGFR vascular endothelial growth factor receptor
  • VGFR1 vascular endothelial growth factor receptor 1
  • VGFR2 vascular endothelial growth factor receptor 2
  • VGFR3 vascular endothelial growth factor receptor 3
  • vascular endothelial growth factor receptor 2 is preferable.
  • Examples of the platelet-derived growth factor receptor include platelet-derived growth factor receptor ⁇ (PDGFR ⁇ ), platelet-derived growth factor receptor ⁇ (PDGFR ⁇ ), and the like.
  • Examples of Raf include A-Raf, B-Raf, C-Raf and the like.
  • the kinase is preferably vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), Raf, or c-Met.
  • kinases include TIE2, fibroblast growth factor receptor (FGFR), stem cell factor receptor (c-Kit), Aurora, CDK, MEK, Akt, ERK, MAPK, Src, epidermal growth factor receptor ( EGFR), epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor 4 (HER4), Abl, Fgr, Fms, Flt3, Ron, Ret, Eph and the like.
  • FGFR fibroblast growth factor receptor
  • c-Kit stem cell factor receptor
  • Aurora CDK
  • MEK Akt
  • ERK MAPK
  • Src epidermal growth factor receptor
  • EGFR epidermal growth factor receptor 2
  • HER4 epidermal growth factor receptor 4
  • Abl Fgr, Fms, Flt3, Ron, Ret, Eph and the like.
  • the vascular endothelial growth factor receptor 2 (VEGFR2) inhibitory activity of the compound of the present invention is in accordance with Test Example 1
  • the vascular endothelial cell growth inhibitory activity is in accordance with Test Example 2
  • hepatocyte growth factor receptor vascular endothelial growth factor receptor 2 (C-Met) inhibitory activity
  • C-Met C-Met inhibitory activity
  • human gastric cancer cell MKN45 growth inhibitory activity according to Test Example 4 can be measured according to Test Example 5.
  • the compound of the present invention exhibits a strong inhibitory activity especially against the vascular endothelial growth factor receptor (VEGFR), among which the selectivity for the vascular endothelial growth factor receptor 2 (VEGFR2, KDR, Flk-1) is high, It also shows strong kinase inhibitory activity against VEGFR1, PDGFR, and Raf.
  • the compound of the present invention exhibits a strong inhibitory action on hepatocyte growth factor receptor (c-Met).
  • the compound of the present invention has a medicinal effect, pharmacokinetics (absorbability, distribution, metabolism, excretion, etc.), solubility (water solubility, etc.), interaction with other pharmaceuticals, safety (acute toxicity, chronic toxicity, Genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, etc.) and stability (chemical stability, stability to enzymes, etc.) are also excellent and useful as pharmaceuticals.
  • the compound of the present invention is a kinase inhibitor, preferably a vascular endothelial growth factor receptor, for mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.). It is useful as a (VEGFR) inhibitor, a platelet derived growth factor receptor (PDGFR) inhibitor, a Raf inhibitor, more preferably a vascular endothelial growth factor receptor 2 (VEGFR2, KDR, Flk-1) inhibitor.
  • the compounds of the present invention are useful as angiogenesis inhibitors and vascular endothelial cell growth inhibitors.
  • the compounds of the present invention can be affected by vascular endothelial growth factors such as cancer (eg, colon cancer (eg, familial colon cancer, hereditary nonpolyposis colon cancer, gastrointestinal stromal tumor, etc.) , Lung cancer (eg, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, etc.), mesothelioma, pancreatic cancer (eg, pancreatic duct cancer, etc.), gastric cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous epithelium) Cancer), breast cancer (eg, invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer, etc.), ovarian cancer (eg, epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovary Low-grade tumors), prostate cancer (eg, hormone-dependent prostate cancer, hormone-independent prostate
  • the compounds of the present invention are effective against patients with lung cancer, colon cancer, ovarian cancer, prostate cancer, and kidney cancer. Further, the compound of the present invention exhibits a cancer invasion / metastasis suppression action based on a strong c-Met inhibitory action.
  • the compound of the present invention can be administered orally or parenterally as it is or in combination with a pharmacologically acceptable carrier.
  • dosage forms for oral administration of the compound of the present invention include tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules and microcapsules), and syrups.
  • dosage forms for parenteral administration include injections, infusions, drops, suppositories, and the like.
  • an appropriate base eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, a mixture of butyric acid polymer and glycolic acid polymer, polyglycerol fatty acid ester, etc. It is also effective to make a combined sustained-release preparation.
  • the compound of the present invention when the compound of the present invention is produced into tablets, it can be produced by containing excipients, binders, disintegrants, lubricants, etc., and when produced into pills and granules. , Excipients, binders, disintegrants and the like.
  • excipients, binders, disintegrants and the like when producing powders and capsules, excipients, etc., when producing syrups, sweeteners, etc., when producing emulsions or suspensions, suspending agents, surfactants It can be produced by containing an emulsifier and the like.
  • excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate and the like.
  • binder examples include 5 to 10% by weight starch paste solution, 10 to 20% by weight gum arabic solution or gelatin solution, 1 to 5% by weight tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, glycerin and the like.
  • disintegrant include starch and calcium carbonate.
  • the lubricant include magnesium stearate, stearic acid, calcium stearate, purified talc and the like.
  • sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like.
  • surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyl 40 stearate and the like.
  • suspending agent include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, bentonite and the like.
  • emulsifiers include gum arabic, tragacanth, gelatin, polysorbate 80 and the like.
  • intravenous injections In addition to intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, intravenous infusions and the like are included as injections, and iontophoretic transdermal agents and the like are included as sustained-release preparations.
  • Such an injection is prepared by a method known per se, that is, by dissolving, suspending or emulsifying the compound of the present invention in a sterile aqueous or oily liquid.
  • Aqueous solutions for injection include isotonic solutions (eg, D-sorbitol, D-mannitol, sodium chloride, etc.) containing physiological saline, glucose and other adjuvants, and suitable solubilizing agents such as You may use together with alcohol (for example, ethanol), polyalcohol (for example, propylene glycol, polyethylene glycol), a nonionic surfactant (for example, polysorbate 80, HCO-50), etc.
  • the oily liquid include sesame oil and soybean oil.
  • benzyl benzoate As a solubilizing agent, benzyl benzoate, benzyl alcohol and the like may be used in combination. Buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), preservatives (For example, benzyl alcohol, phenol, etc.) may be blended.
  • the prepared injection solution is usually filled in an ampoule.
  • the content of the compound of the present invention in the preparation of the present invention varies depending on the form of the preparation, but is generally about 0.01 to 100% by weight, preferably about 2 to 85% by weight, based on the whole preparation, Preferably, it is about 5 to 70% by weight.
  • the content of the additive in the preparation of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.9% by weight, preferably about 10 to 90% by weight, based on the whole preparation.
  • the compound of the present invention can be safely used with stable, low toxicity.
  • the daily dose varies depending on the patient's condition and body weight, the type of compound, the route of administration, etc.
  • the daily dose for an adult (body weight of about 60 kg) Is about 1 to 1000 mg, preferably about 3 to 300 mg, more preferably about 10 to 200 mg as an active ingredient (compound of the present invention), and these can be administered once or divided into 2 to 3 times. .
  • the compound of the present invention When the compound of the present invention is administered parenterally, it is usually administered in the form of a liquid (for example, an injection).
  • a liquid for example, an injection.
  • the single dose varies depending on the administration subject, target organ, symptom, administration method and the like, but is usually about 0.01 to about 100 mg per kg body weight, preferably about 0.01 in the form of injection. It is convenient to administer from about 50 mg, more preferably from about 0.01 to about 20 mg by intravenous injection.
  • the compound of the present invention can be used in combination with other drugs.
  • the compounds of the present invention can be used in combination with drugs such as hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents or drugs that inhibit the action of cell growth factors and their receptors.
  • drugs such as hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents or drugs that inhibit the action of cell growth factors and their receptors.
  • a drug that can be used in combination with the compound of the present invention is abbreviated as a concomitant drug.
  • ⁇ hormone therapeutic agent '' examples include phosfestol, diethylstilbestrol, chlorotrianicene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, Raloxifene, olmeroxifene, levormeroxifene, antiestrogens (eg, tamoxifen citrate, toremifene citrate, etc.), pill formulations, mepithiostan, testrolactone, aminoglutethimide, LH-RH agonists (eg, goserelin acetate, Buserelin, leuprorelin, etc.), droloxifene, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitor (eg, fadrozo
  • chemotherapeutic agent for example, alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents and the like are used.
  • alkylating agent examples include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitoblonitol, Faran, dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine, streptozocin, piprobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambermuthine, dibrospine hydrochloride, fotemustine hydrochloride Predonimustine, pumitepa, ribomustine, temozolomide, treosulphane, trophosphamide Zinostatin Lamar, ado
  • antimetabolite examples include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enositabine, cytarabine, cytarabine okphosphatate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, doxyfluridine, carmofur, galocitabine, emiteful, capecitabine, etc.), aminopterin, nerzarabine, leucovorin calcium, tabloid, butosine, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine pendant, hydroxycarbamide pendant , Idoxyuridine, mitoguazone, thiazofurin, ambamustine, bendamustine and those DDS formulation or the like is used.
  • 5-FU drugs eg, fluorouracil, tegafur, UFT,
  • anticancer antibiotic examples include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride , Neocartinostatin, misramycin, sarcomycin, carcinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and their DDS preparations.
  • plant-derived anticancer agent for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine and their DDS preparations are used.
  • Examples of the “immunotherapy agent (BRM)” include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacteria Umparbum, levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody and the like are used.
  • the “cell growth factor” in the “drug that inhibits the action of the cell growth factor and its receptor” may be any substance that promotes cell growth, and usually has a molecular weight of 20,000 or less.
  • Examples of peptides include factors that exert an action at a low concentration by binding to a receptor.
  • EGF epidermal growth factor
  • IGF insulin, IGF (insulin-like growth factor) -1, IGF-2, etc.
  • FGF fibroblast growth factor
  • Other cell growth factors eg, CSF (erythropoietin), EPO (erythropoietin), IL-2 (interleukin-2) , NGF (near growth factor), PDGF (platelet-derived growth factor), TGF ⁇ (transforming growth factor ⁇ ), HGF (hepatocyte growth factor, thor factor).
  • the “cell growth factor receptor” may be any receptor capable of binding to the above-mentioned cell growth factor. Specifically, EGF receptor, heregulin receptor (HER3, etc.) Insulin receptor, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, VEGF receptor, angiopoietin receptor (Tie2, etc.), PDGF receptor and the like are used.
  • “Agents that inhibit the action of cell growth factors and their receptors” include EGF inhibitors, TGF ⁇ inhibitors, heregulin inhibitors, insulin inhibitors, IGF inhibitors, FGF inhibitors, KGF inhibitors, CSF inhibitors, EPO inhibitor, IL-2 inhibitor, NGF inhibitor, PDGF inhibitor, TGF ⁇ inhibitor, HGF inhibitor, VEGF inhibitor, angiopoietin inhibitor, EGF receptor inhibitor, HER2 inhibitor, HER4 inhibitor, insulin receptor Body, IGF-1 receptor inhibitor, IGF-2 receptor inhibitor, FGF receptor-1 inhibitor, FGF receptor-2 inhibitor, FGF receptor-3 inhibitor, FGF receptor-4 inhibitor , VEGF receptor inhibitor, Tie-2 inhibitor, PDGF receptor inhibitor, Abl inhibitor, Raf inhibitor, FLT3 inhibitor, c-Kit inhibitor, Src Inhibitor, PKC inhibitor, Trk inhibitor, Ret inhibitor, mTOR inhibitor, Aurora inhibitor, PLK inhibitor, MEK (MEK1 / 2) inhibitor, c-Met inhibitor, CDK inhibitor, Akt inhibitor, An ER
  • anti-VEGF antibody Bevacizumab etc.
  • anti-HER2 antibody Trastuzumab, Pertuzumab etc.
  • anti-EGFR antibody Cetuximab, Panitumab, Matusumumab, Nimotozumab etc.
  • anti-VEGFR antibody Ehtitinb
  • anti-HGFb antibody EHtibb
  • Gefitinib Gefitinib
  • Sorafenib Sunitinib
  • Dasatinib Lapatinib, Vatalanib
  • the compound of the present invention By combining the compound of the present invention and a concomitant drug, (1) The dose can be reduced compared to when the compound of the present invention or the concomitant drug is administered alone. (2) Depending on the patient's symptoms (mild, severe, etc.), a drug to be used in combination with the compound of the present invention can be selected. (3) The treatment period can be set longer. (4) The therapeutic effect can be sustained. (5) By using the compound of the present invention in combination with a concomitant drug, excellent effects such as a synergistic effect can be obtained.
  • the concomitant drug of the present invention the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously to the administration subject, with a time difference. May also be administered.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • Examples of the dosage form when the compound of the present invention is used in combination with the concomitant drug include, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and (2) Simultaneous administration of the two preparations obtained by separately formulating the compound and the concomitant drug by the same route of administration, (3) Two preparations obtained by separately formulating the compound of the present invention and the concomitant drug Administration at the same administration route with a time difference, (4) simultaneous administration of two different preparations obtained by separately formulating the compound of the present invention and a concomitant drug by different administration routes, (5) Administration of two types of preparations obtained by separately formulating the compound and the concomitant drug at different time intervals in different administration routes (for example, administration in the order of the compound of the present invention ⁇ the concomitant drug, or in the reverse order) Administration).
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like.
  • the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
  • the concomitant drug of the present invention has low toxicity.
  • the compound of the present invention or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se, for example, a pharmaceutical composition such as a tablet.
  • a pharmaceutical composition such as a tablet.
  • a pharmaceutical composition such as a tablet.
  • powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, etc., orally or parenterally (eg, Topical, rectal, intravenous administration, etc.) can be safely administered.
  • the injection can be administered intravenously, intramuscularly, subcutaneously, or into an organ, or directly to the lesion.
  • the pharmacologically acceptable carrier that may be used for the production of the concomitant drug of the present invention is the same as the pharmacologically acceptable carrier that may be used for the production of the pharmaceutical of the present invention described above. Is given. Further, if necessary, an appropriate amount of additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like that may be used in the production of the medicament of the present invention described above may be appropriately used. it can.
  • the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation. More preferably, it is about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 90% by weight, preferably about 0.1 to 50% by weight, more preferably based on the whole preparation. About 0.5 to 20% by weight.
  • the content of the additive in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. Further, when the compound of the present invention and the concomitant drug are formulated separately, the same content may be used.
  • the compound of the present invention or the concomitant drug includes a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose.
  • a dispersant eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose.
  • solubilizers eg, glycerin, ethanol, etc.
  • buffers eg, Phosphoric acid and alkali metal salts thereof, citric acid and alkali metal salts thereof, isotonic agents (eg, sodium chloride, potassium chloride, mannitol, sorbitol, glucose, etc.), pH regulators (eg, hydrochloric acid, sodium hydroxide) Etc.), preservatives (eg, ethyl paraoxybenzoate, benzoic acid, Ruparaben, propylparaben, benzyl alcohol, etc.), solubilizers (eg, concentrated glycerin, meglumine, etc.), solubilizers (eg, propylene glycol, sucrose, etc.), soothing agents (eg
  • an excipient eg, lactose, sucrose, starch, etc.
  • a disintegrant eg, starch, calcium carbonate, etc.
  • a binder eg, Starch, gum arabic, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, etc.
  • lubricant eg, talc, magnesium stearate, polyethylene glycol 6000, etc.
  • an oral preparation can be obtained by coating by a method known per se.
  • Examples of the coating agent used for coating include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (manufactured by Rohm, Germany, methacrylic acid / acrylic acid copolymer) and pigments (eg, Bengala, titanium dioxide, etc.) are used.
  • the preparation for oral administration may be either an immediate release preparation or a sustained release preparation.
  • the compound of the present invention or the concomitant drug is mixed with an oily base, an aqueous base or an aqueous gel base to give an oily or aqueous solid, semisolid or liquid suppository.
  • oily base include glycerides of higher fatty acids (eg, cacao butter, witepsols (manufactured by Dynamite Nobel, Germany)), glycerides of medium chain fatty acids [eg, miglyols (manufactured by Dynamite Nobel, Germany)] Etc.], or vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.).
  • the aqueous base include polyethylene glycols and propylene glycol.
  • the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers, and the like.
  • sustained-release preparation examples include sustained-release microcapsules.
  • the sustained-release microcapsule is produced according to a method known per se, for example, the method shown in the following [2].
  • the compound of the present invention is preferably molded into a preparation for oral administration such as a solid preparation (eg, powder, granule, tablet, capsule) or into a preparation for rectal administration such as a suppository. Particularly preferred are preparations for oral administration.
  • a preparation for oral administration such as a solid preparation (eg, powder, granule, tablet, capsule) or into a preparation for rectal administration such as a suppository.
  • preparations for oral administration are particularly preferred.
  • the concomitant drug can be in the above-mentioned dosage form depending on the type of drug.
  • injection and preparation thereof An injection prepared by dissolving the compound of the present invention or the concomitant drug in water is preferable.
  • the injection may contain benzoate and / or salicylate.
  • the injection is obtained by dissolving both the compound of the present invention or the concomitant drug and, optionally, a benzoate and / or salicylate in water.
  • benzoic acid and salicylic acid salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, meglumine salts, and salts with other organic bases such as trometamol. It is done.
  • the concentration of the compound of the present invention or the concomitant drug in the injection is 0.5 to 50 w / v%, preferably about 3 to 20 w / v%.
  • the concentration of benzoate or / and salicylate is about 0.5 to 50 w / v%, preferably about 3 to 20 w / v%.
  • the present injection includes additives generally used in injections, such as stabilizers (eg, ascorbic acid, sodium pyrosulfite), surfactants (eg, polysorbate 80, macrogol, etc.), acceptable Solvent (eg, glycerin, ethanol, etc.), buffer (eg, phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), isotonic agents (eg, sodium chloride, potassium chloride, etc.), dispersing agents (Eg, hydroxypropylmethylcellulose, dextrin), pH adjuster (eg, hydrochloric acid, sodium hydroxide, etc.), preservative (eg, ethyl paraoxybenzoate, benzoic acid, etc.), solubilizer (eg, concentrated glycerin, meglumine, etc.) , Solubilizers (eg, propylene glycol, sucrose, etc.), soothing agents (eg, glucose, benzyl alcohol, etc.),
  • the injection may be adjusted to pH 2 to 12, preferably pH 2.5 to 8.0 by adding a pH adjusting agent.
  • An injection is obtained by dissolving both the compound of the present invention or the concomitant drug and optionally a benzoate and / or salicylate, and if necessary, the above additives in water. These dissolutions may be performed in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injection.
  • the aqueous solution for injection is preferably heated, and can be provided as an injection by performing, for example, filtration sterilization, high-pressure heat sterilization, or the like, as in a normal injection.
  • the aqueous solution for injection is preferably sterilized by high-pressure heat at a temperature of 100 to 121 ° C. for 5 to 30 minutes. Furthermore, it is good also as a formulation which provided the antibacterial property of the solution so that it could be used as a multi-dose administration formulation.
  • Sustained-release preparation or immediate-release preparation and preparation thereof Sustained-release preparation comprising a core containing the compound of the present invention or a concomitant drug optionally coated with a coating agent such as a water-insoluble substance or a swellable polymer Is preferred.
  • a coating agent such as a water-insoluble substance or a swellable polymer
  • a once-daily administration type sustained-release preparation for oral administration is preferred.
  • water-insoluble substances used in the coating agent include cellulose ethers such as ethyl cellulose and butyl cellulose, cellulose esters such as cellulose acetate and cellulose propionate, polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate, and acrylic acid.
  • cellulose ethers such as ethyl cellulose and butyl cellulose
  • cellulose esters such as cellulose acetate and cellulose propionate
  • polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate
  • acrylic acid acrylic acid
  • swellable polymer a polymer having an acidic dissociation group and exhibiting pH-dependent swelling is preferable. Swelling is small in an acidic region such as the stomach, and swelling is large in a neutral region such as the small intestine and large intestine.
  • a polymer having an acidic dissociation group is preferred.
  • the polymer having an acidic dissociable group and exhibiting pH-dependent swelling include, for example, Carbomer 934P, 940, 941, 974P, 980, 1342, polycarbophil, calcium polycarbophil, and the like. (Calcium polycarbophil) (all of which are manufactured by BF Goodrich), Hibiswako 103, 104, 105, 304 (all of which are manufactured by Wako Pure Chemical Industries, Ltd.), etc.
  • the film agent used in the sustained release preparation may further contain a hydrophilic substance.
  • the hydrophilic substance include polysaccharides that may have a sulfate group such as pullulan, dextrin, and alkali metal alginate, hydroxyalkyl or carboxyalkyl such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose sodium.
  • examples thereof include polysaccharides, methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, and polyethylene glycol.
  • the content of the water-insoluble substance in the coating agent of the sustained-release preparation is about 30 to about 90% (w / w), preferably about 35 to about 80% (w / w), more preferably about 40 to about 75. % (W / w) and the swellable polymer content is from about 3 to about 30% (w / w), preferably from about 3 to about 15% (w / w).
  • the coating agent may further contain a hydrophilic substance, in which case the content of the hydrophilic substance in the coating agent is about 50% (w / w) or less, preferably about 5 to about 40% (w / w). More preferably, it is about 5 to about 35% (w / w).
  • the above% (w / w) represents the weight% with respect to the coating agent composition obtained by removing the solvent (eg, water, lower alcohol such as methanol, ethanol, etc.) from the coating agent solution.
  • the sustained-release preparation is prepared by preparing a core containing a drug as exemplified below, and then coating the obtained core with a film agent solution in which a water-insoluble substance or a swellable polymer is dissolved by heating or dissolved or dispersed in a solvent. Manufactured by coating.
  • nucleus containing a drug coated with a film agent is not particularly limited, but is preferably formed into a granular shape such as a granule or a fine granule.
  • the average particle size is preferably about 150 to about 2,000 ⁇ m, more preferably about 500 to about 1,400 ⁇ m.
  • the preparation of the nucleus can be carried out by a usual production method. For example, suitable excipients, binders, disintegrants, lubricants, anti-aggregation agents, lubricants, stabilizers, etc.
  • the drug content of the nucleus is about 0.5 to about 95% (w / w), preferably about 5.0 to about 80% (w / w), more preferably about 30 to about 70% (w / w) It is.
  • excipients contained in the core include saccharides such as sucrose, lactose, mannitol, glucose, starch, crystalline cellulose, calcium phosphate, corn starch and the like. Of these, crystalline cellulose and corn starch are preferable.
  • binder for example, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, pluronic F68, gum arabic, gelatin, starch and the like are used.
  • disintegrant for example, carboxymethylcellulose calcium (ECG505), croscarmellose sodium (Ac-Di-Sol), cross-linked polyvinyl pyrrolidone (crospovidone), low substituted hydroxypropylcellulose (L-HPC) and the like are used. . Of these, hydroxypropylcellulose, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose are preferable.
  • talc magnesium stearate and an inorganic salt thereof, and polyethylene glycol or the like as a lubricant
  • polyethylene glycol or the like polyethylene glycol or the like
  • acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used.
  • the core is a drug while spraying a binder dissolved in an appropriate solvent such as water, lower alcohol (eg, methanol, ethanol, etc.) on an inert carrier particle that becomes the center of the core.
  • an appropriate solvent such as water, lower alcohol (eg, methanol, ethanol, etc.)
  • it can also be prepared by a rolling granulation method, a pan coating method, a fluidized bed coating method or a melt granulation method in which a mixture of this and an excipient, a lubricant or the like is added little by little.
  • the inert carrier particles for example, those made of sucrose, lactose, starch, crystalline cellulose, waxes can be used, and those having an average particle size of about 100 ⁇ m to about 1,500 ⁇ m are preferable.
  • the surface of the nucleus may be coated with a protective agent.
  • the protective agent for example, the hydrophilic substance, the water-insoluble substance, or the like is used.
  • the protective agent is preferably a polysaccharide having polyethylene glycol or hydroxyalkyl or carboxyalkyl, more preferably hydroxypropylmethylcellulose or hydroxypropylcellulose.
  • the protective agent may contain an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid or a lubricant such as talc as a stabilizer.
  • the coating amount is about 1 to about 15% (w / w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% of the core ( w / w).
  • the protective agent can be coated by a normal coating method, and specifically, the protective agent can be coated by spraying the nucleus by, for example, a fluidized bed coating method or a pan coating method.
  • the core obtained in the above I is coated with a coating agent solution in which the water-insoluble substance, the pH-dependent swelling polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent.
  • a sustained-release preparation is produced.
  • the coating method using the core coating solution include a spray coating method.
  • the composition ratio of the water-insoluble substance, the swellable polymer, or the hydrophilic substance in the coating agent solution is appropriately selected so that the content of each component in the film is the above content.
  • the coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w) with respect to the core (excluding the coating amount of the protective agent), more preferably About 5 to about 35% (w / w).
  • water or an organic solvent can be used alone or a mixture of the two can be used.
  • the mixing ratio of water and organic solvent (water / organic solvent: weight ratio) in the case of using the mixed liquid can be varied in the range of 1 to 100%, preferably 1 to about 30%.
  • the organic solvent is not particularly limited as long as it dissolves water-insoluble substances.
  • lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and n-butyl alcohol, lower alkanones such as acetone, acetonitrile, chloroform , Methylene chloride and the like are used. Of these, lower alcohols are preferred, and ethyl alcohol and isopropyl alcohol are particularly preferred.
  • Water and a mixed solution of water and an organic solvent are preferably used as a solvent for the film agent.
  • an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid, etc. may be added to the coating agent solution to stabilize the coating agent solution.
  • the operation in the case of coating by spray coating can be carried out by a normal coating method, specifically, by coating the core with a film agent solution, for example, by a fluidized bed coating method, pan coating method or the like. can do. If necessary, plasticize glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol, etc., using talc, titanium oxide, magnesium stearate, calcium stearate, light anhydrous silicic acid as a lubricant. You may add as an agent. After coating with a coating agent, an antistatic agent such as talc may be mixed as necessary.
  • the immediate-release preparation may be liquid (solution, suspension, emulsion, etc.) or solid (particles, pills, tablets, etc.).
  • a parenterally administered agent such as an orally administered agent and an injectable agent is used, and an orally administered agent is preferable.
  • the immediate-release preparation usually contains a carrier, an additive or an excipient (hereinafter sometimes abbreviated as an excipient) commonly used in the pharmaceutical field in addition to the drug as the active ingredient.
  • the excipient used is not particularly limited as long as it is an excipient commonly used as a pharmaceutical excipient.
  • excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (Asahi Kasei Co., Ltd., Avicel PH101, etc.), powdered sugar, granulated sugar, mannitol, light anhydrous silicic acid, magnesium carbonate, carbonate Calcium, L-cysteine and the like can be mentioned, preferably corn starch and mannitol.
  • excipients can be used alone or in combination of two or more.
  • the content of the excipient is, for example, about 4.5 to about 99.4 w / w%, preferably about 20 to about 98.5 w / w%, more preferably about 30, relative to the total amount of the immediate-release preparation. Or about 97 w / w%.
  • the content of the drug in the immediate release preparation can be appropriately selected from the range of about 0.5 to about 95 w / w%, preferably about 1 to about 60 w / w%, based on the total amount of the immediate release preparation.
  • the immediate-release preparation When the immediate-release preparation is an oral solid preparation, it usually contains a disintegrant in addition to the above components.
  • disintegrants include carboxymethylcellulose calcium (manufactured by Gotoku Pharmaceutical Co., ECG-505), croscarmellose sodium (for example, Asahi Kasei Co., Ltd., Akizol), crospovidone (for example, BASF Corp., Kollidon CL ), Low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (manufactured by Matsutani Chemical Co., Ltd.), sodium carboxymethyl starch (manufactured by Kimura Sangyo Co., Ltd., Protab), partially pregelatinized starch (Asahi Kasei ( Co., Ltd., PCS), etc.
  • disintegrants are used, for example, those that disintegrate granules by contacting with water, absorbing water, swelling, or creating channels between the active ingredient constituting the core and excipients. Can be used. These disintegrants can be used alone or in combination of two or more. The amount of the disintegrant is appropriately selected depending on the type and amount of the drug to be used, the design of the releasable preparation, and the like. For example, about 0.05 to about 30 w / w%, Preferably, it is about 0.5 to about 15 w / w%.
  • an additive commonly used in the solid preparation may be further included as desired.
  • additives include binders (for example, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, pullulan, dextrin, etc.), lubricants ( For example, polyethylene glycol, magnesium stearate, talc, light anhydrous silicic acid (for example, Aerosil (manufactured by Nippon Aerosil)), surfactant (for example, anionic surfactant such as sodium alkyl sulfate, polyoxyethylene fatty acid ester and poly Non-ionic surfactants such as oxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, etc.), colorants (eg tar dyes, caramel, bengara, titanium oxide, riboflavins),
  • binder hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone and the like are preferably used.
  • the immediate-release preparation can be prepared by mixing the above-mentioned components, further kneading and molding if necessary, based on a normal preparation manufacturing technique.
  • the above mixing is performed by a generally used method, for example, mixing, kneading and the like.
  • a vertical granulator when the immediate-release preparation is formed into particles, a vertical granulator, a universal kneader (manufactured by Hata Iron Works), by a method similar to the preparation method of the core of the sustained-release preparation, It can be prepared by mixing using a fluidized bed granulator FD-5S (manufactured by POWREC) or the like and then granulating by a wet extrusion granulation method, a fluidized bed granulation method or the like.
  • FD-5S manufactured by POWREC
  • the immediate-release preparation and the sustained-release preparation thus obtained are administered as they are or as appropriate, together with preparation excipients, etc., separately according to a conventional method, and then simultaneously or in combination with an arbitrary administration interval.
  • both of them may be formulated into a single oral preparation (eg, granules, fine granules, tablets, capsules, etc.) as they are or as appropriate together with formulation excipients.
  • Both preparations may be produced into granules or fine granules and filled in the same capsule or the like to prepare a preparation for oral administration.
  • Sublingual tablet, buccal or intraoral quick disintegrating agent and preparation thereof may be a solid preparation such as a tablet, or an oral mucosal patch (film) It may be.
  • a preparation containing the compound of the present invention or the concomitant drug and an excipient is preferable. Further, it may contain auxiliary agents such as a lubricant, an isotonic agent, a hydrophilic carrier, a water-dispersible polymer, and a stabilizer.
  • ⁇ -cyclodextrin or ⁇ -cyclodextrin derivatives may be contained in order to facilitate absorption and increase bioavailability.
  • Examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, and light anhydrous silicic acid.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like, and magnesium stearate and colloidal silica are particularly preferable.
  • Examples of the isotonic agent include sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, urea and the like, and mannitol is particularly preferable.
  • hydrophilic carrier examples include swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, cross-linkable polyvinyl pyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, calcium carbonate, and particularly crystalline cellulose (eg, microcrystalline cellulose, etc. ) Is preferred.
  • swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, cross-linkable polyvinyl pyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, calcium carbonate, and particularly crystalline cellulose (eg, microcrystalline cellulose, etc. ) Is preferred.
  • water-dispersible polymers examples include gums (eg, tragacanth gum, acacia gum, guar gum), alginates (eg, sodium alginate), cellulose derivatives (eg, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), Gelatin, water-soluble starch, polyacrylic acid (eg, carbomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinyl pyrrolidone, polycarbophil, ascorbic acid, palmitate, etc., hydroxypropyl methylcellulose, polyacrylic acid, Alginate, gelatin, carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol and the like are preferable.
  • gums eg, tragacanth gum, acacia gum, guar gum
  • alginates eg, sodium alginate
  • cellulose derivatives eg, methylcellulose, carboxymethylcellulose, hydroxy
  • Hydroxypropyl methylcellulose is particularly preferable.
  • the stabilizer include cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite and the like, and citric acid and ascorbic acid are particularly preferable.
  • a sublingual tablet, buccal or intraoral quick disintegrating agent can be produced by mixing the compound of the present invention or the concomitant drug and an excipient by a method known per se.
  • auxiliary agents such as the above-mentioned lubricants, tonicity agents, hydrophilic carriers, water-dispersible polymers, stabilizers, colorants, sweeteners, preservatives and the like may be mixed as desired.
  • a sublingual tablet, a buccal tablet or an intraoral quick disintegrating tablet is obtained by compression tableting.
  • it may be produced by humidifying and wetting with a solvent such as water or alcohol as necessary before and after the tableting molding process, and drying after molding.
  • Bioadhesive polymers eg, polycarbophil, carbopol, etc. are added to increase the adhesion of the film to the mucosal lining of the oral cavity and to contain glycols such as polyethylene glycol and propylene glycol to give the film moderate elasticity.
  • Casting is performed by pouring the solution onto a non-adhesive surface, spreading it to a uniform thickness (preferably about 10 to 1000 microns) with an application tool such as a doctor blade, and then drying the solution to form a film. Achieved.
  • the film thus formed may be dried at room temperature or under heating and cut to a desired surface area.
  • Preferred intraoral quick disintegrating agents include solid rapid diffusion administration comprising a network of a compound of the present invention or a concomitant drug and a water-soluble or water-diffusible carrier that is inactive with the compound of the present invention or the concomitant drug.
  • Agents. The network is obtained by sublimating a solvent from the solid composition composed of a solution of the compound of the present invention or the concomitant drug in a suitable solvent.
  • composition of the intraoral quick disintegrating agent preferably contains a matrix forming agent and a secondary component.
  • Examples of the matrix forming agent include gelatins, dextrins, and animal or vegetable proteins such as soybean, wheat and psyllium seed proteins; gums such as gum arabic, guar gum, agar and xanthan; Examples include sugars, alginic acids, carboxymethylcelluloses, carrageenans, dextrans, pectins, synthetic polymers such as polyvinylpyrrolidone, gelatin-gum arabic complex, and the like.
  • sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic saccharides such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate; glycine, L-alanine, L-aspartic acid, L- Examples include amino acids having 2 to 12 carbon atoms such as glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine.
  • One or more of the matrix forming agents can be introduced into a solution or suspension before solidification.
  • a matrix forming agent may be present in addition to the surfactant, or may be present with the surfactant excluded.
  • the matrix-forming agent can help maintain the diffusion state of the compound of the invention or the concomitant drug in the solution or suspension.
  • Suitable colorants include red, black and yellow iron oxides and FD & C dyes such as FD & C Blue 2 and FD & C Red 40 from Ellis & Everald.
  • Suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavor and combinations thereof.
  • Suitable pH adjusting agents include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid.
  • Suitable sweeteners include aspartame, acesulfame K, thaumatin and the like.
  • Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbate materials, and microencapsulated apomorphine.
  • the preparation usually contains about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight of a compound of the present invention or a concomitant drug, and is about 1 to about 60 minutes, preferably about 1
  • a preparation capable of dissolving 90% or more of the compound of the present invention or the concomitant drug (in water) between about 2 minutes and about 15 minutes, more preferably between about 2 minutes and about 5 minutes (in the above sublingual tablets) , Buccals, etc.) and intraoral fast disintegrating agents that disintegrate within 1 to 60 seconds, preferably within 1 to 30 seconds, more preferably within 1 to 10 seconds after being placed in the oral cavity are preferred.
  • the content of the above-mentioned excipient in the whole preparation is about 10 to about 99% by weight, preferably about 30 to about 90% by weight.
  • the content of ⁇ -cyclodextrin or ⁇ -cyclodextrin derivative in the whole preparation is 0 to about 30% by weight.
  • the content of the lubricant in the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight.
  • the content of the tonicity agent in the whole preparation is about 0.1 to about 90% by weight, preferably about 10 to about 70% by weight.
  • the content of the hydrophilic carrier in the whole preparation is about 0.1 to about 50% by weight, preferably about 10 to about 30% by weight.
  • the content of the water-dispersible polymer in the whole preparation is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight.
  • the content of the stabilizer in the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight.
  • the above-mentioned preparation may further contain additives such as a coloring agent, a sweetening agent, and a preservative as necessary.
  • the dose of the concomitant drug of the present invention varies depending on the type, age, weight, symptom, dosage form, administration method, administration period, etc. of the compound of the present invention.
  • the compound of the present invention and the concomitant drug are each about 0.01 to about 1000 mg / kg body weight, preferably about 0.01 to about 100 mg / kg body weight, more preferably about 0.1 to about 100 mg / kg per day.
  • the dosage varies depending on various conditions. Therefore, a dosage smaller than the dosage may be sufficient, or the dosage may need to be administered beyond the range.
  • the amount of the concomitant drug can be set as long as side effects do not become a problem.
  • the daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, body weight, sensitivity difference, timing of administration, interval, nature of pharmaceutical preparation, formulation, type, type of active ingredient, etc. Although it is not limited, the amount of the drug is usually about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg per kg body weight of the patient by oral administration. The dose is usually divided into 1 to 4 times a day.
  • the compound of the present invention and the concomitant drug may be administered at the same time, but after the concomitant drug is administered first, the compound of the present invention may be administered.
  • the compound of the present invention may be administered first, followed by administration of the concomitant drug.
  • the time difference varies depending on the active ingredient to be administered, dosage form, and administration method.
  • the concomitant drug when administered first, within 1 minute to 3 days after administering the concomitant drug, preferably A method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour is mentioned.
  • the concomitant drug is administered within 1 minute to 1 day after administration of the compound of the present invention, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour. A method is mentioned.
  • a concomitant drug molded into an orally administered preparation is orally administered, and about 0.005 of the compound of the present invention formed into an orally administered preparation after about 15 minutes.
  • the compound of the present invention or the concomitant drug of the present invention can be used in combination with non-drug therapy.
  • the compound of the present invention or the concomitant drug of the present invention includes, for example, (1) surgery, (2) pressor chemotherapy using angiotensin II, (3) gene therapy, (4) hyperthermia, (5 It can also be combined with non-drug therapies such as)) cryotherapy, (6) laser ablation, and (7) radiation therapy.
  • treatment with the compound of the present invention or the concomitant drug of the present invention and supportive therapy [(i) antibiotics for concurrent occurrence of various infectious diseases (for example, ⁇ -lactams such as pansporin, macrolides such as clarithromycin, etc. ), (Ii) high calorie infusion for improving nutritional disorders, amino acid preparations, administration of multivitamins, (iii) morphine for pain relief, (iv) nausea, vomiting, loss of appetite, diarrhea, leukocytes Reduction, thrombocytopenia, hemoglobin concentration reduction, hair loss, liver damage, kidney damage, DIC, administration of drugs to improve side effects such as fever, and (v) administration of drugs to suppress multidrug resistance of cancer, etc.] Can also be combined.
  • antibiotics for concurrent occurrence of various infectious diseases for example, ⁇ -lactams such as pansporin, macrolides such as clarithromycin, etc.
  • high calorie infusion for improving nutritional disorders, amino acid preparations, administration of multivitamins
  • the compound of the present invention or the combination of the present invention is administered orally (including sustained release), intravenous (including bolus, infusion, inclusion body), subcutaneous and intramuscular injection (including bolus, infusion, sustained release), transdermal, intratumoral and proximal administration.
  • the timing of administering the compound of the present invention or the concomitant drug of the present invention before surgery or the like can be administered once, for example, about 30 minutes to 24 hours before surgery or the like.
  • the administration can be divided into 1 to 3 cycles before about 3 to 6 months.
  • cancer tissue can be reduced, so that surgery and the like are facilitated.
  • the compound of the present invention or the concomitant drug of the present invention When the compound of the present invention or the concomitant drug of the present invention is administered after surgery or the like, it can be repeatedly administered, for example, in units of several weeks to 3 months, about 30 minutes to 24 hours after surgery. Thus, by administering the compound of the present invention or the concomitant drug of the present invention after surgery or the like, the effect of surgery or the like can be enhanced.
  • Ionization method Electron impact ionization method (Electron Spray Ionization: ESI positive and negative ion peaks are detected) The percentage value of the peak area detected at UV of the corresponding product peak at 220 nm was taken as the purity of the compound.
  • preparative HPLC was performed as follows. Preparative HPLC instrument: Gilson high-throughput purification system Column: YMC Combiprep Hydrosphere C18 S-5 5 ⁇ m, 12 nM.
  • a formulation additive eg, lactose, corn starch, magnesium stearate, microcrystalline cellulose
  • JP 14th revised Japanese Pharmacopoeia
  • a product conforming to the Pharmaceutical Additives Standard 2003 is used.
  • Oxalyl chloride (28 mL, 321 mmol) was added dropwise to a suspension of 2-chloroacetamide (25 g, 267 mmol) in 1,2-dichloroethane (125 mL) at 0 ° C. After refluxing for 3 hours, the mixture was cooled to 0 ° C., tert-butyl alcohol / 1,2-dichloroethane (75 mL, 1/1) was added, and the mixture was stirred for 20 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with 1,2-dichloroethane.
  • N- (6-methoxyimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (6650 mg, 29 mmol) in N, N-dimethylformamide (100 mL) was added to sodium ethanethiolate (6020 mg). , 58 mmol) and the mixture was stirred at 140 ° C. for 5 h. After evaporating the solvent under reduced pressure, ethyl acetate / tetrahydrofuran, saturated brine and 6N aqueous hydrochloric acid were added to the residue, and the aqueous layer was extracted 4 times with ethyl acetate / tetrahydrofuran.
  • N- (6-hydroxyimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (350 mg, 1.6 mmol), 2-bromo-5-nitropyridine (490 mg, 2.4 mmol), cesium carbonate ( A mixture of 1320 mg, 4.0 mmol) and dimethyl sulfoxide (4 mL) was stirred at 70 ° C. for 3 hours. Ethyl acetate / tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the mixture, and the aqueous layer was extracted 4 times with ethyl acetate / tetrahydrofuran.
  • N- (6-Chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (4.16 g, 18 mmol), 6-aminopyridin-3-ol (2.7 g, 24 mmol), cesium carbonate ( 14.3 g, 44 mmol) and dimethyl sulfoxide (40 mL) were stirred at 100 ° C. for 15 hours.
  • Ethyl acetate / tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the mixture, and the aqueous layer was extracted 4 times with ethyl acetate / tetrahydrofuran.
  • 6-chloropyridazine-3-amine (100 mg, 0.772 mmol), N- (2-chloroacetyl) cyclopropanecarboxamide (212 mg, 1.31 mmol), disodium hydrogen phosphate (273 mg, 1.92 mmol), N, N-dimethylacetamide (1 mL) was charged, heated to 100 ° C. and stirred for 4 hours. After adding water (2 mL) at the same temperature, the mixture was cooled to room temperature and stirred for 1 hour. The crystals were collected by filtration, washed with water (1 mL), and dried under reduced pressure to give the title compound (88 mg, 0.372 mmol) as brown crystals.
  • 6-chloropyridazine-3-amine (100 mg, 0.772 mmol), N- (2-bromoacetyl) cyclopropanecarboxamide (270 mg, 1.34 mmol), disodium hydrogen phosphate (273 mg, 1.92 mmol), N, N-dimethylacetamide (1 mL) was charged, heated to 85 ° C. and stirred for 2 hours. After adding water (2 mL) at the same temperature, the mixture was cooled to room temperature and stirred for 0.5 hour. The crystals were collected by filtration, washed with water (1 mL), and dried under reduced pressure to give the title compound (169 mg, 0.714 mmol) as brown crystals.
  • Cyclopropanecarboxamide (790 g, 9.28 mol) was dissolved in N, N-dimethylacetamide (3.0 L). Under ice-cooling, bromoacetyl bromide (1400 g, 6.94 mol) and N, N-dimethylacetamide (0.6 L) were sequentially added, and the mixture was heated to 60 ° C. and stirred for 1 hour. After cooling with ice, tripotassium phosphate (1480 g, 6.97 mol), 6-chloropyridazine-3-amine (600 g, 4.63 mol), N, N-dimethylacetamide (1.2 L) were added in that order, and then 80 Heated to ° C. and stirred for 2 hours.
  • the extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure.
  • the obtained residue was dissolved in tetrahydrofuran (1 mL) and methanol (0.3 mL), lithium hydroxide monohydrate (26.9 mg, 0.641 mmol) was added, and the mixture was stirred at room temperature for 4 hr.
  • the reaction mixture was concentrated, 1N hydrochloric acid (1 mL) and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine.
  • 6-Ethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carbonitrile (395 mg, 1.76 mmol) was dissolved in concentrated sulfuric acid (0.4 mL) and water (0.4 mL) and dissolved at 120 ° C. The mixture was heated and stirred for 7 hours. 1N sodium hydroxide was added to the reaction solution to form a basic solution, and then washed with ethyl acetate. 1N Hydrochloric acid was added to the aqueous layer to make an acidic solution, and the mixture was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated brine.
  • Trifluoromethanesulfonic anhydride is added to a solution of 6- (4-fluorophenyl) -5-methylpyridine-2-carbonitrile (16.76 g, 79 mmol) and sodium percarbonate (24.8 g, 158 mmmol) in acetonitrile (200 mL).
  • the product (66.8 g, 237 mmol) was added dropwise at 0 ° C., stirred at 0 ° C. for 1 hour, and further stirred at room temperature overnight.
  • Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate.
  • N- [6- (4-aminophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide 200 mg, 0.647 mmol
  • N, N-dimethylacetamide 4.0 mL
  • 1 -(Phenylcarbonyl) cyclopropanecarboxylic acid 185 mg, 0.970 mmol
  • O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (369 mg) , 0.970 mmol)
  • N, N-diisopropylethylamine 169 ⁇ L, 0.970 mmol
  • Example 21 N- (6- ⁇ 2-fluoro-4-[(phenylacetyl) amino] phenoxy ⁇ imidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (Example 21-1) and N- [6 -(2-Fluoro-4- ⁇ [(phenylacetyl) carbamothioyl] amino ⁇ phenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (Example 21-2)
  • N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclo Propane carboxamide 200 mg, 0.611 mmol was added and stirred at room temperature for 15 hours.
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, The solvent was distilled off under reduced pressure.
  • the obtained solid was dissolved in ethyl acetate, and the organic layer was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound (121 mg, 38% ) Was obtained as a white solid.
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, The solvent was distilled off under reduced pressure.
  • the obtained white powder was dissolved in tetrahydrofuran and ethyl acetate, washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure.
  • N- [6- (4-amino-3-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide 100 mg, 0.31 mmol
  • N, N-dimethylacetamide 0.5 mL
  • Ethyl acetate was added to the resulting reaction solution, and the mixture was extracted twice with 1N sodium hydroxide. The extract was acidified with 1N hydrochloric acid, and the precipitate was filtered to obtain a white powder.
  • N- [6- (4-amino-3-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide 100 mg, 0.306 mmol
  • N, N -A dimethylacetamide 0.5 mL
  • Ethyl acetate was added to the resulting reaction solution, and the mixture was extracted twice with 1N sodium hydroxide.
  • the extract was acidified with 1N hydrochloric acid, and extracted three times with ethyl acetate.
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • Tetrahydrofuran, ethyl acetate and 1N sodium hydroxide (5 mL) were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, The solvent was distilled off under reduced pressure.
  • the obtained white powder was washed with ethyl acetate to give the title compound (175 mg, 73%) as a white powder.
  • the same operation as in Example 28 was carried out using diisopropylethylamine (201 ⁇ L, 1.4 mmol) and N, N-dimethylformamide (2.0 mL) to obtain the title compound (210 mg, 68%) as a white powder.
  • N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.611 mmol), 1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxylic acid (112 mg, 0.733 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (279 mg, 0.733 mmol), N, N-diisopropylethylamine (211 ⁇ L, 1.22 mmol), N, N-dimethylformamide (2.0 mL), and the same operation as in Example 28 was carried out to give the title compound (204 mg, 72% ) Was obtained as a white powder.
  • N- [6- (4-Amino-2-methylphenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (80 mg, 0.247 mmol), 2-oxo-1-phenyl-1, 2-dihydropyridine-3-carboxylic acid (69 mg, 0.321 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (122 mg, 0.320 mmol), N, N-diisopropylethylamine (85 ⁇ L, 0.494 mmol), N, N-dimethylformamide (1.0 mL), and the same operation as in Example 28 was carried out to give the title compound (90 mg, 70% ) Was obtained as a white powder.
  • N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide 200 mg, 0.611 mmol
  • 1-[(phenylcarbonyl) amino] cyclo Propanecarboxylic acid 150 mg, 0.733 mmol
  • O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (279 mg, 0.733 mmol)
  • N , N-diisopropylethylamine (211 ⁇ L, 1.22 mmol) and N, N-dimethylformamide 2.0 mL
  • N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (187 mg, 0.544 mmol), 2-oxo-1-phenylpiperidine-3 -Carboxylic acid (143 mg, 0.652 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (310 mg, 0.815 mmol), N , N-Diisopropylethylamine (187 ⁇ L, 1.09 mmol) and N, N-dimethylformamide (2 mL) were used in the same manner as in Example 28 to give the title compound (150 mg, 52%) as a white powder.
  • 6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (84 mg, 0.367 mmol), N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2 -b] pyridazin-2-yl] cyclopropanecarboxamide (100 mg, 0.306 mmol) in N, N-dimethylformamide (1 mL) and N, N-diisopropylethylamine (105 ⁇ L, 0.612 mmol) and O- ( 7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (140 mg, 0.368 mmol) was added, and the mixture was stirred at room temperature for 6 hours.
  • 6-Phenylpyridine-2-carboxylic acid 1-oxide (79 mg, 0.367 mmol), N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclo
  • propanecarboxamide 100 mg, 0.306 mmol
  • N, N-dimethylformamide (1 mL)
  • N, N-diisopropylethylamine 105 ⁇ L, 0.612 mmol
  • O- (7-azabenzotriazol-1-yl) -1,1,3,3-Tetramethyluronium hexafluorophosphate 140 mg, 0.368 mmol
  • the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
  • the obtained pale yellow powder was washed with ethyl acetate and filtered to give the title compound (150 mg, 7%) as a pale yellow powder.
  • Examples 60 to 123 shown in Tables 1 to 8 were produced in the same manner as in Example 59.
  • N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (100 mg, 0.306 mmol), 1- (2-methylphenyl) -2 -Oxo-1,2-dihydropyridine-3-carboxylic acid (84 mg, 0.367 mmol), N, N-dimethylformamide (1 mL), N, N-diisopropylethylamine (105 ⁇ L, 0.612 mmol), O- (7 -Azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (151 mg, 0.398 mmol) was used for the same operation as in Example 124, and the title compound (134 mg, 81%) was obtained as a white solid.
  • a medicament containing the compound of the present invention as an active ingredient can be produced, for example, according to the following formulation.
  • Tablet (1) Compound obtained in Example 1 40 mg (2) Lactose 58mg (3) Corn starch 18mg (4) Microcrystalline cellulose 3.5mg (5) Magnesium stearate 0.5mg 1 tablet 120mg After mixing 2/3 of (1), (2), (3), (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.
  • VEGFR2 Human Vascular Endothelial Growth Factor Receptor 2
  • VEGFR2 cDNA Library Human Humana
  • PCR was carried out using as a template.
  • the primer used for PCR is based on the VEGFR2 gene base sequence (Genbank Accession AF035121) information, and the flag tag is added to the base sequence encoding the VEGFR2 intracellular domain (2671-4374 in Genbank Access AF035121) at the N-terminus of the protein.
  • VEGFR2-U 5'-AATTAAGTCGACATGGACTACAAGGATGACGATGACAAGAAGCGGGCCAATGGAGGGGAACTGAAGACA-3 '(SEQ ID NO: 1)
  • VEGFR2-L 5'-AATTAAGCATGCTTAAACAGGAGGAGAGCTCAGTGTGGTCCC-3 '(SEQ ID NO: 2)
  • the base sequence of primer VEGFR2-U is shown in SEQ ID NO: 1 in the sequence listing
  • the base sequence of primer VEGFR2-L is shown in SEQ ID NO: 2 in the sequence listing.
  • the PCR reaction was performed using a KOD-plus kit (manufactured by TOYOBO).
  • the obtained PCR product was electrophoresed on an agarose gel (1%), and a DNA fragment amplified by PCR was recovered from the gel and then digested with restriction enzymes Sal I and Sph I.
  • the restriction enzyme-treated DNA was electrophoresed on an agarose gel (1%), and the resulting DNA fragment was recovered, ligated to the plasmid pFASTBAC1 (manufactured by Invitrogen) digested with restriction enzymes Sal I and Sph I, and the expression plasmid pFB- VEGFR2 was produced.
  • baculovirus virus stock BAC-VEGFR2 was prepared using a BAC-TO-BAC Baculovirus Expression System (manufactured by Invitrogen).
  • Vascular Endothelial Growth Factor Receptor 2 Intracellular Domain Protein SF-21 cells were treated with 10% fetal bovine serum (trace), 50 mg / L Gentamin (Invitrogen), 0.1% Pluronic F-68 ( Inoculated at 1 ⁇ 10 6 cells / mL in 1 L of Sf-900IISFM medium (Invitrogen) containing Invitrogen), and cultured with shaking at 27 ° C. and 100 rpm using a 2 L Erlenmeyer flask. After 24 hours of culture, 13.4 mL of recombinant baculovirus BAC-VEGFR2 was added, and further cultured for 3 days.
  • VEGFR2 Vascular Endothelial Growth Factor Receptor 2
  • the culture solution was centrifuged at 2,000 rpm for 5 minutes to obtain virus-infected cells.
  • the infected cells were washed with phosphate physiological buffer (Invitrogen), centrifuged under the same conditions, and the cells were stored at -80 ° C.
  • the cryopreserved cells were thawed in ice and suspended in 30 mL of buffer A (20% Glycerol, 50 mM Tris buffer (pH 7.4) containing 0.15 M NaCl) supplemented with Complete Protease Inhibitor (manufactured by Boehringer). Thereafter, crushing was performed three times using a Polytron homogenizer (manufactured by Kinematica) under the conditions of 20,000 rpm and 30 seconds.
  • the crushed liquid was clarified by centrifugation at 40,000 rpm for 30 minutes, and further filtered using a 0.45 ⁇ m filter.
  • the filtrate was passed through a column packed with 4 mL of Anti-FLAG M2 Affinity Gel (manufactured by Sigma) at a flow rate of about 0.5 mL / min.
  • the column was washed with buffer A and then eluted with buffer A containing 100 ⁇ g / mL FLAG peptide.
  • the eluate was concentrated with Vivaspin 20 (manufactured by Viva Science) having a molecular weight cut off of 30K.
  • the buffer solution was exchanged with a NAP TM 25 column (manufactured by Amersham Bioscience) in which the concentrated solution was equilibrated with buffer A. Fractions containing the VEGFR2 intracellular domain protein were collected, added with glycerol to a final concentration of 50%, and stored frozen at ⁇ 80 ° C.
  • Test Example 1 Measurement of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Kinase Inhibitory Activity Test compounds dissolved in dimethyl sulfoxide (DMSO) were mixed with a buffer solution (50 mM Tris-HCl (pH 7.5), 5 mM MgCl 2 , 5 mM MnCl 2 , Diluted with 2 mM dithiothreitol, 0.01% Tween-20).
  • DMSO dimethyl sulfoxide
  • the reaction solution was left for 16 hours at 25 ° C., were counted using a plate reader Fusion (Fusion TM) (Perkin Elmer).
  • the count of the solution reacted without adding the compound was taken as “control”
  • the count of the solution without adding the compound and ATP was taken as “blank”.
  • the inhibition rate at 1 ⁇ M of the compounds of Examples 6, 27, 35, 36, 47, 54, 55, 126 and 128 was 80% or more.
  • Test Example 2 Growth Inhibition Test of Vascular Endothelial Cells
  • Human umbilical vein-derived vascular endothelial cells (HUVEC, purchased from Kurabo Industries) were obtained at 37 ° C. in a 5% carbon dioxide incubator with 3% fetal calf serum and 2.5 ng / mL basic fiber.
  • the cells were cultured in a vascular endothelial cell medium (manufactured by Invitrogen) containing blast growth factor.
  • HUVEC suspended in the vascular endothelial cell medium containing 3% fetal bovine serum was seeded in a 96-well flat-bottom plate at 50 ⁇ L (3,000 cells).
  • vascular endothelial growth factor 120 ng / mL vascular endothelial growth factor (VEGF) were dissolved in vascular endothelial cell medium containing 3% fetal calf serum, and 50 ⁇ L of each well was added. After culturing for 5 days, 10 ⁇ L of Cell counting kit-8 reagent (manufactured by Dojin Chemical) was added to each well and reacted in a 37 ° C., 5% carbon dioxide incubator for 2-3 hours. Absorbance at 450 nm was measured with a microtiter plate reader to measure cell growth inhibitory activity.
  • VEGF vascular endothelial growth factor
  • Test Example 3 Measurement of Hepatocyte Growth Factor Receptor (c-Met) Kinase Inhibitory Activity
  • DMSO dimethyl sulfoxide
  • 5 mM MgCl 2 5 mM MnCl 2 Diluted with 2 mM dithiothreitol (0.01% Tween-20).
  • 5 ⁇ L of this compound solution contains 2.5 ng / mL c-Met intracellular domain protein (Millipore) and 250 ng / mL biotinylated polypeptide biotinyl-poly-Glu: Tyr (4: 1) (CIS bio International). 10 ⁇ L of buffer was added.
  • the reaction solution was left for 16 hours at 25 ° C., were counted using a plate reader Fusion (Fusion TM) (Perkin Elmer).
  • the count of the solution reacted without adding the compound was taken as “control”
  • the count of the solution without adding the compound and ATP was taken as “blank”.
  • the inhibition rate at 1 ⁇ M of the compounds of Examples 6, 27, 35, 36, 47, 54, 55, 126 and 128 was 80% or more.
  • test substance concentration IC 50 value
  • IC 50 value the test substance concentration at which growth was inhibited by 50% was calculated by GraphPad Prism non-linear regression analysis [Sigma dose response (variable slope)].
  • the human gastric cancer cell line MKN45 growth inhibition rate (%) of the test compound was calculated by the following formula. Dimethyl sulfoxide was added to the positive control (100% growth) instead of the test substance. A large excess (10 ⁇ M) of Reference Example 52 (compound described in Entry 104 of WO2005 / 030140), which is a known c-Met inhibitor, was added to the negative control (0% growth) instead of the test substance.
  • Inhibition rate (%) (1 ⁇ (absorbance when test compound is added ⁇ absorbance of negative control) ⁇ (absorbance of positive control ⁇ absorbance of negative control)) ⁇ 100
  • the inhibition rate at 1 ⁇ M of the compounds of Examples 6, 27, 35, 36, 47, 54, 55, 126 and 128 was 80% or more.
  • the IC 50 values of the compounds of Examples 6, 27, 35, 36, 47, 54, 55, 126 and 128 were 1 ⁇ M or less.
  • Test Example 5 Antitumor Test Cancer cells are cultured in a culture solution containing 10% fetal bovine serum in a 37 ° C., 5% carbon dioxide incubator. The cells are isolated by trypsin / EDTA treatment, washed with HBSS (HANK's Balanced Solution), and then adjusted to a cell density of 5 ⁇ 10 7 cells / mL with HBSS. 0.1 mL (5 ⁇ 10 6 cells) of this cell suspension is injected subcutaneously into the abdomen of a 6-week-old female nude mouse (BALB / c nu / nu, manufactured by CLEA Japan) and transplanted.
  • HBSS HANK's Balanced Solution
  • the compound of the present invention exhibits an excellent inhibitory action on kinases such as vascular endothelial growth factor receptor and hepatocyte growth factor receptor, it is related to the action of vascular endothelial growth factor and hepatocyte growth factor in vivo.
  • a clinically useful prophylactic / therapeutic agent for a disease for example, cancer
  • the compound of the present invention is also useful as a pharmaceutical because it is excellent in terms of drug efficacy, pharmacokinetics, solubility, interaction with other pharmaceuticals, safety, and stability.

Abstract

This invention pertains to compounds represented by Formula and salts thereof, as well as medicines that are kinase inhibitors and cancer-preventing/treating agents that comprise said compounds or prodrugs thereof. [In the formula, each reference has the same meaning as in the main body of the Specification.]

Description

縮合複素環誘導体およびその用途Fused heterocyclic derivatives and uses thereof
　本発明は、縮合複素環誘導体およびその用途に関し、より詳細には、強力なキナーゼ阻害活性を有し、癌の予防・治療等に有用なイミダゾピリダジン誘導体ならびにその用途に関する。 The present invention relates to fused heterocyclic derivatives and uses thereof, and more particularly to imidazopyridazine derivatives having strong kinase inhibitory activity and useful for cancer prevention and treatment and uses thereof.
（発明の背景）
　固形癌がある一定の大きさ以上に増殖するためには、癌細胞に十分な栄養と酸素を供給するための血管が新しくできてくることが必要である（例えば、非特許文献１参照）。腫瘍への血管新生を引き起こす重要な因子の一つとして、血管内皮増殖因子（ＶＥＧＦ）が知られており、ＶＥＧＦは血管内皮細胞上に発現する血管内皮増殖因子受容体（ＶＥＧＦＲ）に結合して、細胞増殖のシグナルを伝達する（例えば、非特許文献２参照）。従って、ＶＥＧＦ－ＶＥＧＦＲシグナル伝達系を阻害することで血管新生を抑制し、腫瘍の増殖を抑えることができると考えられている（例えば、非特許文献３参照）。また腫瘍血管は癌の血行性転移にも関与していることから、血管新生阻害は癌の転移抑制にも有効であると考えられている。
　肝細胞増殖因子（ＨＧＦ）はその受容体（ｃ－Ｍｅｔ）を介し、血管内皮細胞の増殖を促進し、血管新生を引き起こすことが知られている（例えば、非特許文献４参照）。またｃ－Ｍｅｔは様々な癌（大腸癌、胃癌、肺癌、腎臓癌、乳癌、卵巣癌、前立腺癌など）において高発現しており、癌細胞の増殖、生存に深く関与していることが明らかにされている（例えば、非特許文献５参照）。従って、ｃ－Ｍｅｔを阻害することで、癌細胞の増殖を抑制することが期待される。さらにｃ－Ｍｅｔの活性化は癌細胞の浸潤・転移にも関与しており（例えば、非特許文献６参照）、ｃ－Ｍｅｔの阻害は癌の浸潤・転移阻止にも効果があると考えられる。 (Background of the Invention)
In order for a solid cancer to grow to a certain size or more, it is necessary to newly create a blood vessel for supplying sufficient nutrients and oxygen to cancer cells (see, for example, Non-Patent Document 1). Vascular endothelial growth factor (VEGF) is known as one of the important factors that cause angiogenesis in tumors. VEGF binds to vascular endothelial growth factor receptor (VEGFR) expressed on vascular endothelial cells. And transmits a signal of cell proliferation (see, for example, Non-Patent Document 2). Therefore, it is considered that inhibiting the VEGF-VEGFR signaling system can suppress angiogenesis and suppress tumor growth (see, for example, Non-Patent Document 3). In addition, since tumor blood vessels are also involved in hematogenous metastasis of cancer, angiogenesis inhibition is considered to be effective in suppressing cancer metastasis.
It is known that hepatocyte growth factor (HGF) promotes the proliferation of vascular endothelial cells and causes angiogenesis through its receptor (c-Met) (see, for example, Non-Patent Document 4). In addition, c-Met is highly expressed in various cancers (such as colorectal cancer, stomach cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, prostate cancer, etc.), and is clearly involved in the growth and survival of cancer cells. (See, for example, Non-Patent Document 5). Therefore, inhibition of c-Met is expected to suppress cancer cell growth. Furthermore, c-Met activation is also involved in cancer cell invasion / metastasis (see, for example, Non-Patent Document 6), and c-Met inhibition is thought to be effective in preventing cancer invasion / metastasis. .
　ＶＥＧＦＲやｃ－Ｍｅｔをはじめとするキナーゼを阻害する化合物としては、フタラジン誘導体（例えば、特許文献１参照）、ピロール置換２－インドリノン誘導体（例えば、特許文献２参照）、キナゾリン誘導体（例えば、特許文献３参照）、ω－カルボキシアリール置換ジフェニル尿素誘導体（例えば、特許文献４参照）、キノリン誘導体および／またはキナゾリン誘導体（例えば、特許文献５、７、１３参照）、含窒素芳香環誘導体（例えば、特許文献６参照）、ピラゾール置換インドール誘導体（例えば、特許文献８参照）、ピロロピリジンおよび／またはピロロピリミジン誘導体（例えば、特許文献９参照）、イミダゾピリダジン誘導体（例えば、特許文献１０参照）、イミダゾピリジン、トリアゾロピリジン、ベンゾチアゾールおよび／またはチアゾロピリジン誘導体（特許文献１１参照）等が知られている。 Examples of compounds that inhibit kinases including VEGFR and c-Met include phthalazine derivatives (see, for example, Patent Document 1), pyrrole-substituted 2-indolinone derivatives (see, for example, Patent Document 2), and quinazoline derivatives (for example, Patent Document). 3), ω-carboxyaryl-substituted diphenylurea derivatives (for example, see Patent Document 4), quinoline derivatives and / or quinazoline derivatives (for example, see Patent Documents 5, 7, and 13), nitrogen-containing aromatic ring derivatives (for example, Patents) 6), pyrazole-substituted indole derivatives (see, for example, Patent Document 8), pyrrolopyridine and / or pyrrolopyrimidine derivatives (see, for example, Patent Document 9), imidazopyridazine derivatives (see, for example, Patent Document 10), imidazopyridine, Triazolopyridine, benzothiazole And / or thiazolopyridine derivatives is known (Patent Document 11 reference) and the like.
　特許文献１２には、イミダゾピリダジン誘導体が糖尿病治療薬として記載されている。
国際公開第９８／３５９５８号パンフレット 国際公開第０１／６０８１４号パンフレット 国際公開第０１／３２６５１号パンフレット 国際公開第００／４２０１２号パンフレット 国際公開第００／４３３６６号パンフレット 国際公開第０２／３２８７２号パンフレット 国際公開第０３／０００６６０号パンフレット 国際公開第２００５／１１８５８７号パンフレット 国際公開第２００７／００４７４９号パンフレット 国際公開第２００８／０１６１９２号パンフレット 国際公開第２００８／１５００１５号パンフレット 国際公開第２００８／０１６１３１号パンフレット 国際公開第２００５／０３０１４０号パンフレット Ｎｅｗ Ｅｎｇｌａｎｄ Ｊｏｕｒｎａｌ ｏｆ Ｍｅｄｉｃｉｎｅ，１９７１年，第２８５巻，第２１号，１１８２－１１８６頁 Ｅｎｄｏｃｒｉｎｅ Ｒｅｖｉｅｗｓ，１９９７年，第１８巻，第１号，４－２５頁 Ｄｒｕｇ Ｄｉｓｃｏｖｅｒｙ Ｔｏｄａｙ，２００１年，第６巻，第１９号，１００５－１０２４頁 ＥＸＳ，１９９７年，７９巻，１９３－２０８頁 Ｃｙｔｏｋｉｎｅ ＆ Ｇｒｏｗｔｈ Ｆａｃｔｏｒ Ｒｅｖｉｅｗｓ，２００２年，第１３巻，第１号，４１－５９頁 Ｎａｔｕｒｅ Ｒｅｖｉｅｗｓ Ｍｏｌｅｃｕｌａｒ Ｃｅｌｌ Ｂｉｏｌｏｇｙ，２００３年，第４巻，第１２号，９１５－９２５頁 Patent Document 12 describes imidazopyridazine derivatives as antidiabetic agents.
International Publication No. 98/35958 Pamphlet International Publication No. 01/60814 Pamphlet International Publication No. 01/32651 pamphlet International Publication No. 00/42012 Pamphlet International Publication No. 00/43366 Pamphlet International Publication No. 02/32872 Pamphlet International Publication No. 03/000660 pamphlet International Publication No. 2005/118587 Pamphlet International Publication No. 2007/004749 Pamphlet International Publication No. 2008/016192 Pamphlet International Publication No. 2008/150015 Pamphlet International Publication No. 2008/016131 Pamphlet International Publication No. 2005/030140 Pamphlet New England Journal of Medicine, 1971, 285, 21, 1182-1186. Endocrine Reviews, 1997, Vol. 18, No. 1, pp. 4-25 Drug Discovery Today, 2001, Vol. 6, No. 19, pp. 1005-1024 EXS, 1997, 79, 193-208 Cytokine & Growth Factor Reviews, 2002, Vol. 13, No. 1, pp. 41-59 Nature Reviews Molecular Cell Biology, 2003, 4, 12, 915-925
　キナーゼに対する親和性に優れ、薬効発現、薬物動態、溶解性、他の医薬品との相互作用、安全性、安定性の点で優れたキナーゼ阻害薬は、治療上優れた効果を期待することができる。しかしながら、現状では、キナーゼに対する親和性に優れ、薬効発現、薬物動態、溶解性、他の医薬品との相互作用、安全性、安定性の点で十分満足できるものが見いだされていない。そこで、優れたキナーゼ阻害活性を有し、医薬品として十分満足できる化合物の開発が切望されている。従って、本発明の目的は、優れたキナーゼ阻害活性を有し、低毒性であり、かつ医薬品として十分満足できる化合物を提供することにある。 Kinase inhibitors with excellent affinity for kinases, excellent drug efficacy, pharmacokinetics, solubility, interaction with other drugs, safety and stability can be expected to have excellent therapeutic effects. . However, at present, none of them has been found to be excellent in affinity for kinases and sufficiently satisfactory in terms of drug efficacy, pharmacokinetics, solubility, interaction with other pharmaceuticals, safety and stability. Therefore, development of a compound having excellent kinase inhibitory activity and sufficiently satisfactory as a pharmaceutical is eagerly desired. Accordingly, an object of the present invention is to provide a compound having excellent kinase inhibitory activity, low toxicity and sufficiently satisfactory as a pharmaceutical product.
　本発明者らは、上記課題を解決すべく鋭意検討した結果、下記の式で示される化合物またはその塩が優れたキナーゼ阻害活性を有することを見出し、本発明を完成するに至った。
　すなわち、本発明は以下の通りである。
〔１〕式（Ｉａ） As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a compound represented by the following formula or a salt thereof has excellent kinase inhibitory activity, and has completed the present invention.
That is, the present invention is as follows.
[1] Formula (Ia)
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
〔式中、
Ｘは、ＮまたはＣＲ１（Ｒ１は、水素原子、ハロゲン原子またはＣ１－６アルキルを示す）を示し；
Ｙは、ＮまたはＣＲ２（Ｒ２は、水素原子、ハロゲン原子またはＣ１－６アルキルを示す）を示し；
Ｒ３は、水素原子、ハロゲン原子またはＣ１－６アルキルを示し；
Ｒ４は、水素原子、ハロゲン原子またはＣ１－６アルキルを示し；
Ｒ５は、水素原子を示し；
Ｒ６０は、
(1) １ないし３個のハロゲン原子で置換されていてもよい、Ｃ１－６アルキルを有していてもよいＣ６－１０アリールアミノ、
(2) Ｃ７－１２アラルキル－カルボニルアミノ、
(3) Ｃ７－１２アラルキルオキシ、
(4)(a)(i) Ｃ１－６アルコキシ、および
　　　(ii)Ｃ１－６アルキル－カルボニル
から選ばれる置換基を有していてもよいＣ１－６アルキル、
　 (b) Ｃ６－１０アリール、
　 (c) オキソ、
　 (d) ヒドロキシ、および
　 (e) Ｃ１－６アルコキシ
から選ばれる１ないし４個の置換基を有していてもよい含窒素５員環基、
(5)(a) Ｃ１－６アルキル、
　 (b) ハロゲン原子またはＣ１－６アルキルを１ないし３個有していてもよい、Ｃ６－１０アリール、
　 (c) オキソ、
　 (d) Ｃ１－６アルキルを１ないし３個有していてもよい、５員の芳香族複素環基、および
　 (e) エポキシ
から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい含窒素６員環基、
(6) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル、
(7) Ｃ７－１２アラルキル、または
(8)(a) Ｃ６－１０アリール－カルボニル、
　 (b) Ｃ６－１０アリール－カルボニルアミノ、
　 (c) カルボキシル、または
　 (d) 式－ＣＯＮＲ７Ｒ８
（式中、Ｒ７は、
　　　　(a) ５員の芳香族複素環基を有していてもよいＣ１－６アルキル、
　　　　(b) Ｃ１－６アルキルを有していてもよいＣ３－６シクロアルキル、
　　　　(c) ハロゲン原子を有していてもよいＣ７－１２アラルキル、
　　　　(d)(i) ハロゲン原子、
　　　　　 (ii) シアノ、
　　　　　 (iii) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルキル、
　　　　　 (iv) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルコキシ、
　　　　　 (v) Ｃ１－６アルキル－カルボニル、
　　　　　 (vi) Ｃ１－６アルキルチオ、および
　　　　　 (vii) Ｃ１－６アルコキシ－カルボニル
から選ばれる１または２個の置換基を有していてもよいＣ６－１０アリール、または、
　　　　(e)(i) ハロゲン原子、
　　　　　 (ii) Ｃ１－６アルキル、
　　　　　 (iii) Ｃ３－６シクロアルキル、および
　　　　　 (iv) Ｃ１－６アルコキシ
から選ばれる１または２個の置換基を有していてもよい芳香族複素環基
を示し；
　　　　Ｒ８は、水素原子またはＣ１－６アルキルを示すか；
　　　　あるいは、Ｒ７とＲ８が一緒になって、－ＮＲ７Ｒ８で、６員の複素環を形成してもよい）
で表される基を有するＣ３－６シクロアルキルを示すか；
あるいは、Ｒ５とＲ６０は一緒になって縮合複素環を形成してもよく；
Ｚは、ＯまたはＳを示す。
但し、下記４化合物を除く
(1) N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-5-メチル-1-フェニル-1H-ピラゾール-3-カルボキサミド；
(2) N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-3-メチル-1-フェニル-1H-ピラゾール-5-カルボキサミド；
(3) N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-1,3-ジメチル-1H-ピラゾール-5-カルボキサミド；および
(4) N-{6-[4-({[(フェニルアセチル)アミノ]チオカルボニル}アミノ)フェノキシ]イミダゾ[1,2-b]ピリダジン-2-イル}シクロプロパンカルボキサミド〕
で表される化合物またはその塩；
〔２〕式（Ｉｂ） [Where,
X represents N or CR 1 (R 1 represents a hydrogen atom, a halogen atom or C 1-6 alkyl);
Y represents N or CR 2 (R 2 represents a hydrogen atom, a halogen atom or C 1-6 alkyl);
R 3 represents a hydrogen atom, a halogen atom or C 1-6 alkyl;
R 4 represents a hydrogen atom, a halogen atom or C 1-6 alkyl;
R 5 represents a hydrogen atom;
R 60 is
(1) a C 6-10 arylamino optionally having C 1-6 alkyl, optionally substituted by 1 to 3 halogen atoms,
(2) C 7-12 aralkyl-carbonylamino,
(3) C 7-12 aralkyloxy,
(4) (a) (i ) C 1-6 alkoxy, and (ii) C 1-6 alkyl - which may have a substituent group selected from a carbonyl C 1-6 alkyl,
(b) C 6-10 aryl,
(c) oxo,
(d) hydroxy, and (e) a nitrogen-containing 5-membered cyclic group optionally having 1 to 4 substituents selected from C 1-6 alkoxy,
(5) (a) C 1-6 alkyl,
(b) a C 6-10 aryl optionally having 1 to 3 halogen atoms or C 1-6 alkyl,
(c) oxo,
(d) 1 to 3 C 1-6 alkyl optionally having 5 membered aromatic heterocyclic group, and (e) 1 to 3 substituents selected from epoxy Well, a nitrogen-containing 6-membered cyclic group that may be oxidized,
(6) C 6-10 aryl-carbamoyl-C 1-6 alkyl,
(7) C 7-12 aralkyl, or
(8) (a) C 6-10 aryl-carbonyl,
(b) C 6-10 aryl-carbonylamino,
(c) Carboxyl, or (d) Formula —CONR 7 R 8
(Wherein R 7 is
(a) C 1-6 alkyl optionally having a 5-membered aromatic heterocyclic group,
(b) C 3-6 cycloalkyl optionally having C 1-6 alkyl,
(c) a C 7-12 aralkyl optionally having a halogen atom,
(d) (i) a halogen atom,
(ii) cyano,
(iii) C 1-6 alkyl optionally having 1 to 3 halogen atoms,
(iv) C 1-6 alkoxy optionally having 1 to 3 halogen atoms,
(v) C 1-6 alkyl-carbonyl,
(vi) C 1-6 alkylthio, and (vii) C 6-10 aryl optionally having 1 or 2 substituents selected from C 1-6 alkoxy-carbonyl, or
(e) (i) a halogen atom,
(ii) C 1-6 alkyl,
(iii) C 3-6 cycloalkyl, and (iv) an aromatic heterocyclic group optionally having 1 or 2 substituents selected from C 1-6 alkoxy;
R 8 represents a hydrogen atom or C 1-6 alkyl;
Alternatively, R 7 and R 8 may be combined to form a 6-membered heterocyclic ring with —NR 7 R 8.
C 3-6 cycloalkyl having a group represented by:
Alternatively, R 5 and R 60 may together form a fused heterocycle;
Z represents O or S.
However, the following 4 compounds are excluded.
(1) N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -5-methyl-1-phenyl-1H-pyrazole -3-carboxamide;
(2) N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -3-methyl-1-phenyl-1H-pyrazole -5-carboxamide;
(3) N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -1,3-dimethyl-1H-pyrazole-5 -Carboxamide; and
(4) N- {6- [4-({[(Phenylacetyl) amino] thiocarbonyl} amino) phenoxy] imidazo [1,2-b] pyridazin-2-yl} cyclopropanecarboxamide]
Or a salt thereof;
[2] Formula (Ib)
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
〔式中、
Ｘは、ＮまたはＣＲ１（Ｒ１は、水素原子、ハロゲン原子またはＣ１－６アルキルを示す）を示し；
Ｙは、ＮまたはＣＲ２（Ｒ２は、水素原子、ハロゲン原子またはＣ１－６アルキルを示す）を示し；
Ｒ３は、水素原子、ハロゲン原子またはＣ１－６アルキルを示し；
Ｒ４は、水素原子、ハロゲン原子またはＣ１－６アルキルを示し；
Ｒ５は、水素原子を示し；
Ｒ６は、
(1) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルキルを有していてもよいＣ６－１０アリールアミノ、
(2) Ｃ７－１２アラルキル－カルボニルアミノ、
(3) Ｃ７－１２アラルキルオキシ、
(4)(a)(i) Ｃ１－６アルコキシ、および
　　　(ii) Ｃ１－６アルキル－カルボニル
から選ばれる置換基を有していてもよいＣ１－６アルキル、
　 (b) Ｃ６－１０アリール、
　 (c) オキソ、
　 (d) ヒドロキシ、および
　 (e) Ｃ１－６アルコキシから選ばれる１ないし３個の置換基を有していてもよい含窒素５員環基、
(5)(a) Ｃ１－６アルキル、
　 (b) ハロゲン原子またはＣ１－６アルキルを１ないし３個有していてもよいＣ６－１０アリール、
　 (c) オキソ、
　 (d) Ｃ１－６アルキルを１ないし３個有していてもよい５員の芳香族複素環基、および
　 (e)エポキシ
から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい含窒素６員環基、
(6) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル、
(7) Ｃ７－１２アラルキル、または、
(8)(a) Ｃ６－１０アリール－カルボニル、
　 (b) Ｃ６－１０アリール－カルボニルアミノ、
　 (c) カルボキシル、または
　 (d) 式－ＣＯＮＲ７Ｒ８
（式中、Ｒ７は、
　　　　(a) ５員の芳香族複素環基を有していてもよいＣ１－６アルキル、
　　　　(b) Ｃ１－６アルキルを有していてもよいＣ３－６シクロアルキル、
　　　　(c) ハロゲン原子を有していてもよいＣ７－１２アラルキル、
　　　　(d)(i) ハロゲン原子、
　　　　　 (ii) シアノ、
　　　　　 (iii) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルキル、
　　　　　 (iv) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルコキシ、
　　　　　 (v) Ｃ１－６アルキル－カルボニル、
　　　　　 (vi) Ｃ１－６アルキルチオ、および
　　　　　 (vii) Ｃ１－６アルコキシ－カルボニル
から選ばれる１または２個の置換基を有していてもよいＣ６－１０アリール、または、
　　　　(e)(i) ハロゲン原子、
　　　　　 (ii) Ｃ１－６アルキル、および
　　　　　 (iii) Ｃ３－６シクロアルキル
から選ばれる１または２個の置換基を有していてもよい芳香族複素環基を示し；
　　　　Ｒ８は水素原子またはＣ１－６アルキルを示すか；
　　　　あるいは、Ｒ７とＲ８が一緒になって、－ＮＲ７Ｒ８で、６員の複素環を形成してもよい）
で表される基を有するＣ３－６シクロアルキルを示すか；
あるいは、Ｒ５とＲ６は一緒になって縮合複素環を形成してもよく；
Ｚは、ＯまたはＳを示す。
但し、下記４化合物を除く：
(1) N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-5-メチル-1-フェニル-1H-ピラゾール-3-カルボキサミド；
(2) N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-3-メチル-1-フェニル-1H-ピラゾール-5-カルボキサミド；
(3) N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-1,3-ジメチル-1H-ピラゾール-5-カルボキサミド；および
(4) N-{6-[4-({[(フェニルアセチル)アミノ]チオカルボニル}アミノ)フェノキシ]イミダゾ[1,2-b]ピリダジン-2-イル}シクロプロパンカルボキサミド〕
で表される化合物またはその塩；
〔３〕Ｒ１およびＲ２が、独立して、水素原子、フッ素原子、塩素原子またはメチルである、上記〔２〕記載の化合物；
〔４〕Ｒ３が、水素原子またはハロゲン原子である、上記〔２〕記載の化合物；
〔５〕Ｒ４が、水素原子またはハロゲン原子である、上記〔２〕記載の化合物；
〔６〕Ｒ５が、水素原子であり；
Ｒ６が、
(1) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルキルを有していてもよいＣ６－１０アリールアミノ、
(2) Ｃ７－１２アラルキルオキシ、
(3)(a) Ｃ１－６アルキル、
　 (b) ハロゲン原子またはＣ１－６アルキルを１ないし３個有していてもよいＣ６－１０アリール、
　 (c) オキソ、
　 (d) Ｃ１－６アルキルを１ないし３個有していてもよい５員の芳香族複素環基、および
　 (e) エポキシ
から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい含窒素６員環基、
(4) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル、
(5) Ｃ７－１２アラルキル、または
(6) Ｃ６－１０アリール－カルボニル、Ｃ６－１０アリール－カルボニルアミノ、カルボキシルまたは式－ＣＯＮＲ７Ｒ８
（式中、Ｒ７が、
　　　　(a) ５員の芳香族複素環基を有していてもよいＣ１－６アルキル、
　　　　(b) Ｃ１－６アルキルを有していてもよいＣ３－６シクロアルキル、
　　　　(c) ハロゲン原子を有していてもよいＣ７－１２アラルキル、
　　　　(d)(i) ハロゲン原子、
　　　　　 (ii) シアノ、
　　　　　 (iii) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルキル、
　　　　　 (iv) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルコキシ、
　　　　　 (v) Ｃ１－６アルキル－カルボニル、
　　　　　 (vi) Ｃ１－６アルキルチオ、および
　　　　　 (vii) Ｃ１－６アルコキシ－カルボニル
から選ばれる１または２個の置換基を有していてもよいＣ６－１０アリール、または、
　　　　(e)(i) ハロゲン原子、
　　　　　 (ii) Ｃ１－６アルキル、および
　　　　　 (iii) Ｃ３－６シクロアルキル
から選ばれる１または２個の置換基を有していてもよい芳香族複素環基であり；
　　　　Ｒ８が水素原子またはＣ１－６アルキルであるか；
　　　　あるいは、Ｒ７とＲ８が一緒になって、－ＮＲ７Ｒ８で、６員の複素環を形成してもよい）
で表される基を有するＣ３－６シクロアルキルであるか；
あるいは、Ｒ５とＲ６が一緒になって縮合複素環を形成してもよい、上記〔１〕記載の化合物；
〔７〕Ｘが、ＮまたはＣＲ１’（Ｒ１’は、水素原子、フッ素原子、塩素原子またはメチルを示す）であり；
Ｙが、ＮまたはＣＲ２’（Ｒ２’は、水素原子、フッ素原子、塩素原子またはメチルを示す）であり；
Ｒ３が、水素原子またはハロゲン原子であり；
Ｒ４が、水素原子またはハロゲン原子であり；
Ｒ５が、水素原子であり；
Ｒ６が、
(1) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルキルを有していてもよい、Ｃ６－１０アリールアミノ、
(2) Ｃ７－１２アラルキルオキシ、
(3)(a) Ｃ１－６アルキル、
　 (b) ハロゲン原子またはＣ１－６アルキルを１ないし３個有していてもよい、Ｃ６－１０アリール、
　 (c) オキソ、
　 (d) Ｃ１－６アルキルを１ないし３個有していてもよい、５員の芳香族複素環基、および
　 (e) エポキシ
から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい含窒素６員環基、
(4) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル、
(5) Ｃ７－１２アラルキル、または
(6)(a) Ｃ６－１０アリール－カルボニル、
　 (b) Ｃ６－１０アリール－カルボニルアミノ、
　 (c) カルボキシル、または
　 (d) 式－ＣＯＮＲ７Ｒ８
（式中、Ｒ７が、
　　　　(a) ５員の芳香族複素環基を有していてもよいＣ１－６アルキル、
　　　　(b) Ｃ１－６アルキルを有していてもよいＣ３－６シクロアルキル、
　　　　(c) ハロゲン原子を有していてもよいＣ７－１２アラルキル、
　　　　(d)(i) ハロゲン原子、
　　　　　 (ii) シアノ、
　　　　　 (iii) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルキル、
　　　　　 (iv) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルコキシ、
　　　　　 (v) Ｃ１－６アルキル－カルボニル、
　　　　　 (vi) Ｃ１－６アルキルチオ、および
　　　　　 (vii) Ｃ１－６アルコキシ－カルボニル
から選ばれる１または２個の置換基を有していてもよいＣ６－１０アリール、または、
　　　　(e)(i) ハロゲン原子、
　　　　　 (ii) Ｃ１－６アルキル、および
　　　　　 (iii) Ｃ３－６シクロアルキル
から選ばれる１または２個の置換基を有していてもよい芳香族複素環基であり；
　　　　Ｒ８は水素原子またはＣ１－６アルキルであるか；
　　　　あるいは、Ｒ７とＲ８が一緒になって－ＮＲ７Ｒ８で、６員の複素環を形成してもよい）
で表される基を有するＣ３－６シクロアルキルであるか；
あるいは、Ｒ５とＲ６が一緒になって縮合複素環を形成してもよく；
Ｚが、ＯまたはＳである、上記〔２〕記載の化合物；
〔８〕N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-N'-フェニルシクロプロパン-1,1-ジカルボキサミドまたはその塩；
〔９〕N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボキサミドまたはその塩；
〔１０〕N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-6-メチル-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボキサミドまたはその塩；
〔１１〕N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-6-フェニルピリジン-2-カルボキサミド 1-オキシドまたはその塩；
〔１２〕N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-6-(4-フルオロフェニル)-5-メチルピリジン-2-カルボキサミド 1-オキシドまたはその塩；
〔１３〕上記〔１〕または〔２〕記載の化合物のプロドラッグ；
〔１４〕上記〔１〕または〔２〕記載の化合物またはそのプロドラッグを含有してなる医薬；
〔１５〕キナーゼ阻害剤である上記〔１４〕記載の医薬；
〔１６〕癌の予防・治療剤である上記〔１４〕記載の医薬；
〔１７〕哺乳動物に対して上記〔１〕または〔２〕記載の化合物またはそのプロドラッグの有効量を投与することを特徴とする癌の予防・治療方法；および
〔１８〕癌の予防・治療剤を製造するための、上記〔１〕または〔２〕記載の化合物またはそのプロドラッグの使用。
　本明細書中、式（Ｉａ）で表される化合物またはその塩および式（Ｉｂ）で表される化合物またはその塩をまとめて、「化合物（Ｉ）」と称する。 [Where,
X represents N or CR 1 (R 1 represents a hydrogen atom, a halogen atom or C 1-6 alkyl);
Y represents N or CR 2 (R 2 represents a hydrogen atom, a halogen atom or C 1-6 alkyl);
R 3 represents a hydrogen atom, a halogen atom or C 1-6 alkyl;
R 4 represents a hydrogen atom, a halogen atom or C 1-6 alkyl;
R 5 represents a hydrogen atom;
R 6 is
(1) C 6-10 arylamino optionally having C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms,
(2) C 7-12 aralkyl-carbonylamino,
(3) C 7-12 aralkyloxy,
(4) (a) (i ) C 1-6 alkoxy, and (ii) C 1-6 alkyl - which may have a substituent group selected from a carbonyl C 1-6 alkyl,
(b) C 6-10 aryl,
(c) oxo,
(d) hydroxy, and (e) a nitrogen-containing 5-membered cyclic group optionally having 1 to 3 substituents selected from C 1-6 alkoxy,
(5) (a) C 1-6 alkyl,
(b) C 6-10 aryl optionally having 1 to 3 halogen atoms or C 1-6 alkyl,
(c) oxo,
(d) a 5-membered aromatic heterocyclic group optionally having 1 to 3 C 1-6 alkyls, and (e) optionally having 1 to 3 substituents selected from epoxy A nitrogen-containing 6-membered cyclic group which may be oxidized,
(6) C 6-10 aryl-carbamoyl-C 1-6 alkyl,
(7) C 7-12 aralkyl, or
(8) (a) C 6-10 aryl-carbonyl,
(b) C 6-10 aryl-carbonylamino,
(c) Carboxyl, or (d) Formula —CONR 7 R 8
(Wherein R 7 is
(a) C 1-6 alkyl optionally having a 5-membered aromatic heterocyclic group,
(b) C 3-6 cycloalkyl optionally having C 1-6 alkyl,
(c) a C 7-12 aralkyl optionally having a halogen atom,
(d) (i) a halogen atom,
(ii) cyano,
(iii) C 1-6 alkyl optionally having 1 to 3 halogen atoms,
(iv) C 1-6 alkoxy optionally having 1 to 3 halogen atoms,
(v) C 1-6 alkyl-carbonyl,
(vi) C 1-6 alkylthio, and (vii) C 6-10 aryl optionally having 1 or 2 substituents selected from C 1-6 alkoxy-carbonyl, or
(e) (i) a halogen atom,
an aromatic heterocyclic group optionally having 1 or 2 substituents selected from (ii) C 1-6 alkyl, and (iii) C 3-6 cycloalkyl;
R 8 represents a hydrogen atom or C 1-6 alkyl;
Alternatively, R 7 and R 8 may be combined to form a 6-membered heterocyclic ring with —NR 7 R 8.
C 3-6 cycloalkyl having a group represented by:
Alternatively, R 5 and R 6 may be taken together to form a fused heterocycle;
Z represents O or S.
However, the following 4 compounds are excluded:
(1) N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -5-methyl-1-phenyl-1H-pyrazole -3-carboxamide;
(2) N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -3-methyl-1-phenyl-1H-pyrazole -5-carboxamide;
(3) N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -1,3-dimethyl-1H-pyrazole-5 -Carboxamide; and
(4) N- {6- [4-({[(Phenylacetyl) amino] thiocarbonyl} amino) phenoxy] imidazo [1,2-b] pyridazin-2-yl} cyclopropanecarboxamide]
Or a salt thereof;
[3] The compound according to the above [2], wherein R 1 and R 2 are each independently a hydrogen atom, a fluorine atom, a chlorine atom or methyl;
[4] The compound according to [2] above, wherein R 3 is a hydrogen atom or a halogen atom;
[5] The compound according to [2] above, wherein R 4 is a hydrogen atom or a halogen atom;
[6] R 5 is a hydrogen atom;
R 6 is
(1) C 6-10 arylamino optionally having C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms,
(2) C 7-12 aralkyloxy,
(3) (a) C 1-6 alkyl,
(b) C 6-10 aryl optionally having 1 to 3 halogen atoms or C 1-6 alkyl,
(c) oxo,
(d) a 5-membered aromatic heterocyclic group optionally having 1 to 3 C 1-6 alkyls, and (e) optionally having 1 to 3 substituents selected from epoxy A nitrogen-containing 6-membered cyclic group which may be oxidized,
(4) C 6-10 aryl-carbamoyl-C 1-6 alkyl,
(5) C 7-12 aralkyl, or
(6) C 6-10 aryl-carbonyl, C 6-10 aryl-carbonylamino, carboxyl or formula —CONR 7 R 8
(Wherein R 7 is
(a) C 1-6 alkyl optionally having a 5-membered aromatic heterocyclic group,
(b) C 3-6 cycloalkyl optionally having C 1-6 alkyl,
(c) a C 7-12 aralkyl optionally having a halogen atom,
(d) (i) a halogen atom,
(ii) cyano,
(iii) C 1-6 alkyl optionally having 1 to 3 halogen atoms,
(iv) C 1-6 alkoxy optionally having 1 to 3 halogen atoms,
(v) C 1-6 alkyl-carbonyl,
(vi) C 1-6 alkylthio, and (vii) C 6-10 aryl optionally having 1 or 2 substituents selected from C 1-6 alkoxy-carbonyl, or
(e) (i) a halogen atom,
an aromatic heterocyclic group optionally having 1 or 2 substituents selected from (ii) C 1-6 alkyl, and (iii) C 3-6 cycloalkyl;
Whether R 8 is a hydrogen atom or C 1-6 alkyl;
Alternatively, R 7 and R 8 may be combined to form a 6-membered heterocyclic ring with —NR 7 R 8.
Or C 3-6 cycloalkyl having a group represented by:
Alternatively, the compound according to the above [1], wherein R 5 and R 6 may form a condensed heterocyclic ring together;
[7] X is N or CR 1 ′ (R 1 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
Y is N or CR 2 ′ (R 2 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
R 3 is a hydrogen atom or a halogen atom;
R 4 is a hydrogen atom or a halogen atom;
R 5 is a hydrogen atom;
R 6 is
(1) C 6-10 arylamino optionally having C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms,
(2) C 7-12 aralkyloxy,
(3) (a) C 1-6 alkyl,
(b) a C 6-10 aryl optionally having 1 to 3 halogen atoms or C 1-6 alkyl,
(c) oxo,
(d) 1 to 3 C 1-6 alkyl optionally having 5 membered aromatic heterocyclic group, and (e) 1 to 3 substituents selected from epoxy Well, a nitrogen-containing 6-membered cyclic group that may be oxidized,
(4) C 6-10 aryl-carbamoyl-C 1-6 alkyl,
(5) C 7-12 aralkyl, or
(6) (a) C 6-10 aryl-carbonyl,
(b) C 6-10 aryl-carbonylamino,
(c) Carboxyl, or (d) Formula —CONR 7 R 8
(Wherein R 7 is
(a) C 1-6 alkyl optionally having a 5-membered aromatic heterocyclic group,
(b) C 3-6 cycloalkyl optionally having C 1-6 alkyl,
(c) a C 7-12 aralkyl optionally having a halogen atom,
(d) (i) a halogen atom,
(ii) cyano,
(iii) C 1-6 alkyl optionally having 1 to 3 halogen atoms,
(iv) C 1-6 alkoxy optionally having 1 to 3 halogen atoms,
(v) C 1-6 alkyl-carbonyl,
(vi) C 1-6 alkylthio, and (vii) C 6-10 aryl optionally having 1 or 2 substituents selected from C 1-6 alkoxy-carbonyl, or
(e) (i) a halogen atom,
an aromatic heterocyclic group optionally having 1 or 2 substituents selected from (ii) C 1-6 alkyl, and (iii) C 3-6 cycloalkyl;
R 8 is a hydrogen atom or C 1-6 alkyl;
Alternatively, R 7 and R 8 may be taken together as —NR 7 R 8 to form a 6-membered heterocycle)
Or C 3-6 cycloalkyl having a group represented by:
Alternatively, R 5 and R 6 may be taken together to form a fused heterocyclic ring;
The compound according to the above [2], wherein Z is O or S;
[8] N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -N′-phenylcyclopropane- 1,1-dicarboxamide or a salt thereof;
[9] N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -2-oxo-1-phenyl -1,2-dihydropyridine-3-carboxamide or a salt thereof;
[10] N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -6-methyl-2-oxo -1-phenyl-1,2-dihydropyridine-3-carboxamide or a salt thereof;
[11] N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -6-phenylpyridine-2- Carboxamide 1-oxide or a salt thereof;
[12] N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -6- (4-fluorophenyl ) -5-methylpyridine-2-carboxamide 1-oxide or a salt thereof;
[13] A prodrug of the compound according to [1] or [2] above;
[14] A medicament comprising the compound according to [1] or [2] above or a prodrug thereof;
[15] The medicament of the above-mentioned [14], which is a kinase inhibitor;
[16] The medicament according to [14] above, which is a preventive / therapeutic agent for cancer;
[17] A method for preventing or treating cancer, comprising administering an effective amount of the compound or prodrug thereof according to [1] or [2] to a mammal; and [18] Preventing or treating cancer. Use of the compound according to [1] or [2] above or a prodrug thereof for producing an agent.
In the present specification, the compound represented by the formula (Ia) or a salt thereof and the compound represented by the formula (Ib) or a salt thereof are collectively referred to as “compound (I)”.
　本発明の化合物は、血管内皮増殖因子受容体、肝細胞増殖因子受容体、血小板由来増殖因子受容体等のキナーゼに対する阻害作用が強く、また、血管新生阻害作用が強いため、癌の臨床上有用な予防・治療剤、癌の増殖阻害剤、癌の浸潤・転移抑制剤を提供することができる。さらに、本発明の化合物は、慢性関節リウマチ、糖尿病性網膜症等の癌以外の適用においても臨床上有用な予防・治療剤を提供することができ、薬効発現、薬物動態、溶解性、他の医薬品との相互作用、安全性、安定性の点でも優れている。 The compounds of the present invention have a strong inhibitory effect on kinases such as vascular endothelial growth factor receptor, hepatocyte growth factor receptor, platelet-derived growth factor receptor and the like, and also have a strong anti-angiogenic effect, and thus are clinically useful for cancer Prophylactic / therapeutic agents, cancer growth inhibitors, and cancer invasion / metastasis inhibitors can be provided. Furthermore, the compound of the present invention can provide a clinically useful prophylactic / therapeutic agent in applications other than cancer such as rheumatoid arthritis and diabetic retinopathy. It is also excellent in terms of interaction with pharmaceuticals, safety, and stability.
（発明の詳細な説明）
　以下に、本発明を詳細に説明する。
　本明細書中、「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子を示す。
　本明細書中、「Ｃ１－６アルキル」とは、例えば、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、tert-ペンチル、ネオペンチル、ヘキシル、イソヘキシルを示す。
　本明細書中、「Ｃ６－１０アリールアミノ」とは、例えば、フェニルアミノ、ナフチルアミノを示す。
　本明細書中、「Ｃ７－１２アラルキル－カルボニルアミノ」とは、例えば、ベンジルカルボニルアミノ、フェネチルカルボニルアミノ、ナフチルメチルカルボニルアミノを示す。
　本明細書中、「Ｃ７－１２アラルキルオキシ」とは、例えば、ベンジルオキシ、フェネチルオキシ、ナフチルメチルオキシを示す。
　本明細書中、「Ｃ１－６アルコキシ」とは、例えば、メトキシ、エトキシ，プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、sec-ブトキシ、tert-ブトキシ、ペンチルオキシ、ヘキシルオキシを示す。
　本明細書中、「Ｃ１－６アルキル－カルボニル」とは、例えば、アセチル、エチルカルボニル、プロピルカルボニル、イソプロピルカルボニル、ブチルカルボニル、イソブチルカルボニル、sec-ブチルカルボニル、tert-ブチルカルボニル、ペンチルカルボニル、ヘキシルカルボニルを示す。 (Detailed description of the invention)
The present invention is described in detail below.
In the present specification, the “halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
In the present specification, “C 1-6 alkyl” means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl. Indicates.
In the present specification, “C 6-10 arylamino” refers to, for example, phenylamino and naphthylamino.
In the present specification, “C 7-12 aralkyl-carbonylamino” refers to, for example, benzylcarbonylamino, phenethylcarbonylamino, naphthylmethylcarbonylamino.
In the present specification, “C 7-12 aralkyloxy” refers to, for example, benzyloxy, phenethyloxy, naphthylmethyloxy.
In the present specification, “C 1-6 alkoxy” means, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy.
In the present specification, “C 1-6 alkyl-carbonyl” means, for example, acetyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, hexyl. Indicates carbonyl.
　本明細書中、「Ｃ６－１０アリール」とは、例えば、フェニル、ナフチルを示す。
　本明細書中、「含窒素５員環基」とは、環構成原子として炭素原子以外に１ないし４個の窒素原子を含有し、さらに、酸素原子および硫黄原子（該硫黄原子は酸化されていてもよい）から選ばれるヘテロ原子を１または２個含有してもよい、非芳香族含窒素５員環基（例、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル）または５員の芳香族含窒素複素環基（例、ピロリル、イミダゾリル、ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル）を示す。
　本明細書中、「５員の芳香族複素環基」とは、環構成原子として炭素原子以外に酸素原子、硫黄原子（該硫黄原子は酸化されていてもよい）および窒素原子から選ばれるヘテロ原子を１ないし４個含有する、５員の芳香族複素環基（例、チエニル、フリル、ピロリル、イミダゾリル、ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル）を示す。
　本明細書中、「含窒素６員環基」とは、環構成原子として炭素原子以外に１ないし４個の窒素原子を含有し、さらに、酸素原子および硫黄原子（該硫黄原子は酸化されていてもよい）から選ばれるヘテロ原子を１または２個含有してもよい、非芳香族含窒素６員環基（例、ジヒドロピリジル、ピペリジル、ピペラジニル、モルホリニル、チオモルホリニル）または芳香族含窒素６員環基（例、ピリジル、ピラジニル、ピリミジニル、ピリダジニル）を示す。
　本明細書中、「酸化されていてもよい含窒素６員環基」で表される「酸化された含窒素６員環基」とは、上記含窒素６員環基がオキシド化した基（例、ピリジルオキシド）を示す。
　本明細書中、「Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル」とは、例えば、フェニルカルバモイルメチル、１－メチル－１－（フェニルカルバモイル）エチルを示す。
　本明細書中、「Ｃ７－１２アラルキル」とは、例えば、ベンジル、フェネチル、ナフチルメチルを示す。
　本明細書中、「Ｃ６－１０アリール－カルボニル」とは、例えば、ベンゾイル、ナフチルカルボニルを示す。
　本明細書中、「Ｃ６－１０アリール－カルボニルアミノ」とは、例えば、ベンゾイルアミノを示す。
　本明細書中、「Ｃ３－６シクロアルキル」とは、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシルを示す。
　本明細書中、「Ｃ１－６アルキルチオ」とは、メチルチオ、エチルチオ、プロピルチオ、イソプロピルチオ、ブチルチオ、イソブチルチオ、sec-ブチルチオ、tert-ブチルチオ、ペンチルチオ、ヘキシルチオを示す。
　本明細書中、「Ｃ１－６アルコキシ－カルボニル」とは、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、イソブトキシカルボニル、sec-ブトキシカルボニル、tert-ブトキシカルボニル、ペンチルオキシカルボニル、ヘキシルオキシカルボニルを示す。
　本明細書中、「芳香族複素環基」とは、環構成原子として炭素原子以外に酸素原子、硫黄原子（該硫黄原子は酸化されていてもよい）および窒素原子から選ばれるヘテロ原子を１ないし４個含有する、５ないし７員の単環式芳香族複素環基（例、チエニル、フリル、ピロリル、イミダゾリル、ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、チアジアゾリル、ピリジル、ピラジニル、ピリミジニル、ピリダジニル）、５ないし７員の単環式芳香族複素環基に対応する環同士が縮合してなる基、または５ないし７員の単環式芳香族複素環基に対応する環とベンゼン環が縮合してなる基(例えば、キノリル)を示す。
　本明細書中、Ｒ７とＲ８が一緒になって－ＮＲ７Ｒ８で形成する「６員の複素環」とは、上記含窒素６員環基に対応する環（例、ピペリジン、モルホリン、チオモルホリン）を示す。
　本明細書中、Ｒ５とＲ６０またはＲ５とＲ６が一緒になって形成する「縮合複素環」とは、上記含窒素６員環基に対応する環と上記芳香族複素環基に対応する環が縮合した環、上記含窒素６員環基に対応する環とベンゼン環が縮合した環、またはこれらの縮合環が部分飽和した環（例、ジヒドロキナゾリン）を示す。 In the present specification, “C 6-10 aryl” means, for example, phenyl or naphthyl.
In the present specification, the “nitrogen-containing 5-membered ring group” contains 1 to 4 nitrogen atoms in addition to carbon atoms as ring-constituting atoms, and further oxygen and sulfur atoms (the sulfur atoms are oxidized). A non-aromatic nitrogen-containing 5-membered cyclic group (eg, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl) or a 5-membered aromatic group, which may contain 1 or 2 heteroatoms selected from A nitrogen-containing heterocyclic group (eg, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl);
In the present specification, the “5-membered aromatic heterocyclic group” means a hetero atom selected from an oxygen atom, a sulfur atom (the sulfur atom may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring constituent atom. A 5-membered aromatic heterocyclic group containing 1 to 4 atoms (eg, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl) is shown.
In the present specification, the “nitrogen-containing 6-membered ring group” contains 1 to 4 nitrogen atoms in addition to carbon atoms as ring-constituting atoms, and further oxygen atoms and sulfur atoms (the sulfur atoms are oxidized). A non-aromatic nitrogen-containing 6-membered cyclic group (eg, dihydropyridyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl) or an aromatic nitrogen-containing 6-membered group which may contain 1 or 2 heteroatoms selected from A cyclic group (eg, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl) is shown.
In the present specification, the “oxidized nitrogen-containing 6-membered cyclic group” represented by “optionally oxidized nitrogen-containing 6-membered cyclic group” is a group in which the nitrogen-containing 6-membered cyclic group is oxidized ( Example pyridyl oxide).
In the present specification, “C 6-10 aryl-carbamoyl-C 1-6 alkyl” means, for example, phenylcarbamoylmethyl, 1-methyl-1- (phenylcarbamoyl) ethyl.
In the present specification, “C 7-12 aralkyl” refers to, for example, benzyl, phenethyl, and naphthylmethyl.
In the present specification, “C 6-10 aryl-carbonyl” means, for example, benzoyl or naphthylcarbonyl.
In the present specification, “C 6-10 aryl-carbonylamino” refers to, for example, benzoylamino.
In the present specification, “C 3-6 cycloalkyl” means, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.
In the present specification, “C 1-6 alkylthio” refers to methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, hexylthio.
In the present specification, “C 1-6 alkoxy-carbonyl” means methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl Represents hexyloxycarbonyl.
In the present specification, the “aromatic heterocyclic group” means a hetero atom selected from an oxygen atom, a sulfur atom (the sulfur atom may be oxidized) and a nitrogen atom in addition to a carbon atom as a ring constituent atom. 5 to 7-membered monocyclic aromatic heterocyclic group containing 1 to 4 (eg, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl) A group formed by condensation of rings corresponding to a 5- to 7-membered monocyclic aromatic heterocyclic group, or a ring corresponding to a 5- to 7-membered monocyclic aromatic heterocyclic group and a benzene ring are condensed. (For example, quinolyl).
In the present specification, the “6-membered heterocycle” formed by R 7 and R 8 together with —NR 7 R 8 is a ring corresponding to the nitrogen-containing 6-membered ring group (eg, piperidine, morpholine). , Thiomorpholine).
In the present specification, the “fused heterocycle” formed by R 5 and R 60 or R 5 and R 6 together refers to the ring corresponding to the nitrogen-containing 6-membered ring group and the aromatic heterocyclic group. A ring in which the corresponding ring is condensed, a ring in which the ring corresponding to the nitrogen-containing 6-membered ring group and a benzene ring are condensed, or a ring in which these condensed rings are partially saturated (eg, dihydroquinazoline) is shown.
　以下、化合物（Ｉ）について説明する。 Hereinafter, the compound (I) will be described.
　Ｘは、ＮまたはＣＲ１（Ｒ１は水素原子、ハロゲン原子またはＣ１－６アルキルを示す）を示す。
　Ｒ１としては、水素原子、フッ素原子、塩素原子またはメチルが好ましい。
　Ｘとしては、ＮまたはＣＲ１’（Ｒ１’は、水素原子、フッ素原子、塩素原子またはメチルを示す）が好ましい。
　Ｙは、ＮまたはＣＲ２（Ｒ２は水素原子、ハロゲン原子またはＣ１－６アルキルを示す）を示す。
　Ｒ２としては、水素原子、フッ素原子、塩素原子またはメチルが好ましい。
　Ｙとしては、ＮまたはＣＲ２’（Ｒ２’は、水素原子、フッ素原子、塩素原子またはメチルを示す）が好ましい。 X represents N or CR 1 (R 1 represents a hydrogen atom, a halogen atom or C 1-6 alkyl).
R 1 is preferably a hydrogen atom, a fluorine atom, a chlorine atom or methyl.
X is preferably N or CR 1 ′ (R 1 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl).
Y represents N or CR 2 (R 2 represents a hydrogen atom, a halogen atom or C 1-6 alkyl).
R 2 is preferably a hydrogen atom, a fluorine atom, a chlorine atom or methyl.
Y is preferably N or CR 2 ′ (R 2 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl).
　Ｒ３は、水素原子、ハロゲン原子またはＣ１－６アルキルを示す。
　Ｒ３としては、水素原子またはハロゲン原子（特に、フッ素原子）が好ましい。 R 3 represents a hydrogen atom, a halogen atom or C 1-6 alkyl.
R 3 is preferably a hydrogen atom or a halogen atom (particularly a fluorine atom).
　Ｒ４は、水素原子、ハロゲン原子またはＣ１－６アルキルを示す。
　Ｒ４としては、水素原子またはハロゲン原子（特に、フッ素原子）が好ましい。 R 4 represents a hydrogen atom, a halogen atom or C 1-6 alkyl.
R 4 is preferably a hydrogen atom or a halogen atom (particularly a fluorine atom).
　Ｒ５は、水素原子を示す。 R 5 represents a hydrogen atom.
　Ｒ６０は、
(1) １ないし３個のハロゲン原子で置換されていてもよい、Ｃ１－６アルキルを有していてもよいＣ６－１０アリールアミノ、
(2) Ｃ７－１２アラルキル－カルボニルアミノ、
(3) Ｃ７－１２アラルキルオキシ、
(4)(a)(i) Ｃ１－６アルコキシ、および
　　　(ii)Ｃ１－６アルキル－カルボニル
から選ばれる置換基を有していてもよいＣ１－６アルキル、
　 (b) Ｃ６－１０アリール、
　 (c) オキソ、
　 (d) ヒドロキシ、および
　 (e) Ｃ１－６アルコキシ
から選ばれる１ないし４個の置換基を有していてもよい含窒素５員環基、
(5)(a) Ｃ１－６アルキル、
　 (b) ハロゲン原子またはＣ１－６アルキルを１ないし３個有していてもよい、Ｃ６－１０アリール、
　 (c) オキソ、
　 (d) Ｃ１－６アルキルを１ないし３個有していてもよい、５員の芳香族複素環基、および
　 (e) エポキシ
から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい含窒素６員環基、
(6) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル、
(7) Ｃ７－１２アラルキル、または
(8)(a) Ｃ６－１０アリール－カルボニル、
　 (b) Ｃ６－１０アリール－カルボニルアミノ、
　 (c) カルボキシル、または
　 (d) 式－ＣＯＮＲ７Ｒ８
（式中、Ｒ７は、
　　　　(a) ５員の芳香族複素環基を有していてもよいＣ１－６アルキル、
　　　　(b) Ｃ１－６アルキルを有していてもよいＣ３－６シクロアルキル、
　　　　(c) ハロゲン原子を有していてもよいＣ７－１２アラルキル、
　　　　(d)(i) ハロゲン原子、
　　　　　 (ii) シアノ、
　　　　　 (iii) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルキル、
　　　　　 (iv) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルコキシ、
　　　　　 (v) Ｃ１－６アルキル－カルボニル、
　　　　　 (vi) Ｃ１－６アルキルチオ、および
　　　　　 (vii) Ｃ１－６アルコキシ－カルボニル
から選ばれる１または２個の置換基を有していてもよいＣ６－１０アリール、または、
　　　　(e)(i) ハロゲン原子、
　　　　　 (ii) Ｃ１－６アルキル、
　　　　　 (iii) Ｃ３－６シクロアルキル、および
　　　　　 (iv) Ｃ１－６アルコキシ
から選ばれる１または２個の置換基を有していてもよい芳香族複素環基を示し；
　　　　Ｒ８は、水素原子またはＣ１－６アルキルを示すか；
　　　　あるいは、Ｒ７とＲ８が一緒になって、－ＮＲ７Ｒ８で、６員の複素環を形成してもよい）
で表される基を有するＣ３－６シクロアルキルを示す。
　あるいは、Ｒ５とＲ６０は一緒になって縮合複素環を形成してもよい。 R 60 is
(1) a C 6-10 arylamino optionally having C 1-6 alkyl, optionally substituted by 1 to 3 halogen atoms,
(2) C 7-12 aralkyl-carbonylamino,
(3) C 7-12 aralkyloxy,
(4) (a) (i ) C 1-6 alkoxy, and (ii) C 1-6 alkyl - which may have a substituent group selected from a carbonyl C 1-6 alkyl,
(b) C 6-10 aryl,
(c) oxo,
(d) hydroxy, and (e) a nitrogen-containing 5-membered cyclic group optionally having 1 to 4 substituents selected from C 1-6 alkoxy,
(5) (a) C 1-6 alkyl,
(b) a C 6-10 aryl optionally having 1 to 3 halogen atoms or C 1-6 alkyl,
(c) oxo,
(d) 1 to 3 C 1-6 alkyl optionally having 5 membered aromatic heterocyclic group, and (e) 1 to 3 substituents selected from epoxy Well, a nitrogen-containing 6-membered cyclic group that may be oxidized,
(6) C 6-10 aryl-carbamoyl-C 1-6 alkyl,
(7) C 7-12 aralkyl, or
(8) (a) C 6-10 aryl-carbonyl,
(b) C 6-10 aryl-carbonylamino,
(c) Carboxyl, or (d) Formula —CONR 7 R 8
(Wherein R 7 is
(a) C 1-6 alkyl optionally having a 5-membered aromatic heterocyclic group,
(b) C 3-6 cycloalkyl optionally having C 1-6 alkyl,
(c) a C 7-12 aralkyl optionally having a halogen atom,
(d) (i) a halogen atom,
(ii) cyano,
(iii) C 1-6 alkyl optionally having 1 to 3 halogen atoms,
(iv) C 1-6 alkoxy optionally having 1 to 3 halogen atoms,
(v) C 1-6 alkyl-carbonyl,
(vi) C 1-6 alkylthio, and (vii) C 6-10 aryl optionally having 1 or 2 substituents selected from C 1-6 alkoxy-carbonyl, or
(e) (i) a halogen atom,
(ii) C 1-6 alkyl,
(iii) C 3-6 cycloalkyl, and (iv) an aromatic heterocyclic group optionally having 1 or 2 substituents selected from C 1-6 alkoxy;
R 8 represents a hydrogen atom or C 1-6 alkyl;
Alternatively, R 7 and R 8 may be combined to form a 6-membered heterocyclic ring with —NR 7 R 8.
And C 3-6 cycloalkyl having a group represented by the formula:
Alternatively, R 5 and R 60 may be taken together to form a fused heterocyclic ring.
　Ｒ６は、
(1) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルキルを有していてもよいＣ６－１０アリールアミノ、
(2) Ｃ７－１２アラルキル－カルボニルアミノ、
(3) Ｃ７－１２アラルキルオキシ、
(4)(a)(i) Ｃ１－６アルコキシ、および
　　　(ii)Ｃ１－６アルキル－カルボニル
から選ばれる置換基を有していてもよいＣ１－６アルキル、
　 (b) Ｃ６－１０アリール、
　 (c) オキソ、
　 (d) ヒドロキシ、および
　 (e) Ｃ１－６アルコキシ
から選ばれる１ないし３個の置換基を有していてもよい含窒素５員環基、
(5)(a) Ｃ１－６アルキル、
　 (b) ハロゲン原子またはＣ１－６アルキルを１ないし３個有していてもよいＣ６－１０アリール、
　 (c) オキソ、
　 (d) Ｃ１－６アルキルを１ないし３個有していてもよい５員の芳香族複素環基、および
　 (e) エポキシ
から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい含窒素６員環基、
(6) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル、
(7) Ｃ７－１２アラルキル、または、
(8)(a) Ｃ６－１０アリール－カルボニル、
　 (b) Ｃ６－１０アリール－カルボニルアミノ、
　 (c) カルボキシル、または
　 (d) 式－ＣＯＮＲ７Ｒ８
（式中、Ｒ７は、
　　　　(a) ５員の芳香族複素環基を有していてもよいＣ１－６アルキル、
　　　　(b) Ｃ１－６アルキルを有していてもよいＣ３－６シクロアルキル、
　　　　(c) ハロゲン原子を有していてもよいＣ７－１２アラルキル、
　　　　(d)(i) ハロゲン原子、
　　　　　 (ii) シアノ、
　　　　　 (iii) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルキル、
　　　　　 (iv) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルコキシ、
　　　　　 (v) Ｃ１－６アルキル－カルボニル、
　　　　　 (vi) Ｃ１－６アルキルチオ、
　　　　　 (vii) Ｃ１－６アルコキシ－カルボニル
から選ばれる１または２個の置換基を有していてもよいＣ６－１０アリール、または、
　　　　(e)ハロゲン原子、Ｃ１－６アルキル、Ｃ３－６シクロアルキルから選ばれる１または２個の置換基を有していてもよい芳香族複素環基を示し；
　　　　Ｒ８は水素原子またはＣ１－６アルキルを示すか；
　　　　あるいは、Ｒ７とＲ８が一緒になって、－ＮＲ７Ｒ８で、６員の複素環を形成してもよい）
で表される基を有するＣ３－６シクロアルキルを示す。 R 6 is
(1) C 6-10 arylamino optionally having C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms,
(2) C 7-12 aralkyl-carbonylamino,
(3) C 7-12 aralkyloxy,
(4) (a) (i ) C 1-6 alkoxy, and (ii) C 1-6 alkyl - which may have a substituent group selected from a carbonyl C 1-6 alkyl,
(b) C 6-10 aryl,
(c) oxo,
(d) hydroxy, and (e) a nitrogen-containing 5-membered cyclic group optionally having 1 to 3 substituents selected from C 1-6 alkoxy,
(5) (a) C 1-6 alkyl,
(b) C 6-10 aryl optionally having 1 to 3 halogen atoms or C 1-6 alkyl,
(c) oxo,
(d) a 5-membered aromatic heterocyclic group optionally having 1 to 3 C 1-6 alkyls, and (e) optionally having 1 to 3 substituents selected from epoxy A nitrogen-containing 6-membered cyclic group which may be oxidized,
(6) C 6-10 aryl-carbamoyl-C 1-6 alkyl,
(7) C 7-12 aralkyl, or
(8) (a) C 6-10 aryl-carbonyl,
(b) C 6-10 aryl-carbonylamino,
(c) Carboxyl, or (d) Formula —CONR 7 R 8
(Wherein R 7 is
(a) C 1-6 alkyl optionally having a 5-membered aromatic heterocyclic group,
(b) C 3-6 cycloalkyl optionally having C 1-6 alkyl,
(c) a C 7-12 aralkyl optionally having a halogen atom,
(d) (i) a halogen atom,
(ii) cyano,
(iii) C 1-6 alkyl optionally having 1 to 3 halogen atoms,
(iv) C 1-6 alkoxy optionally having 1 to 3 halogen atoms,
(v) C 1-6 alkyl-carbonyl,
(vi) C 1-6 alkylthio,
(vii) C 6-10 aryl optionally having 1 or 2 substituents selected from C 1-6 alkoxy-carbonyl, or
(e) represents an aromatic heterocyclic group optionally having 1 or 2 substituents selected from a halogen atom, C 1-6 alkyl, and C 3-6 cycloalkyl;
R 8 represents a hydrogen atom or C 1-6 alkyl;
Alternatively, R 7 and R 8 may be combined to form a 6-membered heterocyclic ring with —NR 7 R 8.
And C 3-6 cycloalkyl having a group represented by the formula:
　Ｒ６としては、
(1) １ないし３個のハロゲン原子（例、フッ素原子）で置換されていてもよいＣ１－６アルキル（例、メチル）を有していてもよい、Ｃ６－１０アリールアミノ（例、フェニルアミノ）、
(2) Ｃ７－１２アラルキル－カルボニルアミノ（例、ベンジルカルボニルアミノ）、
(3) Ｃ７－１２アラルキルオキシ（例、ベンジルオキシ）、
(4)(a)(i) Ｃ１－６アルコキシ（例、メトキシ）、および
　　　(ii) Ｃ１－６アルキル－カルボニル（例、アセチル）
から選ばれる置換基を有していてもよい、Ｃ１－６アルキル（例、メチル、エチル）、
　 (b) Ｃ６－１０アリール（例、フェニル）、
　 (c) オキソ、
　 (d) ヒドロキシ、および
　 (e) Ｃ１－６アルコキシ（例、メトキシ）
から選ばれる１ないし３個の置換基を有していてもよい、含窒素５員環基（例、ピラゾリル、ピロリジニル、ジヒドロピラゾリル）、
(5)(a) Ｃ１－６アルキル（例、メチル、エチル）、
　 (b) ハロゲン原子（例、フッ素原子）またはＣ１－６アルキル（例、メチル）を１ないし３個有していてもよい、Ｃ６－１０アリール（例、フェニル）、
　 (c) オキソ、
　 (d) Ｃ１－６アルキル（例、メチル）を１ないし３個有していてもよい、５員の芳香族複素環基（例、チアゾリル）、および
　 (e) エポキシ
から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい含窒素６員環基（例、ジヒドロピリジル、ピリジル、ピペリジル）、
(6) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル（例、フェニルカルバモイルメチル、１－メチル－１－（フェニルカルバモイル）メチル、１－メチル－１－（フェニルカルバモイル）エチル）、
(7) Ｃ７－１２アラルキル（例、ベンジル）、または、
(8)(a) Ｃ６－１０アリール－カルボニル（例、ベンゾイル）、
　 (b) Ｃ６－１０アリール－カルボニルアミノ(例、ベンゾイルアミノ）、
　 (c) カルボキシル、または
　 (d) 式－ＣＯＮＲ７Ｒ８
（式中、Ｒ７は、
　　　　(a) ５員の芳香族複素環基（例、フリル）を有していてもよい、Ｃ１－６アルキル（メチル、エチル、プロピル、イソプロピル、tert-ブチル）、
　　　　(b) Ｃ１－６アルキル（例、メチル、tert-ブチル）を有していてもよい、Ｃ３－６シクロアルキル（例、シクロプロピル、シクロペンチル、シクロヘキシル）、
　　　　(c) ハロゲン原子（例、フッ素原子）を有していてもよい、Ｃ７－１２アラルキル（例、ベンジル、フェネチル）、
　　　　(d)(i) ハロゲン原子（例、フッ素原子、塩素原子、臭素原子）、
　　　　　 (ii) シアノ、
　　　　　 (iii) １ないし３個のハロゲン原子（例、フッ素原子）を有していてもよい、Ｃ１－６アルキル（例、メチル、エチル）、
　　　　　 (iv) １ないし３個のハロゲン原子（例、フッ素原子）を有していてもよい、Ｃ１－６アルコキシ（例、メトキシ）、
　　　　　 (v) Ｃ１－６アルキル－カルボニル（例、アセチル）、
　　　　　 (vi) Ｃ１－６アルキルチオ（例、メチルチオ）、および
　　　　　 (vii) Ｃ１－６アルコキシ－カルボニル（例、メトキシカルボニル）
から選ばれる１または２個の置換基を有していてもよい、Ｃ６－１０アリール（例、フェニル）、または、
　　　　(e)(i) ハロゲン原子（例、塩素原子）、
　　　　　 (ii) Ｃ１－６アルキル（例、メチル、エチル）、および
　　　　　 (iii) Ｃ３－６シクロアルキル（例、シクロプロピル）
から選ばれる１または２個の置換基を有していてもよい、芳香族複素環基（例、ピラゾリル、チアゾリル、イソオキサゾリル、チアジアゾリル、ピリジル、キノリル）；
　　　　Ｒ８は水素原子またはＣ１－６アルキル（例、メチル）を示すか；
　　　　あるいは、Ｒ７とＲ８が一緒になって、－ＮＲ７Ｒ８で、６員の複素環（例、ピペリジル、モルホリニル、チオモルホリニル）を形成してもよい）
で表される基を有する、Ｃ３－６シクロアルキル（例、シクロプロピル、シクロブチル）
が好ましく、とりわけ、Ｒ６は、
(1) １ないし３個のハロゲン原子（例、フッ素原子）で置換されていてもよいＣ１－６アルキル（例、メチル）を有していてもよい、Ｃ６－１０アリールアミノ（例、フェニルアミノ）、
(2) Ｃ７－１２アラルキルオキシ（例、ベンジルオキシ）、
(3)(a) Ｃ１－６アルキル（例、メチル、エチル）、
　 (b) ハロゲン原子（例、フッ素原子）またはＣ１－６アルキル（例、メチル）を１ないし３個有していてもよい、Ｃ６－１０アリール（例、フェニル）、
　 (c) オキソ、
　 (d) Ｃ１－６アルキル（例、メチル）を１ないし３個有していてもよい、５員の芳香族複素環基（例、チアゾリル）、および
　 (e) エポキシ
から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい、含窒素６員環基（例、ジヒドロピリジル、ピリジル、ピペリジル）、
(4) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル（例、フェニルカルバモイルメチル、１－メチル－１－（フェニルカルバモイル）メチル、１－メチル－１－（フェニルカルバモイル）エチル）、
(5) Ｃ７－１２アラルキル（例、ベンジル）、または、
(6)(a) Ｃ６－１０アリール－カルボニル（例、ベンゾイル）、
　 (b) Ｃ６－１０アリール－カルボニルアミノ(例、ベンゾイルアミノ）、
　 (c) カルボキシル、または
　 (d) 式－ＣＯＮＲ７Ｒ８
（式中、Ｒ７は、
　　　　(a) ５員の芳香族複素環基（例、フリル）を有していてもよい、Ｃ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル、tert-ブチル）、
　　　　(b) Ｃ１－６アルキル（例、メチル、tert-ブチル）を有していてもよい、Ｃ３－６シクロアルキル（例、シクロプロピル、シクロペンチル、シクロヘキシル）、
　　　　(c) ハロゲン原子（例、フッ素原子）を有していてもよい、Ｃ７－１２アラルキル（例、ベンジル、フェネチル）、
　　　　(d)(i) ハロゲン原子（例、フッ素原子、塩素原子、臭素原子）、
　　　　　 (ii) シアノ、
　　　　　 (iii) １ないし３個のハロゲン原子（例、フッ素原子）を有していてもよい、Ｃ１－６アルキル（例、メチル、エチル）、
　　　　　 (iv) １ないし３個のハロゲン原子（例、フッ素原子）を有していてもよい、Ｃ１－６アルコキシ（例、メトキシ）、
　　　　　 (v) Ｃ１－６アルキル－カルボニル（例、アセチル）、
　　　　　 (vi) Ｃ１－６アルキルチオ（例、メチルチオ）、および
　　　　　 (vii) Ｃ１－６アルコキシ－カルボニル（例、メトキシカルボニル）
から選ばれる１または２個の置換基を有していてもよい、Ｃ６－１０アリール（例、フェニル）、または、
　　　　(e)(i) ハロゲン原子（例、塩素原子）、
　　　　　 (ii) Ｃ１－６アルキル（例、メチル、エチル）、および
　　　　　 (iii) Ｃ３－６シクロアルキル（例、シクロプロピル）
から選ばれる１または２個の置換基を有していてもよい、芳香族複素環基（例、ピラゾリル、チアゾリル、イソオキサゾリル、チアジアゾリル、ピリジル、キノリル）を示し；
　　　　Ｒ８は水素原子またはＣ１－６アルキル（例、メチル）を示すか；
　　　　あるいは、Ｒ７とＲ８が一緒になって、－ＮＲ７Ｒ８で、６員の複素環（例、ピペリジル、モルホリニル、チオモルホリニル）を形成してもよい）
で表される基を１個有する、Ｃ３－６シクロアルキル（例、シクロプロピル、シクロブチル）
が好ましい。
　あるいは、Ｒ５とＲ６は一緒になって縮合複素環（例、ジヒドロキナゾリン環）を形成してもよい。 As R 6 ,
(1) C 6-10 arylamino (eg, optionally having C 1-6 alkyl (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine)) Phenylamino),
(2) C 7-12 aralkyl-carbonylamino (eg, benzylcarbonylamino),
(3) C 7-12 aralkyloxy (eg, benzyloxy),
(4) (a) (i) C 1-6 alkoxy (eg, methoxy), and (ii) C 1-6 alkyl-carbonyl (eg, acetyl)
C 1-6 alkyl (eg, methyl, ethyl), which may have a substituent selected from
(b) C 6-10 aryl (eg, phenyl),
(c) oxo,
(d) hydroxy, and (e) C 1-6 alkoxy (eg, methoxy)
A nitrogen-containing 5-membered cyclic group (for example, pyrazolyl, pyrrolidinyl, dihydropyrazolyl) optionally having 1 to 3 substituents selected from:
(5) (a) C 1-6 alkyl (eg, methyl, ethyl),
(b) C 6-10 aryl (eg, phenyl) optionally having 1 to 3 halogen atoms (eg, fluorine atom) or C 1-6 alkyl (eg, methyl),
(c) oxo,
(d) a 5-membered aromatic heterocyclic group (eg, thiazolyl) optionally having 1 to 3 C 1-6 alkyl (eg, methyl), and (e) 1 to 3 selected from epoxy A nitrogen-containing 6-membered cyclic group (for example, dihydropyridyl, pyridyl, piperidyl) which may have one substituent and may be oxidized,
(6) C 6-10 aryl-carbamoyl-C 1-6 alkyl (eg, phenylcarbamoylmethyl, 1-methyl-1- (phenylcarbamoyl) methyl, 1-methyl-1- (phenylcarbamoyl) ethyl),
(7) C 7-12 aralkyl (eg, benzyl), or
(8) (a) C 6-10 aryl-carbonyl (eg, benzoyl),
(b) C 6-10 aryl-carbonylamino (eg, benzoylamino),
(c) Carboxyl, or (d) Formula —CONR 7 R 8
(Wherein R 7 is
(a) C 1-6 alkyl (methyl, ethyl, propyl, isopropyl, tert-butyl) optionally having a 5-membered aromatic heterocyclic group (eg, furyl),
(b) C 3-6 cycloalkyl (eg cyclopropyl, cyclopentyl, cyclohexyl) optionally having C 1-6 alkyl (eg methyl, tert-butyl),
(c) C 7-12 aralkyl (eg, benzyl, phenethyl) optionally having a halogen atom (eg, fluorine atom),
(d) (i) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(ii) cyano,
(iii) C 1-6 alkyl (eg, methyl, ethyl) optionally having 1 to 3 halogen atoms (eg, fluorine atom),
(iv) C 1-6 alkoxy (eg, methoxy) optionally having 1 to 3 halogen atoms (eg, fluorine atom),
(v) C 1-6 alkyl-carbonyl (eg acetyl),
(vi) C 1-6 alkylthio (eg, methylthio), and (vii) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl)
Optionally having 1 or 2 substituents selected from: C 6-10 aryl (eg, phenyl), or
(e) (i) a halogen atom (eg, a chlorine atom),
(ii) C 1-6 alkyl (eg, methyl, ethyl), and (iii) C 3-6 cycloalkyl (eg, cyclopropyl)
An aromatic heterocyclic group (eg, pyrazolyl, thiazolyl, isoxazolyl, thiadiazolyl, pyridyl, quinolyl) optionally having 1 or 2 substituents selected from:
R 8 represents a hydrogen atom or C 1-6 alkyl (eg, methyl);
Alternatively, R 7 and R 8 may be combined to form a 6-membered heterocycle (eg, piperidyl, morpholinyl, thiomorpholinyl) with —NR 7 R 8 )
C 3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl) having a group represented by
In particular, R 6 is
(1) C 6-10 arylamino (eg, optionally having C 1-6 alkyl (eg, methyl) optionally substituted with 1 to 3 halogen atoms (eg, fluorine)) Phenylamino),
(2) C 7-12 aralkyloxy (eg, benzyloxy),
(3) (a) C 1-6 alkyl (eg, methyl, ethyl),
(b) C 6-10 aryl (eg, phenyl) optionally having 1 to 3 halogen atoms (eg, fluorine atom) or C 1-6 alkyl (eg, methyl),
(c) oxo,
(d) a 5-membered aromatic heterocyclic group (eg, thiazolyl) optionally having 1 to 3 C 1-6 alkyl (eg, methyl), and (e) 1 to 3 selected from epoxy A nitrogen-containing 6-membered cyclic group (for example, dihydropyridyl, pyridyl, piperidyl) which may have one substituent and may be oxidized,
(4) C 6-10 aryl-carbamoyl-C 1-6 alkyl (eg, phenylcarbamoylmethyl, 1-methyl-1- (phenylcarbamoyl) methyl, 1-methyl-1- (phenylcarbamoyl) ethyl),
(5) C 7-12 aralkyl (eg, benzyl), or
(6) (a) C 6-10 aryl-carbonyl (eg, benzoyl),
(b) C 6-10 aryl-carbonylamino (eg, benzoylamino),
(c) Carboxyl, or (d) Formula —CONR 7 R 8
(Wherein R 7 is
(a) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, tert-butyl) optionally having a 5-membered aromatic heterocyclic group (eg, furyl),
(b) C 3-6 cycloalkyl (eg cyclopropyl, cyclopentyl, cyclohexyl) optionally having C 1-6 alkyl (eg methyl, tert-butyl),
(c) C 7-12 aralkyl (eg, benzyl, phenethyl) optionally having a halogen atom (eg, fluorine atom),
(d) (i) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(ii) cyano,
(iii) C 1-6 alkyl (eg, methyl, ethyl) optionally having 1 to 3 halogen atoms (eg, fluorine atom),
(iv) C 1-6 alkoxy (eg, methoxy) optionally having 1 to 3 halogen atoms (eg, fluorine atom),
(v) C 1-6 alkyl-carbonyl (eg acetyl),
(vi) C 1-6 alkylthio (eg, methylthio), and (vii) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl)
Optionally having 1 or 2 substituents selected from: C 6-10 aryl (eg, phenyl), or
(e) (i) a halogen atom (eg, a chlorine atom),
(ii) C 1-6 alkyl (eg, methyl, ethyl), and (iii) C 3-6 cycloalkyl (eg, cyclopropyl)
An aromatic heterocyclic group (eg, pyrazolyl, thiazolyl, isoxazolyl, thiadiazolyl, pyridyl, quinolyl) optionally having one or two substituents selected from:
R 8 represents a hydrogen atom or C 1-6 alkyl (eg, methyl);
Alternatively, R 7 and R 8 may be combined to form a 6-membered heterocycle (eg, piperidyl, morpholinyl, thiomorpholinyl) with —NR 7 R 8 )
A C 3-6 cycloalkyl having one group represented by the formula (eg, cyclopropyl, cyclobutyl)
Is preferred.
Alternatively, R 5 and R 6 may be combined to form a fused heterocyclic ring (eg, dihydroquinazoline ring).
　Ｒ６の好適な具体例は、以下である：
Ａ）Ｒ６が、
(1) トリフルオロメチルを有していてもよいフェニルアミノ、
(2) ベンジルカルボニルアミノ、
(3) ベンジルオキシ、
(4)(a) メトキシおよびアセチルから選ばれる置換基を有していてもよい、Ｃ１－６アルキル（例、メチル、エチル）、
　 (b) フェニル、
　 (c) オキソ、
　 (d) ヒドロキシ、および
　 (e) メトキシ
から選ばれる１ないし３個の置換基を有していてもよい、含窒素５員環基（例、ピラゾリル、ピロリジニル、ジヒドロピラゾリル）、
(5)(a) メチルまたはエチル、
　 (b) フッ素原子またはメチルを１ないし３個有していてもよいフェニル、
　 (c) オキソ、
　 (d) メチルを１ないし３個有していてもよい５員の芳香族複素環基（例、チアゾリル）、および
　 (e) エポキシ
から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい含窒素６員環基（例、ジヒドロピリジル、ピリジル、ピペリジル）、
(6) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル（例、フェニルカルバモイルメチル、１－メチル－１－（フェニルカルバモイル）メチル、１－メチル－１－（フェニルカルバモイル）エチル）、
(7) ベンジル、または、
(8)(a) ベンゾイル、
　 (b) ベンゾイルアミノ、
　 (c) カルボキシル、または
　 (d) 式－ＣＯＮＲ７’Ｒ８’
（式中、Ｒ７’は、
　　　　(a) フリルを有していてもよい、Ｃ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル、tert-ブチル）、
　　　　(b) Ｃ１－６アルキル（例、メチル、tert-ブチル）を有していてもよい、Ｃ３－６シクロアルキル（例、シクロプロピル、シクロペンチル、シクロヘキシル）、
　　　　(c) フッ素原子を有していてもよい、Ｃ７－１２アラルキル（例、ベンジル、フェネチル）、
　　　　(d)(i) ハロゲン原子（例、フッ素原子、塩素原子、臭素原子）、
　　　　　 (ii) シアノ、
　　　　　 (iii) １ないし３個のフッ素原子を有していてもよい、Ｃ１－６アルキル（例、メチル、エチル）、
　　　　　 (iv) １ないし３個のフッ素原子を有していてもよい、メトキシ、
　　　　　 (v) アセチル、
　　　　　 (vi) メチルチオ、および
　　　　　 (vii) メトキシカルボニル
から選ばれる１または２個の置換基を有していてもよいフェニル、または、
　　　　(e)(i) 塩素原子、
　　　　　 (ii) メチルまたはエチル、および
　　　　　 (iii) シクロプロピル
から選ばれる１または２個の置換基を有していてもよい、芳香族複素環基（例、ピラゾリル、チアゾリル、イソオキサゾリル、チアジアゾリル、ピリジル、キノリル）であり；
　　　　Ｒ８’は水素原子またはメチルであるか；
　　　　あるいは、Ｒ７’とＲ８’が一緒になって、－ＮＲ７’Ｒ８’で、ピペリジル、モルホリニルまたはチオモルホリニルを形成してもよい）
で表される基を有する、Ｃ３－６シクロアルキル（例、シクロプロピル、シクロブチル）であるか；
あるいは、Ｒ５とＲ６は一緒になって縮合複素環（例、ジヒドロキナゾリン環）を形成してもよい；
Ｂ）Ｒ６が、
(1) トリフルオロメチルを有していてもよいフェニルアミノ、
(2) ベンジルオキシ、
(3)(a) メチル、
　 (b) フッ素原子またはメチルを１ないし３個有していてもよいフェニル、
　 (c) オキソ、
　 (d) メチルを１ないし３個有していてもよい、５員の芳香族複素環基（例、チアゾリル）、および
　 (e) エポキシ
から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい含窒素６員環基（例、ジヒドロピリジル）、
(4) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル（例、フェニルカルバモイルメチル、１－メチル－１－（フェニルカルバモイル）メチル、１－メチル－１－（フェニルカルバモイル）エチル）、
(5) ベンジル、または、
(6) ベンゾイル、カルボキシルまたは式－ＣＯＮＲ７’Ｒ８’
（式中、Ｒ７’は、
　　　　(a) フリルを有していてもよいＣ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル、tert-ブチル）、
　　　　(b) Ｃ１－６アルキル（例、メチル、tert-ブチル）を有していてもよいＣ３－６シクロアルキル（例、シクロプロピル、シクロペンチル、シクロヘキシル）、
　　　　(c) フッ素原子を有していてもよいＣ７－１２アラルキル（例、ベンジル、フェネチル）、
　　　　(d)(i) ハロゲン原子（例、フッ素原子、塩素原子、臭素原子）、
　　　　　 (ii) シアノ、
　　　　　 (iii) １ないし３個のフッ素原子を有していてもよい、Ｃ１－６アルキル（メチル、エチル）、
　　　　　 (iv) １ないし３個のフッ素原子を有していてもよいメトキシ、
　　　　　 (v) アセチル、
　　　　　 (vi) メチルチオ、および
　　　　　 (vii) メトキシカルボニル
から選ばれる１または２個の置換基を有していてもよいフェニル、または、
　　　　(e)(i) 塩素原子、
　　　　　 (ii) メチルまたはエチル、および
　　　　　 (iii) シクロプロピル
から選ばれる１または２個の置換基を有していてもよい、芳香族複素環基（例、ピラゾリル、チアゾリル、イソオキサゾリル、チアジアゾリル、ピリジル、キノリル）であり；
　　　　Ｒ８’は水素原子またはメチルであるか；
　　　　あるいは、Ｒ７’とＲ８’が一緒になって、－ＮＲ７’Ｒ８’で、ピペリジル、モルホリニルまたはチオモルホリニルを形成してもよい）
で表される基を有する、Ｃ３－６シクロアルキル（例、シクロプロピル、シクロブチル）であるか；
あるいは、Ｒ５とＲ６は一緒になって縮合複素環（例、ジヒドロキナゾリン環）を形成してもよい；
Ｃ）Ｒ６が、
(1) トリフルオロメチルを有していてもよいフェニルアミノ、
(2) ベンジルオキシ、
(3)(a) メチルまたはエチル、
　 (b) フッ素原子またはメチルを１ないし３個有していてもよいフェニル、
　 (c) オキソ、
　 (d) メチルを１ないし３個有していてもよい５員の芳香族複素環基（例、チアゾリル）、および
　 (e) エポキシ
から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい含窒素６員環基（例、ジヒドロピリジル、ピリジル、ピペリジル）、
(4) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル（例、フェニルカルバモイルメチル、１－メチル－１－（フェニルカルバモイル）メチル、１－メチル－１－（フェニルカルバモイル）エチル）、
(5) ベンジル、または、
(6)(a) ベンゾイル、
　 (b) カルボキシル、または
　 (c) 式－ＣＯＮＲ７’Ｒ８’
（式中、Ｒ７’は、
　　　　(a) フリルを有していてもよいＣ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル、tert-ブチル）、
　　　　(b) Ｃ１－６アルキル（例、メチル、tert-ブチル）を有していてもよい、Ｃ３－６シクロアルキル（例、シクロプロピル、シクロペンチル、シクロヘキシル）、
　　　　(c) フッ素原子を有していてもよいＣ７－１２アラルキル（例、ベンジル、フェネチル）、
　　　　(d)(i) ハロゲン原子（例、フッ素原子、塩素原子、臭素原子）、
　　　　　 (ii) シアノ、
　　　　　 (iii) １ないし３個のフッ素原子を有していてもよいＣ１－６アルキル（例、メチル、エチル）、
　　　　　 (iv) １ないし３個のフッ素原子を有していてもよいメトキシ、
　　　　　 (v) アセチル、
　　　　　 (vi) メチルチオ、および
　　　　　 (vii) メトキシカルボニル
から選ばれる１または２個の置換基を有していてもよいフェニル、または、
　　　　(e)(i) 塩素原子、
　　　　　 (ii) メチルまたはエチル、および
　　　　　 (iii) シクロプロピル
から選ばれる１または２個の置換基を有していてもよい、芳香族複素環基（例、ピラゾリル、チアゾリル、イソオキサゾリル、チアジアゾリル、ピリジル、キノリル）であり；
　　　　Ｒ８’は水素原子またはメチルであるか；
　　　　あるいは、Ｒ７’とＲ８’が一緒になって、－ＮＲ７’Ｒ８’で、ピペリジル、モルホリニルまたはチオモルホリニルを形成してもよい）
で表される基を有する、Ｃ３－６シクロアルキル（例、シクロプロピル、シクロブチル）であるか；
あるいは、Ｒ５とＲ６は一緒になって縮合複素環（例、ジヒドロキナゾリン環）を形成してもよい。 Suitable specific examples of R 6 are:
A) R 6 is
(1) phenylamino optionally having trifluoromethyl,
(2) benzylcarbonylamino,
(3) benzyloxy,
(4) (a) C 1-6 alkyl (eg, methyl, ethyl) optionally having a substituent selected from methoxy and acetyl,
(b) phenyl,
(c) oxo,
(d) hydroxy, and (e) a nitrogen-containing 5-membered ring group (eg, pyrazolyl, pyrrolidinyl, dihydropyrazolyl) optionally having 1 to 3 substituents selected from methoxy,
(5) (a) methyl or ethyl,
(b) phenyl optionally having 1 to 3 fluorine atoms or methyl,
(c) oxo,
(d) a 5-membered aromatic heterocyclic group (eg, thiazolyl) optionally having 1 to 3 methyl groups, and (e) 1 to 3 substituents selected from epoxy Well, a nitrogen-containing 6-membered cyclic group (eg, dihydropyridyl, pyridyl, piperidyl) that may be oxidized,
(6) C 6-10 aryl-carbamoyl-C 1-6 alkyl (eg, phenylcarbamoylmethyl, 1-methyl-1- (phenylcarbamoyl) methyl, 1-methyl-1- (phenylcarbamoyl) ethyl),
(7) benzyl or
(8) (a) benzoyl,
(b) benzoylamino,
(c) Carboxyl, or (d) Formula —CONR 7 ′ R 8 ′
(Wherein R 7 ′ is
(a) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, tert-butyl) optionally having furyl,
(b) C 3-6 cycloalkyl (eg cyclopropyl, cyclopentyl, cyclohexyl) optionally having C 1-6 alkyl (eg methyl, tert-butyl),
(c) a C 7-12 aralkyl (eg, benzyl, phenethyl) which may have a fluorine atom,
(d) (i) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(ii) cyano,
(iii) C 1-6 alkyl (eg, methyl, ethyl) optionally having 1 to 3 fluorine atoms,
(iv) methoxy, optionally having 1 to 3 fluorine atoms,
(v) Acetyl,
(vi) methylthio, and (vii) phenyl optionally having 1 or 2 substituents selected from methoxycarbonyl, or
(e) (i) chlorine atom,
(ii) an aromatic heterocyclic group optionally having one or two substituents selected from methyl or ethyl, and (iii) cyclopropyl (eg, pyrazolyl, thiazolyl, isoxazolyl, thiadiazolyl, pyridyl, quinolyl) );
R 8 ′ is a hydrogen atom or methyl;
Alternatively, R 7 ′ and R 8 ′ may be taken together to form piperidyl, morpholinyl or thiomorpholinyl with —NR 7 ′ R 8 ′ )
Or C 3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl) having a group represented by:
Alternatively, R 5 and R 6 may be taken together to form a fused heterocycle (eg, dihydroquinazoline ring);
B) R 6 is
(1) phenylamino optionally having trifluoromethyl,
(2) benzyloxy,
(3) (a) methyl,
(b) phenyl optionally having 1 to 3 fluorine atoms or methyl,
(c) oxo,
(d) optionally having 1 to 3 methyl groups, a 5-membered aromatic heterocyclic group (eg, thiazolyl), and (e) having 1 to 3 substituents selected from epoxy. A nitrogen-containing 6-membered cyclic group (eg, dihydropyridyl) which may be oxidized,
(4) C 6-10 aryl-carbamoyl-C 1-6 alkyl (eg, phenylcarbamoylmethyl, 1-methyl-1- (phenylcarbamoyl) methyl, 1-methyl-1- (phenylcarbamoyl) ethyl),
(5) benzyl or
(6) Benzoyl, carboxyl or formula —CONR 7 ′ R 8 ′
(Wherein R 7 ′ is
(a) C 1-6 alkyl optionally having furyl (eg, methyl, ethyl, propyl, isopropyl, tert-butyl),
(b) C 3-6 cycloalkyl (eg, cyclopropyl, cyclopentyl, cyclohexyl) optionally having C 1-6 alkyl (eg, methyl, tert-butyl),
(c) C 7-12 aralkyl (eg, benzyl, phenethyl) which may have a fluorine atom,
(d) (i) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(ii) cyano,
(iii) C 1-6 alkyl (methyl, ethyl) optionally having 1 to 3 fluorine atoms,
(iv) methoxy optionally having 1 to 3 fluorine atoms,
(v) Acetyl,
(vi) methylthio, and (vii) phenyl optionally having 1 or 2 substituents selected from methoxycarbonyl, or
(e) (i) chlorine atom,
(ii) an aromatic heterocyclic group optionally having one or two substituents selected from methyl or ethyl, and (iii) cyclopropyl (eg, pyrazolyl, thiazolyl, isoxazolyl, thiadiazolyl, pyridyl, quinolyl) );
R 8 ′ is a hydrogen atom or methyl;
Alternatively, R 7 ′ and R 8 ′ may be taken together to form piperidyl, morpholinyl or thiomorpholinyl with —NR 7 ′ R 8 ′ )
Or C 3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl) having a group represented by:
Alternatively, R 5 and R 6 may be taken together to form a fused heterocycle (eg, dihydroquinazoline ring);
C) R 6 is
(1) phenylamino optionally having trifluoromethyl,
(2) benzyloxy,
(3) (a) methyl or ethyl,
(b) phenyl optionally having 1 to 3 fluorine atoms or methyl,
(c) oxo,
(d) a 5-membered aromatic heterocyclic group (eg, thiazolyl) optionally having 1 to 3 methyl groups, and (e) 1 to 3 substituents selected from epoxy Well, a nitrogen-containing 6-membered cyclic group (eg, dihydropyridyl, pyridyl, piperidyl) that may be oxidized,
(4) C 6-10 aryl-carbamoyl-C 1-6 alkyl (eg, phenylcarbamoylmethyl, 1-methyl-1- (phenylcarbamoyl) methyl, 1-methyl-1- (phenylcarbamoyl) ethyl),
(5) benzyl or
(6) (a) benzoyl,
(b) Carboxyl, or (c) Formula —CONR 7 ′ R 8 ′
(Wherein R 7 ′ is
(a) C 1-6 alkyl optionally having furyl (eg, methyl, ethyl, propyl, isopropyl, tert-butyl),
(b) C 3-6 cycloalkyl (eg cyclopropyl, cyclopentyl, cyclohexyl) optionally having C 1-6 alkyl (eg methyl, tert-butyl),
(c) C 7-12 aralkyl (eg, benzyl, phenethyl) which may have a fluorine atom,
(d) (i) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(ii) cyano,
(iii) C 1-6 alkyl (eg, methyl, ethyl) optionally having 1 to 3 fluorine atoms,
(iv) methoxy optionally having 1 to 3 fluorine atoms,
(v) Acetyl,
(vi) methylthio, and (vii) phenyl optionally having 1 or 2 substituents selected from methoxycarbonyl, or
(e) (i) chlorine atom,
(ii) an aromatic heterocyclic group optionally having one or two substituents selected from methyl or ethyl, and (iii) cyclopropyl (eg, pyrazolyl, thiazolyl, isoxazolyl, thiadiazolyl, pyridyl, quinolyl) );
R 8 ′ is a hydrogen atom or methyl;
Alternatively, R 7 ′ and R 8 ′ may be taken together to form piperidyl, morpholinyl or thiomorpholinyl with —NR 7 ′ R 8 ′ )
Or C 3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl) having a group represented by:
Alternatively, R 5 and R 6 may be combined to form a fused heterocyclic ring (eg, dihydroquinazoline ring).
　Ｚは、ＯまたはＳを示す。 Z represents O or S.
　化合物（Ｉ）の好適な具体例としては、以下が挙げられる：
［化合物Ａ］
　式（Ｉ）において、
Ｘが、ＮまたはＣＲ１’（Ｒ１’は、水素原子、フッ素原子、塩素原子またはメチルを示す）であり；
Ｙが、ＮまたはＣＲ２’（Ｒ２’は、水素原子、フッ素原子、塩素原子またはメチルを示す）であり；
Ｒ３が、水素原子またはハロゲン原子（例、フッ素原子）であり；
Ｒ４が、水素原子またはハロゲン原子（例、フッ素原子）であり；
Ｒ５が、水素原子であり；
Ｒ６が、
(1) トリフルオロメチルを有していてもよいフェニルアミノ、
(2) ベンジルカルボニルアミノ、
(3) ベンジルオキシ、
(4)(a) メトキシおよびアセチルから選ばれる置換基を有していてもよい、Ｃ１－６アルキル（例、メチル、エチル）、
　 (b) フェニル、
　 (c) オキソ、
　 (d) ヒドロキシ、および
　 (e) メトキシ
から選ばれる１ないし３個の置換基を有していてもよい、含窒素５員環基（例、ピラゾリル、ピロリジニル、ジヒドロピラゾリル）、
(5)(a) メチルまたはエチル、
　 (b) フッ素原子またはメチルを１ないし３個有していてもよいフェニル、
　 (c) オキソ、
　 (d) メチルを１ないし３個有していてもよい５員の芳香族複素環基（例、チアゾリル）、および
　 (e) エポキシ
から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい含窒素６員環基（例、ジヒドロピリジル、ピリジル、ピペリジル）、
(6) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル（例、フェニルカルバモイルメチル、１－メチル－１－（フェニルカルバモイル）メチル、１－メチル－１－（フェニルカルバモイル）エチル）、
(7) ベンジル、または、
(8)(a) ベンゾイル、
　 (b) ベンゾイルアミノ、
　 (c) カルボキシル、または
　 (d) 式－ＣＯＮＲ７’Ｒ８’
（式中、Ｒ７’は、
　　　　(a) フリルを有していてもよい、Ｃ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル、tert-ブチル）、
　　　　(b) Ｃ１－６アルキル（例、メチル、tert-ブチル）を有していてもよい、Ｃ３－６シクロアルキル（例、シクロプロピル、シクロペンチル、シクロヘキシル）、
　　　　(c) フッ素原子を有していてもよい、Ｃ７－１２アラルキル（例、ベンジル、フェネチル）、
　　　　(d)(i) ハロゲン原子（例、フッ素原子、塩素原子、臭素原子）、
　　　　　 (ii) シアノ、
　　　　　 (iii) １ないし３個のフッ素原子を有していてもよい、Ｃ１－６アルキル（例、メチル、エチル）、
　　　　　 (iv) １ないし３個のフッ素原子を有していてもよい、メトキシ、
　　　　　 (v) アセチル、
　　　　　 (vi) メチルチオ、および
　　　　　 (vii) メトキシカルボニル
から選ばれる１または２個の置換基を有していてもよいフェニル、または、
　　　　(e)(i) 塩素原子、
　　　　　 (ii) メチルまたはエチル、および
　　　　　 (iii) シクロプロピル
から選ばれる１または２個の置換基を有していてもよい、芳香族複素環基（例、ピラゾリル、チアゾリル、イソオキサゾリル、チアジアゾリル、ピリジル、キノリル）であり；
　　　　Ｒ８’は水素原子またはメチルであるか；
　　　　あるいは、Ｒ７’とＲ８’が一緒になって、－ＮＲ７’Ｒ８’で、ピペリジル、モルホリニルまたはチオモルホリニルを形成してもよい）
で表される基を有する、Ｃ３－６シクロアルキル（例、シクロプロピル、シクロブチル）であるか；
あるいは、Ｒ５とＲ６は一緒になって縮合複素環（例、ジヒドロキナゾリン環）を形成してもよく；
Ｚが、ＯまたはＳである、化合物またはその塩。 Preferable specific examples of compound (I) include the following:
[Compound A]
In formula (I),
X is N or CR 1 ′ (R 1 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
Y is N or CR 2 ′ (R 2 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
R 3 is a hydrogen atom or a halogen atom (eg, fluorine atom);
R 4 is a hydrogen atom or a halogen atom (eg, fluorine atom);
R 5 is a hydrogen atom;
R 6 is
(1) phenylamino optionally having trifluoromethyl,
(2) benzylcarbonylamino,
(3) benzyloxy,
(4) (a) C 1-6 alkyl (eg, methyl, ethyl) optionally having a substituent selected from methoxy and acetyl,
(b) phenyl,
(c) oxo,
(d) hydroxy, and (e) a nitrogen-containing 5-membered ring group (eg, pyrazolyl, pyrrolidinyl, dihydropyrazolyl) optionally having 1 to 3 substituents selected from methoxy,
(5) (a) methyl or ethyl,
(b) phenyl optionally having 1 to 3 fluorine atoms or methyl,
(c) oxo,
(d) a 5-membered aromatic heterocyclic group (eg, thiazolyl) optionally having 1 to 3 methyl groups, and (e) 1 to 3 substituents selected from epoxy Well, a nitrogen-containing 6-membered cyclic group (eg, dihydropyridyl, pyridyl, piperidyl) that may be oxidized,
(6) C 6-10 aryl-carbamoyl-C 1-6 alkyl (eg, phenylcarbamoylmethyl, 1-methyl-1- (phenylcarbamoyl) methyl, 1-methyl-1- (phenylcarbamoyl) ethyl),
(7) benzyl or
(8) (a) benzoyl,
(b) benzoylamino,
(c) Carboxyl, or (d) Formula —CONR 7 ′ R 8 ′
(Wherein R 7 ′ is
(a) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, tert-butyl) optionally having furyl,
(b) C 3-6 cycloalkyl (eg cyclopropyl, cyclopentyl, cyclohexyl) optionally having C 1-6 alkyl (eg methyl, tert-butyl),
(c) a C 7-12 aralkyl (eg, benzyl, phenethyl) which may have a fluorine atom,
(d) (i) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(ii) cyano,
(iii) C 1-6 alkyl (eg, methyl, ethyl) optionally having 1 to 3 fluorine atoms,
(iv) methoxy, optionally having 1 to 3 fluorine atoms,
(v) Acetyl,
(vi) methylthio, and (vii) phenyl optionally having 1 or 2 substituents selected from methoxycarbonyl, or
(e) (i) chlorine atom,
(ii) an aromatic heterocyclic group optionally having one or two substituents selected from methyl or ethyl, and (iii) cyclopropyl (eg, pyrazolyl, thiazolyl, isoxazolyl, thiadiazolyl, pyridyl, quinolyl) );
R 8 ′ is a hydrogen atom or methyl;
Alternatively, R 7 ′ and R 8 ′ may be taken together to form piperidyl, morpholinyl or thiomorpholinyl with —NR 7 ′ R 8 ′ )
Or C 3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl) having a group represented by:
Alternatively, R 5 and R 6 may be taken together to form a fused heterocycle (eg, a dihydroquinazoline ring);
A compound or a salt thereof, wherein Z is O or S.
［化合物Ｂ］
　式（Ｉ）において、
Ｘが、ＮまたはＣＲ１’（Ｒ１’は、水素原子、フッ素原子、塩素原子またはメチルを示す）であり；
Ｙが、ＮまたはＣＲ２’（Ｒ２’は、水素原子、フッ素原子、塩素原子またはメチルを示す）であり；
Ｒ３が、水素原子またはフッ素原子であり；
Ｒ４が、水素原子またはフッ素原子であり；
Ｒ５が、水素原子であり；
Ｒ６が、
(1) トリフルオロメチルを有していてもよいフェニルアミノ、
(2) ベンジルオキシ、
(3)(a) メチル、
　 (b) フッ素原子またはメチルを１ないし３個有していてもよいフェニル、
　 (c) オキソ、
　 (d) メチルを１ないし３個有していてもよい、５員の芳香族複素環基（例、チアゾリル）、および
　 (e) エポキシ
から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい含窒素６員環基（例、ジヒドロピリジル）、
(4) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル（例、フェニルカルバモイルメチル、１－メチル－１－（フェニルカルバモイル）メチル、１－メチル－１－（フェニルカルバモイル）エチル）、
(5) ベンジル、または、
(6)(a) ベンゾイル、
　 (b) カルボキシル、または
　 (c) 式－ＣＯＮＲ７’Ｒ８’
（式中、Ｒ７’は、
　　　　(a) フリルを有していてもよいＣ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル、tert-ブチル）、
　　　　(b) Ｃ１－６アルキル（例、メチル、tert-ブチル）を有していてもよいＣ３－６シクロアルキル（例、シクロプロピル、シクロペンチル、シクロヘキシル）、
　　　　(c) フッ素原子を有していてもよいＣ７－１２アラルキル（例、ベンジル、フェネチル）、
　　　　(d)(i) ハロゲン原子（例、フッ素原子、塩素原子、臭素原子）、
　　　　　 (ii) シアノ、
　　　　　 (iii) １ないし３個のフッ素原子を有していてもよい、Ｃ１－６アルキル（メチル、エチル）、
　　　　　 (iv) １ないし３個のフッ素原子を有していてもよいメトキシ、
　　　　　 (v) アセチル、
　　　　　 (vi) メチルチオ、および
　　　　　 (vii) メトキシカルボニル
から選ばれる１または２個の置換基を有していてもよいフェニル、または、
　　　　(e)(i) 塩素原子、
　　　　　 (ii) メチルまたはエチル、および
　　　　　 (iii) シクロプロピル
から選ばれる１または２個の置換基を有していてもよい、芳香族複素環基（例、ピラゾリル、チアゾリル、イソオキサゾリル、チアジアゾリル、ピリジル、キノリル）であり；
　　　　Ｒ８’は水素原子またはメチルであるか；
　　　　あるいは、Ｒ７’とＲ８’が一緒になって、－ＮＲ７’Ｒ８’で、ピペリジル、モルホリニルまたはチオモルホリニルを形成してもよい）
で表される基を有する、Ｃ３－６シクロアルキル（例、シクロプロピル、シクロブチル）であるか；
あるいは、Ｒ５とＲ６は一緒になって縮合複素環（例、ジヒドロキナゾリン環）を形成してもよく；
Ｚが、ＯまたはＳである、化合物またはその塩。 [Compound B]
In formula (I),
X is N or CR 1 ′ (R 1 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
Y is N or CR 2 ′ (R 2 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
R 3 is a hydrogen atom or a fluorine atom;
R 4 is a hydrogen atom or a fluorine atom;
R 5 is a hydrogen atom;
R 6 is
(1) phenylamino optionally having trifluoromethyl,
(2) benzyloxy,
(3) (a) methyl,
(b) phenyl optionally having 1 to 3 fluorine atoms or methyl,
(c) oxo,
(d) optionally having 1 to 3 methyl groups, a 5-membered aromatic heterocyclic group (eg, thiazolyl), and (e) having 1 to 3 substituents selected from epoxy. A nitrogen-containing 6-membered cyclic group (eg, dihydropyridyl) which may be oxidized,
(4) C 6-10 aryl-carbamoyl-C 1-6 alkyl (eg, phenylcarbamoylmethyl, 1-methyl-1- (phenylcarbamoyl) methyl, 1-methyl-1- (phenylcarbamoyl) ethyl),
(5) benzyl or
(6) (a) benzoyl,
(b) Carboxyl, or (c) Formula —CONR 7 ′ R 8 ′
(Wherein R 7 ′ is
(a) C 1-6 alkyl optionally having furyl (eg, methyl, ethyl, propyl, isopropyl, tert-butyl),
(b) C 3-6 cycloalkyl (eg, cyclopropyl, cyclopentyl, cyclohexyl) optionally having C 1-6 alkyl (eg, methyl, tert-butyl),
(c) C 7-12 aralkyl (eg, benzyl, phenethyl) which may have a fluorine atom,
(d) (i) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(ii) cyano,
(iii) C 1-6 alkyl (methyl, ethyl) optionally having 1 to 3 fluorine atoms,
(iv) methoxy optionally having 1 to 3 fluorine atoms,
(v) Acetyl,
(vi) methylthio, and (vii) phenyl optionally having 1 or 2 substituents selected from methoxycarbonyl, or
(e) (i) chlorine atom,
(ii) an aromatic heterocyclic group optionally having one or two substituents selected from methyl or ethyl, and (iii) cyclopropyl (eg, pyrazolyl, thiazolyl, isoxazolyl, thiadiazolyl, pyridyl, quinolyl) );
R 8 ′ is a hydrogen atom or methyl;
Alternatively, R 7 ′ and R 8 ′ may be taken together to form piperidyl, morpholinyl or thiomorpholinyl with —NR 7 ′ R 8 ′ )
Or C 3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl) having a group represented by:
Alternatively, R 5 and R 6 may be taken together to form a fused heterocycle (eg, a dihydroquinazoline ring);
A compound or a salt thereof, wherein Z is O or S.
［化合物Ｃ］
　式（Ｉ）において、
Ｘが、ＮまたはＣＲ１’（Ｒ１’は、水素原子、フッ素原子、塩素原子またはメチルを示す）であり；
Ｙが、ＮまたはＣＲ２’（Ｒ２’は、水素原子、フッ素原子、塩素原子またはメチルを示す）であり；
Ｒ３が、水素原子またはフッ素原子であり；
Ｒ４が、水素原子またはフッ素原子であり；
Ｒ５が、水素原子であり；
Ｒ６が、
(1) トリフルオロメチルを有していてもよいフェニルアミノ、
(2) ベンジルオキシ、
(3)(a) メチルまたはエチル、
　 (b) フッ素原子またはメチルを１ないし３個有していてもよいフェニル、
　 (c) オキソ、
　 (d) メチルを１ないし３個有していてもよい５員の芳香族複素環基（例、チアゾリル）、および
　 (e) エポキシ
から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい含窒素６員環基（例、ジヒドロピリジル、ピリジル、ピペリジル）、
(4) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル（例、フェニルカルバモイルメチル、１－メチル－１－（フェニルカルバモイル）メチル、１－メチル－１－（フェニルカルバモイル）エチル）、
(5) ベンジル、または、
(6)(a) ベンゾイル、
　 (b) カルボキシル、または
　 (c) 式－ＣＯＮＲ７’Ｒ８’
（式中、Ｒ７’は、
　　　　(a) フリルを有していてもよいＣ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル、tert-ブチル）、
　　　　(b) Ｃ１－６アルキル（例、メチル、tert-ブチル）を有していてもよい、Ｃ３－６シクロアルキル（例、シクロプロピル、シクロペンチル、シクロヘキシル）、
　　　　(c) フッ素原子を有していてもよいＣ７－１２アラルキル（例、ベンジル、フェネチル）、
　　　　(d)(i) ハロゲン原子（例、フッ素原子、塩素原子、臭素原子）、
　　　　　 (ii) シアノ、
　　　　　 (iii) １ないし３個のフッ素原子を有していてもよいＣ１－６アルキル（例、メチル、エチル）、
　　　　　 (iv) １ないし３個のフッ素原子を有していてもよいメトキシ、
　　　　　 (v) アセチル、
　　　　　 (vi) メチルチオ、および
　　　　　 (vii) メトキシカルボニル
から選ばれる１または２個の置換基を有していてもよいフェニル、または、
　　　　(e)(i) 塩素原子、
　　　　　 (ii) メチルまたはエチル、および
　　　　　 (iii) シクロプロピル
から選ばれる１または２個の置換基を有していてもよい、芳香族複素環基（例、ピラゾリル、チアゾリル、イソオキサゾリル、チアジアゾリル、ピリジル、キノリル）であり；
　　　　Ｒ８’は水素原子またはメチルであるか；
　　　　あるいは、Ｒ７’とＲ８’が一緒になって、－ＮＲ７’Ｒ８’で、ピペリジル、モルホリニルまたはチオモルホリニルを形成してもよい）
で表される基を有する、Ｃ３－６シクロアルキル（例、シクロプロピル、シクロブチル）であるか；
あるいは、Ｒ５とＲ６は一緒になって縮合複素環（例、ジヒドロキナゾリン環）を形成してもよく；
Ｚが、ＯまたはＳである、化合物またはその塩。 [Compound C]
In formula (I),
X is N or CR 1 ′ (R 1 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
Y is N or CR 2 ′ (R 2 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
R 3 is a hydrogen atom or a fluorine atom;
R 4 is a hydrogen atom or a fluorine atom;
R 5 is a hydrogen atom;
R 6 is
(1) phenylamino optionally having trifluoromethyl,
(2) benzyloxy,
(3) (a) methyl or ethyl,
(b) phenyl optionally having 1 to 3 fluorine atoms or methyl,
(c) oxo,
(d) a 5-membered aromatic heterocyclic group (eg, thiazolyl) optionally having 1 to 3 methyl groups, and (e) 1 to 3 substituents selected from epoxy Well, a nitrogen-containing 6-membered cyclic group (eg, dihydropyridyl, pyridyl, piperidyl) that may be oxidized,
(4) C 6-10 aryl-carbamoyl-C 1-6 alkyl (eg, phenylcarbamoylmethyl, 1-methyl-1- (phenylcarbamoyl) methyl, 1-methyl-1- (phenylcarbamoyl) ethyl),
(5) benzyl or
(6) (a) benzoyl,
(b) Carboxyl, or (c) Formula —CONR 7 ′ R 8 ′
(Wherein R 7 ′ is
(a) C 1-6 alkyl optionally having furyl (eg, methyl, ethyl, propyl, isopropyl, tert-butyl),
(b) C 3-6 cycloalkyl (eg cyclopropyl, cyclopentyl, cyclohexyl) optionally having C 1-6 alkyl (eg methyl, tert-butyl),
(c) C 7-12 aralkyl (eg, benzyl, phenethyl) which may have a fluorine atom,
(d) (i) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom),
(ii) cyano,
(iii) C 1-6 alkyl (eg, methyl, ethyl) optionally having 1 to 3 fluorine atoms,
(iv) methoxy optionally having 1 to 3 fluorine atoms,
(v) Acetyl,
(vi) methylthio, and (vii) phenyl optionally having 1 or 2 substituents selected from methoxycarbonyl, or
(e) (i) chlorine atom,
(ii) an aromatic heterocyclic group optionally having one or two substituents selected from methyl or ethyl, and (iii) cyclopropyl (eg, pyrazolyl, thiazolyl, isoxazolyl, thiadiazolyl, pyridyl, quinolyl) );
R 8 ′ is a hydrogen atom or methyl;
Alternatively, R 7 ′ and R 8 ′ may be taken together to form piperidyl, morpholinyl or thiomorpholinyl with —NR 7 ′ R 8 ′ )
Or C 3-6 cycloalkyl (eg, cyclopropyl, cyclobutyl) having a group represented by:
Alternatively, R 5 and R 6 may be taken together to form a fused heterocycle (eg, a dihydroquinazoline ring);
A compound or a salt thereof, wherein Z is O or S.
［化合物Ｄ］
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-N'-フェニルシクロプロパン-1,1-ジカルボキサミド（実施例３５）；
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボキサミド（実施４７）；
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-6-メチル-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボキサミド（実施例５４）；
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-6-フェニルピリジン-2-カルボキサミド 1-オキシド（実施例５５）；
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-6-(4-フルオロフェニル)-5-メチルピリジン-2-カルボキサミド 1-オキシド（実施例１２８）；
またはそれらの塩。 [Compound D]
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -N'-phenylcyclopropane-1,1 -Dicarboxamide (Example 35);
N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -2-oxo-1-phenyl-1, 2-dihydropyridine-3-carboxamide (Run 47);
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -6-methyl-2-oxo-1- Phenyl-1,2-dihydropyridine-3-carboxamide (Example 54);
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -6-phenylpyridine-2-carboxamide 1- Oxide (Example 55);
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -6- (4-fluorophenyl) -5 -Methylpyridine-2-carboxamide 1-oxide (Example 128);
Or their salts.
　化合物（Ｉ）が塩である場合、このような塩としては、例えば、金属塩、アンモニウム塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性または酸性アミノ酸との塩等が挙げられる。金属塩の好適な例としては、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩、バリウム塩等のアルカリ土類金属塩；アルミニウム塩等が挙げられる。有機塩基との塩の好適な例としては、例えば、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、２，６－ルチジン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、シクロヘキシルアミン、ジシクロヘキシルアミン、Ｎ，Ｎ'－ジベンジルエチレンジアミン等との塩が挙げられる。無機酸との塩の好適な例としては、例えば、塩酸、臭化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。有機酸との塩の好適な例としては、例えば、ギ酸、酢酸、トリフルオロ酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸等との塩が挙げられる。塩基性アミノ酸との塩の好適な例としては、例えば、アルギニン、リジン、オルニチン等との塩が挙げられ、酸性アミノ酸との塩の好適な例としては、例えば、アスパラギン酸、グルタミン酸等との塩が挙げられる。
　このうち、薬学的に許容し得る塩が好ましい。例えば、化合物内に酸性官能基を有する場合には、アルカリ金属塩（例、ナトリウム塩、カリウム塩等）、アルカリ土類金属塩（例、カルシウム塩、マグネシウム塩等）等の無機塩、アンモニウム塩等、また、化合物内に塩基性官能基を有する場合には、例えば、塩酸、臭化水素酸、硝酸、硫酸、リン酸等の無機酸との塩、または酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸等の有機酸との塩が挙げられる。 When the compound (I) is a salt, examples of such a salt include a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a basic or acidic amino acid, and the like. Examples include salts. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl. Examples include salts with ethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene Examples thereof include salts with sulfonic acid, p-toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Is mentioned.
Of these, pharmaceutically acceptable salts are preferred. For example, when the compound has an acidic functional group, inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.), ammonium salts In addition, when the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, And salts with organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid.
　次に、化合物（Ｉ）の製造方法について述べる。
　化合物（Ｉ）は、例えば、以下の反応式で示される方法またはこれに準じた方法等により得られる。
　なお、式中の化合物は、塩を形成している場合も含み、このような塩としては、例えば、上記に例示した化合物（Ｉ）における塩と同様のもの等が用いられる。
　また、各工程で得られた化合物は反応液のままか粗製物として次の反応に用いることもできるが、常法に従って反応混合物から単離することもでき、再結晶、蒸留、クロマトグラフィー等の分離手段により容易に精製することができる。
　以下にその反応式の略図を示すが、略図中の化合物の各記号は前記と同意義を示す。
　また、製造法中の各用語は、以下を意味する。
　「ハロゲン原子」とは、フッ素、塩素、臭素、ヨウ素を示す。
　「置換されていてもよいアルキルスルホニル」とは、ハロゲン原子、ハロゲン化されていてもよいＣ１－６アルキル（例、メチル、エチル、トリフルオロメチル）およびニトロから選ばれる置換基で置換されていてもよいＣ１－６アルキルスルホニル（例、メチルスルホニル、エチルスルホニル等）を示す。
　「置換されていてもよいアルキルスルホニルオキシ」とは、ハロゲン原子、ハロゲン化されていてもよいＣ１－６アルキル（例、メチル、エチル、トリフルオロメチル）およびニトロから選ばれる置換基で置換されていてもよいＣ１－６アルキルスルホニルオキシ（例、メチルスルホニルオキシ、エチルスルホニルオキシ等）を示す。
　「置換されていてもよいアリールスルホニルオキシ」とは、ハロゲン原子、ハロゲン化されていてもよいＣ１－６アルキル（例、メチル、エチル、トリフルオロメチル）およびニトロから選ばれる置換基で置換されていてもよいＣ６－１４アリールスルホニルオキシ（例、フェニルスルホニルオキシ等）を示す。
　「置換されていてもよいアリールオキシ」とは、ハロゲン原子、ハロゲン化されていてもよいＣ１－６アルキル（例、メチル、エチル、トリフルオロメチル）およびニトロから選ばれる置換基で置換されていてもよいＣ６－１４アリールオキシ（例、フェニルオキシ等）を示す。
　「置換されていてもよいアルコキシ」とは、ハロゲン原子、ハロゲン化されていてもよいＣ１－６アルキル（例、メチル、エチル、トリフルオロメチル）およびニトロから選ばれる置換基で置換されていてもよいＣ１－６アルコキシ（例、メトキシ、エトキシ等）を示す。 Next, the manufacturing method of compound (I) is described.
Compound (I) can be obtained, for example, by a method represented by the following reaction formula or a method analogous thereto.
In addition, the compound in a formula also includes the case where the salt is formed, As such a salt, the thing similar to the salt in the compound (I) illustrated above etc. is used, for example.
The compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can be isolated from the reaction mixture according to a conventional method, such as recrystallization, distillation, chromatography, etc. It can be easily purified by separation means.
A schematic diagram of the reaction formula is shown below, and each symbol of the compound in the schematic diagram has the same meaning as described above.
Moreover, each term in a manufacturing method means the following.
“Halogen atom” refers to fluorine, chlorine, bromine and iodine.
The “optionally substituted alkylsulfonyl” is substituted with a substituent selected from a halogen atom, an optionally halogenated C 1-6 alkyl (eg, methyl, ethyl, trifluoromethyl) and nitro. C 1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.) which may be optionally represented.
The “optionally substituted alkylsulfonyloxy” is substituted with a substituent selected from a halogen atom, an optionally halogenated C 1-6 alkyl (eg, methyl, ethyl, trifluoromethyl) and nitro. C 1-6 alkylsulfonyloxy (eg, methylsulfonyloxy, ethylsulfonyloxy and the like) which may be optionally represented.
The “optionally substituted arylsulfonyloxy” is substituted with a substituent selected from a halogen atom, an optionally halogenated C 1-6 alkyl (eg, methyl, ethyl, trifluoromethyl) and nitro. C 6-14 arylsulfonyloxy (eg, phenylsulfonyloxy and the like) which may be optionally represented.
The “optionally substituted aryloxy” is substituted with a substituent selected from a halogen atom, an optionally halogenated C 1-6 alkyl (eg, methyl, ethyl, trifluoromethyl) and nitro. C 6-14 aryloxy (eg, phenyloxy etc.) which may be
The “optionally substituted alkoxy” is substituted with a substituent selected from a halogen atom, an optionally halogenated C 1-6 alkyl (eg, methyl, ethyl, trifluoromethyl) and nitro. Or C 1-6 alkoxy (eg, methoxy, ethoxy, etc.).
［製造法１］
（反応式１） [Production Method 1]
(Reaction Formula 1)
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
（式中、Ｌ１は脱離基を示し、Ｒ０は、Ｒ６０またはＲ６を示す。他の記号は前記と同意義を示す。）
　Ｌ１で示される脱離基としては、例えば、ハロゲン原子、置換されていてもよいアルキルスルホニル、置換されていてもよいアルキルスルホニルオキシ、置換されていてもよいアリールスルホニルオキシ等が用いられる。
工程１－１：　化合物（Ｉ）は、化合物（ＩＩ）と化合物（ＩＩＩ）を塩基存在下、反応させることで製造できる。化合物（ＩＩ）に対して化合物（ＩＩＩ）を０．１ないし１０当量、好ましくは０．３ないし３当量用いる。塩基としては、無機塩基または有機塩基等が用いられるが、具体的には、例えば、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸水素ナトリウム、トリエチルアミン、Ｎ－エチルジイソプロピルアミン、Ｎ－メチルモルホリン、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン、ピリジン、４－（ジメチルアミノ）ピリジン、Ｎ，Ｎ－ジメチルアニリン、ナトリウムメトキシド、ナトリウムエトキシド、カリウム　tert－ブトキシド、水素化ナトリウム、ナトリウムアミド、リチウムジイソプロピルアミド等が挙げられる。これら塩基を、化合物（ＩＩ）に対して１ないし３０当量、好ましくは１ないし１０当量用いる。本反応は反応に不活性な溶媒を用いて行うのが有利である。このような溶媒としては反応が進行する限り特に限定されないが、例えば、メタノール、エタノール、２－プロパノール、２－メチル－２－プロパノール等のアルコール類、ジエチルエーテル、テトラヒドロフラン、１，４－ジオキサン、１，２－ジメトキシエタン等のエーテル類、ベンゼン、トルエン、シクロヘキサン、ヘキサン等の炭化水素類、酢酸エチル、酢酸ブチル等のエステル類、アセトン、メチルエチルケトン等のケトン類、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、１－メチル－２－ピロリドン等のアミド類、ジクロロメタン、クロロホルム、四塩化炭素、１，２－ジクロロエタン等のハロゲン化炭化水素類、アセトニトリル等のニトリル類、ジメチルスルホキシド等のスルホキシド類、ピリジン、水等を単独またはそれらを混合して用いることができる。反応時間は用いる試薬や溶媒により異なるが、通常１分ないし２００時間、好ましくは１０分ないし１００時間である。反応温度は用いる試薬や溶媒により異なるが、通常－１００ないし２５０℃、好ましくは－７８ないし２００℃である。マイクロウエーブ反応装置を用いて反応を行ってもよい。 (In the formula, L 1 represents a leaving group, and R 0 represents R 60 or R 6. Other symbols are as defined above.)
As the leaving group for L 1 , for example, a halogen atom, an optionally substituted alkylsulfonyl, an optionally substituted alkylsulfonyloxy, an optionally substituted arylsulfonyloxy and the like are used.
Step 1-1: Compound (I) can be produced by reacting compound (II) with compound (III) in the presence of a base. Compound (III) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (II). As the base, an inorganic base, an organic base, or the like is used. Specifically, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, triethylamine, N-ethyldiisopropylamine N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, 4- (dimethylamino) pyridine, N, N-dimethylaniline, sodium methoxide, sodium ethoxide, potassium Examples thereof include tert-butoxide, sodium hydride, sodium amide, lithium diisopropylamide and the like. These bases are used in an amount of 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to compound (II). This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds. For example, alcohols such as methanol, ethanol, 2-propanol, 2-methyl-2-propanol, diethyl ether, tetrahydrofuran, 1,4-dioxane, 1 , Ethers such as 2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane, esters such as ethyl acetate and butyl acetate, ketones such as acetone and methyl ethyl ketone, N, N-dimethylformamide, N, Amides such as N-dimethylacetamide and 1-methyl-2-pyrrolidone, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane, nitriles such as acetonitrile, and sulfoxides such as dimethyl sulfoxide , Pyridine, water It can be used alone or as a mixture of them. While the reaction time varies depending on the reagent and solvent to be used, it is generally 1 min to 200 hr, preferably 10 min to 100 hr. While the reaction temperature varies depending on the reagent and solvent to be used, it is generally −100 to 250 ° C., preferably −78 to 200 ° C. The reaction may be carried out using a microwave reactor.
［製造法２］
　化合物（Ｉ）は反応式２で示される方法によっても製造できる。化合物（Ｉ－１）は化合物（Ｉ）に包含される。
（反応式２） [Production Method 2]
Compound (I) can also be produced by the method shown in Reaction Scheme 2. Compound (I-1) is encompassed in compound (I).
(Reaction Formula 2)
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
（式中、Ｌ２は脱離基を、記号は前記と同意義を示す。）
　Ｌ２で示される脱離基としては、例えば、ハロゲン原子、置換されていてもよいアリールオキシ、置換されていてもよいアルコキシ、１－イミダゾリル等が用いられる。
工程２－１：　化合物（Ｖ）は、化合物（ＩＩ）と化合物（ＩＶ）を塩基存在下、反応させることで製造できる。化合物（ＩＩ）に対して化合物（ＩＶ）を０．１ないし１０当量、好ましくは０．３ないし３当量用いる。塩基としては、反応式１で例示した塩基と同様のものが用いられる。化合物（ＩＩ）に対して塩基を１ないし３０当量、好ましくは１ないし１０当量用いる。本反応は反応に不活性な溶媒を用いて行うのが有利である。溶媒としては、反応式１で例示した溶媒と同様のものが用いられる。反応時間は、通常１分ないし２００時間、好ましくは１０分ないし１００時間である。反応温度は、通常－１００ないし２５０℃、好ましくは－７８ないし２００℃である。
工程２－２：　化合物（ＶＩＩ）は、化合物（Ｖ）のニトロ基を還元することで製造できる。ニトロの還元は自体公知の方法、例えば第４版実験化学講座、第２０巻、２７９－２８０等に記載の方法、またはこれらに準じた方法に従って行うことができる。
工程２－３：　化合物（ＶＩＩ）は、化合物（ＩＩ）と化合物（ＶＩ）を塩基存在下、反応させることによっても製造できる。化合物（ＩＩ）に対して化合物（ＶＩ）を０．１ないし１０当量、好ましくは０．３ないし３当量用いる。塩基としては、反応式１で例示した塩基と同様のものが用いられる。化合物（ＩＩ）に対して塩基を１ないし３０当量、好ましくは１ないし１０当量用いる。本反応は反応に不活性な溶媒を用いて行うのが有利である。溶媒としては、反応式１で例示した溶媒と同様のものが用いられる。反応時間は、通常１分ないし２００時間、好ましくは１０分ないし１００時間である。反応温度は、通常－１００ないし２５０℃、好ましくは－７８ないし２００℃である。
工程２－４：　化合物（Ｉ－１）は、化合物（ＶＩＩ）と化合物（ＶＩＩＩ）を縮合剤存在下、反応させることで製造できる。化合物（ＶＩＩ）に対して化合物（ＶＩＩＩ）を０．１ないし１０当量、好ましくは０．３ないし３当量用いる。縮合剤としては、例えば、１－エチル－１－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩、１，３－ジシクロヘキシルカルボジイミド、シアノリン酸ジエチル、アジ化ジフェニルホスホリル、１，１’－カルボニルジイミダゾール、ベンゾトリアゾール－１－イルオキシトリピロリジノホスホニウム　ヘキサフルオロリン酸塩、Ｏ－（ベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウム　ヘキサフルオロリン酸塩、Ｏ－（７－アザベンゾトリアゾール－１－イル）－１，１，３，３－テトラメチルウロニウム　ヘキサフルオロホスファート等を用いることができる。これら縮合剤は、化合物（ＶＩＩ）に対して１ないし１０当量、好ましくは１ないし５当量用いる。必要に応じて適当な縮合促進剤（例えば、１－ヒドロキシベンゾトリアゾール、Ｎ－ヒドロキシスクシンイミド等）を用いることができる。これら縮合促進剤は、化合物（ＶＩＩ）に対して０．１ないし１０当量、好ましくは０．３ないし３当量用いる。また本反応において、塩基を添加することで反応がより円滑に進行する場合がある。塩基としては、反応式１で例示した塩基と同様のものが用いられる。化合物（ＶＩＩ）に対して塩基は０．０１ないし１０当量、好ましくは０．０３ないし５当量用いる。本反応は反応に不活性な溶媒を用いて行うのが有利である。溶媒としては、反応式１で例示した溶媒と同様のものが用いられる。反応時間は、通常１分間ないし２００時間、好ましくは１０分間ないし１００時間である。反応温度は、通常－１００ないし２５０℃、好ましくは－７８ないし２００℃である。
　化合物（Ｉ－１）は、化合物（ＶＩＩ）と化合物（ＩＸ）を反応させることによっても製造できる。化合物（ＶＩＩ）に対して化合物（ＩＸ）を０．１ないし１０当量、好ましくは０．３ないし３当量用いる。化合物（ＶＩＩ）に対して塩基を０．０１ないし１０当量、好ましくは０．０３ないし５当量使用してもよい。塩基としては、反応式１で例示した塩基と同様のものが用いられる。本反応は反応に不活性な溶媒を用いて行うのが有利である。溶媒としては、反応式１で例示した溶媒と同様のものが用いられる。反応時間は、通常１分ないし２００時間、好ましくは１０分ないし１００時間である。反応温度は、通常－１００ないし２５０℃、好ましくは－７８ないし２００℃である。 (In the formula, L 2 is a leaving group, and the symbols are as defined above.)
As the leaving group for L 2 , for example, a halogen atom, optionally substituted aryloxy, optionally substituted alkoxy, 1-imidazolyl and the like are used.
Step 2-1: Compound (V) can be produced by reacting compound (II) with compound (IV) in the presence of a base. Compound (IV) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (II). As the base, those similar to the base exemplified in Reaction Scheme 1 can be used. The base is used in an amount of 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to compound (II). This reaction is advantageously performed using a solvent inert to the reaction. As the solvent, the same solvents as those exemplified in Reaction Scheme 1 can be used. The reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours. The reaction temperature is generally −100 to 250 ° C., preferably −78 to 200 ° C.
Step 2-2: Compound (VII) can be produced by reducing the nitro group of compound (V). The reduction of nitro can be carried out according to a method known per se, for example, the method described in the 4th edition Experimental Chemistry Course, Vol. 20, 279-280 or the like, or a method analogous thereto.
Step 2-3: Compound (VII) can also be produced by reacting Compound (II) with Compound (VI) in the presence of a base. Compound (VI) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (II). As the base, those similar to the base exemplified in Reaction Scheme 1 can be used. The base is used in an amount of 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to compound (II). This reaction is advantageously performed using a solvent inert to the reaction. As the solvent, the same solvents as those exemplified in Reaction Scheme 1 can be used. The reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours. The reaction temperature is generally −100 to 250 ° C., preferably −78 to 200 ° C.
Step 2-4: Compound (I-1) can be produced by reacting Compound (VII) with Compound (VIII) in the presence of a condensing agent. Compound (VIII) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (VII). Examples of the condensing agent include 1-ethyl-1- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1,3-dicyclohexylcarbodiimide, diethyl cyanophosphate, diphenylphosphoryl azide, 1,1′-carbonyldiimidazole, benzoate Triazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate, O— ( 7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate and the like can be used. These condensing agents are used in an amount of 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to compound (VII). If necessary, an appropriate condensation accelerator (for example, 1-hydroxybenzotriazole, N-hydroxysuccinimide, etc.) can be used. These condensation accelerators are used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (VII). In this reaction, the reaction may proceed more smoothly by adding a base. As the base, those similar to the base exemplified in Reaction Scheme 1 can be used. The base is used in an amount of 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents, relative to compound (VII). This reaction is advantageously performed using a solvent inert to the reaction. As the solvent, the same solvents as those exemplified in Reaction Scheme 1 can be used. The reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours. The reaction temperature is generally −100 to 250 ° C., preferably −78 to 200 ° C.
Compound (I-1) can also be produced by reacting compound (VII) with compound (IX). Compound (IX) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (VII). The base may be used in an amount of 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents, relative to compound (VII). As the base, those similar to the base exemplified in Reaction Scheme 1 can be used. This reaction is advantageously performed using a solvent inert to the reaction. As the solvent, the same solvents as those exemplified in Reaction Scheme 1 can be used. The reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours. The reaction temperature is generally −100 to 250 ° C., preferably −78 to 200 ° C.
［製造法３］
　化合物（Ｉ）は反応式３で示される方法によっても製造できる。化合物（Ｉ－２）、（Ｉ－３）は化合物（Ｉ）に包含される。
（反応式３） [Production Method 3]
Compound (I) can also be produced by the method shown in Reaction Scheme 3. Compounds (I-2) and (I-3) are encompassed in compound (I).
(Reaction Formula 3)
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
（式中、Ｒ６Ａは(a)５員の芳香族複素環基を有していてもよいＣ１－６アルキル、(b)Ｃ１－６アルキルを有していてもよいＣ３－６シクロアルキル、(c)ハロゲン原子を有していてもよいＣ７－１２アラルキル、(d)ハロゲン原子、シアノ、１ないし３個のハロゲン原子を有していてもよいＣ１－６アルキル、１ないし３個のハロゲン原子を有していてもよいＣ１－６アルコキシ、Ｃ１－６アルキル－カルボニル、Ｃ１－６アルキルチオ、Ｃ１－６アルコキシ－カルボニルから選ばれる１または２個の置換基を有していてもよいＣ６－１０アリール、または、(e)ハロゲン原子、Ｃ１－６アルキル、Ｃ３－６シクロアルキルから選ばれる１または２個の置換基を有していてもよい芳香族複素環基を示す。他の記号は前記と同意義を示す。）
工程３－１：　化合物（Ｉ－２）は、化合物（ＶＩＩ）と化合物（Ｘ）のモノハロゲン化物を、適当な溶媒（例えば、N,N-ジメチルアセトアミドなど）中で反応させることで製造できる。化合物（Ｘ）のモノハロゲン化物は、化合物（Ｘ）と塩化チオニルを塩基（例えば、トリエチルアミンなど）存在下、適当な溶媒（例えば、テトラヒドロフランなど）中で反応させることで製造できる。
工程３－２：　化合物（Ｉ－３）は、工程２－４と同様の方法により、化合物（Ｉ－２）と化合物（ＸＩ）を縮合させることで製造できる。 (Wherein R 6A is (a) C 1-6 alkyl optionally having a 5-membered aromatic heterocyclic group, and (b) C 3-6 optionally having C 1-6 alkyl. Cycloalkyl, (c) C 7-12 aralkyl optionally having halogen atom, (d) halogen atom, cyano, C 1-6 alkyl optionally having 1 to 3 halogen atoms, 1 1 or 2 substituents selected from C 1-6 alkoxy, C 1-6 alkyl-carbonyl, C 1-6 alkylthio, C 1-6 alkoxy-carbonyl optionally having 3 halogen atoms C 6-10 aryl optionally having 1 or 2 substituents selected from (e) a halogen atom, C 1-6 alkyl, C 3-6 cycloalkyl Represents an aromatic heterocyclic group, and other symbols are as defined above.
Step 3-1: Compound (I-2) can be produced by reacting compound (VII) with a monohalide of compound (X) in an appropriate solvent (eg, N, N-dimethylacetamide, etc.). . The monohalide of compound (X) can be produced by reacting compound (X) with thionyl chloride in the presence of a base (for example, triethylamine) in an appropriate solvent (for example, tetrahydrofuran).
Step 3-2: Compound (I-3) can be produced by condensing compound (I-2) and compound (XI) by the same method as in Step 2-4.
［製造法４］
　化合物（Ｉ）は反応式４で示される方法によっても製造できる。化合物（Ｉ－４）は化合物（Ｉ）に包含される。
（反応式４） [Production Method 4]
Compound (I) can also be produced by the method shown in Reaction Scheme 4. Compound (I-4) is encompassed in compound (I).
(Reaction Formula 4)
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
（式中、Ｒ６Ｂは１ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルキルを有していてもよいＣ６－１０アリールを示す。他の記号は前記と同意義を示す。）
　工程４－１：　化合物（Ｉ－４）は、化合物（ＶＩＩ）とイソシアナート誘導体（ＸＩＩ）を反応させることで化合物（Ｉ－４）を製造できる。化合物（ＶＩＩ）に対してイソシアナート誘導体（ＸＩＩ）を０．１ないし１０当量、好ましくは０．３ないし３当量用いる。また、塩基を０．０１ないし１０当量、好ましくは０．０１ないし３当量使用してもよい。塩基としては、反応式１で例示した塩基と同様のものが用いられる。本反応は反応に不活性な溶媒を用いて行うのが有利である。溶媒としては、反応式１で例示した溶媒と同様のものが用いられる。反応時間は、通常１分ないし２００時間、好ましくは１０分ないし１００時間である。反応温度は、通常－１００ないし２５０℃、好ましくは－７８ないし２００℃である。 (Wherein R 6B represents C 6-10 aryl optionally having C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms. Other symbols are as defined above.) Show.)
Step 4-1: Compound (I-4) can be produced by reacting compound (VII) with isocyanate derivative (XII). The isocyanate derivative (XII) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (VII). Further, 0.01 to 10 equivalents, preferably 0.01 to 3 equivalents of a base may be used. As the base, those similar to the base exemplified in Reaction Scheme 1 can be used. This reaction is advantageously performed using a solvent inert to the reaction. As the solvent, the same solvents as those exemplified in Reaction Scheme 1 can be used. The reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours. The reaction temperature is generally −100 to 250 ° C., preferably −78 to 200 ° C.
［製造法５］
　化合物（Ｉ）は反応式５で示される方法によっても製造できる。化合物（Ｉ－５）は化合物（Ｉ）に包含される。
（反応式５） [Production Method 5]
Compound (I) can also be produced by the method shown in Reaction Scheme 5. Compound (I-5) is encompassed in compound (I).
(Reaction Formula 5)
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
（式中、Ｒ６ＣはＣ７－１２アラルキル－カルボニルを示す。他の記号は前記と同意義を示す。）
　工程５－１：　化合物（Ｉ－５）は、化合物（ＶＩＩ）とアシルチオシアナート誘導体（ＸＩＩＩ）を反応させることで製造できる。化合物（ＶＩＩ）に対して、アシルチオシアナート誘導体（ＸＩＩＩ）を０．１ないし１０当量、好ましくは０．５ないし５当量用いる。本反応は反応に不活性な溶媒を用いて行うのが有利である。溶媒としては、反応式１で例示した溶媒と同様のものが用いられる。反応時間は、通常１分ないし２００時間、好ましくは１０分ないし１００時間である。反応温度は、通常－１００ないし２５０℃、好ましくは－７８ないし２００℃である。 (In the formula, R 6C represents C 7-12 aralkyl-carbonyl. Other symbols are as defined above.)
Step 5-1: Compound (I-5) can be produced by reacting compound (VII) with acyl thiocyanate derivative (XIII). The acyl thiocyanate derivative (XIII) is used in an amount of 0.1 to 10 equivalents, preferably 0.5 to 5 equivalents, relative to compound (VII). This reaction is advantageously performed using a solvent inert to the reaction. As the solvent, the same solvents as those exemplified in Reaction Scheme 1 can be used. The reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours. The reaction temperature is generally −100 to 250 ° C., preferably −78 to 200 ° C.
［製造法６］
　反応式１および２で示した化合物（ＩＩ）は、例えば以下の反応式で示される方法またはこれに準じた方法等により製造できる。
（反応式６） [Production Method 6]
The compound (II) represented by the reaction formulas 1 and 2 can be produced by, for example, the method represented by the following reaction formula or a method analogous thereto.
(Reaction Formula 6)
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
（式中、Ｌ３は脱離基を、Ｒ７は置換されていてもよい炭化水素基を、その他の各記号は前記と同意義を示す。）
　Ｌ３で示される脱離基としては、塩素、臭素、ヨウ素等が用いられる。
　Ｒ７で示される置換されていてもよい炭化水素基としては、例えばメチル、エチル、プロピル、イソプロピル、tert－ブチル等があげられる。
工程６－１：　化合物（ＸＶＩ）は、化合物（ＸＩＶ）とアセチルカルバミン酸誘導体（ＸＶ）を反応させることで製造できる。化合物（ＸＩＶ）に対してアセチルカルバミン酸誘導体（ＸＶ）を０．１ないし１０当量、好ましくは０．３ないし５当量用いる。化合物（ＸＩＶ）に対して塩基を０．１ないし１０当量、好ましくは０．３ないし５当量用いてもよい。塩基としては、無機塩基または有機塩基等が用いられるが、具体的には、例えば、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸水素ナトリウム、リン酸水素二ナトリウム、リン酸水素二カリウム、リン酸水素カルシウム、トリエチルアミン、Ｎ－エチルジイソプロピルアミン、Ｎ－メチルモルホリン、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン、ピリジン、４－（ジメチルアミノ）ピリジン、Ｎ，Ｎ－ジメチルアニリン等が挙げられる。本反応は反応に不活性な溶媒を用いて行うのが有利である。溶媒としては、反応式１で例示した溶媒と同様のものが用いられる。反応時間は、通常１分ないし２００時間、好ましくは１０分ないし１００時間である。反応温度は、通常－１００ないし２５０℃、好ましくは－７８ないし２００℃である。
工程６－２：　化合物（ＸＶＩＩ）は、化合物（ＸＶＩ）を塩基または酸で処理することで製造できる。塩基としては、例えば、水酸化ナトリウム、水酸化カリウム、水酸化セシウム、水酸化バリウム等が挙げられる。化合物（ＸＶＩ）に対して塩基を０．０１ないし１０当量、好ましくは０．０３ないし５当量用いる。酸としては、例えば、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、トリフルオロ酢酸等が挙げられる。化合物（ＸＶＩ）に対して酸を０．１ないし２０当量、好ましくは０．３ないし１０当量用いる。本反応は反応に不活性な溶媒を用いて行うのが有利である。溶媒としては、反応式１で例示した溶媒と同様のものが用いられる。
工程６－３：　化合物（ＩＩ）は、化合物（ＸＶＩＩ）と化合物（ＸＶＩＩＩ）を反応させることで製造できる。化合物（ＸＶＩＩ）に対して化合物（ＸＶＩＩＩ）を０．１ないし１０当量、好ましくは０．３ないし３当量用いる。化合物（ＸＶＩＩ）に対して塩基を０．０１ないし１０当量、好ましくは０．０３ないし５当量使用してもよい。塩基としては、反応式１で例示した塩基と同様のものが用いられる。本反応は反応に不活性な溶媒を用いて行うのが有利である。溶媒としては、反応式１で例示した溶媒と同様のものが用いられる。反応時間は、通常１分ないし２００時間、好ましくは１０分ないし１００時間である。反応温度は、通常－１００ないし２５０℃、好ましくは－７８ないし２００℃である。 (Wherein L 3 represents a leaving group, R 7 represents an optionally substituted hydrocarbon group, and other symbols are as defined above.)
As the leaving group represented by L 3 , chlorine, bromine, iodine and the like are used.
Examples of the optionally substituted hydrocarbon group represented by R 7 include methyl, ethyl, propyl, isopropyl, tert-butyl and the like.
Step 6-1: Compound (XVI) can be produced by reacting compound (XIV) with acetylcarbamic acid derivative (XV). The acetylcarbamic acid derivative (XV) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 5 equivalents, relative to compound (XIV). The base may be used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 5 equivalents, relative to compound (XIV). As the base, an inorganic base or an organic base is used. Specifically, for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, hydrogen phosphate Calcium, triethylamine, N-ethyldiisopropylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, 4- (dimethylamino) pyridine, N, N-dimethylaniline, etc. Is mentioned. This reaction is advantageously performed using a solvent inert to the reaction. As the solvent, the same solvents as those exemplified in Reaction Scheme 1 can be used. The reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours. The reaction temperature is generally −100 to 250 ° C., preferably −78 to 200 ° C.
Step 6-2: Compound (XVII) can be produced by treating compound (XVI) with a base or acid. Examples of the base include sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide and the like. The base is used in an amount of 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents, relative to compound (XVI). Examples of the acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, trifluoroacetic acid and the like. The acid is used in an amount of 0.1 to 20 equivalents, preferably 0.3 to 10 equivalents, relative to compound (XVI). This reaction is advantageously performed using a solvent inert to the reaction. As the solvent, the same solvents as those exemplified in Reaction Scheme 1 can be used.
Step 6-3: Compound (II) can be produced by reacting compound (XVII) with compound (XVIII). Compound (XVIII) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (XVII). The base may be used in an amount of 0.01 to 10 equivalents, preferably 0.03 to 5 equivalents, relative to compound (XVII). As the base, those similar to the base exemplified in Reaction Scheme 1 can be used. This reaction is advantageously performed using a solvent inert to the reaction. As the solvent, the same solvents as those exemplified in Reaction Scheme 1 can be used. The reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours. The reaction temperature is generally −100 to 250 ° C., preferably −78 to 200 ° C.
［製造法７］
　反応式１および２で示した化合物（ＩＩ）は、例えば以下の反応式で示される方法またはこれに準じた方法等によっても製造できる。
（反応式７） [Production Method 7]
Compound (II) represented by Reaction Schemes 1 and 2 can also be produced, for example, by the method represented by the following reaction scheme or a method analogous thereto.
(Reaction Formula 7)
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
（式中、Ｌ４およびＬ５は脱離基を、その他の記号は前記と同意義を示す。）
　Ｌ４およびＬ５で示される脱離基としては、塩素、臭素、ヨウ素等が用いられる。
工程７－１：　化合物（ＸＸＩ）は、化合物（ＸＩＸ）と化合物（ＸＸ）を反応させることで製造できる。化合物（ＸＩＸ）に対して化合物（ＸＸ）を０．１ないし１０当量、好ましくは０．３ないし３当量用いる。化合物（ＸＩＸ）に対して塩基を０．０１ないし１０当量使用してもよい。塩基としては、反応式１で例示した塩基と同様のものが用いられる。本反応は反応に不活性な溶媒を用いて行うのが有利である。溶媒としては、反応式１で例示した溶媒と同様のものが用いられる。反応時間は、通常１分ないし２００時間、好ましくは１０分ないし１００時間である。反応温度は、通常－１００ないし２５０℃、好ましくは－７８ないし２００℃である。
工程７－２：　化合物（ＩＩ）は、化合物（ＸＸＩ）と化合物（ＸＩＶ）を反応させることで製造できる。化合物（ＸＩＶ）に対して化合物（ＸＸＩ）を０．１ないし１０当量、好ましくは０．３ないし５当量用いる。化合物（ＸＩＶ）に対して塩基を０．１ないし１０当量、好ましくは０．３ないし５当量用いてもよい。塩基としては、無機塩基または有機塩基等が用いられるが、具体的には、例えば、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸水素ナトリウム、リン酸三ナトリウム、リン酸三カリウム、リン酸水素二ナトリウム、リン酸水素二カリウム、リン酸水素カルシウム、リン酸二水素一ナトリウム、リン酸二水素一カリウム、トリエチルアミン、Ｎ－エチルジイソプロピルアミン、Ｎ－メチルモルホリン、１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン、ピリジン、４－（ジメチルアミノ）ピリジン、Ｎ，Ｎ－ジメチルアニリン等が挙げられる。本反応は反応に不活性な溶媒を用いて行うのが有利である。溶媒としては、反応式１で例示した溶媒と同様のものが用いられる。反応時間は、通常１分ないし２００時間、好ましくは１０分ないし１００時間である。反応温度は、通常－１００ないし２５０℃、好ましくは－７８ないし２００℃である。
　化合物（ＩＩ）は、化合物（ＸＸＩ）を単離精製することなく、工程７－１と工程７－２を連続して実施することでも製造できる。 (Wherein L 4 and L 5 are leaving groups, and other symbols are as defined above.)
As the leaving group represented by L 4 and L 5 , chlorine, bromine, iodine and the like are used.
Step 7-1: Compound (XXI) can be produced by reacting compound (XIX) with compound (XX). Compound (XX) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (XIX). The base may be used in an amount of 0.01 to 10 equivalents relative to compound (XIX). As the base, those similar to the base exemplified in Reaction Scheme 1 can be used. This reaction is advantageously performed using a solvent inert to the reaction. As the solvent, the same solvents as those exemplified in Reaction Scheme 1 can be used. The reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours. The reaction temperature is generally −100 to 250 ° C., preferably −78 to 200 ° C.
Step 7-2: Compound (II) can be produced by reacting compound (XXI) with compound (XIV). Compound (XXI) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 5 equivalents, relative to compound (XIV). The base may be used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 5 equivalents, relative to compound (XIV). As the base, an inorganic base or an organic base is used. Specifically, for example, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, trisodium phosphate, tripotassium phosphate, disodium hydrogen phosphate. Dipotassium hydrogen phosphate, calcium hydrogen phosphate, monosodium dihydrogen phosphate, monopotassium dihydrogen phosphate, triethylamine, N-ethyldiisopropylamine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] ] Undec-7-ene, pyridine, 4- (dimethylamino) pyridine, N, N-dimethylaniline and the like. This reaction is advantageously performed using a solvent inert to the reaction. As the solvent, the same solvents as those exemplified in Reaction Scheme 1 can be used. The reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours. The reaction temperature is generally −100 to 250 ° C., preferably −78 to 200 ° C.
Compound (II) can also be produced by sequentially performing Step 7-1 and Step 7-2 without isolating and purifying Compound (XXI).
［製造法８］
　反応式２で示した化合物（Ｖ）は、反応式８で示される方法によっても製造できる。
（反応式８） [Production Method 8]
Compound (V) shown in Reaction Scheme 2 can also be produced by the method shown in Reaction Scheme 8.
(Reaction Formula 8)
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
（式中、記号は前記と同意義を示す。）
工程８－１：　化合物（Ｖ）は、化合物（ＸＸＩＩ）と化合物（ＸＸＩＩＩ）を塩基存在下、反応させることで製造できる。化合物（ＸＸＩＩ）に対して化合物（ＸＸＩＩＩ）を０．１ないし１０当量、好ましくは０．３ないし３当量用いる。塩基としては、反応式１で例示した塩基と同様のものが用いられる。化合物（ＸＸＩＩ）に対して塩基を１ないし３０当量、好ましくは１ないし１０当量用いる。本反応は反応に不活性な溶媒を用いて行うのが有利である。溶媒としては、反応式１で例示した溶媒と同様のものが用いられる。反応時間は、通常１分ないし２００時間、好ましくは１０分ないし１００時間である。反応温度は、通常－１００ないし２５０℃、好ましくは－７８ないし２００℃である。 (In the formula, the symbols are as defined above.)
Step 8-1: Compound (V) can be produced by reacting compound (XXII) with compound (XXIII) in the presence of a base. Compound (XXIII) is used in an amount of 0.1 to 10 equivalents, preferably 0.3 to 3 equivalents, relative to compound (XXII). As the base, those similar to the base exemplified in Reaction Scheme 1 can be used. The base is used in the amount of 1 to 30 equivalents, preferably 1 to 10 equivalents, relative to compound (XXII). This reaction is advantageously performed using a solvent inert to the reaction. As the solvent, the same solvents as those exemplified in Reaction Scheme 1 can be used. The reaction time is usually 1 minute to 200 hours, preferably 10 minutes to 100 hours. The reaction temperature is generally −100 to 250 ° C., preferably −78 to 200 ° C.
［製造法９］
　反応式８で示した化合物（ＸＸＩＩ）は、例えば以下の反応式で示される方法またはこれに準じた方法等により製造できる。
（反応式９） [Production Method 9]
Compound (XXII) represented by Reaction Scheme 8 can be produced, for example, by the method represented by the following Reaction Formula or a method analogous thereto.
(Reaction Formula 9)
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
（式中、各記号は前記と同意義を示す。）
工程９－１：　化合物（ＸＸＩＶ）は、化合物（ＸＶＩＩ）とナトリウムメトキシドを、適当な溶媒（例えばメタノールなど）中で反応させることで製造できる。
工程９－２：　化合物（ＸＸＶ）は、工程６－３と同様の方法により、化合物（ＸＸＩＶ）と化合物（ＸＶＩＩＩ）を反応させることで製造できる。
工程９－３：　化合物（ＸＸＩＩ）は、化合物（ＸＸＶ）とナトリウムエタンチオラートを、適当な溶媒（例えば、Ｎ，Ｎ－ジメチルホルムアミドなど）中で反応させることで製造できる。 (In the formula, each symbol is as defined above.)
Step 9-1: Compound (XXIV) can be produced by reacting compound (XVII) with sodium methoxide in an appropriate solvent (eg, methanol).
Step 9-2: Compound (XXV) can be produced by reacting compound (XXIV) with compound (XVIII) by the same method as in Step 6-3.
Step 9-3: Compound (XXII) can be produced by reacting compound (XXV) with sodium ethanethiolate in a suitable solvent (eg, N, N-dimethylformamide and the like).
［製造法１０］
　化合物（Ｉ）は反応式１０で示される方法によっても製造できる。（Ｉ－７）は化合物（Ｉ）に包含される。
（反応式１０） [Production method 10]
Compound (I) can also be produced by the method shown in Reaction Scheme 10. (I-7) is encompassed in compound (I).
(Reaction Formula 10)
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
（式中、各記号は前記と同意義を示す。）
工程１０－１：　化合物（Ｉ－６）は、工程２－４と同様の方法により、化合物（ＶＩＩ）と化合物（ＸＸＶＩ）を反応させることで製造できる。
工程１０－２：　化合物（Ｉ－７）は、化合物（Ｉ－６）とオルトぎ酸トリエチルおよび酢酸を、適当な溶媒（例えば、エタノール、テトラヒドロフランなど）中で反応させることで製造できる。 (In the formula, each symbol is as defined above.)
Step 10-1: Compound (I-6) can be produced by reacting compound (VII) with compound (XXVI) in the same manner as in Step 2-4.
Step 10-2: Compound (I-7) can be produced by reacting compound (I-6) with triethyl orthoformate and acetic acid in a suitable solvent (eg, ethanol, tetrahydrofuran, etc.).
　前記反応式中、化合物（ＩＩＩ）、（ＩＶ）、（ＶＩ）、（ＶＩＩＩ）、（ＩＸ）、（Ｘ）、（ＸＩ）、（ＸＩＩ）、（ＸＩＩＩ）、（ＸＩＶ）、（ＸＶ）、（ＸＶＩＩＩ）、（ＸＩＸ）、(ＸＸ)、（ＸＸＩＩＩ）、（ＸＸＶＩ）は、市販のものを使用するか、または自体公知の方法、例えば「Advanced Organic Chemistry, 4th Ed.」（Jerry March著）、「Comprehensive Organic Transformations, 2nd Ed.」（Richard C. Larock著）等に記載の方法、またはこれらに準じた方法に従って製造することができる。 In the reaction formula, compounds (III), (IV), (VI), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVIII), (XIX), (XX), (XXIII), (XXVI) are commercially available, or a method known per se, for example, “Advanced Organic Chemistry, 4th Ed” (by Jerry March) , “Comprehensive Organic Transformations, 2nd Ed.” (By Richard C. Larock) or the like, or a method based thereon.
　化合物（Ｉ）に、自体公知の手段を適用してさらに置換基の導入や官能基変換を行い、本発明の範囲に含まれる化合物を製造することもできる。置換基変換は公知の一般的方法が用いられるが、例えばエステルの加水分解によるカルボキシへの変換、カルボキシのアミド化によるカルバモイルへの変換、カルボキシの還元によるヒドロキシメチルへの変換、カルボニルの還元やアルキル化によるアルコール体への変換、カルボニルの還元的アミノ化、カルボニルのオキシム化、アミノのアシル化・ウレア化・スルホニル化・アルキル化、アミンによる活性ハロゲンの置換・アミノ化、ニトロの還元によるアミノ化、ヒドロキシのアルキル化、ヒドロキシの置換・アミノ化があげられる。この置換基の導入や官能基変換を行うに際し、目的以外の反応が起きる反応性置換基が存在する場合は、必要に応じて自体公知の手段によりその反応性置換基に事前に保護基を導入し、目的の反応を行った後にその保護基をやはり自体公知の手段により除去して、本発明の範囲に含まれる化合物を製造することもできる。
　例えば、原料化合物や中間体が置換基としてアミノ基、カルボキシル基または水酸基を有する場合、これらの基は、ペプチド化学などで一般的に用いられるような保護基で保護されていてもよい。この場合、反応後に、必要に応じて保護基を除去することにより目的化合物を得ることができる。
　アミノ基の保護基としては、例えば、ホルミル基、Ｃ１－６アルキル－カルボニル基、Ｃ１－６アルコキシ－カルボニル基、ベンゾイル基、Ｃ７－１０アラルキル－カルボニル基（例、ベンジルカルボニル）、Ｃ７－１４アラルキルオキシ－カルボニル基（例、ベンジルオキシカルボニル、９－フルオレニルメトキシカルボニル）、トリチル基、フタロイル基、Ｎ，Ｎ－ジメチルアミノメチレン基、置換シリル基（例、トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、ｔｅｒｔ－ブチルジメチルシリル、ｔｅｒｔ－ブチルジエチルシリル）、Ｃ２－６アルケニル基（例、１－アリル）などが挙げられる。これらの基は、ハロゲン原子、Ｃ１－６アルコキシ基およびニトロ基から選ばれる１ないし３個の置換基で置換されていてもよい。
　カルボキシル基の保護基としては、例えば、Ｃ１－６アルキル基、Ｃ７－１１アラルキル基（例、ベンジル）、フェニル基、トリチル基、置換シリル基（例、トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、ｔｅｒｔ－ブチルジメチルシリル、ｔｅｒｔ－ブチルジエチルシリル）、Ｃ２－６アルケニル基（例、１－アリル）等が挙げられる。
　水酸基の保護基としては、例えば、Ｃ１－６アルキル基、フェニル基、トリチル基、Ｃ７－１０アラルキル基（例、ベンジル）、ホルミル基、Ｃ１－６アルキル－カルボニル基、ベンゾイル基、Ｃ７－１０アラルキル－カルボニル基（例、ベンジルカルボニル）、２－テトラヒドロピラニル基、２－テトラヒドロフラニル基、置換シリル基（例、トリメチルシリル、トリエチルシリル、ジメチルフェニルシリル、ｔｅｒｔ－ブチルジメチルシリル、ｔｅｒｔ－ブチルジエチルシリル）、Ｃ２－６アルケニル基（例、１－アリル）などが挙げられる。
　これらの基は、ハロゲン原子、Ｃ１－６アルキル基、Ｃ１－６アルコキシ基またはニトロ基から選ばれる１ないし３個の置換基で置換されていてもよい。
　上記した保護基の除去方法は、自体公知の方法、例えば、「Protective Groups in Organic Synthesis」, John Wiley and Sons 編(1980)に記載の方法などが挙げられる。具体的には、酸、塩基、紫外光、ヒドラジン、フェニルヒドラジン、Ｎ－メチルジチオカルバミン酸ナトリウム、テトラブチルアンモニウムフルオリド、酢酸パラジウム、トリアルキルシリルハライド（例えば、トリメチルシリルヨージド、トリメチルシリルブロミドなど）などを使用する方法や還元法などが用いられる。 A compound within the scope of the present invention can also be produced by applying means known per se to compound (I) to further introduce substituents or convert functional groups. For the substituent conversion, known general methods are used. For example, conversion to carboxy by hydrolysis of ester, conversion to carbamoyl by amidation of carboxy, conversion to hydroxymethyl by reduction of carboxy, reduction of carbonyl or alkyl To alcohol by rehydration, reductive amination of carbonyl, oximation of carbonyl, acylation / urealation / sulfonylation / alkylation of amino, substitution / amination of active halogen with amine, amination by reduction of nitro , Hydroxy alkylation, hydroxy substitution / amination. When introducing a substituent or converting a functional group, if there is a reactive substituent that causes a reaction other than the intended purpose, a protective group is introduced into the reactive substituent in advance by a publicly known means as necessary. In addition, after carrying out the desired reaction, the protecting group can be removed by means known per se to produce a compound within the scope of the present invention.
For example, when the raw material compound or intermediate has an amino group, carboxyl group or hydroxyl group as a substituent, these groups may be protected with a protecting group generally used in peptide chemistry or the like. In this case, the target compound can be obtained by removing the protecting group as necessary after the reaction.
Examples of the protecting group for amino group include formyl group, C 1-6 alkyl-carbonyl group, C 1-6 alkoxy-carbonyl group, benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), C 7-14 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, Dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkoxy group and a nitro group.
Examples of the protecting group for the carboxyl group include a C 1-6 alkyl group, a C 7-11 aralkyl group (eg, benzyl), a phenyl group, a trityl group, a substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like.
Examples of the hydroxyl protecting group include C 1-6 alkyl group, phenyl group, trityl group, C 7-10 aralkyl group (eg, benzyl), formyl group, C 1-6 alkyl-carbonyl group, benzoyl group, C 7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert- Butyldiethylsilyl), C 2-6 alkenyl groups (eg, 1-allyl) and the like.
These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group or a nitro group.
Examples of the method for removing the protecting group include methods known per se, such as the method described in “Protective Groups in Organic Synthesis”, edited by John Wiley and Sons (1980). Specifically, acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halides (for example, trimethylsilyl iodide, trimethylsilyl bromide, etc.) The method used or the reduction method is used.
　化合物（Ｉ）は、公知の手段、例えば、転溶、濃縮、溶媒抽出、分溜、液性変換、晶出、再結晶、クロマトグラフィー等によって単離、精製することができる。化合物（Ｉ）が遊離化合物として得られた場合には、自体公知の方法あるいはそれに準ずる方法によって、目的とする塩に変換することができ、逆に塩で得られた場合には、自体公知の方法あるいはそれに準ずる方法により、遊離体または目的とする他の塩に変換することができる。 Compound (I) can be isolated and purified by known means such as phase transfer, concentration, solvent extraction, fractionation, liquid conversion, crystallization, recrystallization, chromatography and the like. When compound (I) is obtained as a free compound, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely when it is obtained as a salt, it is known per se. It can be converted into a free form or other desired salt by the method or a method analogous thereto.
　化合物（Ｉ）はプロドラッグとして用いてもよい。化合物（Ｉ）のプロドラッグは、生体内における生理条件下で酵素や胃酸等による反応により化合物（Ｉ）に変換する化合物、すなわち酵素的に酸化、還元、加水分解等を起こして化合物（Ｉ）に変化する化合物、胃酸等により加水分解等を起こして化合物（Ｉ）に変化する化合物をいう。 Compound (I) may be used as a prodrug. A prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) that is enzymatically oxidized, reduced, hydrolyzed, etc. A compound that changes to compound (I) by hydrolysis or the like due to gastric acid or the like.
　化合物（Ｉ）のプロドラッグとしては、化合物（Ｉ）のアミノがアシル化、アルキル化、リン酸化された化合物（例えば、化合物（Ｉ）のアミノがエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、tert-ブチル化された化合物等）；化合物（Ｉ）のヒドロキシルがアシル化、アルキル化、リン酸化、ホウ酸化された化合物（例えば、化合物（Ｉ）のヒドロキシルがアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、スクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物等）；化合物（Ｉ）のカルボキシがエステル化、アミド化された化合物（例えば、化合物（Ｉ）のカルボキシがエチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、エトキシカルボニルオキシエチルエステル化、フタリジルエステル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メチルエステル化、シクロヘキシルオキシカルボニルエチルエステル化、メチルアミド化された化合物等）；等が挙げられる。これらの化合物は、自体公知の方法によって化合物（Ｉ）から製造することができる。 As a prodrug of the compound (I), a compound in which the amino of the compound (I) is acylated, alkylated or phosphorylated (for example, the amino of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, ( 5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); compounds ( Compounds wherein the hydroxyl of I) is acylated, alkylated, phosphorylated, borated (eg, hydroxyl of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, Dimethylaminomethylcarbonylated compounds, etc.); the carboxy of compound (I) is And amidated compounds (for example, carboxy of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl ester , Phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamidated compounds, and the like). These compounds can be produced from compound (I) by a method known per se.
　また、化合物（Ｉ）のプロドラッグは、広川書店１９９０年刊「医薬品の開発」第７巻分子設計１６３頁から１９８頁に記載されているような生理的条件で化合物（Ｉ）に変化するものであってもよい。 The prodrug of compound (I) changes to compound (I) under physiological conditions as described in Hirokawa Shoten, 1990, “Development of Drugs”, Volume 7, Molecular Design, pages 163 to 198. There may be.
　化合物（Ｉ）が、光学異性体、立体異性体、位置異性体、回転異性体等の異性体を有する場合には、いずれか一方の異性体も混合物も化合物（Ｉ）に包含される。例えば、化合物（Ｉ）に光学異性体が存在する場合には、ラセミ体から分割された光学異性体も化合物（Ｉ）に包含される。これらの異性体は、自体公知の合成手法、分離手法（濃縮、溶媒抽出、カラムクロマトグラフィー、再結晶等）によりそれぞれを単品として得ることができる。 When the compound (I) has an isomer such as an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, etc., any one of the isomers and a mixture are included in the compound (I). For example, when compound (I) has an optical isomer, the optical isomer resolved from the racemate is also encompassed in compound (I). Each of these isomers can be obtained as a single product by a known synthesis method or separation method (concentration, solvent extraction, column chromatography, recrystallization, etc.).
　化合物（Ｉ）は、結晶であってもよく、結晶形が単一であっても結晶形混合物であっても化合物（Ｉ）に包含される。結晶は、自体公知の結晶化法を適用して、結晶化することによって製造することができる。
　化合物（Ｉ）は、共結晶であってもよい。
　化合物（Ｉ）は、溶媒和物（例えば、水和物等）であっても、無溶媒和物（例えば、非水和物等）であってもよく、いずれも化合物（Ｉ）に包含される。
　同位元素（例、２Ｈ、３Ｈ、１４Ｃ、３５Ｓ、１２５Ｉ等）等で標識された化合物も、化合物（Ｉ）に包含される。
　さらに、化合物（Ｉ）は、重水素変換体であってもよい。 Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a crystal form mixture. Crystals can be produced by crystallization by applying a crystallization method known per se.
Compound (I) may be a co-crystal.
Compound (I) may be a solvate (eg, hydrate etc.) or non-solvate (eg non-hydrate etc.), both of which are encompassed in compound (I). The
Compounds labeled with isotopes (eg, 2 H, 3 H, 14 C, 35 S, 125 I, etc.) are also encompassed in compound (I).
Further, compound (I) may be a deuterium converter.
　化合物（Ｉ）またはそのプロドラッグ（本明細書中、「本発明の化合物」と略記することがある）は、例えば、キナーゼが有するリン酸化作用に対して、そのリン酸化を阻害する活性を有する。ここで、キナーゼとは、それ自身が全体としてリン酸化作用を有する物質のみならず、その部分がリン酸化作用を有する物質も包含し、キナーゼの有するリン酸化作用とは、自己に対するリン酸化作用および他の物質に対するリン酸化作用のどちらの作用も包含する。
　キナーゼとしては、例えば、血管内皮増殖因子受容体（ＶＥＧＦＲ）、血小板由来増殖因子受容体（ＰＤＧＦＲ）、Ｒａｆ、ｃ－Ｍｅｔ等が挙げられる。血管内皮増殖因子受容体（ＶＥＧＦＲ）としては、血管内皮増殖因子受容体１（ＶＥＧＦＲ１、Ｆｌｔ－１）、血管内皮増殖因子受容体２（ＶＥＧＦＲ２、ＫＤＲ、Ｆｌｋ－１）、血管内皮増殖因子受容体３（ＶＥＧＦＲ３、Ｆｌｔ－４）等が挙げられ、なかでも血管内皮増殖因子受容体２（ＶＥＧＦＲ２）が好ましい。血小板由来増殖因子受容体（ＰＤＧＦＲ）としては、血小板由来増殖因子受容体α（ＰＤＧＦＲα）、血小板由来増殖因子受容体β（ＰＤＧＦＲβ）等が挙げられる。Ｒａｆとしては、Ａ－Ｒａｆ、Ｂ－Ｒａｆ、Ｃ－Ｒａｆ等が挙げられる。特に、キナーゼとしては、血管内皮増殖因子受容体２（ＶＥＧＦＲ２）、血小板由来増殖因子受容体（ＰＤＧＦＲ）、Ｒａｆ、ｃ－Ｍｅｔが好ましい。
　その他、キナーゼとしては、ＴＩＥ２、繊維芽細胞増殖因子受容体（ＦＧＦＲ）、幹細胞因子受容体（ｃ－Ｋｉｔ）、Ａｕｒｏｒａ、ＣＤＫ、ＭＥＫ、Ａｋｔ、ＥＲＫ、ＭＡＰＫ、Ｓｒｃ、上皮細胞増殖因子受容体（ＥＧＦＲ）、上皮細胞増殖因子受容体２（ＨＥＲ２）、上皮細胞増殖因子受容体４（ＨＥＲ４）、Ａｂｌ、Ｆｇｒ、Ｆｍｓ、Ｆｌｔ３、Ｒｏｎ、Ｒｅｔ、Ｅｐｈ等も挙げられる。 Compound (I) or a prodrug thereof (may be abbreviated as “the compound of the present invention” in the present specification) has, for example, an activity of inhibiting its phosphorylation against the phosphorylation action of a kinase. . Here, the kinase includes not only a substance having a phosphorylation action as a whole, but also a substance having a phosphorylation action on its part, and the phosphorylation action of a kinase is a phosphorylation action on self and It includes both effects of phosphorylation on other substances.
Examples of the kinase include vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), Raf, c-Met and the like. As vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 1 (VEGFR1, Flt-1), vascular endothelial growth factor receptor 2 (VEGFR2, KDR, Flk-1), vascular endothelial growth factor receptor 3 (VEGFR3, Flt-4) and the like, among which vascular endothelial growth factor receptor 2 (VEGFR2) is preferable. Examples of the platelet-derived growth factor receptor (PDGFR) include platelet-derived growth factor receptor α (PDGFRα), platelet-derived growth factor receptor β (PDGFRβ), and the like. Examples of Raf include A-Raf, B-Raf, C-Raf and the like. In particular, the kinase is preferably vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), Raf, or c-Met.
Other kinases include TIE2, fibroblast growth factor receptor (FGFR), stem cell factor receptor (c-Kit), Aurora, CDK, MEK, Akt, ERK, MAPK, Src, epidermal growth factor receptor ( EGFR), epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor 4 (HER4), Abl, Fgr, Fms, Flt3, Ron, Ret, Eph and the like.
　例えば、本発明の化合物の血管内皮増殖因子受容体２（ＶＥＧＦＲ２）阻害活性は、試験例１に準じて、血管内皮細胞の増殖阻害活性は、試験例２に準じて、肝細胞増殖因子受容体（ｃ－Ｍｅｔ）阻害活性は、試験例３に準じて、ヒト胃癌細胞ＭＫＮ４５増殖阻害活性は、試験例４に準じて、抗腫瘍活性は試験例５に準じて測定することができる。 For example, the vascular endothelial growth factor receptor 2 (VEGFR2) inhibitory activity of the compound of the present invention is in accordance with Test Example 1, and the vascular endothelial cell growth inhibitory activity is in accordance with Test Example 2, and hepatocyte growth factor receptor. (C-Met) inhibitory activity can be measured according to Test Example 3, human gastric cancer cell MKN45 growth inhibitory activity according to Test Example 4, and antitumor activity can be measured according to Test Example 5.
　本発明の化合物は、特に血管内皮増殖因子受容体（ＶＥＧＦＲ）に対し強い阻害活性を示し、なかでも血管内皮増殖因子受容体２（ＶＥＧＦＲ２、ＫＤＲ、Ｆｌｋ－１）に対する選択性が高く、さらに、ＶＥＧＦＲ１、ＰＤＧＦＲ、Ｒａｆに対しても強いキナーゼ阻害活性を示す。また、本発明の化合物は、肝細胞増殖因子受容体（ｃ－Ｍｅｔ）に対し強い阻害作用を示す。また、本発明の化合物は、薬効発現、薬物動態（吸収性、分布、代謝、排泄等）、溶解性（水溶性等）、他の医薬品との相互作用、安全性（急性毒性、慢性毒性、遺伝毒性、生殖毒性、心臓毒性、癌原性等）、安定性（化学的安定性、酵素に対する安定性等）の点でも優れているので、医薬として有用である。 The compound of the present invention exhibits a strong inhibitory activity especially against the vascular endothelial growth factor receptor (VEGFR), among which the selectivity for the vascular endothelial growth factor receptor 2 (VEGFR2, KDR, Flk-1) is high, It also shows strong kinase inhibitory activity against VEGFR1, PDGFR, and Raf. In addition, the compound of the present invention exhibits a strong inhibitory action on hepatocyte growth factor receptor (c-Met). In addition, the compound of the present invention has a medicinal effect, pharmacokinetics (absorbability, distribution, metabolism, excretion, etc.), solubility (water solubility, etc.), interaction with other pharmaceuticals, safety (acute toxicity, chronic toxicity, Genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity, etc.) and stability (chemical stability, stability to enzymes, etc.) are also excellent and useful as pharmaceuticals.
　従って、本発明の化合物は、哺乳動物（例えば、マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒト等）に対して、キナーゼ阻害剤、好ましくは血管内皮増殖因子受容体（ＶＥＧＦＲ）阻害剤、血小板由来増殖因子受容体（ＰＤＧＦＲ）阻害剤、Ｒａｆ阻害剤、さらに好ましくは血管内皮増殖因子受容体２（ＶＥＧＦＲ２、ＫＤＲ、Ｆｌｋ－１）阻害剤として有用である。また、本発明の化合物は血管新生阻害剤、血管内皮細胞増殖阻害剤として有用である。本発明の化合物は、血管内皮増殖因子により影響される可能性のある疾患、例えば、癌（例えば、大腸癌（例えば、家族性大腸癌、遺伝性非ポリポーシス大腸癌、消化管間質腫瘍など）、肺癌（例えば、非小細胞肺癌、小細胞肺癌、悪性中皮腫など）、中皮腫、膵臓癌（例えば、膵管癌など）、胃癌（例えば、乳頭腺癌、粘液性腺癌、腺扁平上皮癌など）、乳癌（例えば、浸潤性乳管癌、非浸潤性乳管癌、炎症性乳癌など）、卵巣癌（例えば、上皮性卵巣癌、性腺外胚細胞腫瘍、卵巣性胚細胞腫瘍、卵巣低悪性度腫瘍など）、前立腺癌（例えば、ホルモン依存性前立腺癌、ホルモン非依存性前立腺癌など）、肝臓癌（例えば、原発性肝癌、肝外胆管癌など）、甲状腺癌（例えば、甲状腺髄様癌など）、腎臓癌（例えば、腎細胞癌、腎盂と尿管の移行上皮癌など）、子宮癌、脳腫瘍（例えば、松果体星細胞腫瘍、毛様細胞性星細胞腫、びまん性星細胞腫、退形成性星細胞腫など）、黒色腫（メラノーマ）、肉腫、膀胱癌、多発性骨髄腫を含む血液癌等）、糖尿病性網膜症、関節リウマチ、乾癬、アテローム性動脈硬化症、カポジ肉腫、ＣＯＰＤ、痛み、喘息、子宮内膜症、腎炎、変形性関節症等の炎症、高血圧の予防・治療剤、癌の増殖阻害剤、癌の転移抑制剤、アポトーシス促進剤等の医薬として用いられる。なかでも、例えば、大腸癌、肺癌、膵臓癌、胃癌、乳癌、卵巣癌、前立腺癌、肝臓癌、甲状腺癌、腎臓癌、脳腫瘍、黒色腫（メラノーマ）、膀胱癌、血液癌に対して有効であり、特に本発明の化合物は、肺癌、大腸癌、卵巣癌、前立腺癌、腎臓癌の患者に対して有効である。また、本発明の化合物は、強いｃ－Ｍｅｔ阻害作用に基づき、癌の浸潤・転移抑制作用を呈する。 Therefore, the compound of the present invention is a kinase inhibitor, preferably a vascular endothelial growth factor receptor, for mammals (eg, mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey, human etc.). It is useful as a (VEGFR) inhibitor, a platelet derived growth factor receptor (PDGFR) inhibitor, a Raf inhibitor, more preferably a vascular endothelial growth factor receptor 2 (VEGFR2, KDR, Flk-1) inhibitor. The compounds of the present invention are useful as angiogenesis inhibitors and vascular endothelial cell growth inhibitors. The compounds of the present invention can be affected by vascular endothelial growth factors such as cancer (eg, colon cancer (eg, familial colon cancer, hereditary nonpolyposis colon cancer, gastrointestinal stromal tumor, etc.) , Lung cancer (eg, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma, etc.), mesothelioma, pancreatic cancer (eg, pancreatic duct cancer, etc.), gastric cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous epithelium) Cancer), breast cancer (eg, invasive ductal carcinoma, non-invasive ductal carcinoma, inflammatory breast cancer, etc.), ovarian cancer (eg, epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovary Low-grade tumors), prostate cancer (eg, hormone-dependent prostate cancer, hormone-independent prostate cancer, etc.), liver cancer (eg, primary liver cancer, extrahepatic bile duct cancer, etc.), thyroid cancer (eg, medullary thyroid) Like), kidney cancer (eg renal cell carcinoma, renal pelvis and ureter) Transitional cell carcinoma), uterine cancer, brain tumor (eg pineal astrocytoma, ciliary astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), melanoma, sarcoma , Bladder cancer, blood cancer including multiple myeloma, etc.), diabetic retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, Kaposi sarcoma, COPD, pain, asthma, endometriosis, nephritis, degenerative joint It is used as a pharmaceutical agent for inflammation such as infectious disease, prophylactic / therapeutic agent for hypertension, cancer growth inhibitor, cancer metastasis inhibitor, apoptosis promoter and the like. Among them, for example, it is effective for colon cancer, lung cancer, pancreatic cancer, stomach cancer, breast cancer, ovarian cancer, prostate cancer, liver cancer, thyroid cancer, kidney cancer, brain tumor, melanoma, urinary bladder cancer, blood cancer. In particular, the compounds of the present invention are effective against patients with lung cancer, colon cancer, ovarian cancer, prostate cancer, and kidney cancer. Further, the compound of the present invention exhibits a cancer invasion / metastasis suppression action based on a strong c-Met inhibitory action.
　本発明の化合物は、そのままあるいは薬理学的に許容される担体を配合し、経口的または非経口的に投与することができる。
　本発明の化合物を経口投与する場合の剤形としては、例えば、錠剤（糖衣錠、フィルムコーティング錠を含む）、丸剤、顆粒剤、散剤、カプセル剤（ソフトカプセル剤、マイクロカプセル剤を含む）、シロップ剤、乳剤、懸濁剤等が挙げられ、また、非経口投与する場合の剤形としては、例えば、注射剤、注入剤、点滴剤、坐剤等が挙げられる。また、適当な基剤（例、酪酸の重合体、グリコール酸の重合体、酪酸－グリコール酸の共重合体、酪酸の重合体とグリコール酸の重合体との混合物、ポリグリセロール脂肪酸エステル等）と組み合わせ徐放性製剤とすることも有効である。 The compound of the present invention can be administered orally or parenterally as it is or in combination with a pharmacologically acceptable carrier.
Examples of dosage forms for oral administration of the compound of the present invention include tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules and microcapsules), and syrups. Examples of dosage forms for parenteral administration include injections, infusions, drops, suppositories, and the like. In addition, an appropriate base (eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, a mixture of butyric acid polymer and glycolic acid polymer, polyglycerol fatty acid ester, etc.) It is also effective to make a combined sustained-release preparation.
　本発明の化合物を上記の剤形に製造する方法としては、当該分野で一般的に用いられている公知の製造方法を適用することができる。また、上記の剤形に製造する場合には、必要に応じて、その剤形に製造する際に製剤分野において通常用いられる賦形剤、結合剤、崩壊剤、滑沢剤、甘味剤、界面活性剤、懸濁化剤、乳化剤、防腐剤、抗酸化剤、着色剤、吸着剤、湿潤剤等の添加剤を適宜、適量含有させて製造することができる。 As the method for producing the compound of the present invention into the above-mentioned dosage form, known production methods generally used in the field can be applied. In addition, when manufacturing into the above-mentioned dosage forms, excipients, binders, disintegrants, lubricants, sweeteners, interfaces usually used in the pharmaceutical field when manufacturing into the dosage forms, if necessary. An appropriate amount of additives such as an activator, a suspending agent, an emulsifier, an antiseptic, an antioxidant, a coloring agent, an adsorbing agent, and a wetting agent can be appropriately contained.
　例えば、本発明の化合物を錠剤に製造する場合には、賦形剤、結合剤、崩壊剤、滑沢剤等を含有させて製造することができ、丸剤及び顆粒剤に製造する場合には、賦形剤、結合剤、崩壊剤等を含有させて製造することができる。また、散剤及びカプセル剤に製造する場合には賦形剤等を、シロップ剤に製する場合には甘味剤等を、乳剤または懸濁剤に製する場合には懸濁化剤、界面活性剤、乳化剤等を含有させて製造することができる。 For example, when the compound of the present invention is produced into tablets, it can be produced by containing excipients, binders, disintegrants, lubricants, etc., and when produced into pills and granules. , Excipients, binders, disintegrants and the like. In addition, when producing powders and capsules, excipients, etc., when producing syrups, sweeteners, etc., when producing emulsions or suspensions, suspending agents, surfactants It can be produced by containing an emulsifier and the like.
　賦形剤の例としては、乳糖、白糖、ブドウ糖、デンプン、蔗糖、微結晶セルロース、カンゾウ末、マンニトール、炭酸水素ナトリウム、リン酸カルシウム、硫酸カルシウム等が挙げられる。
　結合剤の例としては、５ないし１０重量％デンプンのり液、１０ないし２０重量％アラビアゴム液またはゼラチン液、１ないし５重量％トラガント液、カルボキシメチルセルロース液、アルギン酸ナトリウム液、グリセリン等が挙げられる。
　崩壊剤の例としては、デンプン、炭酸カルシウム等が挙げられる。
　滑沢剤の例としては、ステアリン酸マグネシウム、ステアリン酸、ステアリン酸カルシウム、精製タルク等が挙げられる。
　甘味剤の例としては、ブドウ糖、果糖、転化糖、ソルビトール、キシリトール、グリセリン、単シロップ等が挙げられる。
　界面活性剤の例としては、ラウリル硫酸ナトリウム、ポリソルベート８０、ソルビタンモノ脂肪酸エステル、ステアリン酸ポリオキシル４０等が挙げられる。
　懸濁化剤の例としては、アラビアゴム、アルギン酸ナトリウム、カルボキシメチルセルロースナトリウム、メチルセルロース、ベントナイト等が挙げられる。
　乳化剤の例としては、アラビアゴム、トラガント、ゼラチン、ポリソルベート８０等が挙げられる。 Examples of excipients include lactose, sucrose, glucose, starch, sucrose, microcrystalline cellulose, licorice powder, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate and the like.
Examples of the binder include 5 to 10% by weight starch paste solution, 10 to 20% by weight gum arabic solution or gelatin solution, 1 to 5% by weight tragacanth solution, carboxymethyl cellulose solution, sodium alginate solution, glycerin and the like.
Examples of the disintegrant include starch and calcium carbonate.
Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, purified talc and the like.
Examples of sweeteners include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin, simple syrup and the like.
Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, polyoxyl 40 stearate and the like.
Examples of the suspending agent include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose, bentonite and the like.
Examples of emulsifiers include gum arabic, tragacanth, gelatin, polysorbate 80 and the like.
　更に、本発明の化合物を上記の剤形に製造する場合には、所望により、製剤分野において通常用いられる着色剤、保存剤、芳香剤、矯味剤、安定剤、粘稠剤等を適宜、適量添加することができる。 Furthermore, when the compound of the present invention is produced into the above-mentioned dosage form, an appropriate amount of a coloring agent, preservative, fragrance, flavoring agent, stabilizer, thickener, etc., which is usually used in the pharmaceutical field, is appropriately added if desired. Can be added.
　注射剤としては、静脈注射剤のほか、皮下注射剤、皮内注射剤、筋肉注射剤、点滴注射剤等が含まれ、また持続性製剤としては、イオントフォレシス経皮剤等が含まれる。 In addition to intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, intravenous infusions and the like are included as injections, and iontophoretic transdermal agents and the like are included as sustained-release preparations.
　かかる注射剤は、自体公知の方法、すなわち、本発明の化合物を無菌の水性液もしくは油性液に溶解、懸濁または乳化することによって調製される。注射用の水性液としては生理食塩水、ブドウ糖やその他の補助薬を含む等張液（例えば、Ｄ－ソルビトール、Ｄ－マンニトール、塩化ナトリウム等）等が挙げられ、適当な溶解補助剤、例えば、アルコール（例えば、エタノール）、ポリアルコール（例えば、プロピレングリコール、ポリエチレングリコール）、非イオン性界面活性剤（例えば、ポリソルベート８０、ＨＣＯ－５０）等と併用してもよい。油性液としては、ゴマ油、大豆油等が挙げられ、溶解補助剤として、安息香酸ベンジル、ベンジルアルコール等と併用してもよい。また、緩衝剤（例えば、リン酸緩衝液、酢酸ナトリウム緩衝液）、無痛化剤（例えば、塩化ベンザルコニウム、塩酸プロカイン等）、安定剤（例えば、ヒト血清アルブミン、ポリエチレングリコール等）、保存剤（例えば、ベンジルアルコール、フェノール等）等と配合してもよい。調製された注射液は、通常、アンプルに充填される。 Such an injection is prepared by a method known per se, that is, by dissolving, suspending or emulsifying the compound of the present invention in a sterile aqueous or oily liquid. Aqueous solutions for injection include isotonic solutions (eg, D-sorbitol, D-mannitol, sodium chloride, etc.) containing physiological saline, glucose and other adjuvants, and suitable solubilizing agents such as You may use together with alcohol (for example, ethanol), polyalcohol (for example, propylene glycol, polyethylene glycol), a nonionic surfactant (for example, polysorbate 80, HCO-50), etc. Examples of the oily liquid include sesame oil and soybean oil. As a solubilizing agent, benzyl benzoate, benzyl alcohol and the like may be used in combination. Buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), preservatives (For example, benzyl alcohol, phenol, etc.) may be blended. The prepared injection solution is usually filled in an ampoule.
　本発明製剤中の本発明の化合物の含有量は、製剤の形態に応じて相違するが、通常、製剤全体に対して約０．０１ないし１００重量％、好ましくは約２ないし８５重量％、さらに好ましくは約５ないし７０重量％である。 The content of the compound of the present invention in the preparation of the present invention varies depending on the form of the preparation, but is generally about 0.01 to 100% by weight, preferably about 2 to 85% by weight, based on the whole preparation, Preferably, it is about 5 to 70% by weight.
　本発明製剤中の添加剤の含有量は、製剤の形態に応じて相違するが、通常、製剤全体に対して約１ないし９９．９重量％、好ましくは約１０ないし９０重量％である。 The content of the additive in the preparation of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.9% by weight, preferably about 10 to 90% by weight, based on the whole preparation.
　本発明の化合物は、安定かつ低毒性で安全に使用することができる。その１日の投与量は患者の状態や体重、化合物の種類、投与経路等によって異なるが、例えば、癌治療目的で患者に経口投与する場合には、成人（体重約６０ｋｇ）１日当りの投与量は、有効成分（本発明の化合物）として約１ないし１０００ｍｇ、好ましくは約３ないし３００ｍｇ、さらに好ましくは約１０ないし２００ｍｇであり、これらを１回または２ないし３回に分けて投与することができる。 The compound of the present invention can be safely used with stable, low toxicity. The daily dose varies depending on the patient's condition and body weight, the type of compound, the route of administration, etc. For example, in the case of oral administration to a patient for the purpose of cancer treatment, the daily dose for an adult (body weight of about 60 kg) Is about 1 to 1000 mg, preferably about 3 to 300 mg, more preferably about 10 to 200 mg as an active ingredient (compound of the present invention), and these can be administered once or divided into 2 to 3 times. .
　本発明の化合物を非経口的に投与する場合は、通常、液剤（例えば、注射剤）の形で投与する。その１回投与量は、投与対象、対象臓器、症状、投与方法等によっても異なるが、例えば、注射剤の形にして、通常体重１ｋｇあたり約０．０１ないし約１００ｍｇ、好ましくは約０．０１ないし約５０ｍｇ、より好ましくは約０．０１ないし約２０ｍｇを静脈注射により投与するのが好都合である。 When the compound of the present invention is administered parenterally, it is usually administered in the form of a liquid (for example, an injection). The single dose varies depending on the administration subject, target organ, symptom, administration method and the like, but is usually about 0.01 to about 100 mg per kg body weight, preferably about 0.01 in the form of injection. It is convenient to administer from about 50 mg, more preferably from about 0.01 to about 20 mg by intravenous injection.
　本発明の化合物は、他の薬物と併用して用いることができる。具体的には、本発明の化合物は、ホルモン療法剤、化学療法剤、免疫療法剤または細胞増殖因子ならびにその受容体の作用を阻害する薬剤等の薬物と併用して用いることができる。以下、本発明の化合物と併用し得る薬物を併用薬物と略記する。 The compound of the present invention can be used in combination with other drugs. Specifically, the compounds of the present invention can be used in combination with drugs such as hormone therapeutic agents, chemotherapeutic agents, immunotherapeutic agents or drugs that inhibit the action of cell growth factors and their receptors. Hereinafter, a drug that can be used in combination with the compound of the present invention is abbreviated as a concomitant drug.
　「ホルモン療法剤」としては、例えば、ホスフェストロール、ジエチルスチルベストロール、クロロトリアニセン、酢酸メドロキシプロゲステロン、酢酸メゲストロール、酢酸クロルマジノン、酢酸シプロテロン、ダナゾール、アリルエストレノール、ゲストリノン、メパルトリシン、ラロキシフェン、オルメロキシフェン、レボルメロキシフェン、抗エストロゲン（例、クエン酸タモキシフェン、クエン酸トレミフェン等）、ピル製剤、メピチオスタン、テストロラクトン、アミノグルテチイミド、ＬＨ－ＲＨアゴニスト（例、酢酸ゴセレリン、ブセレリン、リュープロレリン等）、ドロロキシフェン、エピチオスタノール、スルホン酸エチニルエストラジオール、アロマターゼ阻害薬（例、塩酸ファドロゾール、アナストロゾール、レトロゾール、エキセメスタン、ボロゾール、フォルメスタン等）、抗アンドロゲン（例、フルタミド、ビカルタミド、ニルタミド等）、５α－レダクターゼ阻害薬（例、フィナステリド、エプリステリド等）、副腎皮質ホルモン系薬剤（例、デキサメタゾン、プレドニゾロン、ベタメタゾン、トリアムシノロン等）、アンドロゲン合成阻害薬（例、アビラテロン等）、レチノイドおよびレチノイドの代謝を遅らせる薬剤（例、リアロゾール等）等が用いられる。 Examples of the `` hormone therapeutic agent '' include phosfestol, diethylstilbestrol, chlorotrianicene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, allylestrenol, gestrinone, mepartricin, Raloxifene, olmeroxifene, levormeroxifene, antiestrogens (eg, tamoxifen citrate, toremifene citrate, etc.), pill formulations, mepithiostan, testrolactone, aminoglutethimide, LH-RH agonists (eg, goserelin acetate, Buserelin, leuprorelin, etc.), droloxifene, epithiostanol, ethinyl estradiol sulfonate, aromatase inhibitor (eg, fadrozole hydrochloride, anastrozole, reso Rosole, exemestane, borozole, formestane, etc.), antiandrogens (eg, flutamide, bicalutamide, nilutamide, etc.), 5α-reductase inhibitors (eg, finasteride, epristeride, etc.), corticosteroids (eg, dexamethasone, prednisolone, Betamethasone, triamcinolone, etc.), androgen synthesis inhibitors (eg, abiraterone, etc.), retinoids, drugs that delay the metabolism of retinoids (eg, riarosol, etc.), etc. are used.
　「化学療法剤」としては、例えば、アルキル化剤、代謝拮抗剤、抗癌性抗生物質、植物由来抗癌剤等が用いられる。 As the “chemotherapeutic agent”, for example, alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents and the like are used.
　「アルキル化剤」としては、例えば、ナイトロジェンマスタード、塩酸ナイトロジェンマスタード－Ｎ－オキシド、クロラムブチル、シクロフォスファミド、イホスファミド、チオテパ、カルボコン、トシル酸インプロスルファン、ブスルファン、塩酸ニムスチン、ミトブロニトール、メルファラン、ダカルバジン、ラニムスチン、リン酸エストラムスチンナトリウム、トリエチレンメラミン、カルムスチン、ロムスチン、ストレプトゾシン、ピポブロマン、エトグルシド、カルボプラチン、シスプラチン、ミボプラチン、ネダプラチン、オキサリプラチン、アルトレタミン、アンバムスチン、塩酸ジブロスピジウム、フォテムスチン、プレドニムスチン、プミテパ、リボムスチン、テモゾロミド、トレオスルファン、トロフォスファミド、ジノスタチンスチマラマー、アドゼレシン、システムスチン、ビゼレシンおよびそれらのＤＤＳ（Drug Delivery System）製剤等が用いられる。 Examples of the “alkylating agent” include nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride, mitoblonitol, Faran, dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine, streptozocin, piprobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambermuthine, dibrospine hydrochloride, fotemustine hydrochloride Predonimustine, pumitepa, ribomustine, temozolomide, treosulphane, trophosphamide Zinostatin Lamar, adozelesin, cystemustine, Bizereshin and their DDS (Drug Delivery System) preparations and the like are used.
　「代謝拮抗剤」としては、例えば、メルカプトプリン、６－メルカプトプリンリボシド、チオイノシン、メトトレキサート、ペメトレキセド、エノシタビン、シタラビン、シタラビンオクフォスファート、塩酸アンシタビン、５－ＦＵ系薬剤（例、フルオロウラシル、テガフール、ＵＦＴ、ドキシフルリジン、カルモフール、ガロシタビン、エミテフール、カペシタビン等）、アミノプテリン、ネルザラビン、ロイコボリンカルシウム、タブロイド、ブトシン、フォリネイトカルシウム、レボフォリネイトカルシウム、クラドリビン、エミテフール、フルダラビン、ゲムシタビン、ヒドロキシカルバミド、ペントスタチン、ピリトレキシム、イドキシウリジン、ミトグアゾン、チアゾフリン、アンバムスチン、ベンダムスチンおよびそれらのＤＤＳ製剤等が用いられる。 Examples of the “antimetabolite” include mercaptopurine, 6-mercaptopurine riboside, thioinosine, methotrexate, pemetrexed, enositabine, cytarabine, cytarabine okphosphatate, ancitabine hydrochloride, 5-FU drugs (eg, fluorouracil, tegafur, UFT, doxyfluridine, carmofur, galocitabine, emiteful, capecitabine, etc.), aminopterin, nerzarabine, leucovorin calcium, tabloid, butosine, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabine, gemcitabine pendant, hydroxycarbamide pendant , Idoxyuridine, mitoguazone, thiazofurin, ambamustine, bendamustine and those DDS formulation or the like is used.
　「抗癌性抗生物質」としては、例えば、アクチノマイシンＤ、アクチノマイシンＣ、マイトマイシンＣ、クロモマイシンＡ３、塩酸ブレオマイシン、硫酸ブレオマイシン、硫酸ペプロマイシン、塩酸ダウノルビシン、塩酸ドキソルビシン、塩酸アクラルビシン、塩酸ピラルビシン、塩酸エピルビシン、ネオカルチノスタチン、ミスラマイシン、ザルコマイシン、カルチノフィリン、ミトタン、塩酸ゾルビシン、塩酸ミトキサントロン、塩酸イダルビシンおよびそれらのＤＤＳ製剤等が用いられる。 Examples of the “anticancer antibiotic” include actinomycin D, actinomycin C, mitomycin C, chromomycin A3, bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride , Neocartinostatin, misramycin, sarcomycin, carcinophylline, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride and their DDS preparations.
　「植物由来抗癌剤」としては、例えば、エトポシド、リン酸エトポシド、硫酸ビンブラスチン、硫酸ビンクリスチン、硫酸ビンデシン、テニポシド、パクリタキセル、ドセタキセル、ビノレルビンおよびそれらのＤＤＳ製剤等が用いられる。 As the “plant-derived anticancer agent”, for example, etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel, docetaxel, vinorelbine and their DDS preparations are used.
　「免疫療法剤（ＢＲＭ）」としては、例えば、ピシバニール、クレスチン、シゾフィラン、レンチナン、ウベニメクス、インターフェロン、インターロイキン、マクロファージコロニー刺激因子、顆粒球コロニー刺激因子、エリスロポイエチン、リンホトキシン、ＢＣＧワクチン、コリネバクテリウムパルブム、レバミゾール、ポリサッカライドＫ、プロコダゾール、抗ＣＴＬＡ４抗体等が用いられる。 Examples of the “immunotherapy agent (BRM)” include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacteria Umparbum, levamisole, polysaccharide K, procodazole, anti-CTLA4 antibody and the like are used.
　「細胞増殖因子ならびにその受容体の作用を阻害する薬剤」における「細胞増殖因子」としては、細胞の増殖を促進する物質であればどのようなものでもよく、通常、分子量が２０，０００以下のペプチドで、受容体との結合により低濃度で作用が発揮される因子が挙げられ、具体的には、（１）ＥＧＦ（ｅｐｉｄｅｒｍａｌ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）またはそれと実質的に同一の活性を有する物質〔例、ＴＧＦα等〕、（２）インシュリンまたはそれと実質的に同一の活性を有する物質〔例、インシュリン、ＩＧＦ（ｉｎｓｕｌｉｎ－ｌｉｋｅ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）－１、ＩＧＦ－２等〕、（３）ＦＧＦ（ｆｉｂｒｏｂｌａｓｔ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）またはそれと実質的に同一の活性を有する物質〔例、酸性ＦＧＦ、塩基性ＦＧＦ、ＫＧＦ（ｋｅｒａｔｉｎｏｃｙｔｅ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）、ＦＧＦ－１０等〕、（４）その他の細胞増殖因子〔例、ＣＳＦ（ｃｏｌｏｎｙ　ｓｔｉｍｕｌａｔｉｎｇ　ｆａｃｔｏｒ）、ＥＰＯ（ｅｒｙｔｈｒｏｐｏｉｅｔｉｎ）、ＩＬ－２（ｉｎｔｅｒｌｅｕｋｉｎ－２）、ＮＧＦ（ｎｅｒｖｅ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）、ＰＤＧＦ（ｐｌａｔｅｌｅｔ－ｄｅｒｉｖｅｄ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）、ＴＧＦβ（ｔｒａｎｓｆｏｒｍｉｎｇ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ　β）、ＨＧＦ（ｈｅｐａｔｏｃｙｔｅ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）、ＶＥＧＦ（ｖａｓｃｕｌａｒ　ｅｎｄｏｔｈｅｌｉａｌ　ｇｒｏｗｔｈ　ｆａｃｔｏｒ）、ヘレグリン、アンジオポエチン等〕が用いられる。 The “cell growth factor” in the “drug that inhibits the action of the cell growth factor and its receptor” may be any substance that promotes cell growth, and usually has a molecular weight of 20,000 or less. Examples of peptides include factors that exert an action at a low concentration by binding to a receptor. Specifically, (1) EGF (epidemal growth factor) or a substance having substantially the same activity as that (for example, TGFα, etc.], (2) Insulin or a substance having substantially the same activity (eg, insulin, IGF (insulin-like growth factor) -1, IGF-2, etc.), (3) FGF (fibroblast growth factor) Or substances having substantially the same activity (eg, acidic GF, basic FGF, KGF (keratinocyte growth factor), FGF-10, etc.), (4) Other cell growth factors [eg, CSF (erythropoietin), EPO (erythropoietin), IL-2 (interleukin-2) , NGF (near growth factor), PDGF (platelet-derived growth factor), TGFβ (transforming growth factor β), HGF (hepatocyte growth factor, thor factor).
　「細胞増殖因子の受容体」としては、上記の細胞増殖因子と結合能を有する受容体であればいかなるものであってもよく、具体的には、ＥＧＦ受容体、ヘレグリン受容体（HER3等）、インシュリン受容体、ＩＧＦ受容体－１、ＩＧＦ受容体－２、ＦＧＦ受容体－１またはＦＧＦ受容体－２、ＶＥＧＦ受容体、アンジオポエチン受容体（Tie2等）、ＰＤＧＦ受容体等が用いられる。 The “cell growth factor receptor” may be any receptor capable of binding to the above-mentioned cell growth factor. Specifically, EGF receptor, heregulin receptor (HER3, etc.) Insulin receptor, IGF receptor-1, IGF receptor-2, FGF receptor-1 or FGF receptor-2, VEGF receptor, angiopoietin receptor (Tie2, etc.), PDGF receptor and the like are used.
　「細胞増殖因子ならびにその受容体の作用を阻害する薬剤」としては、ＥＧＦ阻害剤、ＴＧＦα阻害剤、ヘレグリン阻害剤、インシュリン阻害剤、ＩＧＦ阻害剤、ＦＧＦ阻害剤、ＫＧＦ阻害剤、ＣＳＦ阻害剤、ＥＰＯ阻害剤、ＩＬ－２阻害剤、ＮＧＦ阻害剤、ＰＤＧＦ阻害剤、ＴＧＦβ阻害剤、ＨＧＦ阻害剤、ＶＥＧＦ阻害剤、アンジオポエチン阻害剤、ＥＧＦ受容体阻害剤、ＨＥＲ２阻害剤、ＨＥＲ４阻害剤、インシュリン受容体、ＩＧＦ－１受容体阻害剤、ＩＧＦ－２受容体阻害剤、ＦＧＦ受容体－１阻害剤、ＦＧＦ受容体－２阻害剤、ＦＧＦ受容体－３阻害剤、、ＦＧＦ受容体－４阻害剤、ＶＥＧＦ受容体阻害剤、Ｔｉｅ－２阻害剤、ＰＤＧＦ受容体阻害剤、Ａｂｌ阻害剤、Ｒａｆ阻害剤、ＦＬＴ３阻害剤、ｃ－Ｋｉｔ阻害剤、Ｓｒｃ阻害剤、ＰＫＣ阻害剤、Ｔｒｋ阻害剤、Ｒｅｔ阻害剤、ｍＴＯＲ阻害剤、Ａｕｒｏｒａ阻害剤、ＰＬＫ阻害剤、ＭＥＫ（ＭＥＫ１／２）阻害剤、ｃ－Ｍｅｔ阻害剤、ＣＤＫ阻害剤、Ａｋｔ阻害剤、ＥＲＫ阻害剤等が用いられる。より具体的に例示すると、抗ＶＥＧＦ抗体（Ｂｅｖａｃｉｚｕｍａｂ等）、抗ＨＥＲ２抗体（Ｔｒａｓｔｕｚｕｍａｂ、Ｐｅｒｔｕｚｕｍａｂ等）、抗ＥＧＦＲ抗体（Ｃｅｔｕｘｉｍａｂ、Ｐａｎｉｔｕｍｕｍａｂ、Ｍａｔｕｚｕｍａｂ、Ｎｉｍｏｔｕｚｕｍａｂ等）、抗ＶＥＧＦＲ抗体、抗ＨＧＦ抗体、Ｉｍａｔｉｎｉｂ、Ｅｒｌｏｔｉｎｉｂ、Ｇｅｆｉｔｉｎｉｂ、Ｓｏｒａｆｅｎｉｂ、Ｓｕｎｉｔｉｎｉｂ、Ｄａｓａｔｉｎｉｂ、Ｌａｐａｔｉｎｉｂ、Ｖａｔａｌａｎｉｂ、４－（４－Ｆｌｕｏｒｏ－２－ｍｅｔｈｙｌ－１Ｈ－ｉｎｄｏｌ－５－ｙｌｏｘｙ）－６－ｍｅｔｈｏｘｙ－７－［３－（１－ｐｙｒｒｏｌｉｄｉｎｙｌ）ｐｒｏｐｏｘｙ］ｑｕｉｎａｚｏｌｉｎｅ（ＡＺＤ－２１７１）、Ｌｅｓｔａｕｒｔｉｎｉｂ、Ｐａｚｏｐａｎｉｂ、Ｃａｎｅｒｔｉｎｉｂ、Ｔａｎｄｕｔｉｎｉｂ、３－（４－Ｂｒｏｍｏ－２，６－ｄｉｆｌｕｏｒｏｂｅｎｚｙｌｏｘｙ）－５－［３－［４－（１－ｐｙｒｒｏｌｉｄｉｎｙｌ）ｂｕｔｙｌ］ｕｒｅｉｄｏ］ｉｓｏｔｈｉａｚｏｌｅ－４－ｃａｒｂｏｘａｍｉｄｅ（ＣＰ－５４７６３２）、Ａｘｉｔｉｎｉｂ、Ｎ－（３，３－Ｄｉｍｅｔｈｙｌ－２，３－ｄｉｈｙｄｒｏ－１Ｈ－ｉｎｄｏｌ－６－ｙｌ）－２－（ｐｙｒｉｄｉｎ－４－ｙｌｍｅｔｈｙｌａｍｉｎｏ）ｐｙｒｉｄｉｎｅ－３－ｃａｒｂｏｘａｍｉｄｅ（ＡＭＧ－７０６）、Ｎｉｌｏｔｉｎｉｂ、６－［４－（４－Ｅｔｈｙｌｐｉｐｅｒａｚｉｎ－１－ｙｌｍｅｔｈｙｌ）ｐｈｅｎｙｌ］－Ｎ－［１（Ｒ）－ｐｈｅｎｙｌｅｔｈｙｌ］－７Ｈ－ｐｙｒｒｏｌｏ［２，３－ｄ］ｐｙｒｉｍｉｄｉｎ－４－ａｍｉｎｅ（ＡＥＥ－７８８）、Ｖａｎｄｅｔａｎｉｂ、Ｔｅｍｓｉｒｏｌｉｍｕｓ、Ｅｖｅｒｏｌｉｍｕｓ、Ｅｎｚａｓｔａｕｒｉｎ、Ｎ－［４－［４－（４－Ｍｅｔｈｙｌｐｉｐｅｒａｚｉｎ－１－ｙｌ）－６－（３－ｍｅｔｈｙｌ－１Ｈ－ｐｙｒａｚｏｌ－５－ｙｌａｍｉｎｏ）ｐｙｒｉｍｉｄｉｎ－２－ｙｌｓｕｌｆａｎｙｌ］ｐｈｅｎｙｌ］ｃｙｃｌｏｐｒｏｐａｎｅｃａｒｂｏｘａｍｉｄｅ（ＶＸ－６８０）、Ｐｈｏｓｐｈｏｒｉｃ　ａｃｉｄ　２－［Ｎ－［３－［４－［５－［Ｎ－（３－ｆｌｕｏｒｏｐｈｅｎｙｌ）ｃａｒｂａｍｏｙｌｍｅｔｈｙｌ］－１Ｈ－ｐｙｒａｚｏｌ－３－ｙｌａｍｉｎｏ］ｑｕｉｎａｚｏｌｉｎ－７－ｙｌｏｘｙ］ｐｒｏｐｙｌ］－Ｎ－ｅｔｈｙｌａｍｉｎｏ］ｅｔｈｙｌ　ｅｓｔｅｒ（ＡＺＤ－１１５２）、４－［９－Ｃｈｌｏｒｏ－７－（２，６－ｄｉｆｌｕｏｒｏｐｈｅｎｙｌ）－５Ｈ－ｐｙｒｉｍｉｄｏ［５，４－ｄ］［２］ｂｅｎｚａｚｅｐｉｎ－２－ｙｌａｍｉｎｏ］ｂｅｎｚｏｉｃ　ａｃｉｄ（ＭＬＮ－８０５４）、Ｎ－［２－Ｍｅｔｈｏｘｙ－５－［（Ｅ）－２－（２，４，６－ｔｒｉｍｅｔｈｏｘｙｐｈｅｎｙｌ）ｖｉｎｙｌｓｕｌｆｏｎｙｌｍｅｔｈｙｌ］ｐｈｅｎｙｌ］ｇｌｙｃｉｎｅ　ｓｏｄｉｕｍ　ｓａｌｔ（ＯＮ－１９１０Ｎａ）、４－［８－Ｃｙｃｌｏｐｅｎｔｙｌ－７（Ｒ）－ｅｔｈｙｌ－５－ｍｅｔｈｙｌ－６－ｏｘｏ－５，６，７，８－ｔｅｔｒａｈｙｄｒｏｐｔｅｒｉｄｉｎ－２－ｙｌａｍｉｎｏ］－３－ｍｅｔｈｏｘｙ－Ｎ－（１－ｍｅｔｈｙｌｐｉｐｅｒｉｄｉｎ－４－ｙｌ）ｂｅｎｚａｍｉｄｅ（ＢＩ－２５３６）、５－（４－Ｂｒｏｍｏ－２－ｃｈｌｏｒｏｐｈｅｎｙｌａｍｉｎｏ）－４－ｆｌｕｏｒｏ－１－ｍｅｔｈｙｌ－１Ｈ－ｂｅｎｚｉｍｉｄａｚｏｌｅ－６－ｃａｒｂｏｈｙｄｒｏｘａｍｉｃ　ａｃｉｄ　２－ｈｙｄｒｏｘｙｅｔｈｙｌ　ｅｓｔｅｒ（ＡＺＤ－６２４４）、Ｎ－［２（Ｒ），３－Ｄｉｈｙｄｒｏｘｙｐｒｏｐｏｘｙ］－３，４－ｄｉｆｌｕｏｒｏ－２－（２－ｆｌｕｏｒｏ－４－ｉｏｄｏｐｈｅｎｙｌａｍｉｎｏ）ｂｅｎｚａｍｉｄｅ（ＰＤ－０３２５９０１）等が用いられる。 “Agents that inhibit the action of cell growth factors and their receptors” include EGF inhibitors, TGFα inhibitors, heregulin inhibitors, insulin inhibitors, IGF inhibitors, FGF inhibitors, KGF inhibitors, CSF inhibitors, EPO inhibitor, IL-2 inhibitor, NGF inhibitor, PDGF inhibitor, TGFβ inhibitor, HGF inhibitor, VEGF inhibitor, angiopoietin inhibitor, EGF receptor inhibitor, HER2 inhibitor, HER4 inhibitor, insulin receptor Body, IGF-1 receptor inhibitor, IGF-2 receptor inhibitor, FGF receptor-1 inhibitor, FGF receptor-2 inhibitor, FGF receptor-3 inhibitor, FGF receptor-4 inhibitor , VEGF receptor inhibitor, Tie-2 inhibitor, PDGF receptor inhibitor, Abl inhibitor, Raf inhibitor, FLT3 inhibitor, c-Kit inhibitor, Src Inhibitor, PKC inhibitor, Trk inhibitor, Ret inhibitor, mTOR inhibitor, Aurora inhibitor, PLK inhibitor, MEK (MEK1 / 2) inhibitor, c-Met inhibitor, CDK inhibitor, Akt inhibitor, An ERK inhibitor or the like is used. More specifically, anti-VEGF antibody (Bevacizumab etc.), anti-HER2 antibody (Trastuzumab, Pertuzumab etc.), anti-EGFR antibody (Cetuximab, Panitumab, Matusumumab, Nimotozumab etc.), anti-VEGFR antibody, Ehtitinb, anti-HGFb antibody, EHtibb , Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib, 4- (4-Fluoro-2-methyl-1H-indol-5-yloxy) -6-methoxy-7- [3- (1-pyrrolidinopropylinpropyl) (AZD-2171), Restaurinib, Pazo anib, Canertinib, Tandutinib, 3- (4-Bromo-2,6-difluorobenzoyloxy) -5- [3- [4- (1-pyrrolidinyl) butyl] ureido] isothiazole-4-carboxamide, CP-547632, N- (3,3-Dimethyl-2,3-dihydro-1H-indol-6-yl) -2- (pyridin-4-ylmethylamino) pyridine-3-carboxamide (AMG-706), Nilotinib, 6- [4 -(4-Ethylperazin-1-ylmethyl) phenyl] -N- [1 (R) -phenylethyl] -7H-pyrolo [2, -D] pyrimidin-4-amine (AEE-788), Vandetanib, Temirolimus, Everolimus, Enzastaurin, N- [4- [4- (4-Methylpiperazin-1-yl) -6- (3-methyl-1H-pyrazin -5-ylamino) pyrimidin-2-ylsulfanyl] phenyl] cyclopropenecarboxamide (VX-680), phosphoacid 2- [N- [3- [4- [5- [N- (3-fluorphenyl) carbamylyl] carboyl] -3-ylamino] quinazolin-7-yloxy] propyl] -N-ethylamino] e thylester (AZD-1152), 4- [9-Chloro-7- (2,6-difluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2-ylamino] benzoic acid (MLN-8054) ), N- [2-Methoxy-5-[(E) -2- (2,4,6-trimethylphenyl) vinylsulfenylmethyl] phenyl] glycine sodium salt (ON-1910Na), 4- [8-Cyclopentyl-7 ( ) -Ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydroterpidin-2-ylamino] -3-methyoxy-N- (1-methylpiperi in-4-yl) benzamide (BI-2536), 5- (4-Bromo-2-chlorophenylamino) -4-fluoro-1-methyl-1H-benzimidazole-6-carbhydroxamic acid 2-hydroxyethyl44 (Hydroxyethyl44) N- [2 (R), 3-Dihydroxypropoxy] -3,4-difluoro-2- (2-fluoro-4-iodophenylamino) benzamide (PD-0325901) or the like is used.
　上記の薬剤の他に、Ｌ－アスパラギナーゼ、アセグラトン、塩酸プロカルバジン、プロトポルフィリン・コバルト錯塩、水銀ヘマトポルフィリン・ナトリウム、トポイソメラーゼＩ阻害薬（例、イリノテカン、トポテカン等）、トポイソメラーゼＩＩ阻害薬（例えば、ソブゾキサン等）、分化誘導剤（例、レチノイド、ビタミンＤ類等）、他の血管新生阻害薬（例えば、フマギリン、さめ抽出物、ＣＯＸ-２阻害薬等）、α－ブロッカー（例、塩酸タムスロシン等）、ビスホスホン酸（パミドロネート、ゾレドロネート等）、サリドマイド、５アザシチジン、デシタビン、ボルテゾミブ、抗ＣＤ２０抗体等の抗腫瘍性抗体、毒素標識抗体等も用いることができる。 In addition to the above-mentioned drugs, L-asparaginase, acegraton, procarbazine hydrochloride, protoporphyrin / cobalt complex, mercury hematoporphyrin / sodium, topoisomerase I inhibitors (eg, irinotecan, topotecan etc.), topoisomerase II inhibitors (eg, sobuzoxane etc.) ), Differentiation inducers (eg, retinoids, vitamin Ds, etc.), other angiogenesis inhibitors (eg, fumagillin, shark extract, COX-2 inhibitor, etc.), α-blockers (eg, tamsulosin hydrochloride, etc.), Bisphosphonic acid (pamidronate, zoledronate, etc.), thalidomide, 5 azacytidine, decitabine, bortezomib, anti-tumor antibodies such as anti-CD20 antibody, toxin-labeled antibodies, and the like can also be used.
　本発明の化合物と併用薬物とを組み合わせることにより、
（１）本発明の化合物または併用薬物を単独で投与する場合に比べて、その投与量を軽減することができる、
（２）患者の症状（軽症、重症等）に応じて、本発明の化合物と併用する薬物を選択することができる、
（３）治療期間を長く設定することができる、
（４）治療効果の持続を図ることができる、
（５）本発明の化合物と併用薬物とを併用することにより、相乗効果が得られる、等の優れた効果を得ることができる。 By combining the compound of the present invention and a concomitant drug,
(1) The dose can be reduced compared to when the compound of the present invention or the concomitant drug is administered alone.
(2) Depending on the patient's symptoms (mild, severe, etc.), a drug to be used in combination with the compound of the present invention can be selected.
(3) The treatment period can be set longer.
(4) The therapeutic effect can be sustained.
(5) By using the compound of the present invention in combination with a concomitant drug, excellent effects such as a synergistic effect can be obtained.
　以下、本発明の化合物と併用薬物を併用する場合を「本発明の併用剤」と称する。
　本発明の併用剤の使用に際しては、本発明の化合物と併用薬物の投与時期は限定されず、本発明の化合物と併用薬物とを、投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよい。併用薬物の投与量は、臨床上用いられている投与量に準ずればよく、投与対象、投与ルート、疾患、組み合わせ等により適宜選択することができる。 Hereinafter, the case where the compound of the present invention is used in combination with the concomitant drug is referred to as “the concomitant drug of the present invention”.
In the use of the concomitant drug of the present invention, the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered simultaneously to the administration subject, with a time difference. May also be administered. The dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
　本発明の化合物と併用薬物を併用する場合の投与形態としては、例えば、（１）本発明の化合物と併用薬物とを同時に製剤化して得られる単一の製剤の投与、（２）本発明の化合物と併用薬物とを別々に製剤化して得られる２種の製剤の同一投与経路での同時投与、（３）本発明の化合物と併用薬物とを別々に製剤化して得られる２種の製剤の同一投与経路での時間差をおいての投与、（４）本発明の化合物と併用薬物とを別々に製剤化して得られる２種の製剤の異なる投与経路での同時投与、（５）本発明の化合物と併用薬物とを別々に製剤化して得られる２種の製剤の異なる投与経路での時間差をおいての投与（例えば、本発明の化合物→併用薬物の順序での投与、あるいは逆の順序での投与）等が挙げられる。併用薬物の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、本発明の化合物と併用薬物との配合比は、投与対象、投与ルート、対象疾患、症状、組み合わせ等により適宜選択することができる。例えば、投与対象がヒトである場合、本発明の化合物１重量部に対し、併用薬物を０．０１ないし１００重量部用いればよい。 Examples of the dosage form when the compound of the present invention is used in combination with the concomitant drug include, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and (2) Simultaneous administration of the two preparations obtained by separately formulating the compound and the concomitant drug by the same route of administration, (3) Two preparations obtained by separately formulating the compound of the present invention and the concomitant drug Administration at the same administration route with a time difference, (4) simultaneous administration of two different preparations obtained by separately formulating the compound of the present invention and a concomitant drug by different administration routes, (5) Administration of two types of preparations obtained by separately formulating the compound and the concomitant drug at different time intervals in different administration routes (for example, administration in the order of the compound of the present invention → the concomitant drug, or in the reverse order) Administration). The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
　本発明の併用剤は、毒性が低く、例えば、本発明の化合物または（および）上記併用薬物を自体公知の方法に従って、薬理学的に許容される担体と混合して医薬組成物、例えば、錠剤（糖衣錠、フィルムコーティング錠を含む）、散剤、顆粒剤、カプセル剤（ソフトカプセル剤を含む）、液剤、注射剤、坐剤、徐放性製剤等とした後に、経口的または非経口的（例、局所、直腸、静脈内投与等）に安全に投与することができる。注射剤は、静脈内、筋肉内、皮下または臓器内投与あるいは直接病巣に投与することができる。 The concomitant drug of the present invention has low toxicity. For example, the compound of the present invention or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se, for example, a pharmaceutical composition such as a tablet. (Including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, etc., orally or parenterally (eg, Topical, rectal, intravenous administration, etc.) can be safely administered. The injection can be administered intravenously, intramuscularly, subcutaneously, or into an organ, or directly to the lesion.
　本発明の併用剤の製造に用いられてもよい薬理学的に許容される担体としては、前記した本発明の医薬の製造に用いられてもよい薬理学的に許容される担体と同様のものがあげられる。また、更に必要に応じ、前記した本発明の医薬の製造に用いられてもよい防腐剤、抗酸化剤、着色剤、甘味剤、吸着剤、湿潤剤等の添加剤を適宜、適量用いることもできる。 The pharmacologically acceptable carrier that may be used for the production of the concomitant drug of the present invention is the same as the pharmacologically acceptable carrier that may be used for the production of the pharmaceutical of the present invention described above. Is given. Further, if necessary, an appropriate amount of additives such as preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like that may be used in the production of the medicament of the present invention described above may be appropriately used. it can.
　本発明の併用剤における本発明の化合物と併用薬物との配合比は、投与対象、投与ルート、疾患等により適宜選択することができる。
　例えば、本発明の併用剤における本発明の化合物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約０．０１ないし１００重量％、好ましくは約０．１ないし５０重量％、さらに好ましくは約０．５ないし２０重量％程度である。
　本発明の併用剤における併用薬物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約０．０１ないし９０重量％、好ましくは約０．１ないし５０重量％、さらに好ましくは約０．５ないし２０重量％程度である。
　本発明の併用剤における添加剤の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約１ないし９９．９９重量％、好ましくは約１０ないし９０重量％程度である。
　また、本発明の化合物および併用薬物をそれぞれ別々に製剤化する場合も同様の含有量でよい。 The compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
For example, the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation. More preferably, it is about 0.5 to 20% by weight.
The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 90% by weight, preferably about 0.1 to 50% by weight, more preferably based on the whole preparation. About 0.5 to 20% by weight.
The content of the additive in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation.
Further, when the compound of the present invention and the concomitant drug are formulated separately, the same content may be used.
　これらの製剤は、製剤工程において通常一般に用いられる自体公知の方法により製造することができる。
　例えば、本発明の化合物または併用薬物は、分散剤（例、ツイーン（Tween）８０（アトラスパウダー社製、米国）、HCO 60（日光ケミカルズ製）、ポリエチレングリコール、カルボキシメチルセルロース、アルギン酸ナトリウム、ヒドロキシプロピルメチルセルロース、デキストリン等）、安定化剤（例、アスコルビン酸、ピロ亜硫酸ナトリウム等）、界面活性剤（例、ポリソルベート８０、マクロゴール等）、可溶剤（例、グリセリン、エタノール等）、緩衝剤（例、リン酸及びそのアルカリ金属塩、クエン酸及びそのアルカリ金属塩等）、等張化剤（例、塩化ナトリウム、塩化カリウム、マンニトール、ソルビトール、ブドウ糖等）、ｐＨ調節剤（例、塩酸、水酸化ナトリウム等）、保存剤（例、パラオキシ安息香酸エチル、安息香酸、メチルパラベン、プロピルパラベン、ベンジルアルコール等）、溶解剤（例、濃グリセリン、メグルミン等）、溶解補助剤（例、プロピレングリコール、白糖等）、無痛化剤（例、ブドウ糖、ベンジルアルコール等）等と共に水性注射剤に、あるいはオリーブ油、ゴマ油、綿実油、コーン油等の植物油、プロピレングリコール等の溶解補助剤に溶解、懸濁あるいは乳化して油性注射剤に成形し、注射剤とすることができる。 These preparations can be produced by a method known per se generally used in the preparation process.
For example, the compound of the present invention or the concomitant drug includes a dispersant (eg, Tween 80 (manufactured by Atlas Powder, USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethylcellulose, sodium alginate, hydroxypropylmethylcellulose. , Dextrin, etc.), stabilizers (eg, ascorbic acid, sodium pyrosulfite, etc.), surfactants (eg, polysorbate 80, macrogol, etc.), solubilizers (eg, glycerin, ethanol, etc.), buffers (eg, Phosphoric acid and alkali metal salts thereof, citric acid and alkali metal salts thereof, isotonic agents (eg, sodium chloride, potassium chloride, mannitol, sorbitol, glucose, etc.), pH regulators (eg, hydrochloric acid, sodium hydroxide) Etc.), preservatives (eg, ethyl paraoxybenzoate, benzoic acid, Ruparaben, propylparaben, benzyl alcohol, etc.), solubilizers (eg, concentrated glycerin, meglumine, etc.), solubilizers (eg, propylene glycol, sucrose, etc.), soothing agents (eg, glucose, benzyl alcohol, etc.) It can be formed into an oily injection by dissolving, suspending or emulsifying in an injection, or in a vegetable oil such as olive oil, sesame oil, cottonseed oil or corn oil, or a solubilizing agent such as propylene glycol.
　また、自体公知の方法に従い、本発明の化合物または併用薬物に、例えば、賦形剤（例、乳糖、白糖、デンプン等）、崩壊剤（例、デンプン、炭酸カルシウム等）、結合剤（例、デンプン、アラビアゴム、カルボキシメチルセルロース、ポリビニルピロリドン、ヒドロキシプロピルセルロース等）または滑沢剤（例、タルク、ステアリン酸マグネシウム、ポリエチレングリコール　６０００等）等を添加して圧縮成形し、次いで必要により、味のマスキング、腸溶性あるいは持続性の目的のため自体公知の方法でコーティングすることにより経口投与製剤とすることができる。コーティングに用いられるコーティング剤としては、例えば、ヒドロキシプロピルメチルセルロース、エチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルセルロース、ポリオキシエチレングリコール、ツイーン　８０、プルロニック　Ｆ６８、セルロースアセテートフタレート、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシメチルセルロースアセテートサクシネート、オイドラギット（ローム社製、ドイツ、メタアクリル酸・アクリル酸共重合体）および色素（例、ベンガラ、二酸化チタン等）等が用いられる。経口投与用製剤は速放性製剤、徐放性製剤のいずれであってもよい。 Further, according to a method known per se, for example, an excipient (eg, lactose, sucrose, starch, etc.), a disintegrant (eg, starch, calcium carbonate, etc.), a binder (eg, Starch, gum arabic, carboxymethyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, etc.) or lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) etc. are added and compression molded. For enteric or long-lasting purposes, an oral preparation can be obtained by coating by a method known per se. Examples of the coating agent used for coating include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (manufactured by Rohm, Germany, methacrylic acid / acrylic acid copolymer) and pigments (eg, Bengala, titanium dioxide, etc.) are used. The preparation for oral administration may be either an immediate release preparation or a sustained release preparation.
　さらに、自体公知の方法に従い、本発明の化合物または併用薬物を、油性基剤、水性基剤または水性ゲル基剤と混合することにより、油性または水性の固状、半固状あるいは液状の坐剤とすることができる。上記油性基剤としては、例えば、高級脂肪酸のグリセリド〔例、カカオ脂、ウイテプゾル類（ダイナマイトノーベル社製、ドイツ）等〕、中鎖脂肪酸のグリセリド〔例、ミグリオール類（ダイナマイトノーベル社製、ドイツ）等〕、あるいは植物油（例、ゴマ油、大豆油、綿実油等）等が挙げられる。また、水性基剤としては、例えば、ポリエチレングリコール類、プロピレングリコール等が挙げられる。水性ゲル基剤としては、例えば、天然ガム類、セルロース誘導体、ビニール重合体、アクリル酸重合体等が挙げられる。 Furthermore, according to a method known per se, the compound of the present invention or the concomitant drug is mixed with an oily base, an aqueous base or an aqueous gel base to give an oily or aqueous solid, semisolid or liquid suppository. It can be. Examples of the oily base include glycerides of higher fatty acids (eg, cacao butter, witepsols (manufactured by Dynamite Nobel, Germany)), glycerides of medium chain fatty acids [eg, miglyols (manufactured by Dynamite Nobel, Germany)] Etc.], or vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.). Examples of the aqueous base include polyethylene glycols and propylene glycol. Examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers, and the like.
　上記徐放性製剤としては、徐放性マイクロカプセル剤等が挙げられる。該徐放性マイクロカプセル剤は、自体公知の方法、例えば、下記〔２〕に示す方法にしたがって製造される。 Examples of the sustained-release preparation include sustained-release microcapsules. The sustained-release microcapsule is produced according to a method known per se, for example, the method shown in the following [2].
　本発明の化合物は、固形製剤（例、散剤、顆粒剤、錠剤、カプセル剤）等の経口投与用製剤に成型するか、坐剤等の直腸投与用製剤に成型するのが好ましい。特に経口投与用製剤が好ましい。
　併用薬物は、薬物の種類に応じて上記した剤形とすることができる。 The compound of the present invention is preferably molded into a preparation for oral administration such as a solid preparation (eg, powder, granule, tablet, capsule) or into a preparation for rectal administration such as a suppository. Particularly preferred are preparations for oral administration.
The concomitant drug can be in the above-mentioned dosage form depending on the type of drug.
　以下に、〔１〕本発明の化合物または併用薬物の注射剤およびその調製、〔２〕本発明の化合物または併用薬物の徐放性製剤または速放性製剤およびその調製、〔３〕本発明の化合物または併用薬物の舌下錠、バッカルまたは口腔内速崩壊剤およびその調製について具体的に示す。 The following are [1] injection of the compound of the present invention or a concomitant drug and preparation thereof, [2] sustained release preparation or immediate release preparation of the compound of the present invention or concomitant drug and preparation thereof, and [3] The sublingual tablet, buccal or intraoral quick disintegrating agent of the compound or the concomitant drug and the preparation thereof will be specifically described.
〔１〕注射剤およびその調製
　本発明の化合物または併用薬物を水に溶解してなる注射剤が好ましい。該注射剤には、安息香酸塩または／およびサリチル酸塩を含有させてもよい。
　該注射剤は、本発明の化合物または併用薬物と所望により安息香酸塩または／およびサリチル酸塩の双方を水に溶解することにより得られる。 [1] Injection and preparation thereof An injection prepared by dissolving the compound of the present invention or the concomitant drug in water is preferable. The injection may contain benzoate and / or salicylate.
The injection is obtained by dissolving both the compound of the present invention or the concomitant drug and, optionally, a benzoate and / or salicylate in water.
　上記安息香酸、サリチル酸の塩としては、例えば、ナトリウム，カリウム等のアルカリ金属塩、カルシウム，マグネシウム等のアルカリ土類金属塩、アンモニウム塩、メグルミン塩、その他トロメタモール等の有機塩基との塩等が挙げられる。 Examples of the benzoic acid and salicylic acid salts include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, meglumine salts, and salts with other organic bases such as trometamol. It is done.
　注射剤中の本発明の化合物または併用薬物の濃度は、０.５ないし５０ｗ／ｖ％、好ましくは３ないし２０ｗ／ｖ％程度である。また安息香酸塩または／およびサリチル酸塩の濃度は、０.５ないし５０ｗ／ｖ％、好ましくは３ないし２０ｗ／ｖ％程度である。 The concentration of the compound of the present invention or the concomitant drug in the injection is 0.5 to 50 w / v%, preferably about 3 to 20 w / v%. The concentration of benzoate or / and salicylate is about 0.5 to 50 w / v%, preferably about 3 to 20 w / v%.
　また、本注射剤には、一般に注射剤に使用される添加剤、例えば、安定化剤（例、アスコルビン酸、ピロ亜硫酸ナトリウム等）、界面活性剤（例、ポリソルベート８０、マクロゴール等）、可溶剤（例、グリセリン、エタノール等）、緩衝剤（例、リン酸及びそのアルカリ金属塩、クエン酸及びそのアルカリ金属塩等）、等張化剤（例、塩化ナトリウム、塩化カリウム等）、分散剤（例、ヒドロキシプロピルメチルセルロース、デキストリン）、ｐＨ調節剤（例、塩酸、水酸化ナトリウム等）、保存剤（例、パラオキシ安息香酸エチル、安息香酸等）、溶解剤（例、濃グリセリン、メグルミン等）、溶解補助剤（例、プロピレングリコール、白糖等）、無痛化剤（例、ブドウ糖、ベンジルアルコール等）等を適宜配合することができる。これらの添加剤は、一般に注射剤に通常用いられる割合で配合される。 In addition, the present injection includes additives generally used in injections, such as stabilizers (eg, ascorbic acid, sodium pyrosulfite), surfactants (eg, polysorbate 80, macrogol, etc.), acceptable Solvent (eg, glycerin, ethanol, etc.), buffer (eg, phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), isotonic agents (eg, sodium chloride, potassium chloride, etc.), dispersing agents (Eg, hydroxypropylmethylcellulose, dextrin), pH adjuster (eg, hydrochloric acid, sodium hydroxide, etc.), preservative (eg, ethyl paraoxybenzoate, benzoic acid, etc.), solubilizer (eg, concentrated glycerin, meglumine, etc.) , Solubilizers (eg, propylene glycol, sucrose, etc.), soothing agents (eg, glucose, benzyl alcohol, etc.) and the like can be appropriately blended. These additives are generally blended in a proportion usually used for injections.
　注射剤は、ｐＨ調節剤の添加により、ｐＨ２ないし１２、好ましくはｐＨ２.５ないし８.０に調整するのがよい。
　注射剤は、本発明の化合物または併用薬物と所望により安息香酸塩または／およびサリチル酸塩の双方を、また必要により上記添加剤を水に溶解することにより得られる。これらの溶解はどのような順序で行ってもよく、従来の注射剤の製法と同様に適宜行うことができる。 The injection may be adjusted to pH 2 to 12, preferably pH 2.5 to 8.0 by adding a pH adjusting agent.
An injection is obtained by dissolving both the compound of the present invention or the concomitant drug and optionally a benzoate and / or salicylate, and if necessary, the above additives in water. These dissolutions may be performed in any order, and can be appropriately performed in the same manner as in the conventional method for producing an injection.
　注射用水溶液は加温するのがよく、また通常の注射剤と同様に、例えば、濾過滅菌、高圧加熱滅菌等を行うことにより注射剤として供することができる。
　注射用水溶液は、例えば、１００ないし１２１℃の条件で５ないし３０分高圧加熱滅菌するのがよい。
　さらに多回分割投与製剤として使用できるように、溶液の抗菌性を付与した製剤としてもよい。 The aqueous solution for injection is preferably heated, and can be provided as an injection by performing, for example, filtration sterilization, high-pressure heat sterilization, or the like, as in a normal injection.
The aqueous solution for injection is preferably sterilized by high-pressure heat at a temperature of 100 to 121 ° C. for 5 to 30 minutes.
Furthermore, it is good also as a formulation which provided the antibacterial property of the solution so that it could be used as a multi-dose administration formulation.
〔２〕徐放性製剤または速放性製剤およびその調製
　本発明の化合物または併用薬物を含んでなる核を所望により水不溶性物質や膨潤性ポリマー等の被膜剤で被覆してなる徐放性製剤が好ましい。例えば、１日１回投与型の経口投与用徐放性製剤が好ましい。 [2] Sustained-release preparation or immediate-release preparation and preparation thereof Sustained-release preparation comprising a core containing the compound of the present invention or a concomitant drug optionally coated with a coating agent such as a water-insoluble substance or a swellable polymer Is preferred. For example, a once-daily administration type sustained-release preparation for oral administration is preferred.
　被膜剤に用いられる水不溶性物質としては、例えば、エチルセルロース、ブチルセルロース等のセルロースエーテル類、セルロースアセテート、セルロースプロピオネート等のセルロースエステル類、ポリビニルアセテート、ポリビニルブチレート等のポリビニルエステル類、アクリル酸／メタクリル酸共重合体、メチルメタクリレート共重合体、エトキシエチルメタクリレート／シンナモエチルメタクリレート／アミノアルキルメタクリレート共重合体、ポリアクリル酸、ポリメタクリル酸、メタクリル酸アルキルアミド共重合体、ポリ（メタクリル酸メチル）、ポリメタクリレート、ポリメタクリルアミド、アミノアルキルメタクリレート共重合体、ポリ（メタクリル酸アンヒドリド）、グリシジルメタクリレート共重合体、とりわけオイドラギットＲＳ－１００、ＲＬ－１００、ＲＳ－３０Ｄ、ＲＬ－３０Ｄ、ＲＬ－ＰＯ、ＲＳ－ＰＯ（アクリル酸エチル・メタアクリル酸メチル・メタアクリル酸塩化トリメチル・アンモニウムエチル共重合体）、オイドラギットＮＥ－３０Ｄ（メタアクリル酸メチル・アクリル酸エチル共重合体）等のオイドラギット類（ローム・ファーマ社）等のアクリル酸系ポリマー、硬化ヒマシ油（例、ラブリワックス（フロイント産業）等）等の硬化油、カルナバワックス、脂肪酸グリセリンエステル、パラフィン等のワックス類、ポリグリセリン脂肪酸エステル等が挙げられる。 Examples of water-insoluble substances used in the coating agent include cellulose ethers such as ethyl cellulose and butyl cellulose, cellulose esters such as cellulose acetate and cellulose propionate, polyvinyl esters such as polyvinyl acetate and polyvinyl butyrate, and acrylic acid. / Methacrylic acid copolymer, methyl methacrylate copolymer, ethoxyethyl methacrylate / cinnamoethyl methacrylate / aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkylamide copolymer, poly (methyl methacrylate) ), Polymethacrylate, polymethacrylamide, aminoalkyl methacrylate copolymer, poly (methacrylic anhydride), glycidyl methacrylate copolymer, especially Hydragit RS-100, RL-100, RS-30D, RL-30D, RL-PO, RS-PO (ethyl acrylate / methyl methacrylate / methacrylic acid trimethyl / ammonium ethyl copolymer), Eudragit NE- 30D (Methyl methacrylate / ethyl acrylate copolymer) and other Eudragits (Rohm Pharma Co.) and other acrylic acid polymers, hydrogenated castor oil (e.g., Labrax wax (Freund Industries) etc.) Examples thereof include carnauba wax, fatty acid glycerin ester, waxes such as paraffin, polyglycerin fatty acid ester and the like.
　膨潤性ポリマーとしては、酸性の解離基を有し、ｐＨ依存性の膨潤を示すポリマーが好ましく、胃内のような酸性領域では膨潤が少なく、小腸や大腸等の中性領域で膨潤が大きくなる酸性の解離基を有するポリマーが好ましい。
　このような酸性の解離基を有し、ｐＨ依存性の膨潤を示すポリマーとしては、例えば、カーボマー（Carbomer）９３４Ｐ、９４０、９４１、９７４Ｐ、９８０、１３４２等、ポリカーボフィル（polycarbophil）、カルシウムポリカーボフィル（calcium polycarbophil）（前記はいずれもＢＦグッドリッチ社製）、ハイビスワコー１０３、１０４、１０５、３０４（いずれも和光純薬（株）製）等の架橋型ポリアクリル酸重合体が挙げられる。 As the swellable polymer, a polymer having an acidic dissociation group and exhibiting pH-dependent swelling is preferable. Swelling is small in an acidic region such as the stomach, and swelling is large in a neutral region such as the small intestine and large intestine. A polymer having an acidic dissociation group is preferred.
Examples of the polymer having an acidic dissociable group and exhibiting pH-dependent swelling include, for example, Carbomer 934P, 940, 941, 974P, 980, 1342, polycarbophil, calcium polycarbophil, and the like. (Calcium polycarbophil) (all of which are manufactured by BF Goodrich), Hibiswako 103, 104, 105, 304 (all of which are manufactured by Wako Pure Chemical Industries, Ltd.), etc.
　徐放性製剤に用いられる被膜剤は、親水性物質をさらに含んでいてもよい。
　該親水性物質としては、例えば、プルラン、デキストリン、アルギン酸アルカリ金属塩等の硫酸基を有していてもよい多糖類、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロースナトリウム等のヒドロキシアルキルまたはカルボキシアルキルを有する多糖類、メチルセルロース、ポリビニルピロリドン、ポリビニルアルコール、ポリエチレングリコール等が挙げられる。 The film agent used in the sustained release preparation may further contain a hydrophilic substance.
Examples of the hydrophilic substance include polysaccharides that may have a sulfate group such as pullulan, dextrin, and alkali metal alginate, hydroxyalkyl or carboxyalkyl such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and carboxymethylcellulose sodium. Examples thereof include polysaccharides, methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, and polyethylene glycol.
　徐放性製剤の被膜剤における水不溶性物質の含有率は、約３０ないし約９０％（ｗ／ｗ）、好ましくは約３５ないし約８０％（ｗ／ｗ）、さらに好ましくは約４０ないし約７５％（ｗ／ｗ）であり、膨潤性ポリマーの含有率は、約３ないし約３０％（ｗ／ｗ）、好ましくは約３ないし約１５％（ｗ／ｗ）である。被膜剤は親水性物質をさらに含んでいてもよく、その場合被膜剤における親水性物質の含有率は、約５０％（ｗ／ｗ）以下、好ましくは約５ないし約４０％（ｗ／ｗ）、さらに好ましくは約５ないし約３５％（ｗ／ｗ）である。ここで上記％（ｗ／ｗ）は、被膜剤液から溶媒（例、水、メタノール、エタノール等の低級アルコール等）を除いた被膜剤組成物に対する重量％を示す。 The content of the water-insoluble substance in the coating agent of the sustained-release preparation is about 30 to about 90% (w / w), preferably about 35 to about 80% (w / w), more preferably about 40 to about 75. % (W / w) and the swellable polymer content is from about 3 to about 30% (w / w), preferably from about 3 to about 15% (w / w). The coating agent may further contain a hydrophilic substance, in which case the content of the hydrophilic substance in the coating agent is about 50% (w / w) or less, preferably about 5 to about 40% (w / w). More preferably, it is about 5 to about 35% (w / w). Here, the above% (w / w) represents the weight% with respect to the coating agent composition obtained by removing the solvent (eg, water, lower alcohol such as methanol, ethanol, etc.) from the coating agent solution.
　徐放性製剤は、以下に例示するように薬物を含む核を調製し、次いで得られた核を、水不溶性物質や膨潤性ポリマー等を加熱溶解あるいは溶媒に溶解または分散させた被膜剤液で被覆することにより製造される。 The sustained-release preparation is prepared by preparing a core containing a drug as exemplified below, and then coating the obtained core with a film agent solution in which a water-insoluble substance or a swellable polymer is dissolved by heating or dissolved or dispersed in a solvent. Manufactured by coating.
Ｉ．薬剤を含む核の調製
　被膜剤で被覆される薬物を含む核（以下、単に核と称することがある）の形態は特に制限されないが、好ましくは顆粒あるいは細粒等の粒子状に形成される。
　核が顆粒または細粒の場合、その平均粒子径は、好ましくは約１５０ないし約２,０００μｍ、さらに好ましくは約５００ないし約１,４００μｍである。
　核の調製は通常の製造方法で実施することができる。例えば、薬物に適当な賦形剤、結合剤、崩壊剤、滑沢剤、凝集防止剤、潤滑剤、安定化剤等を混合し、湿式押し出し造粒法、流動層造粒法等により調製する。
　核の薬物含量は、約０．５ないし約９５％（ｗ／ｗ）、好ましくは約５．０ないし約８０％（ｗ／ｗ）、さらに好ましくは約３０ないし約７０％（ｗ／ｗ）である。 I. Preparation of Nuclei Containing Drug A form of a nucleus containing a drug coated with a film agent (hereinafter sometimes simply referred to as a nucleus) is not particularly limited, but is preferably formed into a granular shape such as a granule or a fine granule.
When the core is a granule or a fine granule, the average particle size is preferably about 150 to about 2,000 μm, more preferably about 500 to about 1,400 μm.
The preparation of the nucleus can be carried out by a usual production method. For example, suitable excipients, binders, disintegrants, lubricants, anti-aggregation agents, lubricants, stabilizers, etc. are mixed with the drug and prepared by wet extrusion granulation method, fluidized bed granulation method, etc. .
The drug content of the nucleus is about 0.5 to about 95% (w / w), preferably about 5.0 to about 80% (w / w), more preferably about 30 to about 70% (w / w) It is.
　核に含まれる賦形剤としては、例えば、白糖、乳糖、マンニトール、グルコース等の糖類、澱粉、結晶セルロース、リン酸カルシウム、コーンスターチ等が用いられる。中でも、結晶セルロース、コーンスターチが好ましい。 Examples of excipients contained in the core include saccharides such as sucrose, lactose, mannitol, glucose, starch, crystalline cellulose, calcium phosphate, corn starch and the like. Of these, crystalline cellulose and corn starch are preferable.
　結合剤としては、例えば、ポリビニルアルコール、ヒドロキシプロピルセルロース、ポリエチレングリコール、ポリビニルピロリドン、プルロニックＦ６８、アラビアゴム、ゼラチン、澱粉等が用いられる。崩壊剤としては、例えば、カルボキシメチルセルロースカルシウム（ＥＣＧ５０５）、クロスカルメロースナトリウム（Ａｃ－Ｄｉ－Ｓｏｌ）、架橋型ポリビニルピロリドン（クロスポビドン）、低置換度ヒドロキシプロピルセルロース（Ｌ－ＨＰＣ）等が用いられる。中でも、ヒドロキシプロピルセルロース、ポリビニルピロリドン、低置換度ヒドロキシプロピルセルロースが好ましい。滑沢剤、凝集防止剤としては、例えば、タルク、ステアリン酸マグネシウムおよびその無機塩、また潤滑剤としてポリエチレングリコール等が用いられる。安定化剤としては、酒石酸、クエン酸、コハク酸、フマル酸、マレイン酸等の酸が用いられる。 As the binder, for example, polyvinyl alcohol, hydroxypropyl cellulose, polyethylene glycol, polyvinyl pyrrolidone, pluronic F68, gum arabic, gelatin, starch and the like are used. As the disintegrant, for example, carboxymethylcellulose calcium (ECG505), croscarmellose sodium (Ac-Di-Sol), cross-linked polyvinyl pyrrolidone (crospovidone), low substituted hydroxypropylcellulose (L-HPC) and the like are used. . Of these, hydroxypropylcellulose, polyvinylpyrrolidone, and low-substituted hydroxypropylcellulose are preferable. As the lubricant and the aggregation inhibitor, for example, talc, magnesium stearate and an inorganic salt thereof, and polyethylene glycol or the like as a lubricant are used. As the stabilizer, acids such as tartaric acid, citric acid, succinic acid, fumaric acid and maleic acid are used.
　核は上記製造法以外にも、例えば、核の中心となる不活性担体粒子上に水、低級アルコール（例、メタノール、エタノール等）等の適当な溶媒に溶解した結合剤をスプレーしながら、薬物あるいはこれと賦形剤、滑沢剤等との混合物を少量ずつ添加して行なう転動造粒法、パンコーティング法、流動層コーティング法や溶融造粒法によっても調製することができる。不活性担体粒子としては、例えば、白糖、乳糖、澱粉、結晶セルロース、ワックス類で製造されたものが使用でき、その平均粒子径は約１００μｍないし約１,５００μｍであるものが好ましい。 In addition to the above production method, for example, the core is a drug while spraying a binder dissolved in an appropriate solvent such as water, lower alcohol (eg, methanol, ethanol, etc.) on an inert carrier particle that becomes the center of the core. Alternatively, it can also be prepared by a rolling granulation method, a pan coating method, a fluidized bed coating method or a melt granulation method in which a mixture of this and an excipient, a lubricant or the like is added little by little. As the inert carrier particles, for example, those made of sucrose, lactose, starch, crystalline cellulose, waxes can be used, and those having an average particle size of about 100 μm to about 1,500 μm are preferable.
　核に含まれる薬物と被膜剤とを分離するために、防護剤で核の表面を被覆してもよい。防護剤としては、例えば、前記親水性物質や、水不溶性物質等が用いられる。防護剤は、好ましくはポリエチレングリコールやヒドロキシアルキルまたはカルボキシアルキルを有する多糖類、より好ましくはヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロースが用いられる。該防護剤は、安定化剤として、酒石酸、クエン酸、コハク酸、フマル酸、マレイン酸等の酸や、タルク等の滑沢剤を含んでいてもよい。防護剤を用いる場合、その被覆量は核に対して約１ないし約１５％（ｗ／ｗ）、好ましくは約１ないし約１０％（ｗ／ｗ）、さらに好ましくは約２ないし約８％（ｗ／ｗ）である。 In order to separate the drug contained in the nucleus and the coating agent, the surface of the nucleus may be coated with a protective agent. As the protective agent, for example, the hydrophilic substance, the water-insoluble substance, or the like is used. The protective agent is preferably a polysaccharide having polyethylene glycol or hydroxyalkyl or carboxyalkyl, more preferably hydroxypropylmethylcellulose or hydroxypropylcellulose. The protective agent may contain an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid or a lubricant such as talc as a stabilizer. When a protective agent is used, the coating amount is about 1 to about 15% (w / w), preferably about 1 to about 10% (w / w), more preferably about 2 to about 8% of the core ( w / w).
　防護剤は通常のコーティング法により被覆することができ、具体的には、防護剤を、例えば、流動層コーティング法、パンコーティング法等により核にスプレーすることで被覆することができる。 The protective agent can be coated by a normal coating method, and specifically, the protective agent can be coated by spraying the nucleus by, for example, a fluidized bed coating method or a pan coating method.
ＩＩ．核の被膜剤による被覆
　前記Ｉで得られた核を、前記水不溶性物質及びpＨ依存性の膨潤性ポリマー、および親水性物質を加熱溶解あるいは溶媒に溶解または分散させた被膜剤液により被覆することにより、徐放性製剤が製造される。
　核の被膜剤液による被覆方法として、例えば、噴霧コーティングする方法等が挙げられる。
　被膜剤液中の水不溶性物質、膨潤性ポリマーまたは親水性物質の組成比は、被膜中の各成分の含有率がそれぞれ前記含有率となるように適宜選ばれる。
　被膜剤の被覆量は、核（防護剤の被覆量を含まない）に対して約１ないし約９０％（ｗ／ｗ）、好ましくは約５ないし約５０％（ｗ／ｗ）、さらに好ましくは約５ないし約３５％（ｗ／ｗ）である。 II. Coating of the core with the coating agent The core obtained in the above I is coated with a coating agent solution in which the water-insoluble substance, the pH-dependent swelling polymer, and the hydrophilic substance are dissolved by heating or dissolved or dispersed in a solvent. As a result, a sustained-release preparation is produced.
Examples of the coating method using the core coating solution include a spray coating method.
The composition ratio of the water-insoluble substance, the swellable polymer, or the hydrophilic substance in the coating agent solution is appropriately selected so that the content of each component in the film is the above content.
The coating amount of the coating agent is about 1 to about 90% (w / w), preferably about 5 to about 50% (w / w) with respect to the core (excluding the coating amount of the protective agent), more preferably About 5 to about 35% (w / w).
　被膜剤液の溶媒としては、水または有機溶媒を単独であるいは両者の混液を用いることができる。混液を用いる際の水と有機溶媒との混合比（水／有機溶媒：重量比）は、１ないし１００％の範囲で変化させることができ、好ましくは１ないし約３０％である。該有機溶媒としては、水不溶性物質を溶解するものであれば特に限定されないが、例えば、メチルアルコール、エチルアルコール、イソプロピルアルコール、ｎ－ブチルアルコール等の低級アルコール、アセトン等の低級アルカノン、アセトニトリル、クロロホルム、メチレンクロライド等が用いられる。このうち低級アルコールが好ましく、エチルアルコール、イソプロピルアルコールが特に好ましい。水及び水と有機溶媒との混液が、被膜剤の溶媒として好ましく用いられる。この時、必要であれば被膜剤液中に、被膜剤液安定化のために、酒石酸、クエン酸、コハク酸、フマル酸、マレイン酸等の酸を加えてもよい。 As a solvent for the coating agent solution, water or an organic solvent can be used alone or a mixture of the two can be used. The mixing ratio of water and organic solvent (water / organic solvent: weight ratio) in the case of using the mixed liquid can be varied in the range of 1 to 100%, preferably 1 to about 30%. The organic solvent is not particularly limited as long as it dissolves water-insoluble substances. For example, lower alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol and n-butyl alcohol, lower alkanones such as acetone, acetonitrile, chloroform , Methylene chloride and the like are used. Of these, lower alcohols are preferred, and ethyl alcohol and isopropyl alcohol are particularly preferred. Water and a mixed solution of water and an organic solvent are preferably used as a solvent for the film agent. At this time, if necessary, an acid such as tartaric acid, citric acid, succinic acid, fumaric acid, maleic acid, etc. may be added to the coating agent solution to stabilize the coating agent solution.
　噴霧コーティングにより被覆する場合の操作は、通常のコーティング法により実施することができ、具体的には、被膜剤液で、例えば、流動層コーティング法、パンコーティング法等により核を被覆することで実施することができる。この時必要であれば、タルク、酸化チタン、ステアリン酸マグネシウム、ステアリン酸カルシウム、軽質無水ケイ酸等を滑沢剤として、グリセリン脂肪酸エステル、硬化ヒマシ油、クエン酸トリエチル、セチルアルコール、ステアリルアルコール等を可塑剤として添加してもよい。
　被膜剤による被膜後、必要に応じてタルク等の帯電防止剤を混合してもよい。 The operation in the case of coating by spray coating can be carried out by a normal coating method, specifically, by coating the core with a film agent solution, for example, by a fluidized bed coating method, pan coating method or the like. can do. If necessary, plasticize glycerin fatty acid ester, hydrogenated castor oil, triethyl citrate, cetyl alcohol, stearyl alcohol, etc., using talc, titanium oxide, magnesium stearate, calcium stearate, light anhydrous silicic acid as a lubricant. You may add as an agent.
After coating with a coating agent, an antistatic agent such as talc may be mixed as necessary.
　速放性製剤は、液状（溶液、懸濁液、乳化物等）であっても固形状（粒子、丸剤、錠剤等）であってもよい。速放性製剤としては、経口投与剤、注射剤等の非経口投与剤が用いられるが、経口投与剤が好ましい。 The immediate-release preparation may be liquid (solution, suspension, emulsion, etc.) or solid (particles, pills, tablets, etc.). As the immediate-release preparation, a parenterally administered agent such as an orally administered agent and an injectable agent is used, and an orally administered agent is preferable.
　速放性製剤は、通常、活性成分である薬物に加えて、製剤分野で慣用される担体、添加剤や賦形剤（以下、賦形剤と略称することがある）を含んでいてもよい。用いられる賦形剤は、製剤賦形剤として常用される賦形剤であれば特に限定されない。例えば、経口固形製剤用の賦形剤としては、乳糖、デンプン、コーンスターチ、結晶セルロース（旭化成（株）製、アビセルＰＨ１０１等）、粉糖、グラニュー糖、マンニトール、軽質無水ケイ酸、炭酸マグネシウム、炭酸カルシウム、Ｌ－システイン等が挙げられ、好ましくはコーンスターチおよびマンニトール等が挙げられる。これらの賦形剤は、一種または二種以上を組み合わせて使用できる。賦形剤の含有量は、速放性製剤全量に対して、例えば、約４．５ないし約９９．４ｗ/ｗ％、好ましくは約２０ないし約９８．５ｗ/ｗ％、さらに好ましくは約３０ないし約９７ｗ/ｗ％である。 The immediate-release preparation usually contains a carrier, an additive or an excipient (hereinafter sometimes abbreviated as an excipient) commonly used in the pharmaceutical field in addition to the drug as the active ingredient. . The excipient used is not particularly limited as long as it is an excipient commonly used as a pharmaceutical excipient. For example, excipients for oral solid preparations include lactose, starch, corn starch, crystalline cellulose (Asahi Kasei Co., Ltd., Avicel PH101, etc.), powdered sugar, granulated sugar, mannitol, light anhydrous silicic acid, magnesium carbonate, carbonate Calcium, L-cysteine and the like can be mentioned, preferably corn starch and mannitol. These excipients can be used alone or in combination of two or more. The content of the excipient is, for example, about 4.5 to about 99.4 w / w%, preferably about 20 to about 98.5 w / w%, more preferably about 30, relative to the total amount of the immediate-release preparation. Or about 97 w / w%.
　速放性製剤における薬物の含量は、速放性製剤全量に対して、約０．５ないし約９５ｗ/ｗ％、好ましくは約１ないし約６０ｗ/ｗ％の範囲から適宜選択することができる。 The content of the drug in the immediate release preparation can be appropriately selected from the range of about 0.5 to about 95 w / w%, preferably about 1 to about 60 w / w%, based on the total amount of the immediate release preparation.
　速放性製剤が経口固形製剤の場合、通常上記成分に加えて、崩壊剤を含有する。このような崩壊剤としては、例えば、カルボキシメチルセルロースカルシウム（五徳薬品製、ＥＣＧ－５０５）、クロスカルメロースナトリウム（例えば、旭化成（株）製、アクジゾル）、クロスポビドン（例えば、ＢＡＳＦ社製、コリドンＣＬ）、低置換度ヒドロキシプロピルセルロース（信越化学（株）製）、カルボキシメチルスターチ（松谷化学（株）製）、カルボキシメチルスターチナトリウム（木村産業製、エキスプロタブ）、部分α化デンプン（旭化成（株）製、ＰＣＳ）等が用いられ、例えば、水と接触して吸水、膨潤、あるいは核を構成している有効成分と賦形剤との間にチャネルを作る等により顆粒を崩壊させるものを用いることができる。これらの崩壊剤は、一種または二種以上を組み合わせて使用できる。崩壊剤の配合量は、用いる薬物の種類や配合量、放出性の製剤設計等により適宜選択されるが、速放性製剤全量に対して、例えば、約０．０５ないし約３０ｗ/ｗ％、好ましくは約０．５ないし約１５ｗ/ｗ％である。 When the immediate-release preparation is an oral solid preparation, it usually contains a disintegrant in addition to the above components. Examples of such disintegrants include carboxymethylcellulose calcium (manufactured by Gotoku Pharmaceutical Co., ECG-505), croscarmellose sodium (for example, Asahi Kasei Co., Ltd., Akizol), crospovidone (for example, BASF Corp., Kollidon CL ), Low-substituted hydroxypropyl cellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), carboxymethyl starch (manufactured by Matsutani Chemical Co., Ltd.), sodium carboxymethyl starch (manufactured by Kimura Sangyo Co., Ltd., Protab), partially pregelatinized starch (Asahi Kasei ( Co., Ltd., PCS), etc. are used, for example, those that disintegrate granules by contacting with water, absorbing water, swelling, or creating channels between the active ingredient constituting the core and excipients. Can be used. These disintegrants can be used alone or in combination of two or more. The amount of the disintegrant is appropriately selected depending on the type and amount of the drug to be used, the design of the releasable preparation, and the like. For example, about 0.05 to about 30 w / w%, Preferably, it is about 0.5 to about 15 w / w%.
　速放性製剤が経口固形製剤である場合、上記の組成に加えて、所望により固形製剤において慣用の添加剤をさらに含んでいてもよい。このような添加剤としては、例えば、結合剤（例えば、ショ糖、ゼラチン、アラビアゴム末、メチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、カルボキシメチルセルロース、ポリビニルピロリドン、プルラン、デキストリン等)、滑沢剤（例えば、ポリエチレングリコール、ステアリン酸マグネシウム、タルク、軽質無水ケイ酸（例えば、アエロジル（日本アエロジル製）)、界面活性剤（例えば、アルキル硫酸ナトリウム等のアニオン系界面活性剤、ポリオキシエチレン脂肪酸エステルおよびポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレンヒマシ油誘導体等の非イオン系界面活性剤等)、着色剤（例えば、タール系色素、カラメル、ベンガラ、酸化チタン、リボフラビン類)、必要ならば、矯味剤（例えば、甘味剤、香料等)、吸着剤、防腐剤、湿潤剤、帯電防止剤等が用いられる。また、安定化剤として酒石酸、クエン酸、コハク酸、フマル酸等の有機酸を加えてもよい。 When the immediate-release preparation is an oral solid preparation, in addition to the above-described composition, an additive commonly used in the solid preparation may be further included as desired. Examples of such additives include binders (for example, sucrose, gelatin, gum arabic powder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, pullulan, dextrin, etc.), lubricants ( For example, polyethylene glycol, magnesium stearate, talc, light anhydrous silicic acid (for example, Aerosil (manufactured by Nippon Aerosil)), surfactant (for example, anionic surfactant such as sodium alkyl sulfate, polyoxyethylene fatty acid ester and poly Non-ionic surfactants such as oxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, etc.), colorants (eg tar dyes, caramel, bengara, titanium oxide, riboflavins), essential If necessary, flavoring agents (for example, sweeteners, fragrances, etc.), adsorbents, preservatives, wetting agents, antistatic agents, etc. Further, tartaric acid, citric acid, succinic acid, fumaric acid, etc. are used as stabilizers. Organic acids may be added.
　上記結合剤としては、ヒドロキシプロピルセルロース、ポリエチレングリコールおよびポリビニルピロリドン等が好ましく用いられる。 As the binder, hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone and the like are preferably used.
　速放性製剤は、通常の製剤の製造技術に基づき、前記各成分を混合し、必要により、さらに練合し、成型することにより調製することができる。上記混合は、一般に用いられる方法、例えば、混合、練合等により行われる。具体的には、例えば、速放性製剤を粒子状に形成する場合、前記徐放性製剤の核の調製法と同様の手法により、バーチカルグラニュレーター、万能練合機（畑鉄工所製)、流動層造粒機ＦＤ－５Ｓ（パウレック社製）等を用いて混合しその後、湿式押し出し造粒法、流動層造粒法等により造粒することにより調製することができる。 The immediate-release preparation can be prepared by mixing the above-mentioned components, further kneading and molding if necessary, based on a normal preparation manufacturing technique. The above mixing is performed by a generally used method, for example, mixing, kneading and the like. Specifically, for example, when the immediate-release preparation is formed into particles, a vertical granulator, a universal kneader (manufactured by Hata Iron Works), by a method similar to the preparation method of the core of the sustained-release preparation, It can be prepared by mixing using a fluidized bed granulator FD-5S (manufactured by POWREC) or the like and then granulating by a wet extrusion granulation method, a fluidized bed granulation method or the like.
　このようにして得られた速放性製剤と徐放性製剤とは、そのままあるいは適宜、製剤賦形剤等と共に常法により別々に製剤化後、同時あるいは任意の投与間隔を挟んで組み合わせて投与する製剤としてもよく、また両者をそのままあるいは適宜、製剤賦形剤等と共に一つの経口投与製剤（例、顆粒剤、細粒剤、錠剤、カプセル等）に製剤化してもよい。両製剤を顆粒あるいは細粒に製造して、同一のカプセル等に充填して経口投与用製剤としてもよい。 The immediate-release preparation and the sustained-release preparation thus obtained are administered as they are or as appropriate, together with preparation excipients, etc., separately according to a conventional method, and then simultaneously or in combination with an arbitrary administration interval. Alternatively, both of them may be formulated into a single oral preparation (eg, granules, fine granules, tablets, capsules, etc.) as they are or as appropriate together with formulation excipients. Both preparations may be produced into granules or fine granules and filled in the same capsule or the like to prepare a preparation for oral administration.
〔３〕舌下錠、バッカルまたは口腔内速崩壊剤およびその調製
　舌下錠、バッカル製剤、口腔内速崩壊剤は、錠剤等の固形製剤であってもよいし、口腔粘膜貼付錠（フィルム）であってもよい。
　舌下錠、バッカルまたは口腔内速崩壊剤としては、本発明の化合物または併用薬物と賦形剤とを含有する製剤が好ましい。また、滑沢剤、等張化剤、親水性担体、水分散性ポリマー、安定化剤等の補助剤を含有していてもよい。また、吸収を容易にし、生体内利用率を高めるためにβ－シクロデキストリンまたはβ－シクロデキストリン誘導体（例、ヒドロキシプロピル－β－シクロデキストリン等）等を含有していてもよい。 [3] Sublingual tablet, buccal or intraoral quick disintegrating agent and preparation thereof The sublingual tablet, buccal preparation and intraoral quick disintegrating agent may be a solid preparation such as a tablet, or an oral mucosal patch (film) It may be.
As the sublingual tablet, buccal or intraoral quick disintegrating agent, a preparation containing the compound of the present invention or the concomitant drug and an excipient is preferable. Further, it may contain auxiliary agents such as a lubricant, an isotonic agent, a hydrophilic carrier, a water-dispersible polymer, and a stabilizer. Further, β-cyclodextrin or β-cyclodextrin derivatives (eg, hydroxypropyl-β-cyclodextrin, etc.) may be contained in order to facilitate absorption and increase bioavailability.
　上記賦形剤としては、乳糖、白糖、Ｄ－マンニトール、デンプン、結晶セルロース、軽質無水ケイ酸等が挙げられる。滑沢剤としては、ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、コロイドシリカ等が挙げられ、特に、ステアリン酸マグネシウムやコロイドシリカが好ましい。等張化剤としては、塩化ナトリウム、グルコース、フルクトース、マンニトール、ソルビトール、ラクトース、サッカロース、グリセリン、尿素等が挙げられ、特にマンニトールが好ましい。親水性担体としては、結晶セルロース、エチルセルロース、架橋性ポリビニルピロリドン、軽質無水珪酸、珪酸、リン酸二カルシウム、炭酸カルシウム等の膨潤性親水性担体が挙げられ、特に結晶セルロース（例、微結晶セルロース等）が好ましい。水分散性ポリマーとしては、ガム（例、トラガカントガム、アカシアガム、グアーガム）、アルギン酸塩（例、アルギン酸ナトリウム）、セルロース誘導体（例、メチルセルロース、カルボキシメチルセルロース、ヒドロキシメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース）、ゼラチン、水溶性デンプン、ポリアクリル酸（例、カーボマー）、ポリメタクリル酸、ポリビニルアルコール、ポリエチレングリコール、ポリビニルピロリドン、ポリカーボフィル、アスコルビン酸、パルミチン酸塩等が挙げられ、ヒドロキシプロピルメチルセルロース、ポリアクリル酸、アルギン酸塩、ゼラチン、カルボキシメチルセルロース、ポリビニルピロリドン、ポリエチレングリコール等が好ましい。特にヒドロキシプロピルメチルセルロースが好ましい。安定化剤としては、システイン、チオソルビトール、酒石酸、クエン酸、炭酸ナトリウム、アスコルビン酸、グリシン、亜硫酸ナトリウム等が挙げられ、特に、クエン酸やアスコルビン酸が好ましい。 Examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, and light anhydrous silicic acid. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like, and magnesium stearate and colloidal silica are particularly preferable. Examples of the isotonic agent include sodium chloride, glucose, fructose, mannitol, sorbitol, lactose, saccharose, glycerin, urea and the like, and mannitol is particularly preferable. Examples of the hydrophilic carrier include swellable hydrophilic carriers such as crystalline cellulose, ethyl cellulose, cross-linkable polyvinyl pyrrolidone, light anhydrous silicic acid, silicic acid, dicalcium phosphate, calcium carbonate, and particularly crystalline cellulose (eg, microcrystalline cellulose, etc. ) Is preferred. Examples of water-dispersible polymers include gums (eg, tragacanth gum, acacia gum, guar gum), alginates (eg, sodium alginate), cellulose derivatives (eg, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose), Gelatin, water-soluble starch, polyacrylic acid (eg, carbomer), polymethacrylic acid, polyvinyl alcohol, polyethylene glycol, polyvinyl pyrrolidone, polycarbophil, ascorbic acid, palmitate, etc., hydroxypropyl methylcellulose, polyacrylic acid, Alginate, gelatin, carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol and the like are preferable. Hydroxypropyl methylcellulose is particularly preferable. Examples of the stabilizer include cysteine, thiosorbitol, tartaric acid, citric acid, sodium carbonate, ascorbic acid, glycine, sodium sulfite and the like, and citric acid and ascorbic acid are particularly preferable.
　舌下錠、バッカルまたは口腔内速崩壊剤は、本発明の化合物または併用薬物と賦形剤とを自体公知の方法により混合することにより製造することができる。さらに、所望により上記した滑沢剤、等張化剤、親水性担体、水分散性ポリマー、安定化剤、着色剤、甘味剤、防腐剤等の補助剤を混合してもよい。上記成分を同時に若しくは時間差をおいて混合した後、加圧打錠成形することにより舌下錠、バッカル錠または口腔内速崩壊錠が得られる。適度な硬度を得るため、打錠成形の過程の前後において必要に応じ水やアルコール等の溶媒を用いて加湿・湿潤させ、成形後、乾燥させて製造してもよい。 A sublingual tablet, buccal or intraoral quick disintegrating agent can be produced by mixing the compound of the present invention or the concomitant drug and an excipient by a method known per se. Furthermore, auxiliary agents such as the above-mentioned lubricants, tonicity agents, hydrophilic carriers, water-dispersible polymers, stabilizers, colorants, sweeteners, preservatives and the like may be mixed as desired. After mixing the above components simultaneously or at a time difference, a sublingual tablet, a buccal tablet or an intraoral quick disintegrating tablet is obtained by compression tableting. In order to obtain an appropriate hardness, it may be produced by humidifying and wetting with a solvent such as water or alcohol as necessary before and after the tableting molding process, and drying after molding.
　粘膜貼付錠（フィルム）に成型する場合は、本発明の化合物または併用薬物および上記した水分散性ポリマー（好ましくは、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース）、賦形剤等を水等の溶媒に溶解させ、得られる溶液を流延させて(cast)フィルムとする。さらに、可塑剤、安定剤、酸化防止剤、保存剤、着色剤、緩衝剤、甘味剤等の添加物を加えてもよい。フィルムに適度の弾性を与えるために、ポリエチレングリコールやプロピレングリコール等のグリコール類を含有させたり、口腔の粘膜ライニングへのフィルムの接着を高めるために、生物接着性ポリマー（例、ポリカーボフィル、カルボポール）を含有させてもよい。流延は、非接着性表面に溶液を注ぎ、ドクターブレード等の塗布用具で均一な厚さ（好ましくは１０ないし１０００ミクロン程度）にそれを広げ、次いで溶液を乾燥してフィルムを形成することにより達成される。このように形成されたフィルムは、室温若しくは加温下乾燥させ、所望の表面積に切断すればよい。 When molding into a mucous membrane adhesive tablet (film), dissolve the compound of the present invention or the concomitant drug and the above-mentioned water-dispersible polymer (preferably hydroxypropylcellulose, hydroxypropylmethylcellulose), excipients, etc. in a solvent such as water. The resulting solution is cast into a film. Furthermore, additives such as a plasticizer, a stabilizer, an antioxidant, a preservative, a colorant, a buffering agent, and a sweetener may be added. Bioadhesive polymers (eg, polycarbophil, carbopol, etc.) are added to increase the adhesion of the film to the mucosal lining of the oral cavity and to contain glycols such as polyethylene glycol and propylene glycol to give the film moderate elasticity. ) May be included. Casting is performed by pouring the solution onto a non-adhesive surface, spreading it to a uniform thickness (preferably about 10 to 1000 microns) with an application tool such as a doctor blade, and then drying the solution to form a film. Achieved. The film thus formed may be dried at room temperature or under heating and cut to a desired surface area.
　好ましい口腔内速崩壊剤としては、本発明の化合物または併用薬物と、本発明の化合物または併用薬物とは不活性である水溶性若しくは水拡散性キャリヤーとの網状体からなる固体状の急速拡散投与剤が挙げられる。該網状体は、本発明の化合物または併用薬物を適当な溶媒に溶解した溶液とから構成されている固体状の該組成物から溶媒を昇華することによって得られる。 Preferred intraoral quick disintegrating agents include solid rapid diffusion administration comprising a network of a compound of the present invention or a concomitant drug and a water-soluble or water-diffusible carrier that is inactive with the compound of the present invention or the concomitant drug. Agents. The network is obtained by sublimating a solvent from the solid composition composed of a solution of the compound of the present invention or the concomitant drug in a suitable solvent.
　該口腔内速崩壊剤の組成物中には、本発明の化合物または併用薬物に加えて、マトリックス形成剤と二次成分とを含んでいるのが好ましい。 In addition to the compound of the present invention or the concomitant drug, the composition of the intraoral quick disintegrating agent preferably contains a matrix forming agent and a secondary component.
　該マトリックス形成剤としては、ゼラチン類、デキストリン類ならびに大豆、小麦ならびにオオバコ(psyllium)種子蛋白等の動物性蛋白類若しくは植物性タンパク類；アラビアゴム、グアーガム、寒天ならびにキサンタン等のゴム質物質；多糖類；アルギン酸類；カルボキシメチルセルロース類；カラゲナン類；デキストラン類；ペクチン類；ポリビニルピロリドン等の合成ポリマー類；ゼラチン－アラビアゴムコンプレックス等から誘導される物質が含まれる。さらに、マンニトール、デキストロース、ラクトース、ガラクトースならびにトレハロース等の糖類；シクロデキストリン等の環状糖類；リン酸ナトリウム、塩化ナトリウムならびにケイ酸アルミニウム等の無機塩類；グリシン、Ｌ－アラニン、Ｌ－アスパラギン酸、Ｌ－グルタミン酸、Ｌ－ヒドロシキプロリン、Ｌ－イソロイシン、Ｌ－ロイシンならびにＬ－フェニルアラニン等の炭素原子数が２から１２までのアミノ酸等が含まれる。 Examples of the matrix forming agent include gelatins, dextrins, and animal or vegetable proteins such as soybean, wheat and psyllium seed proteins; gums such as gum arabic, guar gum, agar and xanthan; Examples include sugars, alginic acids, carboxymethylcelluloses, carrageenans, dextrans, pectins, synthetic polymers such as polyvinylpyrrolidone, gelatin-gum arabic complex, and the like. Furthermore, sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic saccharides such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate; glycine, L-alanine, L-aspartic acid, L- Examples include amino acids having 2 to 12 carbon atoms such as glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine.
　マトリックス形成剤は、その１種若しくはそれ以上を、固形化の前に、溶液または懸濁液中に導入することができる。かかるマトリックス形成剤は、界面活性剤に加えて存在していてもよく、また界面活性剤が排除されて存在していてもよい。マトリックス形成剤は、そのマトリックスを形成することに加えて、本発明の化合物または併用薬物の拡散状態をその溶液または懸濁液中に維持する助けをすることができる。 One or more of the matrix forming agents can be introduced into a solution or suspension before solidification. Such a matrix forming agent may be present in addition to the surfactant, or may be present with the surfactant excluded. In addition to forming the matrix, the matrix-forming agent can help maintain the diffusion state of the compound of the invention or the concomitant drug in the solution or suspension.
　保存剤、酸化防止剤、界面活性剤、増粘剤、着色剤、ｐＨ調整剤、香味料、甘味料若しくは食味マスキング剤等の二次成分を組成物中に含有していてよい。適当な着色剤としては、赤色、黒色ならびに黄色酸化鉄類およびエリス・アンド・エベラールド社のＦＤ＆Ｃブルー２号ならびにＦＤ＆Ｃレッド４０号等のＦＤ＆Ｃ染料が挙げられる。適当な香味料には、ミント、ラズベリー、甘草、オレンジ、レモン、グレープフルーツ、カラメル、バニラ、チェリーならびにグレープフレーバーおよびこれらを組合せたものが含まれる。適当なｐＨ調整剤には、クエン酸、酒石酸、リン酸、塩酸およびマレイン酸が含まれる。適当な甘味料としては、アスパルテーム、アセスルフェームＫならびにタウマチン等が含まれる。適当な食味マスキング剤としては、重炭酸ナトリウム、イオン交換樹脂、シクロデキストリン包接化合物、吸着質物質ならびにマイクロカプセル化アポモルフィンが含まれる。 Secondary components such as preservatives, antioxidants, surfactants, thickeners, colorants, pH adjusters, flavoring agents, sweeteners or taste masking agents may be contained in the composition. Suitable colorants include red, black and yellow iron oxides and FD & C dyes such as FD & C Blue 2 and FD & C Red 40 from Ellis & Everald. Suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavor and combinations thereof. Suitable pH adjusting agents include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Suitable sweeteners include aspartame, acesulfame K, thaumatin and the like. Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbate materials, and microencapsulated apomorphine.
　製剤は、通常約０．１ないし約５０重量％、好ましくは約０．１ないし約３０重量％の本発明の化合物または併用薬物を含み、約１分ないし約６０分の間、好ましくは約１分ないし約１５分の間、より好ましくは約２分ないし約５分の間に（水に）本発明の化合物または併用薬物の９０％以上を溶解させることが可能な製剤（上記、舌下錠、バッカル等）や、口腔内に入れられて１ないし６０秒以内に、好ましくは１ないし３０秒以内に、さらに好ましくは１ないし１０秒以内に崩壊する口腔内速崩壊剤が好ましい。 The preparation usually contains about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight of a compound of the present invention or a concomitant drug, and is about 1 to about 60 minutes, preferably about 1 A preparation capable of dissolving 90% or more of the compound of the present invention or the concomitant drug (in water) between about 2 minutes and about 15 minutes, more preferably between about 2 minutes and about 5 minutes (in the above sublingual tablets) , Buccals, etc.) and intraoral fast disintegrating agents that disintegrate within 1 to 60 seconds, preferably within 1 to 30 seconds, more preferably within 1 to 10 seconds after being placed in the oral cavity are preferred.
　上記賦形剤の製剤全体に対する含有量は、約１０ないし約９９重量％、好ましくは約３０ないし約９０重量％である。β－シクロデキストリンまたはβ－シクロデキストリン誘導体の製剤全体に対する含有量は、０ないし約３０重量％である。滑沢剤の製剤全体に対する含有量は、約０．０１ないし約１０重量％、好ましくは約１ないし約５重量％である。等張化剤の製剤全体に対する含有量は、約０．１ないし約９０重量％、好ましくは、約１０ないし約７０重量％である。親水性担体の製剤全体に対する含有量は、約０．１ないし約５０重量％、好ましくは約１０ないし約３０重量％である。水分散性ポリマーの製剤全体に対する含有量は、約０．１ないし約３０重量％、好ましくは約１０ないし約２５重量％である。安定化剤の製剤全体に対する含有量は、約０．１ないし約１０重量％、好ましくは約１ないし約５重量％である。上記製剤はさらに、着色剤、甘味剤、防腐剤等の添加剤を必要に応じて含有していてもよい。 The content of the above-mentioned excipient in the whole preparation is about 10 to about 99% by weight, preferably about 30 to about 90% by weight. The content of β-cyclodextrin or β-cyclodextrin derivative in the whole preparation is 0 to about 30% by weight. The content of the lubricant in the whole preparation is about 0.01 to about 10% by weight, preferably about 1 to about 5% by weight. The content of the tonicity agent in the whole preparation is about 0.1 to about 90% by weight, preferably about 10 to about 70% by weight. The content of the hydrophilic carrier in the whole preparation is about 0.1 to about 50% by weight, preferably about 10 to about 30% by weight. The content of the water-dispersible polymer in the whole preparation is about 0.1 to about 30% by weight, preferably about 10 to about 25% by weight. The content of the stabilizer in the whole preparation is about 0.1 to about 10% by weight, preferably about 1 to about 5% by weight. The above-mentioned preparation may further contain additives such as a coloring agent, a sweetening agent, and a preservative as necessary.
　本発明の併用剤の投与量は、本発明の化合物の種類、年齢、体重、症状、剤形、投与方法、投与期間等により異なるが、例えば、癌患者（成人、体重約６０ｋｇ）に対し、通常、本発明の化合物および併用薬物として、それぞれ１日約０．０１ないし約１０００ｍｇ／ｋｇ体重、好ましくは約０．０１ないし約１００ｍｇ／ｋｇ体重、より好ましくは約０．１ないし約１００ｍｇ／ｋｇ体重、とりわけ約０．１ないし約５０ｍｇ／ｋｇ体重を、なかでも約１．５ないし約３０ｍｇ／ｋｇ体重を１日１回から数回に分けて静脈投与される。もちろん、前記したように投与量は種々の条件で変動するので、前記投与量より少ない量で十分な場合もあり、また範囲を超えて投与する必要のある場合もある。 The dose of the concomitant drug of the present invention varies depending on the type, age, weight, symptom, dosage form, administration method, administration period, etc. of the compound of the present invention. For example, for cancer patients (adults, body weight of about 60 kg), Usually, the compound of the present invention and the concomitant drug are each about 0.01 to about 1000 mg / kg body weight, preferably about 0.01 to about 100 mg / kg body weight, more preferably about 0.1 to about 100 mg / kg per day. Body weight, particularly about 0.1 to about 50 mg / kg body weight, especially about 1.5 to about 30 mg / kg body weight, is intravenously administered in portions from once to several times a day. Of course, as described above, the dosage varies depending on various conditions. Therefore, a dosage smaller than the dosage may be sufficient, or the dosage may need to be administered beyond the range.
　併用薬物は、副作用が問題とならない範囲でどのような量を設定することも可能である。併用薬物としての一日投与量は、症状の程度、投与対象の年齢、性別、体重、感受性差、投与の時期、間隔、医薬製剤の性質、調剤、種類、有効成分の種類等によって異なり、特に限定されないが、薬物の量として通常、たとえば経口投与で患者１ｋｇ体重あたり約０.００１ないし２０００ｍｇ、好ましくは約０.０１ないし５００ｍｇ、さらに好ましくは、約０.１ないし１００ｍｇ程度であり、これを通常１日１ないし４回に分けて投与する。 The amount of the concomitant drug can be set as long as side effects do not become a problem. The daily dose as a concomitant drug varies depending on the degree of symptoms, age of the subject, sex, body weight, sensitivity difference, timing of administration, interval, nature of pharmaceutical preparation, formulation, type, type of active ingredient, etc. Although it is not limited, the amount of the drug is usually about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, more preferably about 0.1 to 100 mg per kg body weight of the patient by oral administration. The dose is usually divided into 1 to 4 times a day.
　本発明の併用剤を投与するに際しては、本発明の化合物と併用薬物とを同時期に投与してもよいが、併用薬物を先に投与した後、本発明の化合物を投与してもよいし、本発明の化合物を先に投与し、その後で併用薬物を投与してもよい。時間差をおいて投与する場合、時間差は投与する有効成分、剤形、投与方法により異なるが、例えば、併用薬物を先に投与する場合、併用薬物を投与した後１分ないし３日以内、好ましくは１０分ないし１日以内、より好ましくは１５分ないし１時間以内に本発明の化合物を投与する方法が挙げられる。本発明の化合物を先に投与する場合、本発明の化合物を投与した後、１分ないし１日以内、好ましくは１０分ないし６時間以内、より好ましくは１５分から１時間以内に併用薬物を投与する方法が挙げられる。 When administering the concomitant drug of the present invention, the compound of the present invention and the concomitant drug may be administered at the same time, but after the concomitant drug is administered first, the compound of the present invention may be administered. The compound of the present invention may be administered first, followed by administration of the concomitant drug. When administered at a time difference, the time difference varies depending on the active ingredient to be administered, dosage form, and administration method. For example, when administering the concomitant drug first, within 1 minute to 3 days after administering the concomitant drug, preferably A method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour is mentioned. When the compound of the present invention is administered first, the concomitant drug is administered within 1 minute to 1 day after administration of the compound of the present invention, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour. A method is mentioned.
　好ましい投与方法としては、例えば、経口投与製剤に成型された併用薬物約０.００１ないし２００ｍｇ／ｋｇ体重を経口投与し、約１５分後に経口投与製剤に成型された本発明の化合物約０.００５ないし１００ｍｇ／ｋｇ体重を１日量として経口投与する。 As a preferable administration method, for example, about 0.001 to 200 mg / kg body weight of a concomitant drug molded into an orally administered preparation is orally administered, and about 0.005 of the compound of the present invention formed into an orally administered preparation after about 15 minutes. Orally administered as a daily dose of 100 mg / kg body weight.
　さらに、本発明の化合物または本発明の併用剤は、非薬剤療法と併用して用いることができる。具体的には、本発明の化合物または本発明の併用剤は、例えば、（１）手術、（２）アンジオテンシンＩＩ等を用いる昇圧化学療法、（３）遺伝子療法、（４）温熱療法、（５）凍結療法、（６）レーザー焼灼法、（７）放射線療法等の非薬剤療法と組み合わせることもできる。 Furthermore, the compound of the present invention or the concomitant drug of the present invention can be used in combination with non-drug therapy. Specifically, the compound of the present invention or the concomitant drug of the present invention includes, for example, (1) surgery, (2) pressor chemotherapy using angiotensin II, (3) gene therapy, (4) hyperthermia, (5 It can also be combined with non-drug therapies such as)) cryotherapy, (6) laser ablation, and (7) radiation therapy.
　例えば、本発明の化合物または本発明の併用剤を手術等の前または後に、あるいはこれら２、３種を組み合わせた治療前または後に使用することによって、耐性発現の阻止、無病期（Disease-Free Survival）の延長、癌転移あるいは再発の抑制、延命等の効果が得られる。 For example, by using the compound of the present invention or the concomitant drug of the present invention before or after surgery, etc., or before or after treatment with a combination of these two or three kinds, prevention of resistance development, disease-free (Disease-Free Survival ), Suppression of metastasis or recurrence, prolongation of life, etc. are obtained.
　また、本発明の化合物または本発明の併用剤による治療と、支持療法〔（ｉ）各種感染病の併発に対する抗生物質（例えば、パンスポリン等のβ－ラクタム系、クラリスロマイシン等のマクロライド系等）の投与、（ｉｉ）栄養障害改善のための高カロリー輸液、アミノ酸製剤、総合ビタミン剤の投与、（ｉｉｉ）疼痛緩和のためのモルヒネ投与、（ｉｖ）悪心、嘔吐、食欲不振、下痢、白血球減少、血小板減少、ヘモグロビン濃度低下、脱毛、肝障害、腎障害、ＤＩＣ、発熱等のような副作用を改善する薬剤の投与および（ｖ）癌の多剤耐性を抑制するための薬剤の投与等〕を組み合わせることもできる。 In addition, treatment with the compound of the present invention or the concomitant drug of the present invention and supportive therapy [(i) antibiotics for concurrent occurrence of various infectious diseases (for example, β-lactams such as pansporin, macrolides such as clarithromycin, etc. ), (Ii) high calorie infusion for improving nutritional disorders, amino acid preparations, administration of multivitamins, (iii) morphine for pain relief, (iv) nausea, vomiting, loss of appetite, diarrhea, leukocytes Reduction, thrombocytopenia, hemoglobin concentration reduction, hair loss, liver damage, kidney damage, DIC, administration of drugs to improve side effects such as fever, and (v) administration of drugs to suppress multidrug resistance of cancer, etc.] Can also be combined.
　前記の処置を施す前または施した後に、本発明の化合物または本発明の併用剤を経口（徐放性を含む）、静脈内（bolus、infusion、包接体を含む）、皮下および筋注（bolus、infusion、徐放性を含む）、経皮、腫瘍内および近位投与によって投与するのが好ましい。 Before or after the treatment described above, the compound of the present invention or the combination of the present invention is administered orally (including sustained release), intravenous (including bolus, infusion, inclusion body), subcutaneous and intramuscular injection ( (including bolus, infusion, sustained release), transdermal, intratumoral and proximal administration.
　手術等の前に本発明の化合物または本発明の併用剤を投与する場合の時期としては、例えば、手術等の約３０分ないし２４時間前に１回投与することもできるし、あるいは手術等の約３ないし６ヶ月前に１ないし３サイクルに分けて投与することもできる。このように、手術等の前に本発明の化合物または本発明の併用剤を投与することにより、例えば、癌組織を縮小させることができるので、手術等がしやすくなる。 The timing of administering the compound of the present invention or the concomitant drug of the present invention before surgery or the like can be administered once, for example, about 30 minutes to 24 hours before surgery or the like. The administration can be divided into 1 to 3 cycles before about 3 to 6 months. Thus, by administering the compound of the present invention or the concomitant drug of the present invention before surgery or the like, for example, cancer tissue can be reduced, so that surgery and the like are facilitated.
　手術等の後に本発明の化合物または本発明の併用剤を投与する場合の時期としては、手術等の約３０分ないし２４時間後に、例えば、数週間ないし３ヶ月単位で反復投与することができる。このように、手術等の後に本発明の化合物または本発明の併用剤を投与することにより、手術等の効果を高めることができる。 When the compound of the present invention or the concomitant drug of the present invention is administered after surgery or the like, it can be repeatedly administered, for example, in units of several weeks to 3 months, about 30 minutes to 24 hours after surgery. Thus, by administering the compound of the present invention or the concomitant drug of the present invention after surgery or the like, the effect of surgery or the like can be enhanced.
　以下に参考例、実施例、製剤例、実験例および試験例を挙げて、本発明を更に具体的に説明するが、これによって本発明が限定されるものではない。
　実施例におけるLC/MS分析は以下の条件により実施した。
測定機器：ウオーターズ社　ZQ
カラム：資生堂社製CAPCELL　PAK C18 UG120 S-3　3μｍ, 35 X 1.5 mm
溶媒：A液；　5 mM　酢酸アンモニウム水/アセトニトリル＝98/2
　　　　B液；　100 mM　酢酸アンモニウム水/アセトニトリル＝5/95
グラジエントサイクル: 0.00分（A液/B液＝100/0）, 2.00分（A液/B液＝0/100）, 3.00分（A液/B液＝0/100）, 3.01分（A液/B液＝100/0）, 3.80分（A液/B液＝100/0）
流速：0.5 mL/min、カラム温度は室温であり、温度制御は行っていない。
イオン化法：電子衝撃イオン化法（Electron　Spray Ionization ：　ESI　ポジティブ及びネガティブイオンピークを検出）
該当生成物ピークのUV:220 nmにおいて検出されるピーク面積の百分率値をもって化合物の純度とした。
　実施例において、分取HPLCは以下のように実施した。
分取HPLC機器：ギルソン社ハイスループット精製システム
カラム：YMC Combiprep　Hydrosphere C18 S-5　5 μｍ, 12 nM. 50 X 20 mm
溶媒：A液；　水
　　　　B液；　アセトニトリル
グラジエントサイクル: 0.00分（A液/B液＝98/2）, 1.10分（A液/B液＝98/2）, 5.00分（A液/B液＝0/100）, 6.40分（A液/B液＝0/100）, 6.50分（A液/B液＝2/98）, 6.52分（A液/B液＝2/98）
流速：25 mL/min、検出法：UV　220 nm Hereinafter, the present invention will be described more specifically with reference to Reference Examples, Examples, Formulation Examples, Experimental Examples and Test Examples, but the present invention is not limited thereto.
LC / MS analysis in the examples was performed under the following conditions.
Measuring equipment: Waters ZQ
Column: Shiseido CAPCELL PAK C18 UG120 S-3 3μm, 35 X 1.5 mm
Solvent: Liquid A; 5 mM ammonium acetate water / acetonitrile = 98/2
B solution: 100 mM ammonium acetate water / acetonitrile = 5/95
Gradient cycle: 0.00 minutes (A liquid / B liquid = 100/0), 2.00 minutes (A liquid / B liquid = 0/100), 3.00 minutes (A liquid / B liquid = 0/100), 3.01 minutes (A liquid / B liquid = 100/0), 3.80 minutes (A liquid / B liquid = 100/0)
Flow rate: 0.5 mL / min, column temperature is room temperature, temperature is not controlled.
Ionization method: Electron impact ionization method (Electron Spray Ionization: ESI positive and negative ion peaks are detected)
The percentage value of the peak area detected at UV of the corresponding product peak at 220 nm was taken as the purity of the compound.
In the examples, preparative HPLC was performed as follows.
Preparative HPLC instrument: Gilson high-throughput purification system Column: YMC Combiprep Hydrosphere C18 S-5 5 μm, 12 nM. 50 X 20 mm
Solvent: Liquid A; Water Liquid B; Acetonitrile Gradient Cycle: 0.00 min (A liquid / B liquid = 98/2), 1.10 min (A liquid / B liquid = 98/2), 5.00 min (A liquid / B liquid = 0/100), 6.40 minutes (A liquid / B liquid = 0/100), 6.50 minutes (A liquid / B liquid = 2/98), 6.52 minutes (A liquid / B liquid = 2/98)
Flow rate: 25 mL / min, detection method: UV 220 nm
　参考例、実施例のカラムクロマトグラフィーにおける溶出は、特に言及しない限り、ＴＬＣ（Ｔｈｉｎ　Ｌａｙｅｒ　Ｃｈｒｏｍａｔｏｇｒａｐｈｙ、薄層クロマトグラフィー）による観察下に行った。ＴＬＣ観察においては、ＴＬＣプレートとしてメルク（Ｍｅｒｃｋ）社製の６０Ｆ２５４、または富士シリシア化学（ＦＵＪＩ　ＳＩＬＹＳＩＡ　ＣＨＥＭＩＣＡＬ）社製のＮＨ　ＴＬＣプレートを用い、展開溶媒として、カラムクロマトグラフィーで溶出溶媒として用いた溶媒を用いた。また、検出にはＵＶ検出器を採用した。カラムクロマトグラフィー用のシリカゲルとしては、メルク社製のシリカゲル６０（７０－２３０メッシュ）または富士シリシア化学社製のＮＨシリカゲル（１００－２００メッシュ）等を用いた。室温とあるのは通常約１０℃から３５℃の温度を意味する。さらに、抽出液の乾燥には無水硫酸ナトリウムまたは無水硫酸マグネシウムを用いた。 The elution in the column chromatography of Reference Examples and Examples was performed under observation by TLC (Thin Layer Chromatography) unless otherwise specified. In TLC observation, 60F254 made by Merck or NH TLC plate made by Fuji Silysia Chemical (FUJI SILYSIA CHEMICAL) was used as a TLC plate, and the solvent used as an elution solvent in column chromatography was used as a developing solvent. Using. A UV detector was used for detection. As silica gel for column chromatography, silica gel 60 (70-230 mesh) manufactured by Merck or NH silica gel (100-200 mesh) manufactured by Fuji Silysia Chemical Ltd. was used. Room temperature usually means a temperature of about 10 ° C to 35 ° C. Furthermore, anhydrous sodium sulfate or anhydrous magnesium sulfate was used for drying the extract.
　製剤例において、製剤添加剤（例、ラクトース、コーンスターチ、ステアリン酸マグネシウム、微結晶セルロース）としては、第14改正日本薬局方（以下、日局という）あるいは医薬品添加物規格２００３適合品を用いる。 In formulation examples, as a formulation additive (eg, lactose, corn starch, magnesium stearate, microcrystalline cellulose), the 14th revised Japanese Pharmacopoeia (hereinafter referred to as JP) or a product conforming to the Pharmaceutical Additives Standard 2003 is used.
実施例、参考例における略号の意味は以下の通りである。
　ＬＣ：液体クロマトグラフィー
　ＭＳ：質量分析スペクトル
　ＥＳＩ：エレクトロスプレーイオン化法
　ＦＡＢ：高速原子衝撃法
　Ｍ：分子イオンピーク
　ＮＭＲ：核磁気共鳴スペクトル
　Ｈz：ヘルツ
　Ｊ：カップリング定数
　ｍ：マルチプレット
　ｑ：クワルテット
　ｔ：トリプレット
　ｄ：ダブレット
　ｓ：シングレット
　ｂｒ：ブロード
　ｄｔ：ダブルトリプレット
　ｂｒｓ：ブロードシングレット
　ｗｔ％：重量パーセント
　ＤＭＳＯ：ジメチルスルホキシド The meanings of the abbreviations in Examples and Reference Examples are as follows.
LC: liquid chromatography MS: mass spectrometry spectrum ESI: electrospray ionization method FAB: fast atom bombardment method M: molecular ion peak NMR: nuclear magnetic resonance spectrum Hz: hertz J: coupling constant m: multiplet q: quartet t: Triplet d: Doublet s: Singlet br: Broad dt: Double triplet brs: Broad singlet wt%: Weight percent DMSO: Dimethyl sulfoxide
参考例１
(クロロアセチル)カルバミン酸 tert-ブチルの製造 Reference example 1
Production of tert-butyl (chloroacetyl) carbamate
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　2-クロロアセトアミド（25 g, 267 mmol）の1,2-ジクロロエタン（125 mL）懸濁液に、0℃にてオキサリルクロライド（28 mL, 321 mmol）を滴下した。3時間加熱還流後、0℃に冷却し、tert-ブチルアルコール／1,2-ジクロロエタン（75 mL, 1／1）を加え、20分間撹拌した。反応液に飽和重曹水を加え、1,2-ジクロロエタンにて抽出した。飽和重曹水、水にて洗浄後、無水硫酸マグネシウムにて乾燥、ろ過した。減圧下溶媒を留去、残渣をシクロヘキサンにて再結晶し、表題化合物（25.6 g, 49%）を白色結晶として得た。
1H-NMR (CDCl3, 300 MHz) δ 1.58 (9H, s), 4.46 (2H, s), 7.59 (1H, br). Oxalyl chloride (28 mL, 321 mmol) was added dropwise to a suspension of 2-chloroacetamide (25 g, 267 mmol) in 1,2-dichloroethane (125 mL) at 0 ° C. After refluxing for 3 hours, the mixture was cooled to 0 ° C., tert-butyl alcohol / 1,2-dichloroethane (75 mL, 1/1) was added, and the mixture was stirred for 20 minutes. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with 1,2-dichloroethane. The extract was washed with saturated aqueous sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was recrystallized from cyclohexane to obtain the title compound (25.6 g, 49%) as white crystals.
1 H-NMR (CDCl 3 , 300 MHz) δ 1.58 (9H, s), 4.46 (2H, s), 7.59 (1H, br).
参考例２
(6-ヨードイミダゾ[1,2-b]ピリダジン-2-イル)カルバミン酸 tert-ブチルの製造 Reference example 2
Preparation of tert-butyl (6-iodoimidazo [1,2-b] pyridazin-2-yl) carbamate
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　3-アミノ-6-ヨードピリダジン（10.0 g, 45.2 mmol）のN,N-ジメチルアセトアミド（100 mL）溶液に、(クロロアセチル)カルバミン酸 tert-ブチル（14.0 g, 72.4 mmol）、リン酸水素二ナトリウム（16.1 g, 113 mmol）を加え、120℃にて3時間撹拌した。室温に冷却後、水（400 mL）を加え、析出した結晶をろ過し、アセトニトリル、石油エーテルにて洗浄し、表題化合物（10.2 g, 63%）を緑色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 1.49 (9H, s), 7.45 (1H, d, J = 9.5 Hz), 7.69 (1H, d, J = 9.5 Hz), 8.01 (1H, brs), 10.20 (1H, brs). To a solution of 3-amino-6-iodopyridazine (10.0 g, 45.2 mmol) in N, N-dimethylacetamide (100 mL), tert-butyl (chloroacetyl) carbamate (14.0 g, 72.4 mmol), dihydrogen phosphate Sodium (16.1 g, 113 mmol) was added, and the mixture was stirred at 120 ° C. for 3 hours. After cooling to room temperature, water (400 mL) was added, and the precipitated crystals were filtered and washed with acetonitrile and petroleum ether to give the title compound (10.2 g, 63%) as a green powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 1.49 (9H, s), 7.45 (1H, d, J = 9.5 Hz), 7.69 (1H, d, J = 9.5 Hz), 8.01 (1H, brs ), 10.20 (1H, brs).
参考例３
(6-ヨードイミダゾ[1,2-b]ピリダジン-2-イル)カルバミン酸エチルの製造 Reference example 3
Preparation of ethyl (6-iodoimidazo [1,2-b] pyridazin-2-yl) carbamate
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　3-アミノ-6-ヨードピリダジン（27.0 g, 122 mmol）のN,N-ジメチルアセトアミド（270mL）溶液に、(クロロアセチル)カルバミン酸エチル（32.4 g, 195 mmol）、リン酸水素二ナトリウム（43.4 g, 305 mmol）を加え、110℃にて3時間撹拌した。室温に冷却後、水（810 mL）を加え、析出した結晶をろ過、アセトニトリル、エーテルにて洗浄し、表題化合物（33.0 g, 81%）を茶褐色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 1.26 (3H, t, J = 7.1 Hz), 4.17 (2H, q, J = 7.1 Hz), 7.47 (1H, d, J = 9.2 Hz), 7.70 (1H, d, J = 9.2 Hz), 8.06 (1H, s), 10.51 (1H, brs). To a solution of 3-amino-6-iodopyridazine (27.0 g, 122 mmol) in N, N-dimethylacetamide (270 mL), ethyl (chloroacetyl) carbamate (32.4 g, 195 mmol), disodium hydrogen phosphate (43.4 g, 305 mmol) was added, and the mixture was stirred at 110 ° C. for 3 hours. After cooling to room temperature, water (810 mL) was added, and the precipitated crystals were filtered and washed with acetonitrile and ether to give the title compound (33.0 g, 81%) as a brown powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 1.26 (3H, t, J = 7.1 Hz), 4.17 (2H, q, J = 7.1 Hz), 7.47 (1H, d, J = 9.2 Hz), 7.70 (1H, d, J = 9.2 Hz), 8.06 (1H, s), 10.51 (1H, brs).
参考例４－１
6-ヨードイミダゾ[1,2-b]ピリダジン-2-アミンの製造 Reference Example 4-1
Preparation of 6-iodoimidazo [1,2-b] pyridazin-2-amine
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
　(6-ヨードイミダゾ[1,2-b]ピリダジン-2-イル)カルバミン酸 tert-ブチル（10.2 g, 28.3 mmol）の酢酸エチル（50 mL）懸濁液に4規定塩酸／酢酸エチル（75 mL）を加え、室温にて4時間撹拌した。反応液にジエチルエーテル（200 mL）を加え、析出物をろ過した。飽和重曹水で洗浄後、水、アセトニトリル、ジエチルエーテルにて洗浄し、表題化合物（4.9 g, 67%）を緑色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 5.61 (2H, s), 7.22 (1H, d, J = 8.7 Hz), 7.36 (1H, s), 7.39 (1H, d, J = 8.7 Hz). To a suspension of tert-butyl (6-iodoimidazo [1,2-b] pyridazin-2-yl) carbamate (10.2 g, 28.3 mmol) in ethyl acetate (50 mL) was added 4N hydrochloric acid / ethyl acetate (75 mL). ) And stirred at room temperature for 4 hours. Diethyl ether (200 mL) was added to the reaction solution, and the precipitate was filtered. The extract was washed with saturated aqueous sodium hydrogen carbonate and then with water, acetonitrile and diethyl ether to give the title compound (4.9 g, 67%) as a green powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 5.61 (2H, s), 7.22 (1H, d, J = 8.7 Hz), 7.36 (1H, s), 7.39 (1H, d, J = 8.7 Hz ).
参考例４－２
6-ヨードイミダゾ[1,2-b]ピリダジン-2-アミンの製造 Reference Example 4-2
Preparation of 6-iodoimidazo [1,2-b] pyridazin-2-amine
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
　水酸化バリウム・8水和物（14.5 g, 46.1 mmol）に水（240 mL）を加え、80℃にて15分間撹拌した。(6-ヨードイミダゾ[1,2-b]ピリダジン-2-イル)カルバミン酸エチル（10.2 g, 30.7 mmol）のN-メチルピロリドン（80 mL）溶液を加え、120℃にて8時間撹拌した。室温に冷却後、反応液に水（480 mL）を加え、1時間撹拌した。酢酸エチル／テトラヒドロフランを用いて２回抽出し、飽和食塩水にて洗浄後、無水硫酸マグネシウムにて乾燥、ろ過した。減圧下溶媒を留去、残渣にジイソプロピルエーテルを加え、析出した結晶をろ過し、表題化合物（6.1 g, 76%）を茶色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 5.61 (2H, s), 7.22 (1H, d, J = 8.7 Hz), 7.36 (1H, s), 7.39 (1H, d, J = 8.7 Hz). Water (240 mL) was added to barium hydroxide octahydrate (14.5 g, 46.1 mmol), and the mixture was stirred at 80 ° C. for 15 minutes. A solution of ethyl (6-iodoimidazo [1,2-b] pyridazin-2-yl) carbamate (10.2 g, 30.7 mmol) in N-methylpyrrolidone (80 mL) was added and stirred at 120 ° C. for 8 hours. After cooling to room temperature, water (480 mL) was added to the reaction solution and stirred for 1 hour. The mixture was extracted twice with ethyl acetate / tetrahydrofuran, washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, diisopropyl ether was added to the residue, and the precipitated crystals were filtered to give the title compound (6.1 g, 76%) as a brown powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 5.61 (2H, s), 7.22 (1H, d, J = 8.7 Hz), 7.36 (1H, s), 7.39 (1H, d, J = 8.7 Hz ).
参考例５
N-(6-ヨードイミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミドの製造 Reference Example 5
Production of N- (6-iodoimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
　6-ヨードイミダゾ[1,2-b]ピリダジン-2-アミン（1.0 g, 3.85 mmol）のN,N-ジメチルアセトアミド溶液（10 mL）にシクロプロピルカルボニルクロライド（0.38 mL, 4.23 mmol）を加え、室温にて4時間撹拌した。反応液に水を加え、酢酸エチル／テトラヒドロフランにて抽出した。飽和食塩水にて洗浄後、無水硫酸マグネシウムにて乾燥、ろ過した。減圧下溶媒を留去、残渣をヘキサン／酢酸エチル（4／1）にて洗浄、表題化合物（1.01 g, 80%）を茶褐色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.82 - 0.86 (4H, m), 1.90 - 2.00 (1H, m), 7.49 (1H, d, J = 9.3 Hz), 7.73 (1H, d, J = 9.3 Hz), 8.23 (1H, s), 11.20 (1H, s). To a solution of 6-iodoimidazo [1,2-b] pyridazin-2-amine (1.0 g, 3.85 mmol) in N, N-dimethylacetamide (10 mL) was added cyclopropylcarbonyl chloride (0.38 mL, 4.23 mmol). Stir at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate / tetrahydrofuran. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane / ethyl acetate (4/1) to give the title compound (1.01 g, 80%) as a brown powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.82-0.86 (4H, m), 1.90-2.00 (1H, m), 7.49 (1H, d, J = 9.3 Hz), 7.73 (1H, d, J = 9.3 Hz), 8.23 (1H, s), 11.20 (1H, s).
参考例６
1-(2-メトキシエチル)-5-メチル-1H-ピラゾール-3-カルボン酸の製造 Reference Example 6
Preparation of 1- (2-methoxyethyl) -5-methyl-1H-pyrazole-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
　水素化ナトリウム(310 mg, 7.8 mmol)のN,N-ジメチルホルムアミド(10 mL)懸濁液に、氷冷下、3-メチル-1H-ピラゾール-5-カルボン酸エチル(1000 mg, 6.5 mmol)のN,N-ジメチルホルムアミド(5 mL)溶液をゆっくり加え、混合物を0℃で10分、次いで室温で20分撹拌した。この反応混合物に、1-ブロモ-2-メトキシエタン(1090 mg, 7.8 mmol)のN,N-ジメチルホルムアミド(4 mL)溶液を加え、混合物を室温で7時間撹拌した。溶媒を減圧留去後、残渣に酢酸エチル／テトラヒドロフラン、水を加え、水層を酢酸エチル／テトラヒドロフランで３回抽出した。合わせ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、ろ過した。ろ液を減圧濃縮し、残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル／ヘキサン＝5／95→70／30)で精製し、1-(2-メトキシエチル)-5-メチル-1H-ピラゾール-3-カルボン酸エチル(734 mg, 53%)を無色液体として得た。得られた1-(2-メトキシエチル)-5-メチル-1H-ピラゾール-3-カルボン酸エチル(490 mg, 2.3 mmol)のテトラヒドロフラン(3 mL)溶液に、2Ｎ水酸化ナトリウム水溶液(2.4 mL)を加え、混合物を室温で3時間撹拌した。反応混合物に1Ｎ塩酸(5 mL)、酢酸エチルを加え、水層を酢酸エチルで３回抽出した。合わせ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、ろ過した。ろ液を減圧濃縮し、残留物を酢酸エチル／ヘキサンで洗浄し、表題化合物(423 mg, 99%)を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 2.27 (3H, s), 3.21 (3H, s), 3.66 (2H, t, J = 5.4 Hz), 4.23 (2H, t, J = 5.4 Hz), 6.44 (1H, s), 12.50 (1H, brs). To a suspension of sodium hydride (310 mg, 7.8 mmol) in N, N-dimethylformamide (10 mL) under ice-cooling, ethyl 3-methyl-1H-pyrazole-5-carboxylate (1000 mg, 6.5 mmol) Of N, N-dimethylformamide (5 mL) was added slowly and the mixture was stirred at 0 ° C. for 10 minutes and then at room temperature for 20 minutes. To this reaction mixture, a solution of 1-bromo-2-methoxyethane (1090 mg, 7.8 mmol) in N, N-dimethylformamide (4 mL) was added and the mixture was stirred at room temperature for 7 hours. After evaporating the solvent under reduced pressure, ethyl acetate / tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted three times with ethyl acetate / tetrahydrofuran. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 5/95 → 70/30) to give 1- (2-methoxyethyl) -5-methyl-1H-pyrazole-3. -Ethyl carboxylate (734 mg, 53%) was obtained as a colorless liquid. To a solution of the obtained ethyl 1- (2-methoxyethyl) -5-methyl-1H-pyrazole-3-carboxylate (490 mg, 2.3 mmol) in tetrahydrofuran (3 mL) was added 2N aqueous sodium hydroxide solution (2.4 mL). Was added and the mixture was stirred at room temperature for 3 hours. To the reaction mixture were added 1N hydrochloric acid (5 mL) and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate / hexane to give the title compound (423 mg, 99%) as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 2.27 (3H, s), 3.21 (3H, s), 3.66 (2H, t, J = 5.4 Hz), 4.23 (2H, t, J = 5.4 Hz ), 6.44 (1H, s), 12.50 (1H, brs).
参考例７
5-メチル-1-(2-オキソプロピル)-1H-ピラゾール-3-カルボン酸の製造 Reference Example 7
Preparation of 5-methyl-1- (2-oxopropyl) -1H-pyrazole-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
　参考例６と同様にして、水素化ナトリウム(770 mg, 19 mmol)、3-メチル-1H-ピラゾール-5-カルボン酸エチル(2480 mg, 16 mmol)、1-ブロモアセトン(3180 mg, 21 mmol)、N,N-ジメチルホルムアミド(30 mL)を原料として用い、5-メチル-1-(2-オキソプロピル)-1H-ピラゾール-3-カルボン酸エチル(1890 mg, 56%)を無色液体として得た。得られた5-メチル-1-(2-オキソプロピル)-1H-ピラゾール-3-カルボン酸エチル(1770 mg, 8.4 mmol)、テトラヒドロフラン(10 mL)、2Ｎ水酸化ナトリウム水溶液(8.5 mL)を原料として用い、表題化合物(1320 mg, 86%)を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 2.14 (3H, s), 2.17 (3H, s), 5.20 (2H, s), 6.47 - 6.51 (1H, m), 12.58 (1H, brs). In the same manner as in Reference Example 6, sodium hydride (770 mg, 19 mmol), ethyl 3-methyl-1H-pyrazole-5-carboxylate (2480 mg, 16 mmol), 1-bromoacetone (3180 mg, 21 mmol) ), N, N-dimethylformamide (30 mL) as a raw material, ethyl 5-methyl-1- (2-oxopropyl) -1H-pyrazole-3-carboxylate (1890 mg, 56%) as a colorless liquid Obtained. Raw material was ethyl 5-methyl-1- (2-oxopropyl) -1H-pyrazole-3-carboxylate (1770 mg, 8.4 mmol), tetrahydrofuran (10 mL), 2N aqueous sodium hydroxide solution (8.5 mL) To give the title compound (1320 mg, 86%) as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 2.14 (3H, s), 2.17 (3H, s), 5.20 (2H, s), 6.47-6.51 (1H, m), 12.58 (1H, brs) .
参考例８
6-メトキシイミダゾ[1,2-b]ピリダジン-2-アミンの製造 Reference Example 8
Preparation of 6-methoxyimidazo [1,2-b] pyridazin-2-amine
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
　6-ヨードイミダゾ[1,2-b]ピリダジン-2-アミン(16 g, 63 mmol)のメタノール(40 mL)懸濁液に、28%ナトリウムメトキサイド/メタノール溶液(85g, 440 mmol)を加え、混合物を39時間加熱還流した。溶媒を減圧留去後、残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル／ヘキサン＝40／60→100／0)で精製し、表題化合物（6240 mg, 61%）を淡緑色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 3.87 (3H, s), 5.15 (2H, brs), 6.59 (1H, d, J = 9.4 Hz), 7.12 (1H, s), 7.58 (1H, d, J = 9.4 Hz). To a suspension of 6-iodoimidazo [1,2-b] pyridazin-2-amine (16 g, 63 mmol) in methanol (40 mL) was added 28% sodium methoxide / methanol solution (85 g, 440 mmol). The mixture was heated to reflux for 39 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 40/60 → 100/0) to obtain the title compound (6240 mg, 61%) as a pale green solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 3.87 (3H, s), 5.15 (2H, brs), 6.59 (1H, d, J = 9.4 Hz), 7.12 (1H, s), 7.58 (1H , d, J = 9.4 Hz).
参考例９
N-(6-メトキシイミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミドの製造 Reference Example 9
Production of N- (6-methoxyimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide
　6-メトキシイミダゾ[1,2-b]ピリダジン-2-アミン(6230 mg, 38 mmol)のN,N-ジメチルアセトアミド(10 mL)溶液に、氷冷下、シクロプロパンカルボニルクロリド(4600 mg, 42 mmol)を加え、混合物を室温で1時間撹拌した。混合物に酢酸エチル／テトラヒドロフラン、飽和炭酸水素ナトリウム水溶液を加え、水層を酢酸エチル／テトラヒドロフランで４回抽出した。合わせた有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥、ろ過した。ろ液を減圧濃縮し、残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル／ヘキサン＝40／60→100／0)で精製し、表題化合物（6660 mg, 76%）を淡緑色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.75 - 0.88 (4H, m), 1.88 - 1.98 (1H, m), 3.93 (3H, s), 6.84 (1H, d, J = 9.4 Hz), 7.87 (1H, d, J = 9.4 Hz), 8.00 (1H, s), 11.01 (1H, s). To a solution of 6-methoxyimidazo [1,2-b] pyridazin-2-amine (6230 mg, 38 mmol) in N, N-dimethylacetamide (10 mL) under ice-cooling, cyclopropanecarbonyl chloride (4600 mg, 42 mmol) was added and the mixture was stirred at room temperature for 1 h. Ethyl acetate / tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the mixture, and the aqueous layer was extracted 4 times with ethyl acetate / tetrahydrofuran. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 40/60 → 100/0) to give the title compound (6660 mg, 76%) as a pale green solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.75-0.88 (4H, m), 1.88-1.98 (1H, m), 3.93 (3H, s), 6.84 (1H, d, J = 9.4 Hz) , 7.87 (1H, d, J = 9.4 Hz), 8.00 (1H, s), 11.01 (1H, s).
参考例１０
N-(6-ヒドロキシイミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミドの製造 Reference Example 10
Production of N- (6-hydroxyimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
　N-(6-メトキシイミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミド(6650 mg, 29 mmol)のN, N-ジメチルホルムアミド(100 mL)溶液に、ナトリウムエタンチオラート(6020 mg, 58 mmol)を加え、混合物を140℃で5時間撹拌した。溶媒を減圧留去後、残留物に酢酸エチル／テトラヒドロフラン、飽和食塩水、6Ｎ塩酸水溶液を加え、水層を酢酸エチル／テトラヒドロフランで４回抽出した。合わせ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、ろ過した。ろ液を減圧濃縮し、残留物を酢酸エチル／ヘキサンで洗浄し、表題化合物（4830 mg, 77%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.73 - 0.89 (4H, m), 1.86 - 1.99 (1H, m), 6.76 (1H, d, J = 9.6 Hz), 7.83 (1H, d, J = 9.6 Hz), 7.91 (1H, s), 11.05 (1H, s), 11.66 (1H, brs). A solution of N- (6-methoxyimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (6650 mg, 29 mmol) in N, N-dimethylformamide (100 mL) was added to sodium ethanethiolate (6020 mg). , 58 mmol) and the mixture was stirred at 140 ° C. for 5 h. After evaporating the solvent under reduced pressure, ethyl acetate / tetrahydrofuran, saturated brine and 6N aqueous hydrochloric acid were added to the residue, and the aqueous layer was extracted 4 times with ethyl acetate / tetrahydrofuran. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate / hexane to give the title compound (4830 mg, 77%) as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.73-0.89 (4H, m), 1.86-1.99 (1H, m), 6.76 (1H, d, J = 9.6 Hz), 7.83 (1H, d, J = 9.6 Hz), 7.91 (1H, s), 11.05 (1H, s), 11.66 (1H, brs).
参考例１１
N-{6-[(5-ニトロピリジン-2-イル)オキシ]イミダゾ[1,2-b]ピリダジン-2-イル}シクロプロパンカルボキサミドの製造 Reference Example 11
Preparation of N- {6-[(5-nitropyridin-2-yl) oxy] imidazo [1,2-b] pyridazin-2-yl} cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
　N-(6-ヒドロキシイミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミド(350 mg, 1.6 mmol)、2-ブロモ-5-ニトロピリジン(490 mg, 2.4 mmol)、炭酸セシウム(1320 mg, 4.0 mmol)、ジメチルスルホキシド(4 mL)の混合物を、70℃で3時間撹拌した。混合物に酢酸エチル／テトラヒドロフラン、飽和炭酸水素ナトリウム水溶液を加え、水層を酢酸エチル／テトラヒドロフランで４回抽出した。合わせた有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥、ろ過した。ろ液を減圧濃縮し、残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル／ヘキサン＝40／60→100／0)で精製し、表題化合物（340 mg, 62%）を黄色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.73 - 0.89 (4H, m), 1.89 - 2.01 (1H, m), 7.25 (1H, d, J = 9.6 Hz), 7.52 (1H, d, J = 9.1 Hz), 8.11 - 8.20 (2H, m), 8.73 (1H, dd, J = 9.1, 2.8 Hz), 9.07 (1H, d, J = 2.8 Hz), 11.20 (1H, s). N- (6-hydroxyimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (350 mg, 1.6 mmol), 2-bromo-5-nitropyridine (490 mg, 2.4 mmol), cesium carbonate ( A mixture of 1320 mg, 4.0 mmol) and dimethyl sulfoxide (4 mL) was stirred at 70 ° C. for 3 hours. Ethyl acetate / tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the mixture, and the aqueous layer was extracted 4 times with ethyl acetate / tetrahydrofuran. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 40/60 → 100/0) to give the title compound (340 mg, 62%) as a yellow solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.73-0.89 (4H, m), 1.89-2.01 (1H, m), 7.25 (1H, d, J = 9.6 Hz), 7.52 (1H, d, J = 9.1 Hz), 8.11-8.20 (2H, m), 8.73 (1H, dd, J = 9.1, 2.8 Hz), 9.07 (1H, d, J = 2.8 Hz), 11.20 (1H, s).
参考例１２
N-{6-[(5-アミノピリジン-2-イル)オキシ]イミダゾ[1,2-b]ピリダジン-2-イル}シクロプロパンカルボキサミドの製造 Reference Example 12
Preparation of N- {6-[(5-aminopyridin-2-yl) oxy] imidazo [1,2-b] pyridazin-2-yl} cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
　N-{6-[(5-ニトロピリジン-2-イル)オキシ]イミダゾ[1,2-b]ピリダジン-2-イル}シクロプロパンカルボキサミド(940 mg, 2.8 mmol)のN, N-ジメチルホルムアミド(8 mL)、メタノール(8 mL)溶液に、トリエチルアミン(4 mL)、10％パラジウム／カーボン(190 mg)を加え、水素雰囲気下、室温で混合物を20時間撹拌した。反応混合物をろ過し、ろ液を減圧留去後、残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル／ヘキサン＝40／60→100／0)で精製し、表題化合物（740 mg, 86%）を淡黄色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.73 - 0.88 (4H, m), 1.86 - 2.00 (1H, m), 5.28 (2H, s), 6.95 (2H, d, J = 9.3 Hz), 7.12 (1H, dd, J = 8.5, 1.9 Hz), 7.57 (1H, d, J = 1.9 Hz), 7.92 - 8.03 (2H, m), 11.09 (1H, s). N- {6-[(5-Nitropyridin-2-yl) oxy] imidazo [1,2-b] pyridazin-2-yl} cyclopropanecarboxamide (940 mg, 2.8 mmol) in N, N-dimethylformamide ( To a solution of 8 mL) and methanol (8 mL), triethylamine (4 mL) and 10% palladium / carbon (190 mg) were added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 20 hours. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 40/60 → 100/0) to give the title compound (740 mg, 86%) Obtained as a yellow solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.73-0.88 (4H, m), 1.86-2.00 (1H, m), 5.28 (2H, s), 6.95 (2H, d, J = 9.3 Hz) , 7.12 (1H, dd, J = 8.5, 1.9 Hz), 7.57 (1H, d, J = 1.9 Hz), 7.92-8.03 (2H, m), 11.09 (1H, s).
参考例１３
N-{6-[(6-アミノピリジン-3-イル)オキシ]イミダゾ[1,2-b]ピリダジン-2-イル}シクロプロパンカルボキサミドの製造 Reference Example 13
Preparation of N- {6-[(6-aminopyridin-3-yl) oxy] imidazo [1,2-b] pyridazin-2-yl} cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
　N-(6-クロロイミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミド(4.16 g, 18 mmol)、6-アミノピリジン-3-オール(2.7 g, 24 mmol)、炭酸セシウム(14.3 g, 44 mmol)、ジメチルスルホキシド(40 mL)の混合物を、100℃で15時間撹拌した。混合物に酢酸エチル／テトラヒドロフラン、飽和炭酸水素ナトリウム水溶液を加え、水層を酢酸エチル／テトラヒドロフランで４回抽出した。合わせた有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥、ろ過した。ろ液を減圧濃縮し、残留物をシリカゲルカラムクロマトグラフィー(ＮＨシリカゲル、酢酸エチル／ヘキサン＝40／60→100／0)で精製し、表題化合物（5.39 g, 99%）を淡黄色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.72 - 0.87 (4H, m), 1.85 - 1.97 (1H, m), 5.98 (2H, s), 6.51 (1H, d, J = 8.9 Hz), 7.01 (1H, d, J = 9.6 Hz), 7.37 (1H, d, J = 8.9 Hz), 7.84 - 7.93 (2H, m), 7.94 - 8.01 (1H, m), 11.04 (1H, s). N- (6-Chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (4.16 g, 18 mmol), 6-aminopyridin-3-ol (2.7 g, 24 mmol), cesium carbonate ( 14.3 g, 44 mmol) and dimethyl sulfoxide (40 mL) were stirred at 100 ° C. for 15 hours. Ethyl acetate / tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the mixture, and the aqueous layer was extracted 4 times with ethyl acetate / tetrahydrofuran. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 40/60 → 100/0) to give the title compound (5.39 g, 99%) as a pale yellow solid. It was.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.72-0.87 (4H, m), 1.85-1.97 (1H, m), 5.98 (2H, s), 6.51 (1H, d, J = 8.9 Hz) , 7.01 (1H, d, J = 9.6 Hz), 7.37 (1H, d, J = 8.9 Hz), 7.84-7.93 (2H, m), 7.94-8.01 (1H, m), 11.04 (1H, s).
参考例１４
N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミドの製造 Reference Example 14
Preparation of N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
　N-(6-ヨードイミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミド（4.8 g, 14.6 mmol）と4-アミノ-2-フルオロフェノール（2.48 g, 19.5 mmol）のジメチルスルフォキシド（25 mL）溶液に、炭酸セシウム（9.77 g, 30.0 mmol）を加え、100℃にて5時間撹拌した。反応液に水とテトラヒドロフランを加え、セライトを用いてろ過し、ろ液を酢酸エチルにて3回抽出した。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後、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル／ヘキサン＝2／1）にて精製し、表題化合物（3.5 g, 71%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.49 - 0.96 (4H, m), 1.77 - 2.02 (1H, m), 5.41 (2H, s), 6.37 - 6.43 (1H, m), 6.49 (1H, dd, J = 13.2, 2.5 Hz), 6.99 - 7.09 (2H, m), 7.88 (1H, s), 7.99 (1H, d, J = 9.6 Hz), 11.04 (1H, s). N- (6-Iodoimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (4.8 g, 14.6 mmol) and 4-amino-2-fluorophenol (2.48 g, 19.5 mmol) in dimethyl sulfo Cesium carbonate (9.77 g, 30.0 mmol) was added to the xoxide (25 mL) solution, and the mixture was stirred at 100 ° C. for 5 hours. Water and tetrahydrofuran were added to the reaction mixture, and the mixture was filtered through celite. The filtrate was extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 2/1) to give the title compound (3.5 g, 71%) as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.49-0.96 (4H, m), 1.77-2.02 (1H, m), 5.41 (2H, s), 6.37-6.43 (1H, m), 6.49 ( 1H, dd, J = 13.2, 2.5 Hz), 6.99-7.09 (2H, m), 7.88 (1H, s), 7.99 (1H, d, J = 9.6 Hz), 11.04 (1H, s).
参考例１５
1-(フェニルカルバモイル)シクロブタンカルボン酸エチルの製造 Reference Example 15
Preparation of ethyl 1- (phenylcarbamoyl) cyclobutanecarboxylate
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
　1-(エトキシカルボニル)シクロブタンカルボン酸(1.48 g, 8.6 mmol)、N,N-ジメチルホルムアミド(0.1 mL)、オキザリルクロライド (738 μL, 8.6 mmol)、アニリン（775 μL, 8.5 mmol）、N,N-ジメチルアセトアミド(5.0 mL)とテトラヒドロフラン（2 mL）を用いて実施例２２と同様の操作を行い、表題化合物（1.15 g, 54%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 1.17 (3H, t, J = 7.1 Hz), 1.71 - 2.05 (2H, m), 2.35 - 2.70 (4H, m), 4.14 (2H, q, J= 7.1 Hz), 6.97 - 7.10 (1H, m), 7.20 - 7.37 (2H, m), 7.57 - 7.71 (2H, m), 9.67 (1H, s). 1- (ethoxycarbonyl) cyclobutanecarboxylic acid (1.48 g, 8.6 mmol), N, N-dimethylformamide (0.1 mL), oxalyl chloride (738 μL, 8.6 mmol), aniline (775 μL, 8.5 mmol), N, The same operation as in Example 22 was performed using N-dimethylacetamide (5.0 mL) and tetrahydrofuran (2 mL) to obtain the title compound (1.15 g, 54%) as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 1.17 (3H, t, J = 7.1 Hz), 1.71-2.05 (2H, m), 2.35-2.70 (4H, m), 4.14 (2H, q, J = 7.1 Hz), 6.97-7.10 (1H, m), 7.20-7.37 (2H, m), 7.57-7.71 (2H, m), 9.67 (1H, s).
参考例１６
1-(フェニルカルバモイル)シクロブタンカルボン酸の製造 Reference Example 16
Production of 1- (phenylcarbamoyl) cyclobutanecarboxylic acid
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
　エチル 1-(フェニルカルバモイル)シクロブタンカルボキシラート(1.15 g, 4.65 mmol)のエタノール溶液（35 mL）に、1Ｎ水酸化ナトリウム（10 mL）を加え、4 時間加熱還流を行った。反応溶液を濃縮し、水溶液を6Ｎ塩酸（1.5 mL）にて中和した。析出物をろ過し、水を用いて洗浄し、表題化合物（739 mg, 72%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 1.60 - 2.06 (2H, m), 2.38 - 2.58 (4H, m), 6.98 - 7.09 (1H, m), 7.23 - 7.34 (2H, m), 7.64 (2H, dd, J = 8.7, 1.1 Hz), 9.66 (1H, s), 12.73 (1H, brs). 1N sodium hydroxide (10 mL) was added to an ethanol solution (35 mL) of ethyl 1- (phenylcarbamoyl) cyclobutanecarboxylate (1.15 g, 4.65 mmol), and the mixture was heated to reflux for 4 hours. The reaction solution was concentrated, and the aqueous solution was neutralized with 6N hydrochloric acid (1.5 mL). The precipitate was filtered and washed with water to give the title compound (739 mg, 72%) as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 1.60-2.06 (2H, m), 2.38-2.58 (4H, m), 6.98-7.09 (1H, m), 7.23-7.34 (2H, m), 7.64 (2H, dd, J = 8.7, 1.1 Hz), 9.66 (1H, s), 12.73 (1H, brs).
参考例１７
N-[6-(4-アミノ-3-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミドの製造 Reference Example 17
Preparation of N- [6- (4-amino-3-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
　N-(6-クロロイミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミド（3.7 g, 15.7 mmol）と4-アミノ-3-フルオロフェノール（3.0 g, 23.6 mmol）のジメチルスルフォキシド（23 mL）溶液に、炭酸セシウム（12.8 g, 39.3 mmol）を加え、110℃にて17時間撹拌した。反応液に水とテトラヒドロフランを加え、酢酸エチルを用いて3回抽出した。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後、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチルのみ）にて精製し、紫色固体を得た。得られた紫色固体に酢酸エチルを加え、ろ過して表題化合物（3.76 g, 73%）を灰白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.71 - 0.88 (4H, m), 1.82 - 1.98 (1H, m), 5.13 (2H, s), 6.50 - 7.13 (4H, m), 7.65 - 8.15 (2H, m), 11.04 (1H, s). Dimethyl sulfone of N- (6-chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (3.7 g, 15.7 mmol) and 4-amino-3-fluorophenol (3.0 g, 23.6 mmol) Cesium carbonate (12.8 g, 39.3 mmol) was added to the xoxide (23 mL) solution, and the mixture was stirred at 110 ° C for 17 hours. Water and tetrahydrofuran were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate only) to obtain a purple solid. Ethyl acetate was added to the obtained purple solid and filtered to obtain the title compound (3.76 g, 73%) as an off-white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.71-0.88 (4H, m), 1.82-1.98 (1H, m), 5.13 (2H, s), 6.50-7.13 (4H, m), 7.65- 8.15 (2H, m), 11.04 (1H, s).
参考例１８
N-[6-(4-アミノ-2-クロロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミドの製造 Reference Example 18
Preparation of N- [6- (4-amino-2-chlorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
　N-(6-クロロイミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミド（1.0 g, 4.23 mmol）、4-アミノ-2-クロロフェノール（626 mg, 5.08 mmol）、ジメチルスルフォキシド（10 mL）と炭酸セシウム（2.76 g, 8.47 mmol）を用いて、参考例１４と同様の方法にて、表題化合物（1.02 g, 70%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.66 - 0.87 (4H, m), 1.80 - 1.97 (1H, m), 5.41 (2H, s), 6.57 (1H, dd, J = 8.8, 2.5 Hz), 6.72 (1H, d, J = 2.5 Hz), 7.01 (1H, d, J = 9.8 Hz), 7.07 (1H, d, J = 8.8 Hz), 7.88 (1H, s), 7.99 (1H, d, J = 9.8 Hz), 11.04 (1H, s). N- (6-Chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (1.0 g, 4.23 mmol), 4-amino-2-chlorophenol (626 mg, 5.08 mmol), dimethylsulfo The title compound (1.02 g, 70%) was obtained as a white powder in the same manner as in Reference Example 14 using xoxide (10 mL) and cesium carbonate (2.76 g, 8.47 mmol).
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.66-0.87 (4H, m), 1.80-1.97 (1H, m), 5.41 (2H, s), 6.57 (1H, dd, J = 8.8, 2.5 Hz), 6.72 (1H, d, J = 2.5 Hz), 7.01 (1H, d, J = 9.8 Hz), 7.07 (1H, d, J = 8.8 Hz), 7.88 (1H, s), 7.99 (1H, d, J = 9.8 Hz), 11.04 (1H, s).
参考例１９
N-[6-(4-アミノ-3-クロロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミドの製造 Reference Example 19
Preparation of N- [6- (4-amino-3-chlorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
　N-(6-クロロイミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミド（1.0 g, 4.23 mmol）、4-アミノ-3-クロロフェノール（626 mg, 5.08 mmol）、ジメチルスルフォキシド（10 mL）と炭酸セシウム（2.75 g, 8.46 mmol）を用いて、参考例１４と同様の方法にて、表題化合物（660 mg, 45%）を茶褐色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.66 - 0.93 (4H, m), 1.82 - 1.98 (1H, m), 5.36 (2H, s), 6.76 - 6.88 (1H, m), 6.91 - 7.03 (2H, m), 7.20 (1H, s), 7.81 - 8.10 (2H, m), 11.04 (1H, s). N- (6-Chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (1.0 g, 4.23 mmol), 4-amino-3-chlorophenol (626 mg, 5.08 mmol), dimethyl sulfo The title compound (660 mg, 45%) was obtained as a brown powder in the same manner as in Reference Example 14 using xoxide (10 mL) and cesium carbonate (2.75 g, 8.46 mmol).
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.66-0.93 (4H, m), 1.82-1.98 (1H, m), 5.36 (2H, s), 6.76-6.88 (1H, m), 6.91- 7.03 (2H, m), 7.20 (1H, s), 7.81-8.10 (2H, m), 11.04 (1H, s).
参考例２０
N-[6-(4-アミノ-3-メチルフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミドの製造 Reference Example 20
Preparation of N- [6- (4-amino-3-methylphenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
　N-(6-クロロイミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミド（1.0 g, 4.23 mmol）、4-アミノ-3-メチルフェノール（781 mg, 6.35 mmol）、ジメチルスルフォキシド（10 mL）と炭酸セシウム（2.75 g, 8.46 mmol）を用いて、参考例１４と同様の方法にて、表題化合物（1.21 g, 88%）を茶褐色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.69 - 0.86 (4H, m), 1.86 - 1.95 (1H, m), 1.99 (3H, s), 5.00 (2H, s), 6.43 (1H, dd, J = 8.5, 2.6 Hz), 6.48 (1H, d, J = 2.6 Hz), 6.81 (1H, d, J = 8.5 Hz), 6.92 (1H, d, J = 9.6 Hz), 7.87 (1H, s), 7.95 (1H, d, J = 9.6 Hz), 11.01 (1H, s). N- (6-Chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (1.0 g, 4.23 mmol), 4-amino-3-methylphenol (781 mg, 6.35 mmol), dimethyl sulfo The title compound (1.21 g, 88%) was obtained as a brown powder in the same manner as in Reference Example 14 using xoxide (10 mL) and cesium carbonate (2.75 g, 8.46 mmol).
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.69-0.86 (4H, m), 1.86-1.95 (1H, m), 1.99 (3H, s), 5.00 (2H, s), 6.43 (1H, dd, J = 8.5, 2.6 Hz), 6.48 (1H, d, J = 2.6 Hz), 6.81 (1H, d, J = 8.5 Hz), 6.92 (1H, d, J = 9.6 Hz), 7.87 (1H, s), 7.95 (1H, d, J = 9.6 Hz), 11.01 (1H, s).
参考例２１
N-[6-(4-アミノ-2-メチルフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミドの製造 Reference Example 21
Preparation of N- [6- (4-amino-2-methylphenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
　N-(6-クロロイミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミド（1.0 g, 4.23 mmol）、4-アミノ-2-メチルフェノール（782 mg, 6.35 mmol）、ジメチルスルフォキシド（10 mL）と炭酸セシウム（2.75 g, 8.46 mmol）を用いて、参考例１４と同様の操作を行い、表題化合物（1.1 g, 80%）を茶褐色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.69 - 0.86 (4H, m), 1.86 - 1.95 (1H, m), 1.99 (3H, s), 5.00 (2H, s), 6.43 (1H, dd, J = 8.5, 2.6 Hz), 6.48 (1H, d, J = 2.6 Hz), 6.81 (1H, d, J = 8.5 Hz), 6.92 (1H, d, J = 9.6 Hz), 7.87 (1H, s), 7.95 (1H, d, J = 9.6 Hz), 11.01 (1H, s). N- (6-Chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (1.0 g, 4.23 mmol), 4-amino-2-methylphenol (782 mg, 6.35 mmol), dimethyl sulfo The same operation as in Reference Example 14 was carried out using xoxide (10 mL) and cesium carbonate (2.75 g, 8.46 mmol) to obtain the title compound (1.1 g, 80%) as a brown powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.69-0.86 (4H, m), 1.86-1.95 (1H, m), 1.99 (3H, s), 5.00 (2H, s), 6.43 (1H, dd, J = 8.5, 2.6 Hz), 6.48 (1H, d, J = 2.6 Hz), 6.81 (1H, d, J = 8.5 Hz), 6.92 (1H, d, J = 9.6 Hz), 7.87 (1H, s), 7.95 (1H, d, J = 9.6 Hz), 11.01 (1H, s).
参考例２２
N-[6-(4-アミノ-2,6-ジフルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミドの製造 Reference Example 22
Preparation of N- [6- (4-amino-2,6-difluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
　N-(6-クロロイミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミド（500 mg, 2.11 mmol）、4-アミノ-2,6-ジフルオロフェノール（368 mg, 2.54 mmol）、ジメチルスルフォキシド（5 mL）と炭酸セシウム（1.0 g, 3.17 mmol）を用いて、参考例１４と同様の方法にて、表題化合物（278 mg, 38%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.63 - 0.93 (4H, m), 1.83 - 1.98 (1H, m), 5.75 (2H, s), 6.24 - 6.43 (2H, m), 7.15 (1H, d, J= 9.4 Hz), 7.91 (1H, s), 7.99 - 8.09 (1H, m), 11.07 (1H, s). N- (6-Chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (500 mg, 2.11 mmol), 4-amino-2,6-difluorophenol (368 mg, 2.54 mmol), dimethyl The title compound (278 mg, 38%) was obtained as a white powder in the same manner as in Reference Example 14 using sulfoxide (5 mL) and cesium carbonate (1.0 g, 3.17 mmol).
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.63-0.93 (4H, m), 1.83-1.98 (1H, m), 5.75 (2H, s), 6.24-6.43 (2H, m), 7.15 ( 1H, d, J = 9.4 Hz), 7.91 (1H, s), 7.99-8.09 (1H, m), 11.07 (1H, s).
参考例２３
1-(4-メチル-1,3-チアゾール-2-イル)-2-オキソ-1,2-ジヒドロピリジン-3-カルボン酸メチルの製造 Reference Example 23
Preparation of methyl 1- (4-methyl-1,3-thiazol-2-yl) -2-oxo-1,2-dihydropyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
　2-オキソ-2H-ピラン-3-カルボン酸メチル(3 g, 19.5 mmol)のテトラヒドロフラン（30 mL）／N,N-ジメチルホルムアミド（10 mL）溶液に、4-メチル-1,3-チアゾール-2-アミン（2.2 g, 19.5 mmol）を加えた。室温にて7時間撹拌した後、反応液に4-ジメチルアミノピリジン（119 mg, 0.974 mmol）と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(4.48 g, 23.4 mmol)を加え、さらに17時間撹拌した。反応溶液に1Ｎ塩酸を加え、酢酸エチルを用いて3回抽出した。有機層を飽和炭酸水素ナトリウム水溶液にて洗浄し、無水硫酸マグネシウムで乾燥後、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝1／1→2／1）及びシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル／ヘキサン＝1／2→1／1）にて精製し、表題化合物（715 mg, 15%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 2.40 (3H, d, J = 0.9 Hz), 3.81 (3H, s), 6.68 (1H, t, J = 7.1 Hz), 7.27 (1H, d, J = 0.9 Hz), 8.22 (1H, dd, J = 7.1, 2.1 Hz), 9.00 (1H, dd, J = 7.1, 2.1 Hz). To a solution of methyl 2-oxo-2H-pyran-3-carboxylate (3 g, 19.5 mmol) in tetrahydrofuran (30 mL) / N, N-dimethylformamide (10 mL) was added 4-methyl-1,3-thiazole- 2-Amine (2.2 g, 19.5 mmol) was added. After stirring at room temperature for 7 hours, 4-dimethylaminopyridine (119 mg, 0.974 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (4.48 g, 23.4 mmol) were added to the reaction solution. The mixture was further stirred for 17 hours. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1 → 2/1) and silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 1/2 → 1/1), The title compound (715 mg, 15%) was obtained as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 2.40 (3H, d, J = 0.9 Hz), 3.81 (3H, s), 6.68 (1H, t, J = 7.1 Hz), 7.27 (1H, d , J = 0.9 Hz), 8.22 (1H, dd, J = 7.1, 2.1 Hz), 9.00 (1H, dd, J = 7.1, 2.1 Hz).
参考例２４
1-(4-メチル-1,3-チアゾール-2-イル)-2-オキソ-1,2-ジヒドロピリジン-3-カルボン酸の製造 Reference Example 24
Preparation of 1- (4-methyl-1,3-thiazol-2-yl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
　1-(4-メチル-1,3-チアゾール-2-イル)-2-オキソ-1,2-ジヒドロピリジン-3-カルボン酸メチル(600 mg, 2.40 mmol)のメタノール（6 mL）溶液に、1Ｎ水酸化ナトリウム水溶液（3 mL）を加え、室温にて1時間撹拌した。反応液を濃縮し、1Ｎ塩酸を加え、析出物をろ取し、水とジエチルエーテルにて洗浄し、表題化合物（500 mg, 88%）を微黄色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 2.42 (3H, s), 6.81 (1H, t, J = 7.1 Hz), 7.34 (1H, s), 8.36 (1H, dd, J = 7.1, 2.1 Hz), 9.06 (1H, dd, J = 7.1, 2.1 Hz), 13.24 (1H, brs). To a solution of methyl 1- (4-methyl-1,3-thiazol-2-yl) -2-oxo-1,2-dihydropyridine-3-carboxylate (600 mg, 2.40 mmol) in methanol (6 mL) was added 1N Aqueous sodium hydroxide (3 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, 1N hydrochloric acid was added, the precipitate was collected by filtration, and washed with water and diethyl ether to give the title compound (500 mg, 88%) as a pale yellow powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 2.42 (3H, s), 6.81 (1H, t, J = 7.1 Hz), 7.34 (1H, s), 8.36 (1H, dd, J = 7.1, 2.1 Hz), 9.06 (1H, dd, J = 7.1, 2.1 Hz), 13.24 (1H, brs).
参考例２５
6-フェニルピリジン-2-カルボン酸メチル 1-オキシドの製造 Reference Example 25
Preparation of methyl 6-phenylpyridine-2-carboxylate 1-oxide
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
　6-フェニルピリジン-2-カルボン酸メチル（509 mg, 6.24 mmol）のジクロロメタン（5 mL）溶液に、m-クロロ過安息香酸（2.87 g, 12.5 mmol）を加え、室温にて3日間撹拌した。反応液に飽和チオ硫酸ナトリウム水溶液を加え、酢酸エチルにて3回抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸マグネシウムで乾燥後、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル／ヘキサン＝1／2→1／1）にて精製し、表題化合物（142 mg, 10%）を無色油状物として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 3.88 (3H, s), 7.45 - 7.55 (4H, m), 7.69 (1H, dd, J = 7.8, 2.1 Hz), 7.76 (1H, dd, J = 7.8, 2.1 Hz), 7.78 - 7.84 (2H, m). M-Chloroperbenzoic acid (2.87 g, 12.5 mmol) was added to a solution of methyl 6-phenylpyridine-2-carboxylate (509 mg, 6.24 mmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 3 days. A saturated aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 1/2 → 1/1) to give the title compound (142 mg, 10%) as a colorless oil.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 3.88 (3H, s), 7.45-7.55 (4H, m), 7.69 (1H, dd, J = 7.8, 2.1 Hz), 7.76 (1H, dd, J = 7.8, 2.1 Hz), 7.78-7.84 (2H, m).
参考例２６
6-フェニルピリジン-2-カルボン酸 1-オキシドの製造 Reference Example 26
Preparation of 6-phenylpyridine-2-carboxylic acid 1-oxide
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
　6-フェニルピリジン-2-カルボン酸メチル 1-オキシドのメタノール（2 mL）溶液に、1Ｎ水酸化ナトリウム水溶液（1 mL）を加え、室温にて3時間撹拌した。反応液を濃縮し、1Ｎ塩酸を加え、析出物をろ取し、水を用いて洗浄し、表題化合物（120 mg, 90%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 7.52 - 7.63 (3H, m), 7.76 - 7.85 (2H, m), 7.91 - 8.09 (2H, m), 8.35 (1H, dd, J = 7.7, 2.3 Hz). To a solution of methyl 6-phenylpyridine-2-carboxylate 1-oxide in methanol (2 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, 1N hydrochloric acid was added, the precipitate was collected by filtration, and washed with water to give the title compound (120 mg, 90%) as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 7.52-7.63 (3H, m), 7.76-7.85 (2H, m), 7.91-8.09 (2H, m), 8.35 (1H, dd, J = 7.7 , 2.3 Hz).
参考例２７
エチル 3-メチル-2-(フェニルカルバモイル)ブタ-2-エノアートの製造 Reference Example 27
Preparation of ethyl 3-methyl-2- (phenylcarbamoyl) but-2-enoate
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
　ジエチル (1-メチルエチリデン)プロパンジオアート（15 g, 74.9 mmol）、アニリン（1.71 mL, 18.7 mmol）、イミダゾール（1.27 g, 18.7 mmol）の混合物を、200℃にて3時間撹拌した。混合物を濃縮後、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝1／5→1／1）にて精製し、表題化合物（2.86 g, 62%）を黄色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 1.16 (3H, t, J = 7.0 Hz), 1.89 (3H, s), 2.16 (3H, s), 4.13 (2H, q, J = 7.0 Hz), 7.00 - 7.13 (1H, m), 7.27 - 7.45 (2H, m), 7.50 - 7.88 (2H, m), 10.20 (1H, s). A mixture of diethyl (1-methylethylidene) propanedioate (15 g, 74.9 mmol), aniline (1.71 mL, 18.7 mmol) and imidazole (1.27 g, 18.7 mmol) was stirred at 200 ° C. for 3 hours. After the mixture was concentrated, the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/5 → 1/1) to obtain the title compound (2.86 g, 62%) as a yellow solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 1.16 (3H, t, J = 7.0 Hz), 1.89 (3H, s), 2.16 (3H, s), 4.13 (2H, q, J = 7.0 Hz ), 7.00-7.13 (1H, m), 7.27-7.45 (2H, m), 7.50-7.88 (2H, m), 10.20 (1H, s).
参考例２８
4-メチル-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボン酸エチルの製造 Reference Example 28
Preparation of ethyl 4-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
　エチル 3-メチル-2-(フェニルカルバモイル)ブタ-2-エノアート（2.80 g, 11.0 mmol）と1,1-ジメトキシ-N,N-ジメチルメタンアミン（6 mL, 45 mmol）の混合物を、100℃にて2時間撹拌した。減圧下反応液を濃縮し、残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル／ヘキサン＝1／2→1／1）にて精製し、表題化合物（1.0 g, 33%）を黄色油状物として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 1.25 (3H, t, J = 7.0 Hz), 2.17 (3H, s), 4.25 (2H, q, J = 7.0 Hz), 6.28 (1H, d, J = 6.9 Hz), 7.34 - 7.58 (5H, m), 7.66 (1H, d, J = 6.9 Hz). A mixture of ethyl 3-methyl-2- (phenylcarbamoyl) but-2-enoate (2.80 g, 11.0 mmol) and 1,1-dimethoxy-N, N-dimethylmethanamine (6 mL, 45 mmol) was added at 100 ° C. For 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 1/2 → 1/1) to give the title compound (1.0 g, 33%) as a yellow oil. Obtained.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 1.25 (3H, t, J = 7.0 Hz), 2.17 (3H, s), 4.25 (2H, q, J = 7.0 Hz), 6.28 (1H, d , J = 6.9 Hz), 7.34-7.58 (5H, m), 7.66 (1H, d, J = 6.9 Hz).
参考例２９
4-メチル-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボン酸の製造 Reference Example 29
Preparation of 4-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
　4-メチル-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボン酸エチル(1 g, 3.88 mmol)と1Ｎ水酸化ナトリウム水溶液（20 mL）の混合物を、100℃にて3時間撹拌した。混合物を酢酸エチルにて2回洗浄し、水溶液を1Ｎ塩酸（30 mL）にて処理した。析出物をろ取した後、水を用いて洗浄し、表題化合物（700 mg, 79%）を微黄色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 2.54 (3H, s), 6.57 (1H, d, J = 7.0 Hz), 7.37 - 7.64 (5H, m), 7.92 (1H, d, J = 7.0 Hz), 14.55 (1H, brs). A mixture of ethyl 4-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (1 g, 3.88 mmol) and 1N aqueous sodium hydroxide solution (20 mL) at 100 ° C. for 3 hours. Stir. The mixture was washed twice with ethyl acetate and the aqueous solution was treated with 1N hydrochloric acid (30 mL). The precipitate was collected by filtration and washed with water to give the title compound (700 mg, 79%) as a pale yellow powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 2.54 (3H, s), 6.57 (1H, d, J = 7.0 Hz), 7.37-7.64 (5H, m), 7.92 (1H, d, J = 7.0 Hz), 14.55 (1H, brs).
参考例３０
2-オキソ-3-フェニル-7-オキサ-3-アザビシクロ[4.1.0]ヘプタン-1-カルボン酸メチルの製造 Reference Example 30
Preparation of methyl 2-oxo-3-phenyl-7-oxa-3-azabicyclo [4.1.0] heptane-1-carboxylate
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
　氷冷した50％水素化ナトリウム（51.5 mg, 1.07 mmol）のテトラヒドロフラン（2 mL）懸濁液に、2-オキソ-1-フェニルピペリジン-3-カルボン酸メチル(209 mg, 0.895 mmol)のテトラヒドロフラン（1 mL）溶液を加え、室温にて15分撹拌した。反応液に塩化フェニルセレニル（205 mg, 1.07 mmol）を0℃にて添加し、2時間同温度にて撹拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルにて抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸マグネシウムで乾燥後、ろ過し、減圧下溶媒を留去した。
　残渣のジクロロメタン（2 mL）溶液に30％過酸化水素水溶液（2 mL）を加え、0℃にて30分撹拌した。反応溶液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルにて抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸マグネシウムで乾燥後、ろ過し、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル／ヘキサン＝3／7→1／1）にて精製し、表題化合物（78.5 mg, 35%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 2.28 - 2.44 (2H, m), 3.34 - 3.44 (1H, m), 3.63 - 3.73 (1H, m), 3.74 (3H, s), 4.04 - 4.13 (1H, m), 7.22 - 7.33 (3H, m), 7.36 - 7.44 (2H, m). To a suspension of ice-cooled 50% sodium hydride (51.5 mg, 1.07 mmol) in tetrahydrofuran (2 mL) was added tetrahydrofuran of methyl 2-oxo-1-phenylpiperidine-3-carboxylate (209 mg, 0.895 mmol) (209 mg, 0.895 mmol). 1 mL) solution was added and stirred at room temperature for 15 minutes. Phenylselenyl chloride (205 mg, 1.07 mmol) was added to the reaction solution at 0 ° C., and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure.
To a solution of the residue in dichloromethane (2 mL) was added 30% aqueous hydrogen peroxide (2 mL), and the mixture was stirred at 0 ° C. for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 3/7 → 1/1) to obtain the title compound (78.5 mg, 35%) as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 2.28-2.44 (2H, m), 3.34-3.44 (1H, m), 3.63-3.73 (1H, m), 3.74 (3H, s), 4.04- 4.13 (1H, m), 7.22-7.33 (3H, m), 7.36-7.44 (2H, m).
参考例３１
2-オキソ-3-フェニル-7-オキサ-3-アザビシクロ[4.1.0]ヘプタン-1-カルボン酸の製造 Reference Example 31
Preparation of 2-oxo-3-phenyl-7-oxa-3-azabicyclo [4.1.0] heptane-1-carboxylic acid
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
　2-オキソ-3-フェニル-7-オキサ-3-アザビシクロ[4.1.0]ヘプタン-1-カルボン酸メチル(78.5 mg, 0.317 mmol)のメタノール（1 mL）溶液に、1Ｎ水酸化ナトリウム水溶液（1 mL）を加え、室温にて1時間撹拌した。反応混合物を濃縮し、1Ｎ塩酸（1.0 mL）にて処理し、水溶液を酢酸エチルにて2回抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸マグネシウムで乾燥後、ろ過し、減圧下溶媒を留去し、表題化合物（61.5 mg, 83%）を無色油状物として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 2.24 - 2.43 (2H, m), 3.36 - 3.44 (1H, m), 3.57 - 3.77 (1H, m), 3.96 - 4.01 (1H, m), 7.23 - 7.31 (3H, m), 7.36 - 7.46 (2H, m). To a solution of methyl 2-oxo-3-phenyl-7-oxa-3-azabicyclo [4.1.0] heptane-1-carboxylate (78.5 mg, 0.317 mmol) in methanol (1 mL) was added 1N aqueous sodium hydroxide solution (1 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was concentrated, treated with 1N hydrochloric acid (1.0 mL), and the aqueous solution was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound (61.5 mg, 83%) as a colorless oil.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 2.24-2.43 (2H, m), 3.36-3.44 (1H, m), 3.57-3.77 (1H, m), 3.96-4.01 (1H, m), 7.23-7.31 (3H, m), 7.36-7.46 (2H, m).
参考例３２
N－(2－クロロアセチル)シクロプロパンカルボキサミドの製造 Reference Example 32
Production of N- (2-chloroacetyl) cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
　シクロプロパンカルボキサミド（2.00 g, 23.5 mmol）、酢酸n－ブチル（20 mL）を仕込み、室温でクロロアセチルクロリド（2.92 g, 25.9 mmol）を滴下した。100℃に加熱して3時間撹拌した後、室温に冷却して1時間撹拌した。結晶を濾取、酢酸n－ブチル（10 mL）で洗浄した。減圧乾燥して白色結晶の表題化合物（2.55 g, 15.8 mmol）を得た。収率67%
1H NMR (300 MHz, DMSO-d6) δ 0.82 - 0.94 (m, 4H), 1.96 - 2.05 (m, 1H), 4.59 (s, 2H), 11.29 (s, 1H). Cyclopropanecarboxamide (2.00 g, 23.5 mmol) and n-butyl acetate (20 mL) were charged, and chloroacetyl chloride (2.92 g, 25.9 mmol) was added dropwise at room temperature. The mixture was heated to 100 ° C. and stirred for 3 hours, then cooled to room temperature and stirred for 1 hour. The crystals were collected by filtration and washed with n-butyl acetate (10 mL). The title compound (2.55 g, 15.8 mmol) was obtained by drying under reduced pressure. Yield 67%
1 H NMR (300 MHz, DMSO-d 6 ) δ 0.82-0.94 (m, 4H), 1.96-2.05 (m, 1H), 4.59 (s, 2H), 11.29 (s, 1H).
参考例３３
N－(6－クロロイミダゾ[1,2－b]ピリダジン－2－イル)シクロプロパンカルボキサミドの製造 Reference Example 33
Production of N- (6-chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
　6－クロロピリダジン－3－アミン（100 mg, 0.772 mmol）、N－(2－クロロアセチル)シクロプロパンカルボキサミド（212 mg, 1.31 mmol）、リン酸水素二ナトリウム（273 mg, 1.92 mmol）、N，N－ジメチルアセトアミド（1 mL）を仕込み、100℃に加熱して4時間撹拌した。同温度で水（2 mL）を添加した後、室温に冷却して1時間撹拌した。結晶を濾取、水（1 mL）で洗浄、減圧乾燥して褐色結晶の表題化合物（88 mg, 0.372 mmol）を得た。収率48%
1H NMR (300 MHz, DMSO-d6) δ 0.77 - 0.82 (m, 4H), 1.89 - 1.97 (m, 1H), 7.30 (d, J = 9.4 Hz, 1H), 8.03 (d, J = 9.4 Hz, 1H), 8.22 (s, 1H), 11.21 (s, 1H). 6-chloropyridazine-3-amine (100 mg, 0.772 mmol), N- (2-chloroacetyl) cyclopropanecarboxamide (212 mg, 1.31 mmol), disodium hydrogen phosphate (273 mg, 1.92 mmol), N, N-dimethylacetamide (1 mL) was charged, heated to 100 ° C. and stirred for 4 hours. After adding water (2 mL) at the same temperature, the mixture was cooled to room temperature and stirred for 1 hour. The crystals were collected by filtration, washed with water (1 mL), and dried under reduced pressure to give the title compound (88 mg, 0.372 mmol) as brown crystals. Yield 48%
1 H NMR (300 MHz, DMSO-d 6 ) δ 0.77-0.82 (m, 4H), 1.89-1.97 (m, 1H), 7.30 (d, J = 9.4 Hz, 1H), 8.03 (d, J = 9.4 Hz, 1H), 8.22 (s, 1H), 11.21 (s, 1H).
参考例３４
N－(2－ブロモアセチル)シクロプロパンカルボキサミドの製造 Reference Example 34
Production of N- (2-bromoacetyl) cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
　シクロプロパンカルボキサミド（2.00 g, 23.5 mmol）、酢酸n－ブチル（20 mL）を仕込み、40～50℃でブロモアセチルブロミド（5.23 g, 25.9 mmol）を滴下した。80℃に加熱して5分撹拌した後、室温に冷却して0.5時間撹拌した。結晶を濾取、酢酸n－ブチル（5 mL）で洗浄、減圧乾燥して白色結晶の表題化合物（1.73 g, 8.40 mmol）を得た。収率36%
1H NMR (300 MHz, CDCl3) δ 0.99 - 1.05 (m, 2H), 1.10 - 1.19 (m, 2H), 1.98 - 2.12 (m, 1H), 4.25 (s, 2H), 8.64 (s, 1H). Cyclopropanecarboxamide (2.00 g, 23.5 mmol) and n-butyl acetate (20 mL) were charged, and bromoacetyl bromide (5.23 g, 25.9 mmol) was added dropwise at 40-50 ° C. The mixture was heated to 80 ° C. and stirred for 5 minutes, then cooled to room temperature and stirred for 0.5 hours. The crystals were collected by filtration, washed with n-butyl acetate (5 mL), and dried under reduced pressure to give the title compound (1.73 g, 8.40 mmol) as white crystals. Yield 36%
1 H NMR (300 MHz, CDCl 3 ) δ 0.99-1.05 (m, 2H), 1.10-1.19 (m, 2H), 1.98-2.12 (m, 1H), 4.25 (s, 2H), 8.64 (s, 1H ).
参考例３５
N－(6－クロロイミダゾ[1,2－b]ピリダジン－2－イル)シクロプロパンカルボキサミドの製造 Reference Example 35
Production of N- (6-chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
　6－クロロピリダジン－3－アミン（100 mg, 0.772 mmol）、N－(2－ブロモアセチル)シクロプロパンカルボキサミド（270 mg, 1.34 mmol）、リン酸水素二ナトリウム（273 mg, 1.92 mmol）、N，N－ジメチルアセトアミド（1 mL）を仕込み、85℃に加熱して2時間撹拌した。同温度で水（2 mL）を添加した後、室温に冷却して0.5時間撹拌した。結晶を濾取、水（1 mL）で洗浄、減圧乾燥して褐色結晶の表題化合物（169 mg, 0.714 mmol）を得た。収率93%
1H NMR (300 MHz, DMSO-d6) δ 0.77 - 0.82 (m, 4H), 1.89 - 1.97 (m, 1H), 7.30 (d, J = 9.4 Hz, 1H), 8.03 (d, J = 9.4 Hz, 1H), 8.22 (s, 1H), 11.21 (s, 1H). 6-chloropyridazine-3-amine (100 mg, 0.772 mmol), N- (2-bromoacetyl) cyclopropanecarboxamide (270 mg, 1.34 mmol), disodium hydrogen phosphate (273 mg, 1.92 mmol), N, N-dimethylacetamide (1 mL) was charged, heated to 85 ° C. and stirred for 2 hours. After adding water (2 mL) at the same temperature, the mixture was cooled to room temperature and stirred for 0.5 hour. The crystals were collected by filtration, washed with water (1 mL), and dried under reduced pressure to give the title compound (169 mg, 0.714 mmol) as brown crystals. Yield 93%
1 H NMR (300 MHz, DMSO-d 6 ) δ 0.77-0.82 (m, 4H), 1.89-1.97 (m, 1H), 7.30 (d, J = 9.4 Hz, 1H), 8.03 (d, J = 9.4 Hz, 1H), 8.22 (s, 1H), 11.21 (s, 1H).
参考例３６
N－(6－クロロイミダゾ[1,2－b]ピリダジン－2－イル)シクロプロパンカルボキサミドの製造 Reference Example 36
Production of N- (6-chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
　シクロプロパンカルボキサミド（790 g, 9.28 mol）をN，N－ジメチルアセトアミド（3.0 L）に溶解した。氷冷下、ブロモアセチルブロミド（1400 g, 6.94 mol）、N，N－ジメチルアセトアミド（0.6 L）を順に添加した後、60℃に加熱して1時間撹拌した。氷冷して、リン酸三カリウム（1480 g, 6.97 mol）、6－クロロピリダジン－3－アミン（600 g, 4.63 mol）、N，N－ジメチルアセトアミド（1.2 L）を順に添加した後、80℃に加熱して2時間撹拌した。室温に冷却して1時間撹拌した後、不溶物を濾去、N，N－ジメチルアセトアミド（2.4 L）で洗浄した。濾洗液に水（14.4 L）を添加し、同温度で2時間撹拌した。結晶を濾取、水（1.8 L）で洗浄した。湿結晶をN，N－ジメチルアセトアミド（6.0 L）に溶解し、40℃に昇温して水（6.0 L）を滴下した。同温度で2時間、室温に冷却して2時間、氷冷して2時間撹拌した後、結晶を濾取、水（1.8 L）で洗浄、減圧乾燥して褐色結晶の表題化合物（527 g, 2.23 mol）を得た。収率48%
1H NMR (300 MHz, DMSO-d6) δ 0.77 - 0.82 (m, 4H), 1.89 - 1.97 (m, 1H), 7.30 (d, J = 9.4 Hz, 1H), 8.03 (d, J = 9.4 Hz, 1H), 8.22 (s, 1H), 11.21 (s, 1H). Cyclopropanecarboxamide (790 g, 9.28 mol) was dissolved in N, N-dimethylacetamide (3.0 L). Under ice-cooling, bromoacetyl bromide (1400 g, 6.94 mol) and N, N-dimethylacetamide (0.6 L) were sequentially added, and the mixture was heated to 60 ° C. and stirred for 1 hour. After cooling with ice, tripotassium phosphate (1480 g, 6.97 mol), 6-chloropyridazine-3-amine (600 g, 4.63 mol), N, N-dimethylacetamide (1.2 L) were added in that order, and then 80 Heated to ° C. and stirred for 2 hours. After cooling to room temperature and stirring for 1 hour, the insoluble material was filtered off and washed with N, N-dimethylacetamide (2.4 L). Water (14.4 L) was added to the filtrate and stirred at the same temperature for 2 hours. The crystals were collected by filtration and washed with water (1.8 L). Wet crystals were dissolved in N, N-dimethylacetamide (6.0 L), heated to 40 ° C., and water (6.0 L) was added dropwise. After cooling to room temperature for 2 hours, cooling to room temperature for 2 hours, and ice-cooling for 2 hours, the crystals were collected by filtration, washed with water (1.8 L) and dried under reduced pressure to give the title compound (527 g, 2.23 mol) was obtained. Yield 48%
1 H NMR (300 MHz, DMSO-d 6 ) δ 0.77-0.82 (m, 4H), 1.89-1.97 (m, 1H), 7.30 (d, J = 9.4 Hz, 1H), 8.03 (d, J = 9.4 Hz, 1H), 8.22 (s, 1H), 11.21 (s, 1H).
参考例３７
N－(6－クロロイミダゾ[1,2－b]ピリダジン－2－イル)シクロプロパンカルボキサミドの製造
　N－(6－クロロイミダゾ[1,2－b]ピリダジン－2－イル)シクロプロパンカルボキサミド（500 g, 2.11 mol）、ジメチルスルホキシド（1.5 L）を仕込み、70℃に加熱して溶解した。室温に冷却して、水（0.15 L）を滴下した後、氷冷して1時間撹拌した。結晶を濾取、ジメチルスルホキシド（0.4 L）/水（0.1 L）の混液、水（3.0 L）で順に洗浄、減圧乾燥して淡黄色結晶の表題化合物（451 g, 1.91 mol）を得た。収率91%
1H NMR (300 MHz, DMSO-d6) δ 0.77 - 0.82 (m, 4H), 1.89 - 1.97 (m, 1H), 7.30 (d, J = 9.4 Hz, 1H), 8.03 (d, J = 9.4 Hz, 1H), 8.22 (s, 1H), 11.21 (s, 1H); Anal. Calcd for C10H9N4OCl, C:50.75, H:3.83, N:23.67, O:6.76, Cl:14.98; Found C:50.72, H:3.77, N:23.71, Cl:15.06.  Reference Example 37
Preparation of N- (6-Chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide N- (6-Chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (500 g, 2.11 mol) and dimethyl sulfoxide (1.5 L) were charged and dissolved by heating to 70 ° C. After cooling to room temperature, water (0.15 L) was added dropwise, and the mixture was cooled with ice and stirred for 1 hour. The crystals were collected by filtration, washed successively with a mixed solution of dimethyl sulfoxide (0.4 L) / water (0.1 L), water (3.0 L), and dried under reduced pressure to give the title compound (451 g, 1.91 mol) as pale yellow crystals. Yield 91%
1 H NMR (300 MHz, DMSO-d 6 ) δ 0.77-0.82 (m, 4H), 1.89-1.97 (m, 1H), 7.30 (d, J = 9.4 Hz, 1H), 8.03 (d, J = 9.4 Hz, 1H), 8.22 (s, 1H), 11.21 (s, 1H); Anal.Calcd for C 10 H 9 N 4 OCl, C: 50.75, H: 3.83, N: 23.67, O: 6.76, Cl: 14.98 ; Found C: 50.72, H: 3.77, N: 23.71, Cl: 15.06.
参考例３８
N-[6-(4-アミノフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミドの製造 Reference Example 38
Preparation of N- [6- (4-aminophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
　4-アミノフェノール（0.33 g, 3.05 mmol）のN,N-ジメチルホルムアミド（10 mL）溶液に、カリウム　tert-ブトキシド（0.36 g, 3.17 mmol）を加え、室温にて2時間撹拌した。反応液に、N-(6-ヨードイミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミド（0.80 g, 2.44 mmol）、炭酸カリウム（0.17 g, 1.22 mmol）を加え、マイクロウエーブ反応装置を用い、150℃で30分間加熱撹拌した。反応混合物を冷却後、飽和食塩水を加え、酢酸エチル／テトラヒドロフランにて抽出した。飽和食塩水にて洗浄後、無水硫酸マグネシウムにて乾燥、ろ過した。減圧下溶媒を留去、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＝1／2→酢酸エチル）にて精製し、表題化合物（376 mg, 50%）を茶褐色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.76 - 0.81 (4H, m), 1.88 - 1.95 (1H, m), 5.09 (2H, s), 6.57 - 6.61 (2H, s), 6.88 - 6.94 (3H, m), 7.89 - 7.97 (2H, m), 11.05 (1H, s). To a solution of 4-aminophenol (0.33 g, 3.05 mmol) in N, N-dimethylformamide (10 mL) was added potassium tert-butoxide (0.36 g, 3.17 mmol), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, N- (6-iodoimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (0.80 g, 2.44 mmol) and potassium carbonate (0.17 g, 1.22 mmol) were added and the microwave reaction The apparatus was heated and stirred at 150 ° C. for 30 minutes. The reaction mixture was cooled, saturated brine was added, and the mixture was extracted with ethyl acetate / tetrahydrofuran. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/2 → ethyl acetate) to obtain the title compound (376 mg, 50%) as a brown powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.76-0.81 (4H, m), 1.88-1.95 (1H, m), 5.09 (2H, s), 6.57-6.61 (2H, s), 6.88- 6.94 (3H, m), 7.89-7.97 (2H, m), 11.05 (1H, s).
参考例３９
2-オキソ-1-フェニルピペリジン-3-カルボン酸メチルの製造 Reference Example 39
Preparation of methyl 2-oxo-1-phenylpiperidine-3-carboxylate
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
　2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボン酸メチル(400 mg, 1.85 mmol)のメタノール(4 mL)溶液に、10%パラジウム／カーボン(40 mg)を添加して、水素雰囲気下室温にて1日間攪拌した。反応液をろ過し、減圧下メタノールを留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝20／80→50／50）にて精製し、表題化合物（371 mg, 86%）を無色油状物として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 1.75 - 2.24 (4H, m), 3.49 - 3.80 (6H, m), 7.17 - 7.31 (3H, m), 7.34 - 7.47 (2H, m). To a solution of methyl 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (400 mg, 1.85 mmol) in methanol (4 mL) was added 10% palladium / carbon (40 mg) and hydrogen was added. The mixture was stirred at room temperature for 1 day. The reaction solution was filtered, and methanol was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 20/80 → 50/50) to give the title compound (371 mg, 86%) as a colorless oil.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 1.75-2.24 (4H, m), 3.49-3.80 (6H, m), 7.17-7.31 (3H, m), 7.34-7.47 (2H, m).
参考例４０
3-メチル-2-オキソ-1-フェニルピペリジン-3-カルボン酸の製造 Reference Example 40
Production of 3-methyl-2-oxo-1-phenylpiperidine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
　2-オキソ-1-フェニルピペリジン-3-カルボン酸メチル(129 mg, 0.558 mmol)のN,N-ジメチルホルムアミド（2.0 mL）溶液に、50%水素化ナトリウム(35 mg, 0.725 mmol)を加え、0℃にて30分攪拌した。反応液にヨウ化メチル（52.1 μL, 0.837 mmol）を加え、さらに0℃にて1時間攪拌した。反応液に酢酸エチルと飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルを用いて抽出後、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥、ろ過し、減圧下溶媒を留去した。得られた残渣をテトラヒドロフラン（1 mL）とメタノール（0.3 mL）に溶解した後、水酸化リチウム一水和物(26.9 mg, 0.641 mmol)を加えて、4時間室温にて攪拌した。反応液を濃縮後、1Ｎ塩酸（1 mL）と酢酸エチルを加え、酢酸エチルを用いて抽出後、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥、ろ過し、減圧下溶媒を留去し、表題化合物（90 mg, 69%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 1.37 (3H, s), 1.71 - 2.02 (3H, m), 2.13 - 2.34 (1H, m), 3.56 - 3.74 (2H, m), 7.19 - 7.28 (3H, m), 7.33 - 7.44 (2H, m), 12.66 (1H, s). To a solution of methyl 2-oxo-1-phenylpiperidine-3-carboxylate (129 mg, 0.558 mmol) in N, N-dimethylformamide (2.0 mL) was added 50% sodium hydride (35 mg, 0.725 mmol), The mixture was stirred at 0 ° C for 30 minutes. Methyl iodide (52.1 μL, 0.837 mmol) was added to the reaction solution, and the mixture was further stirred at 0 ° C. for 1 hour. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (1 mL) and methanol (0.3 mL), lithium hydroxide monohydrate (26.9 mg, 0.641 mmol) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, 1N hydrochloric acid (1 mL) and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure to give the title compound (90 mg, 69%) as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 1.37 (3H, s), 1.71-2.02 (3H, m), 2.13-2.34 (1H, m), 3.56-3.74 (2H, m), 7.19- 7.28 (3H, m), 7.33-7.44 (2H, m), 12.66 (1H, s).
参考例４１
6-エチル-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボニトリルの製造 Reference Example 41
Preparation of 6-ethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carbonitrile
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
　2-シアノ-N-フェニルアセトアミド(1.08 g, 6.73 mmol)、(1E)-1-メトキシペンタ-1-エン-3-オン(1.0 g, 8.76 mmol)、1,4-ジアザビシクロ[2,2,2]オクタン(755 mg, 6.73 mmol)のジエチレングリコールモノメチルエーテル(10 mL)溶液を、120℃にて7時間加熱攪拌した。反応液に1Ｎ塩酸を加え、酢酸エチルにて抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸マグネシウムで乾燥後、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（NHシリカゲル、酢酸エチル／ヘキサン＝2／1→4／1）にて精製し、表題化合物（412 mg, 27%）を淡褐色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 1.00 (3H, t, J = 7.5 Hz), 2.24 (2H, q, J = 7.5 Hz), 6.44 (1H, d, J = 7.7 Hz), 7.31 - 7.39 (2H, m), 7.43 - 7.62 (3H, m), 8.20 (1H, d, J = 7.7 Hz). 2-cyano-N-phenylacetamide (1.08 g, 6.73 mmol), (1E) -1-methoxypent-1-en-3-one (1.0 g, 8.76 mmol), 1,4-diazabicyclo [2,2, 2] A solution of octane (755 mg, 6.73 mmol) in diethylene glycol monomethyl ether (10 mL) was stirred with heating at 120 ° C for 7 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 2/1 → 4/1) to obtain the title compound (412 mg, 27%) as a light brown solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 1.00 (3H, t, J = 7.5 Hz), 2.24 (2H, q, J = 7.5 Hz), 6.44 (1H, d, J = 7.7 Hz), 7.31-7.39 (2H, m), 7.43-7.62 (3H, m), 8.20 (1H, d, J = 7.7 Hz).
参考例４２
6-エチル-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボン酸の製造 Reference Example 42
Preparation of 6-ethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
　6-エチル-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボニトリル(395 mg, 1.76 mmol)を濃硫酸(0.4 mL)と水(0.4 mL)に溶解し、120℃にて7時間加熱攪拌した。反応溶液に1Ｎ水酸化ナトリウムを加え、塩基性溶液とした後、酢酸エチルを用いて洗浄した。水層に1Ｎ塩酸を加え、酸性溶液とした後、酢酸エチルにて３回抽出後、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥、ろ過し、減圧下溶媒を留去した。残渣を酢酸エチルにて洗浄し、表題化合物（310 mg, 72%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 1.04 (3H, t, J = 7.5 Hz), 2.32 (2H, q, J = 7.5 Hz), 6.77 (1H, d, J = 7.7 Hz), 7.38 - 7.49 (2H, m), 7.51 - 7.67 (3H, m), 8.46 (1H, d, J = 7.7 Hz), 14.28 (1H, s). 6-Ethyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carbonitrile (395 mg, 1.76 mmol) was dissolved in concentrated sulfuric acid (0.4 mL) and water (0.4 mL) and dissolved at 120 ° C. The mixture was heated and stirred for 7 hours. 1N sodium hydroxide was added to the reaction solution to form a basic solution, and then washed with ethyl acetate. 1N Hydrochloric acid was added to the aqueous layer to make an acidic solution, and the mixture was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The residue was washed with ethyl acetate to give the title compound (310 mg, 72%) as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 1.04 (3H, t, J = 7.5 Hz), 2.32 (2H, q, J = 7.5 Hz), 6.77 (1H, d, J = 7.7 Hz), 7.38-7.49 (2H, m), 7.51-7.67 (3H, m), 8.46 (1H, d, J = 7.7 Hz), 14.28 (1H, s).
参考例４３
1-(4-フルオロフェニル)-6-メチル-2-オキソ-1,2-ジヒドロピリジン-3-カルボニトリルの製造 Reference Example 43
Preparation of 1- (4-fluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
　2-シアノ-N-(4-フルオロフェニル)アセトアミド(15 g, 84.2 mmol)、(3E)-4-メトキシブタ-3-エン-2-オン(12.6 g, 125.9 mmol)、1,4-ジアザビシクロ[2,2,2]オクタン(9.4 g, 84.2 mmol)のジエチレングリコールモノメチルエーテル(150 mL)溶液を、120℃にて5時間加熱攪拌した。さらに、反応液に(3E)-4-メトキシブタ-3-エン-2-オン(4.2 g, 41.9 mmol)、1,4-ジアザビシクロ[2,2,2]オクタン(4.7 g, 41.9 mmol)を加え、120℃にて1時間加熱攪拌した。反応液に2Ｎ塩酸を加え、酢酸エチルにて抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸マグネシウムで乾燥後、ろ過し、減圧下溶媒を留去した。得られた残渣を酢酸エチルにて洗浄し、表題化合物（6.0 g, 31%）を淡褐色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 2.01 (3H, s), 6.45 - 6.52 (1H, m), 7.35 - 7.48 (4H, m), 8.15 (1H, d, J = 7.4 Hz). 2-Cyano-N- (4-fluorophenyl) acetamide (15 g, 84.2 mmol), (3E) -4-methoxybut-3-en-2-one (12.6 g, 125.9 mmol), 1,4-diazabicyclo [ A solution of 2,2,2] octane (9.4 g, 84.2 mmol) in diethylene glycol monomethyl ether (150 mL) was heated and stirred at 120 ° C. for 5 hours. Furthermore, (3E) -4-methoxybut-3-en-2-one (4.2 g, 41.9 mmol) and 1,4-diazabicyclo [2,2,2] octane (4.7 g, 41.9 mmol) were added to the reaction solution. The mixture was heated and stirred at 120 ° C. for 1 hour. 2N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (6.0 g, 31%) as a pale brown solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 2.01 (3H, s), 6.45-6.52 (1H, m), 7.35-7.48 (4H, m), 8.15 (1H, d, J = 7.4 Hz) .
参考例４４
1-(4-フルオロフェニル)-6-メチル-2-オキソ-1,2-ジヒドロピリジン-3-カルボン酸の製造 Reference Example 44
Preparation of 1- (4-fluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
　1-(4-フルオロフェニル)-6-メチル-2-オキソ-1,2-ジヒドロピリジン-3-カルボニトリル(3 g, 13.1 mmol)を濃硫酸(6.0 mL)と水(6.0 mL)に溶解し、120℃にて20時間加熱攪拌した。反応溶液に8Ｎ水酸化ナトリウムを加え、塩基性溶液とした後、酢酸エチルを用いて洗浄した。水層に2Ｎ塩酸を加え、酸性溶液とした後、酢酸エチルにて２回抽出した。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、ろ過し、減圧下溶媒を留去した。残渣をジエチルエーテルにて洗浄し、表題化合物（2.41 g, 74%）を淡褐色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 2.10 (3H, s), 6.80 (1H, d, J = 7.9 Hz), 7.37 - 7.58 (4H, m), 8.41 (1H, d, J = 7.9 Hz), 14.21 (1H, s). 1- (4-Fluorophenyl) -6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (3 g, 13.1 mmol) was dissolved in concentrated sulfuric acid (6.0 mL) and water (6.0 mL). The mixture was heated and stirred at 120 ° C. for 20 hours. 8N sodium hydroxide was added to the reaction solution to make a basic solution, and then washed with ethyl acetate. 2N Hydrochloric acid was added to the aqueous layer to make an acidic solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was washed with diethyl ether to give the title compound (2.41 g, 74%) as a light brown solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 2.10 (3H, s), 6.80 (1H, d, J = 7.9 Hz), 7.37-7.58 (4H, m), 8.41 (1H, d, J = 7.9 Hz), 14.21 (1H, s).
参考例４５
1-(2-メチルフェニル)-2-オキソ-1,2-ジヒドロピリジン-3-カルボン酸メチルの製造 Reference Example 45
Preparation of methyl 1- (2-methylphenyl) -2-oxo-1,2-dihydropyridine-3-carboxylate
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
　2-オキソ-2H-ピラン-3-カルボン酸メチル(3 g, 19.5 mmol)と2-メチルアニリン（2.09 g, 19.5 mmol）のテトラヒドロフラン（30 mL）／N,N-ジメチルホルムアミド（10 mL）溶液を、室温にて７時間攪拌した。反応液に4-ジメチルアミノピリジン（119 mg, 0.974 mmol）と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(4.48 g, 23.4 mmol)を加え、さらに17時間攪拌した。反応溶液に1Ｎ塩酸を加え、酢酸エチルを用いて３回抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸マグネシウムで乾燥後、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル／ヘキサン＝1／1）にて精製し、表題化合物（882 mg, 19%）を黄色油状物質として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 2.04 (3H, s), 3.75 (3H, s), 6.36 - 6.47 (1H, m), 7.17 - 7.45 (4H, m), 7.86 (1H, dd, J = 6.6, 2.3 Hz), 8.16 (1H, dd, J = 7.2, 2.3 Hz). A solution of methyl 2-oxo-2H-pyran-3-carboxylate (3 g, 19.5 mmol) and 2-methylaniline (2.09 g, 19.5 mmol) in tetrahydrofuran (30 mL) / N, N-dimethylformamide (10 mL) Was stirred at room temperature for 7 hours. 4-Dimethylaminopyridine (119 mg, 0.974 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (4.48 g, 23.4 mmol) were added to the reaction solution, and the mixture was further stirred for 17 hours. 1N Hydrochloric acid was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 1/1) to obtain the title compound (882 mg, 19%) as a yellow oily substance.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 2.04 (3H, s), 3.75 (3H, s), 6.36-6.47 (1H, m), 7.17-7.45 (4H, m), 7.86 (1H, dd, J = 6.6, 2.3 Hz), 8.16 (1H, dd, J = 7.2, 2.3 Hz).
参考例４６
1-(2-メチルフェニル)-2-オキソ-1,2-ジヒドロピリジン-3-カルボン酸の製造 Reference Example 46
Preparation of 1- (2-methylphenyl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
　1-(2-メチルフェニル)-2-オキソ-1,2-ジヒドロピリジン-3-カルボン酸メチル(880 mg, 3.62 mmol)のメタノール（9 mL）溶液に、1Ｎ水酸化ナトリウム水溶液（5 mL）を加え、室温にて４時間攪拌した。反応液に、1Ｎ塩酸を加え、溶媒を減圧下留去し、残渣を水にて洗浄し、表題化合物（704 mg, 85%）を黄色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 2.07 (3H, s), 6.74 - 6.88 (1H, m), 7.35 - 7.51 (4H, m), 8.14 (1H, dd, J = 6.6, 2.1 Hz), 8.52 (1H, dd, J = 7.4, 2.1 Hz), 14.25 (1H, br s). To a solution of methyl 1- (2-methylphenyl) -2-oxo-1,2-dihydropyridine-3-carboxylate (880 mg, 3.62 mmol) in methanol (9 mL) was added 1N aqueous sodium hydroxide solution (5 mL). In addition, the mixture was stirred at room temperature for 4 hours. 1N Hydrochloric acid was added to the reaction mixture, the solvent was evaporated under reduced pressure, and the residue was washed with water to give the title compound (704 mg, 85%) as a yellow solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 2.07 (3H, s), 6.74-6.88 (1H, m), 7.35-7.51 (4H, m), 8.14 (1H, dd, J = 6.6, 2.1 Hz), 8.52 (1H, dd, J = 7.4, 2.1 Hz), 14.25 (1H, br s).
参考例４７
2-(4-フルオロフェニル)-3-メチルピリジン 1-オキシドの製造 Reference Example 47
Preparation of 2- (4-fluorophenyl) -3-methylpyridine 1-oxide
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
　2-(4-フルオロフェニル)-3-メチルピリジン(26.8 g, 0.143 mol)と69% m-クロロ過安息香酸(39 g, 0.157 mol)のテトラヒドロフラン(100 mL)溶液を50℃にて5時間加熱攪拌した。反応溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル）にて３回精製し、白色固体を得た。得られた固体を酢酸エチルにて洗浄し表題化合物(24.7 g, 85%)を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 2.04 (3H, s), 7.21 - 7.46 (6H, m), 8.16 - 8.24 (1H, m). A solution of 2- (4-fluorophenyl) -3-methylpyridine (26.8 g, 0.143 mol) and 69% m-chloroperbenzoic acid (39 g, 0.157 mol) in tetrahydrofuran (100 mL) at 50 ° C for 5 hours Stir with heating. The reaction solvent was distilled off, and the resulting residue was purified three times by silica gel column chromatography (NH silica gel, ethyl acetate) to obtain a white solid. The obtained solid was washed with ethyl acetate to give the title compound (24.7 g, 85%) as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 2.04 (3H, s), 7.21-7.46 (6H, m), 8.16-8.24 (1H, m).
参考例４８
6-(4-フルオロフェニル)-5-メチルピリジン-2-カルボニトリルの製造 Reference Example 48
Preparation of 6- (4-fluorophenyl) -5-methylpyridine-2-carbonitrile
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
　2-(4-フルオロフェニル)-3-メチルピリジン 1-オキシド(24 g, 0.118 mol)のテトラヒドロン（200 mL）溶液に、トリメチルシリルシアニド(19.2 mL, 0.153 mol)とジメチルカルバモイルクロリド（14.1 mL, 0.153 mmol）を加え、2時間加熱還流した。反応液に、酢酸エチルと飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルにて３回抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸マグネシウムで乾燥後、ろ過し、減圧下溶媒を留去した。得られた残渣をジエチルエーテルにて洗浄し、表題化合物（16.7 g, 67%）を白色固体として得た。ろ液を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝1／9）にて精製し、表題化合物（3.0 g, 12%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 2.41 (3H, s), 7.07 - 7.43 (2H, m), 7.53 - 7.76 (2H, m), 7.90 - 8.07 (2H, m). 2- (4-Fluorophenyl) -3-methylpyridine 1-oxide (24 g, 0.118 mol) in tetrahydrone (200 mL) was added to trimethylsilylcyanide (19.2 mL, 0.153 mol) and dimethylcarbamoyl chloride (14.1 mL). , 0.153 mmol) was added, and the mixture was heated to reflux for 2 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diethyl ether to give the title compound (16.7 g, 67%) as a white solid. The filtrate was concentrated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9) to give the title compound (3.0 g, 12%) as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 2.41 (3H, s), 7.07-7.43 (2H, m), 7.53-7.76 (2H, m), 7.90-8.07 (2H, m).
参考例４９
6-(4-フルオロフェニル)-5-メチルピリジン-2-カルボニトリル 1-オキシドの製造 Reference Example 49
Preparation of 6- (4-fluorophenyl) -5-methylpyridine-2-carbonitrile 1-oxide
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
　6-(4-フルオロフェニル)-5-メチルピリジン-2-カルボニトリル(16.76 g, 79 mmol)と過炭酸ナトリウム(24.8 g, 158 mmmol)のアセトニトリル（200 mL）溶液に、トリフルオロメタンスルホン酸無水物(66.8 g, 237 mmol)を0℃にて滴下し、0℃にて1時間攪拌し、さらに室温にて終夜攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルにて３回抽出した。有機層を飽和食塩水にて洗浄し、無水硫酸マグネシウムで乾燥後、ろ過し、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝1／2→1／1）にて精製し、表題化合物（6.2 g, 40%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 2.11 (3H, s), 7.30 - 7.42 (2H, m), 7.42 - 7.53 (3H, m), 8.03 (1 H, d, J = 8.3 Hz). Trifluoromethanesulfonic anhydride is added to a solution of 6- (4-fluorophenyl) -5-methylpyridine-2-carbonitrile (16.76 g, 79 mmol) and sodium percarbonate (24.8 g, 158 mmmol) in acetonitrile (200 mL). The product (66.8 g, 237 mmol) was added dropwise at 0 ° C., stirred at 0 ° C. for 1 hour, and further stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/2 → 1/1) to give the title compound (6.2 g, 40%) as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 2.11 (3H, s), 7.30-7.42 (2H, m), 7.42-7.53 (3H, m), 8.03 (1 H, d, J = 8.3 Hz ).
参考例５０
6-(4-フルオロフェニル)-5-メチルピリジン-2-カルボン酸 1-オキシドの製造 Reference Example 50
Preparation of 6- (4-fluorophenyl) -5-methylpyridine-2-carboxylic acid 1-oxide
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
　6-(4-フルオロフェニル)-5-メチルピリジン-2-カルボニトリル 1-オキシド(6.07 g, 26.6 mmol)、濃硫酸(18 mL)、水(18 mL)を用いて参考例４２と同様の操作を行い、表題化合物（5.72 g, 87%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 2.18 (3H, s), 7.35 - 7.47 (2H, m), 7.50 - 7.62 (2H, m), 7.93 (1H, d, J = 8.9 Hz), 8.30 (1H, d, J = 8.1 Hz). Similar to Reference Example 42 using 6- (4-fluorophenyl) -5-methylpyridine-2-carbonitrile 1-oxide (6.07 g, 26.6 mmol), concentrated sulfuric acid (18 mL), water (18 mL) The operation was performed to give the title compound (5.72 g, 87%) as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 2.18 (3H, s), 7.35-7.47 (2H, m), 7.50-7.62 (2H, m), 7.93 (1H, d, J = 8.9 Hz) , 8.30 (1H, d, J = 8.1 Hz).
参考例５１
４－［（６，７－ジメトキシキノリン－４－イル）オキシ］アニリンの製造 Reference Example 51
Preparation of 4-[(6,7-dimethoxyquinolin-4-yl) oxy] aniline
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
　４－クロロ－６，７－ジメトキシキノリン（１５６６ｍｇ，７．００ｍｍｏｌ）、４－アミノフェノール（９１７ｍｇ，８．４０ｍｍｏｌ）、炭酸セシウム（４５６１ｍｇ，１４．０ｍｍｏｌ）のジメチルスルホキシド（１４ｍｌ）懸濁液を、１００℃にて１８時間撹拌した。反応液に水を加え、酢酸エチル／テトラヒドロフラン（＝１／１）にて３回抽出した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル→酢酸エチル／メタノール＝６０／４０）にて精製した。得られた残渣に酢酸エチルを加え、濾取して標題化合物（１２６７ｍｇ，６１％）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 3.93 (6H, s), 5.16 (2H, s), 6.37 (1H, d, J = 5.4 Hz), 6.67 (2H, d, J = 8.7 Hz), 6.93 (2H, d, J = 8.7 Hz), 7.36 (1H, s), 7.50 (1H, s), 8.43 (1H, d, J = 5.4 Hz). A suspension of 4-chloro-6,7-dimethoxyquinoline (1566 mg, 7.00 mmol), 4-aminophenol (917 mg, 8.40 mmol), cesium carbonate (4561 mg, 14.0 mmol) in dimethyl sulfoxide (14 ml) Stir at 100 ° C. for 18 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate / tetrahydrofuran (= 1/1). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate → ethyl acetate / methanol = 60/40). Ethyl acetate was added to the obtained residue and collected by filtration to give the title compound (1267 mg, 61%) as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 3.93 (6H, s), 5.16 (2H, s), 6.37 (1H, d, J = 5.4 Hz), 6.67 (2H, d, J = 8.7 Hz ), 6.93 (2H, d, J = 8.7 Hz), 7.36 (1H, s), 7.50 (1H, s), 8.43 (1H, d, J = 5.4 Hz).
参考例５２
Ｎ－｛４－［（６，７－ジメトキシキノリン４－イル］フェニル｝－Ｎ'－フェニルシクロプロパン－ジカルボキサミドの製造 Reference Example 52
Preparation of N- {4-[(6,7-dimethoxyquinolin-4-yl] phenyl} -N′-phenylcyclopropane-dicarboxamide
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
　１－（フェニルカルバモイル）シクロプロパンカルボン酸（２３７ｍｇ，１．０４ｍｍｏｌ）のテトラヒドロン（１０ｍＬ）溶液に、Ｎ，Ｎ－ジメチルホルムアミド（１滴）、オキザリルクロライド（１７８μＬ，２．０８ｍｍｏｌ）を加え、室温にて２時間攪拌した。減圧下溶媒を留去し、得られた残渣にＮ，Ｎ－ジメチルアセトアミド（３ｍｌ）、４－［（６，７－ジメトキシキノリン－４－イル）オキシ］アニリン（２１３ｍｇ，１．０４ｍｍｏｌ）を加え、室温にて１８時間攪拌した。反応液に水を加え、酢酸エチル／テトラヒドロフランにて抽出した。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（酢酸エチル→酢酸エチル／メタノール＝７５／２５）にて精製した。得られた粉末を酢酸エチル／ジイソプロピルエーテルにて再結晶して、標題化合物（２８６ｍｇ、７４％）を白色結晶として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 1.49 (4H, s), 3.93 (3H, s), 3.95 (3H, s), 6.43 (1H, d, J = 5.3 Hz), 7.07 (1H, t, J = 7.4 Hz), 7.23 (2H, d, J = 9.2 Hz), 7.27 - 7.35 (2H, m), 7.39 (1H, s), 7.51 (1H, s), 7.63 (2H, d, J = 7.4 Hz), 8.47 (1H, d, J = 5.3 Hz), 10.05(1H, brs), 10.26 (1H, brs).　 To a solution of 1- (phenylcarbamoyl) cyclopropanecarboxylic acid (237 mg, 1.04 mmol) in tetrahydrone (10 mL) was added N, N-dimethylformamide (1 drop) and oxalyl chloride (178 μL, 2.08 mmol). Stir at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and N, N-dimethylacetamide (3 ml) and 4-[(6,7-dimethoxyquinolin-4-yl) oxy] aniline (213 mg, 1.04 mmol) were added to the resulting residue. And stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate / tetrahydrofuran. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate → ethyl acetate / methanol = 75/25). The obtained powder was recrystallized from ethyl acetate / diisopropyl ether to give the title compound (286 mg, 74%) as white crystals.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 1.49 (4H, s), 3.93 (3H, s), 3.95 (3H, s), 6.43 (1H, d, J = 5.3 Hz), 7.07 (1H , t, J = 7.4 Hz), 7.23 (2H, d, J = 9.2 Hz), 7.27-7.35 (2H, m), 7.39 (1H, s), 7.51 (1H, s), 7.63 (2H, d, J = 7.4 Hz), 8.47 (1H, d, J = 5.3 Hz), 10.05 (1H, brs), 10.26 (1H, brs).
実施例１
N-(6-{4-[(フェニルカルバモイル)アミノ]フェノキシ}イミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミドの製造 Example 1
Preparation of N- (6- {4-[(phenylcarbamoyl) amino] phenoxy} imidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
　N-[6-(4-アミノフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.647 mmol）のトルエン（12.0 mL）懸濁液を100℃にて加熱し、イソシアン酸フェニル（84.3 μL, 0.776 mmol）を加えて、110℃にて1時間撹拌した。室温に冷却後、水を加え、酢酸エチル／テトラヒドロフランにて抽出した。飽和食塩水にて洗浄後、無水硫酸マグネシウムにて乾燥、ろ過した。減圧下溶媒を留去し、残渣に酢酸エチルを加え、ろ取して表題化合物（211 mg, 76%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.76 - 0.83 (4H, m), 1.85 - 1.96 (1H, m), 6.97 (1H, t, J = 7.4 Hz), 7.02 (1H, d, J = 9.6 Hz), 7.19 (2H, d, J = 9.2 Hz), 7.43 - 7.47 (4H, m), 7.52 (2H, d, J = 9.2 Hz), 7.92 (1H, s), 8.01 (1H, d, J = 9.6 Hz), 8.71 (1H, s), 8.78 (1H, s), 11.05 (1H, s). Heat a suspension of N- [6- (4-aminophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.647 mmol) in toluene (12.0 mL) at 100 ° C. Then, phenyl isocyanate (84.3 μL, 0.776 mmol) was added, and the mixture was stirred at 110 ° C. for 1 hour. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate / tetrahydrofuran. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure, ethyl acetate was added to the residue, and the mixture was collected by filtration to give the title compound (211 mg, 76%) as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.76-0.83 (4H, m), 1.85-1.96 (1H, m), 6.97 (1H, t, J = 7.4 Hz), 7.02 (1H, d, J = 9.6 Hz), 7.19 (2H, d, J = 9.2 Hz), 7.43-7.47 (4H, m), 7.52 (2H, d, J = 9.2 Hz), 7.92 (1H, s), 8.01 (1H, d, J = 9.6 Hz), 8.71 (1H, s), 8.78 (1H, s), 11.05 (1H, s).
実施例２
[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]カルバミン酸ベンジルの製造 Example 2
Preparation of benzyl [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] carbamate
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
　N-[6-(4-アミノフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（150 mg, 0.485 mmol）のテトラヒドロフラン（3.0 mL）懸濁液に、飽和重曹水（3.0 mL）、ベンジルオキシカルボニルクロライド（83μL, 0.582 mmol）を加えて、室温にて16時間撹拌した。反応液に水を加え、酢酸エチル／テトラヒドロフランにて抽出した。飽和食塩水にて洗浄後、無水硫酸マグネシウムにて乾燥、ろ過した。減圧下溶媒を留去し、残渣に酢酸エチルを加え、70℃に加熱した。室温に冷却後、析出物をろ取し表題化合物（96 mg, 45%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.76 - 0.83 (4H, m), 1.85 - 1.96 (1H, m), 5.17 (2H, s), 7.01 (1H, d, J = 9.3 Hz), 7.20 (2H, d, J = 9.0 Hz), 7.30 - 7.47 (5H, m), 7.53 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 8.00 (1H, d, J = 9.3 Hz), 9.87 (1H, s), 11.05 (1H, s). To a suspension of N- [6- (4-aminophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (150 mg, 0.485 mmol) in tetrahydrofuran (3.0 mL) was added saturated aqueous sodium bicarbonate ( 3.0 mL) and benzyloxycarbonyl chloride (83 μL, 0.582 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate / tetrahydrofuran. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, and the mixture was heated to 70 ° C. After cooling to room temperature, the precipitate was collected by filtration to give the title compound (96 mg, 45%) as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.76-0.83 (4H, m), 1.85-1.96 (1H, m), 5.17 (2H, s), 7.01 (1H, d, J = 9.3 Hz) , 7.20 (2H, d, J = 9.0 Hz), 7.30-7.47 (5H, m), 7.53 (2H, d, J = 9.0 Hz), 7.91 (1H, s), 8.00 (1H, d, J = 9.3 Hz), 9.87 (1H, s), 11.05 (1H, s).
実施例３
N-{6-[4-({[3-(トリフルオロメチル)フェニル]カルバモイル}アミノ)フェノキシ]イミダゾ[1,2-b]ピリダジン-2-イル}シクロプロパンカルボキサミドの製造 Example 3
Preparation of N- {6- [4-({[3- (trifluoromethyl) phenyl] carbamoyl} amino) phenoxy] imidazo [1,2-b] pyridazin-2-yl} cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
　N-[6-(4-アミノフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.647 mmol）のトルエン（12.0 mL）懸濁液を100℃にて加熱し、イソシアン酸 3-(トリフルオロメチル)フェニル（108 μL, 0.776 mmol）を加えて、110℃にて20分撹拌した。室温に冷却後、水を加え、酢酸エチル／テトラヒドロフランにて抽出した。飽和食塩水にて洗浄後、無水硫酸マグネシウムにて乾燥、ろ過した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール＝100／0→90／10）にて精製し、表題化合物（193 mg, 60%）を薄茶色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.75 - 0.84 (4H, m), 1.85 - 1.96 (1H, m), 7.02 (1H, d, J = 9.6 Hz), 7.21 (2H, d, J = 9.0 Hz), 7.28 - 7.34 (1H, m), 7.48 - 7.63 (2H, m), 7.54 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 8.01 (2H, d, J = 9.6 Hz), 8.92 (1H, s), 9.10 (1H, s), 11.06 (1H, s). Heat a suspension of N- [6- (4-aminophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.647 mmol) in toluene (12.0 mL) at 100 ° C. Then, 3- (trifluoromethyl) phenyl isocyanate (108 μL, 0.776 mmol) was added, and the mixture was stirred at 110 ° C. for 20 minutes. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate / tetrahydrofuran. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100/0 → 90/10) to obtain the title compound (193 mg, 60%) as a light brown solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.75-0.84 (4H, m), 1.85-1.96 (1H, m), 7.02 (1H, d, J = 9.6 Hz), 7.21 (2H, d, J = 9.0 Hz), 7.28-7.34 (1H, m), 7.48-7.63 (2H, m), 7.54 (2H, d, J = 9.0 Hz), 7.92 (1H, s), 8.01 (2H, d, J = 9.6 Hz), 8.92 (1H, s), 9.10 (1H, s), 11.06 (1H, s).
実施例４
N-{6-[4-({[4-(トリフルオロメチル)フェニル]カルバモイル}アミノ)フェノキシ]イミダゾ[1,2-b]ピリダジン-2-イル}シクロプロパンカルボキサミドの製造 Example 4
Preparation of N- {6- [4-({[4- (trifluoromethyl) phenyl] carbamoyl} amino) phenoxy] imidazo [1,2-b] pyridazin-2-yl} cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
　N-[6-(4-アミノフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.647 mmol）、トルエン（12.0 mL）、イソシアン酸 4-(トリフルオロメチル)フェニル（158 mg, 0.776 mmol）を用いて、実施例３と同様の方法にて、表題化合物（204 mg, 64%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.76 - 0.83 (4H, m), 1.86 - 1.96 (1H, m), 7.02 (1H, d, J = 9.5 Hz), 7.21 (2H, d, J = 9.0 Hz), 7.51 (2H, d, J = 9.0 Hz), 7.61 - 7.71 (4H, m), 7.92 (1H, s), 8.01 (1H, d, J = 9.5 Hz), 8.95 (1H, s), 9.18 (1H, s), 11.06 (1H, s). N- [6- (4-Aminophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.647 mmol), toluene (12.0 mL), 4- (trifluoromethyl isocyanate) ) The title compound (204 mg, 64%) was obtained as a white solid in the same manner as in Example 3 using phenyl (158 mg, 0.776 mmol).
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.76-0.83 (4H, m), 1.86-1.96 (1H, m), 7.02 (1H, d, J = 9.5 Hz), 7.21 (2H, d, J = 9.0 Hz), 7.51 (2H, d, J = 9.0 Hz), 7.61-7.71 (4H, m), 7.92 (1H, s), 8.01 (1H, d, J = 9.5 Hz), 8.95 (1H, s), 9.18 (1H, s), 11.06 (1H, s).
実施例５
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-1-(フェニルカルボニル)シクロプロパンカルボキサミドの製造 Example 5
Preparation of N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -1- (phenylcarbonyl) cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
　N-[6-(4-アミノフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.647 mmol）のN,N-ジメチルアセトアミド（4.0 mL）溶液に、1-(フェニルカルボニル)シクロプロパンカルボン酸（185 mg, 0.970 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスファート（369 mg, 0.970 mmol）、N,N-ジイソプロピルエチルアミン（169μL, 0.970 mmol）を加えて、室温にて４時間撹拌した。反応液に飽和重曹水を加えて、酢酸エチル／テトラヒドロフランにて抽出した。飽和食塩水にて洗浄後、無水硫酸マグネシウムにて乾燥、ろ過した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチルのみ）にて精製した。得られた白色粉末にヘキサン／酢酸エチルを加え、ろ取して表題化合物（170 mg, 55%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.75 - 0.83 (4H, m), 1.45 - 1.50 (2H, m), 1.57 - 1.63 (2H, m), 1.86 - 1.96 (1H, m), 6.99 (1H, d, J = 9.6 Hz), 7.12 (2H, d, J = 9.0 Hz), 7.45 - 7.61 (5H, m), 7.88 - 7.92 (2H, m), 7.90 (1H, s), 7.99 (1H, d, J = 9.6 Hz), 9.98 (1H, s), 11.04 (1H, s). To a solution of N- [6- (4-aminophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.647 mmol) in N, N-dimethylacetamide (4.0 mL), 1 -(Phenylcarbonyl) cyclopropanecarboxylic acid (185 mg, 0.970 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (369 mg) , 0.970 mmol), N, N-diisopropylethylamine (169 μL, 0.970 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate / tetrahydrofuran. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate only). Hexane / ethyl acetate was added to the obtained white powder and collected by filtration to give the title compound (170 mg, 55%) as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.75-0.83 (4H, m), 1.45-1.50 (2H, m), 1.57-1.63 (2H, m), 1.86-1.96 (1H, m), 6.99 (1H, d, J = 9.6 Hz), 7.12 (2H, d, J = 9.0 Hz), 7.45-7.61 (5H, m), 7.88-7.92 (2H, m), 7.90 (1H, s), 7.99 (1H, d, J = 9.6 Hz), 9.98 (1H, s), 11.04 (1H, s).
実施例６
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-N'-フェニルシクロプロパン-1,1-ジカルボキサミドの製造 Example 6
Of N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -N'-phenylcyclopropane-1,1-dicarboxamide Manufacturing
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
　1-(フェニルカルバモイル)シクロプロパンカルボン酸（213 mg, 1.04 mmol）のテトラヒドロフラン（10 mL）溶液にN,N-ジメチルホルムアミド（2滴）、続いてオキサリルクロリド（0.178 mL）を加え、混合物を室温で3時間撹拌した。混合物を減圧濃縮後、残留物をN,N-ジメチルアセトアミド（5 mL）で希釈し、N-[6-(4-アミノフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（247 mg, 0.80 mmol）を加えた。混合物を室温で18時間撹拌後、1Ｎ水酸化ナトリウム水溶液で希釈し、酢酸エチル/テトラヒドロフラン（＝1／1）で抽出した。有機層を水で洗浄後、減圧濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール＝100／0→75／25）に付した。目的画分を減圧濃縮後、酢酸エチルより再結晶化させて、表題化合物（250 mg, 63%）を単黄色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.73 - 0.87 (4H, m), 1.48 (4H, s), 1.85 - 1.99 (1H, m), 7.02 (1H, d, J = 9.6Hz), 7.03 - 7.10 (1H, m), 7.21 (2H, d, J = 9.0Hz), 7.27 - 7.34 (2H, m), 7.60 - 7.65 (2H, m), 7.68 (2H, d, J = 9.0Hz), 7.92 (1H, s), 8.01 (1H, dd, J = 9.6, 0.6Hz), 10.06 (1H, s), 10.09 (1H, s), 11.05 (1H, s). To a solution of 1- (phenylcarbamoyl) cyclopropanecarboxylic acid (213 mg, 1.04 mmol) in tetrahydrofuran (10 mL) was added N, N-dimethylformamide (2 drops), followed by oxalyl chloride (0.178 mL), and the mixture was stirred at room temperature. For 3 hours. After the mixture was concentrated under reduced pressure, the residue was diluted with N, N-dimethylacetamide (5 mL), and N- [6- (4-aminophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropane Carboxamide (247 mg, 0.80 mmol) was added. The mixture was stirred at room temperature for 18 hours, diluted with 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate / tetrahydrofuran (= 1/1). The organic layer was washed with water and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / methanol = 100/0 → 75/25). The objective fraction was concentrated under reduced pressure and recrystallized from ethyl acetate to give the title compound (250 mg, 63%) as a single yellow solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.73-0.87 (4H, m), 1.48 (4H, s), 1.85-1.99 (1H, m), 7.02 (1H, d, J = 9.6Hz) , 7.03-7.10 (1H, m), 7.21 (2H, d, J = 9.0Hz), 7.27-7.34 (2H, m), 7.60-7.65 (2H, m), 7.68 (2H, d, J = 9.0Hz ), 7.92 (1H, s), 8.01 (1H, dd, J = 9.6, 0.6Hz), 10.06 (1H, s), 10.09 (1H, s), 11.05 (1H, s).
実施例７
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-1-(2-メトキシエチル)-5-メチル-1H-ピラゾール-3-カルボキサミドの製造 Example 7
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -1- (2-methoxyethyl) -5-methyl-1H -Pyrazole-3-carboxamide production
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
　1-(2-メトキシエチル)-5-メチル-1H-ピラゾール-3-カルボン酸(155 mg, 0.84 mmol)のテトラヒドロフラン(3 mL)溶液に、N,N-ジメチルホルムアミド(1滴)、二塩化オキサリル(140 μL, 1.7 mmol)を加え、混合物を室温で30分撹拌した。溶媒を減圧留去後、得られた残渣をN,N-ジメチルアセトアミド(2 mL)に溶解させ、これをN-[6-(4-アミノフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド(200 mg, 0.65 mmol)のN,N-ジメチルアセトアミド(5 mL)溶液に加え、混合物を室温で50分撹拌した。混合物に酢酸エチル／テトラヒドロフラン、飽和炭酸水素ナトリウム水溶液を加え、水層を酢酸エチル／テトラヒドロフランで４回抽出した。合わせた有機層を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥、ろ過した。ろ液を減圧濃縮し、残留物をシリカゲルカラムクロマトグラフィー(酢酸エチル／ヘキサン＝40／60→100／0)で精製し、表題化合物（230 mg, 76%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.74 - 0.85 (4H, m), 1.86 - 1.98 (1H, m), 2.33 (3H, s), 3.24 (3H, s), 3.73 (2H, t, J = 5.3 Hz), 4.30 (2H, t, J = 5.3 Hz), 6.56 (1H, s), 7.03 (1H, d, J = 9.6 Hz), 7.18 - 7.27 (2H, m), 7.82 - 7.96 (3H, m), 8.01 (1H, d, J = 9.6 Hz), 10.02 (1H, s), 11.06 (1H, s). To a solution of 1- (2-methoxyethyl) -5-methyl-1H-pyrazole-3-carboxylic acid (155 mg, 0.84 mmol) in tetrahydrofuran (3 mL) was added N, N-dimethylformamide (1 drop), dichloride. Oxalyl (140 μL, 1.7 mmol) was added and the mixture was stirred at room temperature for 30 minutes. After the solvent was distilled off under reduced pressure, the obtained residue was dissolved in N, N-dimethylacetamide (2 mL), and this was dissolved in N- [6- (4-aminophenoxy) imidazo [1,2-b] pyridazine-2. -Il] cyclopropanecarboxamide (200 mg, 0.65 mmol) in N, N-dimethylacetamide (5 mL) was added and the mixture was stirred at room temperature for 50 minutes. Ethyl acetate / tetrahydrofuran and saturated aqueous sodium hydrogen carbonate solution were added to the mixture, and the aqueous layer was extracted 4 times with ethyl acetate / tetrahydrofuran. The combined organic layers were washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 40/60 → 100/0) to give the title compound (230 mg, 76%) as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.74-0.85 (4H, m), 1.86-1.98 (1H, m), 2.33 (3H, s), 3.24 (3H, s), 3.73 (2H, t, J = 5.3 Hz), 4.30 (2H, t, J = 5.3 Hz), 6.56 (1H, s), 7.03 (1H, d, J = 9.6 Hz), 7.18-7.27 (2H, m), 7.82- 7.96 (3H, m), 8.01 (1H, d, J = 9.6 Hz), 10.02 (1H, s), 11.06 (1H, s).
実施例８
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-2-オキソ-1-フェニルピロリジン-3-カルボキサミドの製造 Example 8
Preparation of N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -2-oxo-1-phenylpyrrolidine-3-carboxamide
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
　2-オキソ-1-フェニルピロリジン-3-カルボン酸(170 mg, 0.84 mmol)、テトラヒドロフラン(3 mL)、N,N-ジメチルホルムアミド(1滴)、二塩化オキサリル(144 μL, 1.7 mmol)、N-[6-(4-アミノフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド(200 mg, 0.65 mmol)、N,N-ジメチルアセトアミド(7 mL)を原料として用い、実施例７と同様にして、表題化合物（160 mg, 50%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.75 - 0.84 (4H, m), 1.87 - 1.97 (1H, m), 2.30 - 2.48 (2H, m), 3.78 (1H, t, J = 8.6 Hz), 3.85 - 4.01 (2H, m), 7.03 (1H, d, J = 9.6 Hz), 7.14 - 7.27 (3H, m), 7.36 - 7.44 (2H, m), 7.64 - 7.79 (4H, m), 7.93 (1H, s), 7.99 - 8.04 (1H, m), 10.42 (1H, s), 11.06 (1H, s). 2-oxo-1-phenylpyrrolidine-3-carboxylic acid (170 mg, 0.84 mmol), tetrahydrofuran (3 mL), N, N-dimethylformamide (1 drop), oxalyl dichloride (144 μL, 1.7 mmol), N Using-[6- (4-aminophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.65 mmol), N, N-dimethylacetamide (7 mL) as a raw material, In the same manner as in Example 7, the title compound (160 mg, 50%) was obtained as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.75-0.84 (4H, m), 1.87-1.97 (1H, m), 2.30-2.48 (2H, m), 3.78 (1H, t, J = 8.6 Hz), 3.85-4.01 (2H, m), 7.03 (1H, d, J = 9.6 Hz), 7.14-7.27 (3H, m), 7.36-7.44 (2H, m), 7.64-7.79 (4H, m) , 7.93 (1H, s), 7.99-8.04 (1H, m), 10.42 (1H, s), 11.06 (1H, s).
実施例９
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-5-メチル-1-(2-オキソプロピル)-1H-ピラゾール-3-カルボキサミドの製造 Example 9
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -5-methyl-1- (2-oxopropyl) -1H -Pyrazole-3-carboxamide production
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075
　5-メチル-1-(2-オキソプロピル)-1H-ピラゾール-3-カルボン酸(350 mg, 1.9 mmol)、テトラヒドロフラン(6 mL)、N,N-ジメチルホルムアミド(1滴)、二塩化オキサリル(330 μL, 3.9 mmol)、N-[6-(4-アミノフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド(500 mg, 1.6 mmol)、N,N-ジメチルアセトアミド(14 mL)を原料として用い、実施例７と同様にして、表題化合物（440 mg, 57%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.76 - 0.84 (4H, m), 1.86 - 1.97 (1H, m), 2.20 (3H, s), 2.21 (3H, s), 5.24 (2H, s), 6.62 (1H, d, J = 0.8 Hz), 7.03 (1H, d, J = 9.6 Hz), 7.18 - 7.25 (2H, m), 7.83 - 7.89 (2H, m), 7.93 (1H, s), 8.01 (1H, d, J = 9.6 Hz), 10.07 (1H, s), 11.05 (1H, s). 5-methyl-1- (2-oxopropyl) -1H-pyrazole-3-carboxylic acid (350 mg, 1.9 mmol), tetrahydrofuran (6 mL), N, N-dimethylformamide (1 drop), oxalyl dichloride ( 330 μL, 3.9 mmol), N- [6- (4-aminophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (500 mg, 1.6 mmol), N, N-dimethylacetamide ( 14 mL) was used as a starting material, and the title compound (440 mg, 57%) was obtained as a white solid in the same manner as in Example 7.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.76-0.84 (4H, m), 1.86-1.97 (1H, m), 2.20 (3H, s), 2.21 (3H, s), 5.24 (2H, s), 6.62 (1H, d, J = 0.8 Hz), 7.03 (1H, d, J = 9.6 Hz), 7.18-7.25 (2H, m), 7.83-7.89 (2H, m), 7.93 (1H, s ), 8.01 (1H, d, J = 9.6 Hz), 10.07 (1H, s), 11.05 (1H, s).
実施例１０
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-5-メトキシ-1-フェニル-1H-ピラゾール-4-カルボキサミドの製造 Example 10
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -5-methoxy-1-phenyl-1H-pyrazole-4- Carboxamide production
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
　5-メトキシ-1-フェニル-1H-ピラゾール-4-カルボン酸(220 mg, 1.0 mmol)、テトラヒドロフラン(3 mL)、N,N-ジメチルホルムアミド(1滴)、二塩化オキサリル(175 μL, 2.0 mmol)、N-[6-(4-アミノフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド(260 mg, 0.85 mmol)、N,N-ジメチルアセトアミド(7 mL)を原料として用い、実施例７と同様にして、表題化合物（217 mg, 50%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.74 - 0.85 (4H, m), 1.87 - 1.96 (1H, m), 4.10 (3H, s), 7.04 (1H, d, J = 9.6 Hz), 7.22 - 7.29 (2H, m), 7.40 - 7.48 (1H, m), 7.51 - 7.59 (2H, m), 7.63 - 7.68 (2H, m), 7.76 - 7.83 (2H, m), 7.94 (1H, s), 8.02 (1H, d, J = 9.6 Hz), 8.20 (1H, s), 10.03 (1H, s), 11.07 (1H, s). 5-methoxy-1-phenyl-1H-pyrazole-4-carboxylic acid (220 mg, 1.0 mmol), tetrahydrofuran (3 mL), N, N-dimethylformamide (1 drop), oxalyl dichloride (175 μL, 2.0 mmol) ), N- [6- (4-aminophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (260 mg, 0.85 mmol), N, N-dimethylacetamide (7 mL) And the title compound (217 mg, 50%) was obtained as a white solid in the same manner as in Example 7.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.74-0.85 (4H, m), 1.87-1.96 (1H, m), 4.10 (3H, s), 7.04 (1H, d, J = 9.6 Hz) , 7.22-7.29 (2H, m), 7.40-7.48 (1H, m), 7.51-7.59 (2H, m), 7.63-7.68 (2H, m), 7.76-7.83 (2H, m), 7.94 (1H, s), 8.02 (1H, d, J = 9.6 Hz), 8.20 (1H, s), 10.03 (1H, s), 11.07 (1H, s).
実施例１１
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-1-メチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミドの製造 Example 11
N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -1-methyl-3-oxo-2-phenyl-2, Preparation of 3-dihydro-1H-pyrazole-4-carboxamide
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
　1-メチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボン酸(210 mg, 0.97 mmol)、N-[6-(4-アミノフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド(200 mg, 0.65 mmol)、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスファート(370 mg, 0.97 mmol)、N,N-ジイソプロピルエチルアミン(250 mg, 1.9 mmol)、N,N-ジメチルホルムアミド(4 mL)の混合物を室温で3時間撹拌した。減圧下溶媒を留去後、残渣に酢酸エチル／テトラヒドロフラン、水を加え、水層を酢酸エチル／テトラヒドロフランで４回抽出した。合わせ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、ろ過した。ろ液を減圧濃縮し、残留物をシリカゲルカラムクロマトグラフィー(ＮＨシリカゲル、酢酸エチル／ヘキサン＝40／60→100／0)で精製し、表題化合物(210 mg, 64%)を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.75 - 0.84 (4H, m), 1.87 - 1.96 (1H, m), 3.48 (3H, s), 7.03 (1H, d, J = 9.6 Hz), 7.20 - 7.27 (2H, m), 7.46 - 7.64 (5H, m), 7.65 - 7.71 (2H, m), 7.93 (1H, s), 8.01 (1H, d, J = 9.6 Hz), 8.62 (1H, s), 10.39 (1H, s), 11.06 (1H, s). 1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (210 mg, 0.97 mmol), N- [6- (4-aminophenoxy) imidazo [1,2 -b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.65 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate A mixture of (370 mg, 0.97 mmol), N, N-diisopropylethylamine (250 mg, 1.9 mmol) and N, N-dimethylformamide (4 mL) was stirred at room temperature for 3 hours. After evaporating the solvent under reduced pressure, ethyl acetate / tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted 4 times with ethyl acetate / tetrahydrofuran. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 40/60 → 100/0) to obtain the title compound (210 mg, 64%) as a white solid. .
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.75-0.84 (4H, m), 1.87-1.96 (1H, m), 3.48 (3H, s), 7.03 (1H, d, J = 9.6 Hz) , 7.20-7.27 (2H, m), 7.46-7.64 (5H, m), 7.65-7.71 (2H, m), 7.93 (1H, s), 8.01 (1H, d, J = 9.6 Hz), 8.62 (1H , s), 10.39 (1H, s), 11.06 (1H, s).
実施例１２
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミドの製造 Example 12
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -1,5-dimethyl-3-oxo-2-phenyl- Preparation of 2,3-dihydro-1H-pyrazole-4-carboxamide
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078
　1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボン酸(225 mg, 0.97 mmol)、N-[6-(4-アミノフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド(200 mg, 0.65 mmol)、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスファート(370 mg, 0.97 mmol)、N,N-ジイソプロピルエチルアミン(250 mg, 1.9 mmol)、N,N-ジメチルホルムアミド(4 mL)を原料として用い、実施例１１と同様にして、表題化合物（179 mg, 53%）を淡橙色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.76 - 0.85 (4H, m), 1.87 - 1.96 (1H, m), 2.71 (3H, s), 3.36 (3H, s), 7.03 (1H, d, J = 9.4 Hz), 7.22 (2H, d, J = 8.1 Hz), 7.44 (2H, d, J = 8.1 Hz), 7.48 - 7.70 (5H, m), 7.92 (1H, s), 8.01 (1H, d, J = 9.4 Hz), 10.80 (1H, s), 11.06 (1H, s). 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (225 mg, 0.97 mmol), N- [6- (4-aminophenoxy) imidazo [1 , 2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.65 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluoro Using the phosphate (370 mg, 0.97 mmol), N, N-diisopropylethylamine (250 mg, 1.9 mmol) and N, N-dimethylformamide (4 mL) as raw materials, the title compound ( 179 mg, 53%) was obtained as a pale orange solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.76-0.85 (4H, m), 1.87-1.96 (1H, m), 2.71 (3H, s), 3.36 (3H, s), 7.03 (1H, d, J = 9.4 Hz), 7.22 (2H, d, J = 8.1 Hz), 7.44 (2H, d, J = 8.1 Hz), 7.48-7.70 (5H, m), 7.92 (1H, s), 8.01 ( 1H, d, J = 9.4 Hz), 10.80 (1H, s), 11.06 (1H, s).
実施例１４
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-1-メチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミドの製造 Example 14
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -1-methyl-3-oxo-2- Preparation of phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079
　1-メチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボン酸(270 mg, 1.2 mmol)、N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド(200 mg, 0.61 mmol)、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスファート(460 mg, 1.2 mmol)、N,N-ジイソプロピルエチルアミン(320 mg, 2.4 mmol)、N,N-ジメチルホルムアミド(5 mL)を原料として用い、実施例１１と同様にして、表題化合物（200 mg, 62%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.74 - 0.84 (4H, m), 1.86 - 1.96 (1H, m), 3.49 (3H, s), 7.14 (1H, d, J = 9.6 Hz), 7.30 - 7.35 (1H, m), 7.41 (1H, t, J = 8.8 Hz), 7.47 - 7.64 (5H, m), 7.88 - 7.97 (2H, m), 8.05 (1H, d, J = 9.6 Hz), 8.65 (1H, s), 10.52 (1H, s), 11.06 (1H, s). 1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (270 mg, 1.2 mmol), N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.61 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium Hexafluorophosphate (460 mg, 1.2 mmol), N, N-diisopropylethylamine (320 mg, 2.4 mmol), N, N-dimethylformamide (5 mL) were used as raw materials in the same manner as in Example 11, and the title was changed. The compound (200 mg, 62%) was obtained as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.74-0.84 (4H, m), 1.86-1.96 (1H, m), 3.49 (3H, s), 7.14 (1H, d, J = 9.6 Hz) , 7.30-7.35 (1H, m), 7.41 (1H, t, J = 8.8 Hz), 7.47-7.64 (5H, m), 7.88-7.97 (2H, m), 8.05 (1H, d, J = 9.6 Hz ), 8.65 (1H, s), 10.52 (1H, s), 11.06 (1H, s).
実施例１５
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミドの製造 Example 15
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -1,5-dimethyl-3-oxo- Preparation of 2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080
　1,5-ジメチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボン酸(213 mg, 0.92 mmol)、N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド(200 mg, 0.61 mmol)、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスファート(350 mg, 0.92 mmol)、N,N-ジイソプロピルエチルアミン(240 mg, 1.8 mmol)、N,N-ジメチルホルムアミド(5 mL)を原料として用い、実施例１１と同様にして、表題化合物（240 mg, 73%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.74 - 0.84 (4H, m), 1.86 - 1.96 (1H, m), 2.71 (3H, s), 3.37 (3H, s), 7.14 (1H, d, J = 9.6 Hz), 7.26 - 7.31 (1H, m), 7.38 (1H, d, J = 8.7 Hz), 7.42 - 7.64 (5H, m), 7.88 - 7.97 (2H, m), 8.05 (1H, d, J = 9.6 Hz), 10.94 (1H, s), 11.06 (1H, s). 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (213 mg, 0.92 mmol), N- [6- (4-amino-2-fluorophenoxy) ) Imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.61 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyl Using uronium hexafluorophosphate (350 mg, 0.92 mmol), N, N-diisopropylethylamine (240 mg, 1.8 mmol), N, N-dimethylformamide (5 mL) as raw materials in the same manner as in Example 11. To give the title compound (240 mg, 73%) as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.74-0.84 (4H, m), 1.86-1.96 (1H, m), 2.71 (3H, s), 3.37 (3H, s), 7.14 (1H, d, J = 9.6 Hz), 7.26-7.31 (1H, m), 7.38 (1H, d, J = 8.7 Hz), 7.42-7.64 (5H, m), 7.88-7.97 (2H, m), 8.05 (1H , d, J = 9.6 Hz), 10.94 (1H, s), 11.06 (1H, s).
実施例１６
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-1-エチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボキサミドの製造 Example 16
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -1-ethyl-3-oxo-2- Preparation of phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide
Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000081
　1-エチル-3-オキソ-2-フェニル-2,3-ジヒドロ-1H-ピラゾール-4-カルボン酸(160 mg, 0.69 mmol)、N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド(150 mg, 0.46 mmol)、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスファート(260 mg, 0.69 mmol)、N,N-ジイソプロピルエチルアミン(180 mg, 1.4 mmol)、N,N-ジメチルホルムアミド(4 mL)を原料として用い、実施例１１と同様にして、表題化合物（150 mg, 60%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.75 - 0.86 (4H, m), 1.08 (3H, t, J = 7.2 Hz), 1.84 - 1.96 (1H, m), 3.88 (2H, q, J = 7.2 Hz), 7.14 (1H, d, J = 9.6 Hz), 7.31 - 7.36 (1H, m), 7.42 (1H, t, J = 8.7 Hz), 7.46 - 7.66 (5H, m), 7.87 - 7.97 (2H, m), 8.05 (1H, d, J = 9.6 Hz), 8.74 (1H, s), 10.50 (1H, s), 11.07 (1H, s). 1-ethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (160 mg, 0.69 mmol), N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (150 mg, 0.46 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium Hexafluorophosphate (260 mg, 0.69 mmol), N, N-diisopropylethylamine (180 mg, 1.4 mmol), N, N-dimethylformamide (4 mL) were used as raw materials in the same manner as in Example 11, The compound (150 mg, 60%) was obtained as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.75-0.86 (4H, m), 1.08 (3H, t, J = 7.2 Hz), 1.84-1.96 (1H, m), 3.88 (2H, q, J = 7.2 Hz), 7.14 (1H, d, J = 9.6 Hz), 7.31-7.36 (1H, m), 7.42 (1H, t, J = 8.7 Hz), 7.46-7.66 (5H, m), 7.87- 7.97 (2H, m), 8.05 (1H, d, J = 9.6 Hz), 8.74 (1H, s), 10.50 (1H, s), 11.07 (1H, s).
実施例１７
N-[6-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)ピリジン-3-イル]-N'-フェニルシクロプロパン-1,1-ジカルボキサミドの製造 Example 17
N- [6-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) pyridin-3-yl] -N'-phenylcyclopropane-1,1 -Production of dicarboxamide
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000082
　1-(フェニルカルバモイル)シクロプロパンカルボン酸(150 mg, 0.73 mmol)、N-{6-[(5-アミノピリジン-2-イル)オキシ]イミダゾ[1,2-b]ピリダジン-2-イル}シクロプロパンカルボキサミド(150 mg, 0.48 mmol)、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスファート(280 mg, 0.73 mmol)、N,N-ジイソプロピルエチルアミン(190 mg, 1.5 mmol)、N,N-ジメチルホルムアミド(4 mL)を原料として用い、実施例１１と同様にして、表題化合物（230 mg, 95%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.76 - 0.88 (4H, m), 1.42 - 1.52 (4H, m), 1.88 - 1.96 (1H, m), 7.02 - 7.11 (2H, m), 7.22 - 7.35 (3H, m), 7.62 (2H, d, J = 8.1 Hz), 8.02 - 8.08 (2H, m), 8.17 (1H, d, J = 8.9 Hz), 8.44 (1H, s), 10.08 (1H, s), 10.22 (1H, s), 11.13 (1H, s). 1- (phenylcarbamoyl) cyclopropanecarboxylic acid (150 mg, 0.73 mmol), N- {6-[(5-aminopyridin-2-yl) oxy] imidazo [1,2-b] pyridazin-2-yl} Cyclopropanecarboxamide (150 mg, 0.48 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (280 mg, 0.73 mmol), N , N-Diisopropylethylamine (190 mg, 1.5 mmol) and N, N-dimethylformamide (4 mL) were used as raw materials in the same manner as in Example 11 to obtain the title compound (230 mg, 95%) as a white solid. It was.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.76-0.88 (4H, m), 1.42-1.52 (4H, m), 1.88-1.96 (1H, m), 7.02-7.11 (2H, m), 7.22-7.35 (3H, m), 7.62 (2H, d, J = 8.1 Hz), 8.02-8.08 (2H, m), 8.17 (1H, d, J = 8.9 Hz), 8.44 (1H, s), 10.08 (1H, s), 10.22 (1H, s), 11.13 (1H, s).
実施例１８
N-[6-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)ピリジン-3-イル]-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 18
N- [6-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) pyridin-3-yl] -2-oxo-1-phenyl-1, Preparation of 2-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083
　2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボン酸(160 mg, 0.73 mmol)、N-{6-[(5-アミノピリジン-2-イル)オキシ]イミダゾ[1,2-b]ピリダジン-2-イル}シクロプロパンカルボキサミド(150 mg, 0.48 mmol)、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスファート(280 mg, 0.73 mmol)、N,N-ジイソプロピルエチルアミン(190 mg, 1.5 mmol)、N,N-ジメチルホルムアミド(4 mL)を原料として用い、実施例１１と同様にして、表題化合物（210 mg, 86%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.77 - 0.89 (4H, m), 1.88 - 2.00 (1H, m), 6.69 - 6.76 (1H, m), 7.10 (1H, d, J = 9.8 Hz), 7.29 (1H, d, J = 8.7 Hz), 7.48 - 7.62 (5H, m), 8.06 (2H, t, J = 4.6 Hz), 8.13 (1H, d, J = 6.4 Hz), 8.34 (1H, d, J = 8.7 Hz), 8.52 (1H, s), 8.59 (1H, d, J = 7.2 Hz), 11.13 (1H, s), 12.02 (1H, s). 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (160 mg, 0.73 mmol), N- {6-[(5-aminopyridin-2-yl) oxy] imidazo [1,2- b] pyridazin-2-yl} cyclopropanecarboxamide (150 mg, 0.48 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate ( 280 mg, 0.73 mmol), N, N-diisopropylethylamine (190 mg, 1.5 mmol), N, N-dimethylformamide (4 mL) were used as raw materials in the same manner as in Example 11, and the title compound (210 mg, 86%) was obtained as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.77-0.89 (4H, m), 1.88-2.00 (1H, m), 6.69-6.76 (1H, m), 7.10 (1H, d, J = 9.8 Hz), 7.29 (1H, d, J = 8.7 Hz), 7.48-7.62 (5H, m), 8.06 (2H, t, J = 4.6 Hz), 8.13 (1H, d, J = 6.4 Hz), 8.34 ( 1H, d, J = 8.7 Hz), 8.52 (1H, s), 8.59 (1H, d, J = 7.2 Hz), 11.13 (1H, s), 12.02 (1H, s).
実施例１９
N-[5-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)ピリジン-2-イル]-N'-フェニルシクロプロパン-1,1-ジカルボキサミドの製造 Example 19
N- [5-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) pyridin-2-yl] -N'-phenylcyclopropane-1,1 -Production of dicarboxamide
Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000084
　1-(フェニルカルバモイル)シクロプロパンカルボン酸(200 mg, 0.98 mmol)、テトラヒドロフラン(4 mL)、N,N-ジメチルホルムアミド(1滴)、二塩化オキサリル(170 μL, 2.0 mmol)、N-{6-[(6-アミノピリジン-3-イル)オキシ]イミダゾ[1,2-b]ピリダジン-2-イル}シクロプロパンカルボキサミド(230 mg, 0.75 mmol)、N,N-ジメチルアセトアミド(6 mL)を原料として用い、実施例７と同様にして、表題化合物（91 mg, 24%）を黄色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.74 - 0.84 (4H, m), 1.51 - 1.63 (4H, m), 1.86 - 1.97 (1H, m), 7.06 - 7.14 (2H, m), 7.29 - 7.36 (2H, m), 7.57 - 7.63 (2H, m), 7.82 (1H, dd, J = 9.1, 2.8 Hz), 7.92 (1H, s), 8.05 (1H, d, J = 10.2 Hz), 8.15 (1H, d, J = 9.1 Hz), 8.34 (1H, d, J = 2.8 Hz), 9.74 (1H, s), 11.06 (2H, s). 1- (phenylcarbamoyl) cyclopropanecarboxylic acid (200 mg, 0.98 mmol), tetrahydrofuran (4 mL), N, N-dimethylformamide (1 drop), oxalyl dichloride (170 μL, 2.0 mmol), N- {6 -[(6-Aminopyridin-3-yl) oxy] imidazo [1,2-b] pyridazin-2-yl} cyclopropanecarboxamide (230 mg, 0.75 mmol), N, N-dimethylacetamide (6 mL) The title compound (91 mg, 24%) was obtained as a yellow solid in the same manner as Example 7 using as a raw material.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.74-0.84 (4H, m), 1.51-1.63 (4H, m), 1.86-1.97 (1H, m), 7.06-7.14 (2H, m), 7.29-7.36 (2H, m), 7.57-7.63 (2H, m), 7.82 (1H, dd, J = 9.1, 2.8 Hz), 7.92 (1H, s), 8.05 (1H, d, J = 10.2 Hz) , 8.15 (1H, d, J = 9.1 Hz), 8.34 (1H, d, J = 2.8 Hz), 9.74 (1H, s), 11.06 (2H, s).
実施例２０
N-[5-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)ピリジン-2-イル]-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 20
N- [5-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) pyridin-2-yl] -2-oxo-1-phenyl-1, Preparation of 2-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000085
Figure JPOXMLDOC01-appb-C000085
　2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボン酸(120 mg, 0.54 mmol)、テトラヒドロフラン(6 mL)、N,N-ジメチルホルムアミド(1滴)、二塩化オキサリル(93 μL, 1.1 mmol)、N-{6-[(6-アミノピリジン-3-イル)オキシ]イミダゾ[1,2-b]ピリダジン-2-イル}シクロプロパンカルボキサミド(130 mg, 0.42 mmol)、N,N-ジメチルアセトアミド(6 mL)を原料として用い、実施例７と同様にして、表題化合物（83 mg, 39%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.73 - 0.84 (4H, m), 1.84 - 1.97 (1H, m), 6.71 - 6.76 (1H, m), 7.12 (1H, d, J = 9.6 Hz), 7.49 - 7.63 (5H, m), 7.87 (1H, dd, J = 9.1, 2.9 Hz), 7.93 (1H, s), 8.05 (1H, d, J = 9.6 Hz), 8.15 (1H, dd, J = 6.6, 2.3 Hz), 8.35 (1H, d, J = 2.3 Hz), 8.38 (1H, d, J = 9.1 Hz), 8.63 (1H, dd, J = 7.3, 2.2 Hz), 11.06 (1H, s), 12.41 (1H, s). 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (120 mg, 0.54 mmol), tetrahydrofuran (6 mL), N, N-dimethylformamide (1 drop), oxalyl dichloride (93 μL, 1.1 mmol), N- {6-[(6-aminopyridin-3-yl) oxy] imidazo [1,2-b] pyridazin-2-yl} cyclopropanecarboxamide (130 mg, 0.42 mmol), N, N -Dimethylacetamide (6 mL) was used as a starting material, and the title compound (83 mg, 39%) was obtained as a white solid in the same manner as in Example 7.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.73-0.84 (4H, m), 1.84-1.97 (1H, m), 6.71-6.76 (1H, m), 7.12 (1H, d, J = 9.6 Hz), 7.49-7.63 (5H, m), 7.87 (1H, dd, J = 9.1, 2.9 Hz), 7.93 (1H, s), 8.05 (1H, d, J = 9.6 Hz), 8.15 (1H, dd , J = 6.6, 2.3 Hz), 8.35 (1H, d, J = 2.3 Hz), 8.38 (1H, d, J = 9.1 Hz), 8.63 (1H, dd, J = 7.3, 2.2 Hz), 11.06 (1H , s), 12.41 (1H, s).
実施例２１
N-(6-{2-フルオロ-4-[(フェニルアセチル)アミノ]フェノキシ}イミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミド（実施例２１－１）及びN-[6-(2-フルオロ-4-{[(フェニルアセチル)カルバモチオイル]アミノ}フェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（実施例２１－２）の製造 Example 21
N- (6- {2-fluoro-4-[(phenylacetyl) amino] phenoxy} imidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (Example 21-1) and N- [6 -(2-Fluoro-4-{[(phenylacetyl) carbamothioyl] amino} phenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (Example 21-2)
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086
　チオシアン酸カリウム（119 mg, 1.22 mmol）のアセトニトリル（50 mL）溶液にフェニルアセチルクロライド（162 μL, 1.22 mmol）を加え、40℃ にて 2時間撹拌した。減圧下溶媒を留去し、残渣に飽和炭酸水素ナトリウム水溶液と酢酸エチルを加え、室温にて 1 時間撹拌した。反応液を酢酸エチルにて 3 回抽出後、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、ろ過し、減圧下溶媒を留去した。得られた残渣のエタノール（１ mL）／トルエン（１ mL）の混合溶液にN-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.611 mmol）を加え、室温にて 15時間撹拌した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル／ヘキサン＝60／40→80／20）にて精製し、N-(6-{2-フルオロ-4-[(フェニルアセチル)アミノ]フェノキシ}イミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミド（21 mg, 4%）およびN-[6-(2-フルオロ-4-{[(フェニルアセチル)カルバモチオイル]アミノ}フェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（228 mg, 74%）を、それぞれ白色固体として得た。
N-(6-{2-フルオロ-4-[(フェニルアセチル)アミノ]フェノキシ}イミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミド
1H-NMR (DMSO-d6, 300 MHz) δ 0.58 - 0.92 (4H, m), 1.46 - 2.13 (1H, m), 3.67 (2H, s), 7.13 (1H, d, J = 9.4 Hz), 7.21 - 7.51 (7H, m), 7.74 - 7.83 (1H, m), 7.88 (1H, s), 8.04 (1H, d, J = 9.4 Hz), 10.48 (1H, s), 11.06 (1H, s).
N-[6-(2-フルオロ-4-{[(フェニルアセチル)カルバモチオイル]アミノ}フェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド
1H-NMR (DMSO-d6, 300 MHz) δ 0.73 - 0.86 (4H, m), 1.83 - 1.96 (1H, m), 3.83 (2H, s), 7.16 (1H, d, J = 9.7 Hz), 7.22 - 7.41 (5H, m), 7.43 - 7.55 (2H, m), 7.88 - 7.99 (2H, m), 8.07 (1H, d, J = 9.7 Hz), 11.07 (1H, s), 11.80 (1H, brs), 12.46 (1H, brs). To a solution of potassium thiocyanate (119 mg, 1.22 mmol) in acetonitrile (50 mL) was added phenylacetyl chloride (162 μL, 1.22 mmol), and the mixture was stirred at 40 ° C. for 2 hr. The solvent was evaporated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the residue, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. To a mixed solution of the obtained residue in ethanol (1 mL) / toluene (1 mL), N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclo Propane carboxamide (200 mg, 0.611 mmol) was added and stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 60/40 → 80/20), and N- (6- {2-fluoro-4-[( Phenylacetyl) amino] phenoxy} imidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (21 mg, 4%) and N- [6- (2-fluoro-4-{[(phenylacetyl)] Carbamothioyl] amino} phenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (228 mg, 74%) was obtained as a white solid, respectively.
N- (6- {2-Fluoro-4-[(phenylacetyl) amino] phenoxy} imidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.58-0.92 (4H, m), 1.46-2.13 (1H, m), 3.67 (2H, s), 7.13 (1H, d, J = 9.4 Hz) , 7.21-7.51 (7H, m), 7.74-7.83 (1H, m), 7.88 (1H, s), 8.04 (1H, d, J = 9.4 Hz), 10.48 (1H, s), 11.06 (1H, s ).
N- [6- (2-Fluoro-4-{[(phenylacetyl) carbamothioyl] amino} phenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.73-0.86 (4H, m), 1.83-1.96 (1H, m), 3.83 (2H, s), 7.16 (1H, d, J = 9.7 Hz) , 7.22-7.41 (5H, m), 7.43-7.55 (2H, m), 7.88-7.99 (2H, m), 8.07 (1H, d, J = 9.7 Hz), 11.07 (1H, s), 11.80 (1H , brs), 12.46 (1H, brs).
実施例２２
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-N'-フェニルシクロブタン-1,1-ジカルボキサミドの製造 Example 22
N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -N'-phenylcyclobutane-1,1- Production of dicarboxamide
Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087
　1-(フェニルカルバモイル)シクロブタンカルボン酸（126 mg, 0.733 mmol）のテトラヒドロフラン（2 mL）溶液に、N,N-ジメチルホルムアミド (2 滴) とオキザリルクロライド (126 μL, 1.47 mmol)を加え、室温にて4時間撹拌した。反応溶液を、減圧下溶媒を留去した。残渣のテトラヒドロフラン溶液（1 mL）を、N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.611 mmol）のN,N-ジメチルアセトアミド（2 mL）溶液に加え、室温にて15時間撹拌した。反応液にテトラヒドロフランと酢酸エチル、そして、1Ｎ塩酸（5 mL）を加え、酢酸エチルを用いて3回抽出後、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、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル／ヘキサン＝90／10→100／0）にて精製し、表題化合物（30 mg, 9%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.72 - 0.86 (4H, m), 1.79 - 1.95 (3H, m), 2.60 - 2.74 (4H, m), 7.02 - 7.17 (2H, m), 7.25 - 7.44 (3H, m), 7.54 (1H, m), 7.62 - 7.72 (2H, m), 7.80 - 7.92 (2H, m), 8.04 (1H, d, J= 9.4 Hz), 9.62 (1H, s), 9.93 (1H, s), 11.05 (1H, s). To a solution of 1- (phenylcarbamoyl) cyclobutanecarboxylic acid (126 mg, 0.733 mmol) in tetrahydrofuran (2 mL) was added N, N-dimethylformamide (2 drops) and oxalyl chloride (126 μL, 1.47 mmol) at room temperature. For 4 hours. The solvent was distilled off from the reaction solution under reduced pressure. A solution of the residue in tetrahydrofuran (1 mL) was added to N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.611 mmol). To the N, N-dimethylacetamide (2 mL) solution, the mixture was stirred at room temperature for 15 hours. Tetrahydrofuran, ethyl acetate, and 1N hydrochloric acid (5 mL) were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and reduced pressure. The solvent was distilled off. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 90/10 → 100/0) to give the title compound (30 mg, 9%) as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.72-0.86 (4H, m), 1.79-1.95 (3H, m), 2.60-2.74 (4H, m), 7.02-7.17 (2H, m), 7.25-7.44 (3H, m), 7.54 (1H, m), 7.62-7.72 (2H, m), 7.80-7.92 (2H, m), 8.04 (1H, d, J = 9.4 Hz), 9.62 (1H, s), 9.93 (1H, s), 11.05 (1H, s).
実施例２３
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-2,2-ジメチル-N'-フェニルプロパンジアミドの製造 Example 23
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -2,2-dimethyl-N'-phenyl Propane diamide production
Figure JPOXMLDOC01-appb-C000088
Figure JPOXMLDOC01-appb-C000088
　2,2-ジメチル-3-オキソ-3-(フェニルアミノ)プロパン酸（152 mg, 0.733 mmol）のテトラヒドロフラン（2 mL）溶液に、N,N-ジメチルホルムアミド（2 滴）とオキザリルクロライド（105 μL, 1.22 mmol）を加え、室温にて4時間撹拌した。反応溶液を、減圧下溶媒を留去した。残渣のテトラヒドロフラン溶液（1 mL）を、N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.611 mmol）のN,N-ジメチルアセトアミド（2 mL）溶液に加え、室温にて18時間撹拌した。反応液にテトラヒドロフランと酢酸エチル、そして、1Ｎ水酸化ナトリウム（5 mL）を加え、酢酸エチルを用いて3回抽出後、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、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル／ヘキサン＝60／40→100／0）にて精製し、白色固体を得た。得られた固体を酢酸エチルに溶解し、有機層を1Ｎ塩酸、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、ろ過し、減圧下溶媒を留去して、表題化合物（121 mg, 38%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.71 - 0.84 (4H, m), 1.56 (6H, s), 1.83 - 1.97 (1H, m), 7.00 - 7.10 (1H, m), 7.13 (1H, d, J = 9.8 Hz), 7.25 - 7.44 (3H, m), 7.46 - 7.58 (1H, m), 7.67 (2H, dd, J =8.7, 1.1 Hz), 7.80 - 7.92 (2H, m), 8.05 (1H, d, J = 9.8 Hz), 9.46 (1H, s), 9.74 (1H, s), 11.05 (1H, s). To a solution of 2,2-dimethyl-3-oxo-3- (phenylamino) propanoic acid (152 mg, 0.733 mmol) in tetrahydrofuran (2 mL), N, N-dimethylformamide (2 drops) and oxalyl chloride (105 μL, 1.22 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off from the reaction solution under reduced pressure. A solution of the residue in tetrahydrofuran (1 mL) was added to N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.611 mmol). To the N, N-dimethylacetamide (2 mL) solution, the mixture was stirred at room temperature for 18 hours. Tetrahydrofuran, ethyl acetate and 1N sodium hydroxide (5 mL) were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 60/40 → 100/0) to obtain a white solid. The obtained solid was dissolved in ethyl acetate, and the organic layer was washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the title compound (121 mg, 38% ) Was obtained as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.71-0.84 (4H, m), 1.56 (6H, s), 1.83-1.97 (1H, m), 7.00-7.10 (1H, m), 7.13 ( 1H, d, J = 9.8 Hz), 7.25-7.44 (3H, m), 7.46-7.58 (1H, m), 7.67 (2H, dd, J = 8.7, 1.1 Hz), 7.80-7.92 (2H, m) , 8.05 (1H, d, J = 9.8 Hz), 9.46 (1H, s), 9.74 (1H, s), 11.05 (1H, s).
実施例２４
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-N'-フェニルプロパンジアミドの製造 Example 24
Preparation of N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -N'-phenylpropanediamide
Figure JPOXMLDOC01-appb-C000089
Figure JPOXMLDOC01-appb-C000089
　3-オキソ-3-(フェニルアミノ)プロパン酸（164 mg, 0.917 mmol）とN-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.611 mmol）のN,N-ジメチルホルムアミド（2 mL）溶液に、N,N-ジイソプロピルエチルアミン（0.32 mL, 1.86 mmol）とO-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（348 mg, 0.917 mmol）を加え、室温にて20時間撹拌した。反応液に1Ｎ塩酸（5 mL）を加え、酢酸エチルを用いて3回抽出後、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後、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル／ヘキサン＝80／20→100／0）にて精製し、表題化合物（40.3 mg, 14%）を白色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.74 - 0.86 (4H, m), 1.85 - 1.96 (1H, m), 3.51 (2H, s), 7.01 - 7.18 (2H, m), 7.27 - 7.47 (4H, m), 7.61 (2H, m), 7.80 (1H, dd, J = 13.0, 1.9 Hz), 7.90 (1H, s), 8.05 (1H, d, J = 10.0 Hz), 10.19 (1H, s), 10.49 (1H, s), 11.06 (1H, s). 3-oxo-3- (phenylamino) propanoic acid (164 mg, 0.917 mmol) and N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclo To a solution of propanecarboxamide (200 mg, 0.611 mmol) in N, N-dimethylformamide (2 mL), N, N-diisopropylethylamine (0.32 mL, 1.86 mmol) and O- (7-azabenzotriazol-1-yl) -1,1,3,3-Tetramethyluronium hexafluorophosphate (348 mg, 0.917 mmol) was added, and the mixture was stirred at room temperature for 20 hours. 1N Hydrochloric acid (5 mL) was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 80/20 → 100/0) to obtain the title compound (40.3 mg, 14%) as a white solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.74-0.86 (4H, m), 1.85-1.96 (1H, m), 3.51 (2H, s), 7.01-7.18 (2H, m), 7.27- 7.47 (4H, m), 7.61 (2H, m), 7.80 (1H, dd, J = 13.0, 1.9 Hz), 7.90 (1H, s), 8.05 (1H, d, J = 10.0 Hz), 10.19 (1H , s), 10.49 (1H, s), 11.06 (1H, s).
実施例２５
N-[6-(3-フルオロ-4-{[(フェニルアセチル)カルバモチオイル]アミノ}フェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミドの製造 Example 25
Production of N- [6- (3-fluoro-4-{[(phenylacetyl) carbamothioyl] amino} phenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090
　チオシアン酸カリウム（119 mg, 1.22 mmol）、アセトニトリル（50 mL）、フェニルアセチルクロライド（162 μL, 1.22 mmol）、エタノール（１ mL）、トルエン（１ mL）、N-[6-(4-アミノ-3-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.611 mmol）を用いて、実施例２１と同様の方法にて、表題化合物（166 mg, 54％）を淡緑色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.67 - 0.87 (4H, m), 1.80 - 1.97 (1H, m), 3.83 (2H, s), 7.01 - 7.48 (8H, m), 7.87 - 8.15 (3H, m), 11.09 (1H, s), 11.87 (1H, brs), 12.18 (1H, brs). Potassium thiocyanate (119 mg, 1.22 mmol), acetonitrile (50 mL), phenylacetyl chloride (162 μL, 1.22 mmol), ethanol (1 mL), toluene (1 mL), N- [6- (4-amino- 3-Fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.611 mmol) was used in the same manner as in Example 21 for the title compound (166 mg, 54 %) As a pale green powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.67-0.87 (4H, m), 1.80-1.97 (1H, m), 3.83 (2H, s), 7.01-7.48 (8H, m), 7.87- 8.15 (3H, m), 11.09 (1H, s), 11.87 (1H, brs), 12.18 (1H, brs).
実施例２６
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-2-フルオロフェニル]-2,2-ジメチル-N'-フェニルプロパンジアミドの製造 Example 26
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -2-fluorophenyl] -2,2-dimethyl-N'-phenyl Propane diamide production
Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091
　2,2-ジメチル-3-オキソ-3-(フェニルアミノ)プロパン酸（152 mg, 0.733 mmol）のテトラヒドロフラン（2 mL）溶液に、N,N-ジメチルホルムアミド（2 滴）とオキザリルクロライド（105 μL, 1.22 mmol）を加え、室温にて4時間撹拌した。反応溶液を、減圧下溶媒を留去した。残渣のテトラヒドロフラン溶液（1 mL）を、N-[6-(4-アミノ-3-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.611 mmol）のN,N-ジメチルアセトアミド（2 mL）溶液に加え、室温にて17時間撹拌した。反応液にテトラヒドロフランと酢酸エチル、そして、1Ｎ水酸化ナトリウム（5 mL）を加え、酢酸エチルを用いて3回抽出後、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、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル／ヘキサン＝80／20→100／0）にて精製し、白色粉末を得た。続いて、得られた白色粉末を酢酸エチルを用いて洗浄、ろ過し、表題化合物（127 mg, 40%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.67 - 0.88 (4H, m), 1.55 (6H, s), 1.81 - 1.97 (1H, m), 6.98 - 7.18 (3H, m), 7.22 - 7.43 (3H, m), 7.53 - 7.72 (3H, m), 7.82 - 8.20 (2H, m), 9.47 (2H, brs), 11.07 (1H, s). To a solution of 2,2-dimethyl-3-oxo-3- (phenylamino) propanoic acid (152 mg, 0.733 mmol) in tetrahydrofuran (2 mL), N, N-dimethylformamide (2 drops) and oxalyl chloride (105 μL, 1.22 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off from the reaction solution under reduced pressure. A solution of the residue in tetrahydrofuran (1 mL) was added to N- [6- (4-amino-3-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.611 mmol). To the N, N-dimethylacetamide (2 mL) solution, the mixture was stirred at room temperature for 17 hours. Tetrahydrofuran, ethyl acetate and 1N sodium hydroxide (5 mL) were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 80/20 → 100/0) to obtain a white powder. Subsequently, the obtained white powder was washed with ethyl acetate and filtered to obtain the title compound (127 mg, 40%) as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.67-0.88 (4H, m), 1.55 (6H, s), 1.81-1.97 (1H, m), 6.98-7.18 (3H, m), 7.22- 7.43 (3H, m), 7.53-7.72 (3H, m), 7.82-8.20 (2H, m), 9.47 (2H, brs), 11.07 (1H, s).
実施例２７
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-2-フルオロフェニル]-N'-フェニルシクロプロパン-1,1-ジカルボキサミドの製造 Example 27
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -2-fluorophenyl] -N'-phenylcyclopropane-1,1 -Production of dicarboxamide
Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-C000092
　1-(フェニルカルバモイル)シクロプロパンカルボン酸（150 mg, 0.733 mmol）のテトラヒドロフラン（2 mL）溶液に、N,N-ジメチルホルムアミド（2 滴）とオキサリルクロライド（126 μL, 1.46 mmol）を加え、室温にて 4 時間撹拌した。反応溶液を、減圧下溶媒を留去した。残渣のテトラヒドロフラン溶液（1 mL）を、N-[6-(4-アミノ-3-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.611 mmol）のN,N-ジメチルアセトアミド（2 mL）溶液に加え、室温にて17時間撹拌した。反応液にテトラヒドロフランと酢酸エチル、そして、1Ｎ水酸化ナトリウム（5 mL）を加え、酢酸エチルを用いて3回抽出後、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、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝70／30→100／0）にて精製した。得られた白色粉末をテトラヒドロフランおよび酢酸エチルに溶解し、1Ｎ塩酸、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥、ろ過し、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル／ヘキサン＝70／30→100／0）にて精製し、表題化合物（26 mg, 8%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.64 - 0.92 (4H, m), 1.48 - 1.65 (4H, m), 1.80 - 1.97 (1H, m), 7.00 - 7.16 (3H, m), 7.25 - 7.40 (3H, m), 7.60 (2H, m), 7.78 - 8.08 (3H, m), 10.01 (1H, brs), 10.47 (1H, brs), 11.07 (1H, s). To a solution of 1- (phenylcarbamoyl) cyclopropanecarboxylic acid (150 mg, 0.733 mmol) in tetrahydrofuran (2 mL) is added N, N-dimethylformamide (2 drops) and oxalyl chloride (126 μL, 1.46 mmol) at room temperature. For 4 hours. The solvent was distilled off from the reaction solution under reduced pressure. A solution of the residue in tetrahydrofuran (1 mL) was added to N- [6- (4-amino-3-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.611 mmol). To the N, N-dimethylacetamide (2 mL) solution, the mixture was stirred at room temperature for 17 hours. Tetrahydrofuran, ethyl acetate and 1N sodium hydroxide (5 mL) were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 70/30 → 100/0). The obtained white powder was dissolved in tetrahydrofuran and ethyl acetate, washed with 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 70/30 → 100/0) to obtain the title compound (26 mg, 8%) as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.64-0.92 (4H, m), 1.48-1.65 (4H, m), 1.80-1.97 (1H, m), 7.00-7.16 (3H, m), 7.25-7.40 (3H, m), 7.60 (2H, m), 7.78-8.08 (3H, m), 10.01 (1H, brs), 10.47 (1H, brs), 11.07 (1H, s).
実施例２８
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-2-フルオロフェニル]-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 28
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -2-fluorophenyl] -2-oxo-1-phenyl-1, Preparation of 2-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-C000093
　2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボン酸（43 mg, 0.199 mmol）、N-[6-(4-アミノ-3-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（50 mg, 0.153 mmol）のN,N-ジメチルホルムアミド（1 mL）溶液に、N,N-ジイソプロピルエチルアミン（53 μL, 0.305 mmol）とO-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（87 mg, 0.229 mmol）を加え、室温にて6時間撹拌した。反応液に水を加え、酢酸エチルを用いて3回抽出後、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後、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル／ヘキサン＝70／30→100／0）にて精製し、白色粉末を得た。得られた粉末を、酢酸エチルにて洗浄、ろ過し、表題化合物（47.2 mg, 59%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.72 - 0.87 (4H, m), 1.84 - 1.98 (1H, m), 6.65 - 6.81 (1H, m), 7.07 (1H, d, J = 9.5 Hz), 7.12 - 7.21 (1H, m), 7.41 (1H, m), 7.49 - 7.69 (5H, m), 7.96 (1H, s), 8.04 (1H, d, J = 9.5 Hz), 8.14 (1H, m), 8.52 (1H, m), 8.62 (1H, m), 11.08 (1H, s), 12.25 (1H, s). 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (43 mg, 0.199 mmol), N- [6- (4-amino-3-fluorophenoxy) imidazo [1,2-b] pyridazine -2-yl] cyclopropanecarboxamide (50 mg, 0.153 mmol) in N, N-dimethylformamide (1 mL) was mixed with N, N-diisopropylethylamine (53 μL, 0.305 mmol) and O- (7-azabenzo Triazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (87 mg, 0.229 mmol) was added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 70/30 → 100/0) to obtain a white powder. The obtained powder was washed with ethyl acetate and filtered to give the title compound (47.2 mg, 59%) as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.72-0.87 (4H, m), 1.84-1.98 (1H, m), 6.65-6.81 (1H, m), 7.07 (1H, d, J = 9.5 Hz), 7.12-7.21 (1H, m), 7.41 (1H, m), 7.49-7.69 (5H, m), 7.96 (1H, s), 8.04 (1H, d, J = 9.5 Hz), 8.14 (1H , m), 8.52 (1H, m), 8.62 (1H, m), 11.08 (1H, s), 12.25 (1H, s).
実施例２９
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-2-フルオロフェニル]-N'-フェニルシクロブタン-1,1-ジカルボキサミドの製造 Example 29
N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -2-fluorophenyl] -N'-phenylcyclobutane-1,1- Production of dicarboxamide
Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000094
　1-(フェニルカルバモイル)シクロブタンカルボン酸（100 mg, 0.306 mmol）、N-[6-(4-アミノ-3-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（87 mg, 0.4 mmol）、N,N-ジメチルホルムアミド（1 mL）溶液に、N,N-ジイソプロピルエチルアミン（105 μL, 0.456 mmol）とO-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（174 mg, 0.458 mmol）を加え、室温にて3日間撹拌した。反応液に水を加え、酢酸エチルを用いて3回抽出後、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後、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝70／30→100／0）にて精製し、白色無定形状固体を得た。得られた白色無定形状固体を、分取HPLCにて精製した後、得られた粉末をジエチルエーテルを用いて洗浄、ろ過し、表題化合物（39.3 mg, 24%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.68 - 0.87 (4H, m), 1.69 - 2.00 (3H, m), 2.58 - 2.75 (4H, m), 7.01 - 7.14 (3H, m), 7.26 - 7.39 (3H, m), 7.62 - 7.74 (3H, m), 7.96 (1H, s), 8.04 (1H, d, J = 9.4 Hz), 9.47 (1H, brs), 9.70 (1H, s), 11.07 (1H, s). 1- (phenylcarbamoyl) cyclobutanecarboxylic acid (100 mg, 0.306 mmol), N- [6- (4-amino-3-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide ( 87 mg, 0.4 mmol), N, N-dimethylformamide (1 mL) solution, N, N-diisopropylethylamine (105 μL, 0.456 mmol) and O- (7-azabenzotriazol-1-yl) -1, 1,3,3-Tetramethyluronium hexafluorophosphate (174 mg, 0.458 mmol) was added, and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 70/30 → 100/0) to obtain a white amorphous solid. The obtained white amorphous solid was purified by preparative HPLC, and the obtained powder was washed with diethyl ether and filtered to give the title compound (39.3 mg, 24%) as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.68-0.87 (4H, m), 1.69-2.00 (3H, m), 2.58-2.75 (4H, m), 7.01-7.14 (3H, m), 7.26-7.39 (3H, m), 7.62-7.74 (3H, m), 7.96 (1H, s), 8.04 (1H, d, J = 9.4 Hz), 9.47 (1H, brs), 9.70 (1H, s) , 11.07 (1H, s).
実施例３０
1-{[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]カルバモイル}シクロプロパンカルボン酸の製造 Example 30
Preparation of 1-{[4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] carbamoyl} cyclopropanecarboxylic acid
Figure JPOXMLDOC01-appb-C000095
Figure JPOXMLDOC01-appb-C000095
　シクロプロパン-1,1-ジカルボン酸(95 mg, 0.73 mmol)のテトラヒドロフラン（1.0 mL）溶液に、氷冷下トリエチルアミン（0.10 mL, 0.73 mmol）を加え、室温にて30分撹拌した。反応液に塩化チオニル（54 μL, 0.73 mmol）を加えて、0℃にて2時間撹拌した。反応混合物に、N-[6-(4-アミノ-3-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（100 mg, 0.31 mmol）のN,N-ジメチルアセトアミド（0.5 mL）溶液を加え、50℃にて30分間撹拌した。得られた反応液に酢酸エチルを加え、1Ｎ水酸化ナトリウムにて2回抽出した後、抽出物に1Ｎ塩酸を加え、酸性とし、析出物をろ過し、白色粉末を得た。得られた白色粉末をろ過し、水を用いて2回洗浄し、最後に酢酸エチルにて洗浄し、表題化合物（121 mg, 90%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.73 - 0.94 (4H, m), 1.42 (4H, s), 1.83 - 1.97 (1H, m), 7.13 (1H, d, J = 9.6 Hz), 7.34 - 7.47 (2H, m), 7.76 - 7.84 (1H, m), 7.90 (1H, s), 8.05 (1H, d, J = 9.6 Hz), 10.81 (1H, s), 11.05 (1H, s), 13.09 (1H, brs). To a solution of cyclopropane-1,1-dicarboxylic acid (95 mg, 0.73 mmol) in tetrahydrofuran (1.0 mL) was added triethylamine (0.10 mL, 0.73 mmol) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Thionyl chloride (54 μL, 0.73 mmol) was added to the reaction solution, and the mixture was stirred at 0 ° C. for 2 hours. To the reaction mixture, N- [6- (4-amino-3-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (100 mg, 0.31 mmol) N, N-dimethylacetamide (0.5 mL) solution was added and stirred at 50 ° C. for 30 minutes. Ethyl acetate was added to the resulting reaction solution, and the mixture was extracted twice with 1N sodium hydroxide. The extract was acidified with 1N hydrochloric acid, and the precipitate was filtered to obtain a white powder. The obtained white powder was filtered, washed twice with water, and finally washed with ethyl acetate to obtain the title compound (121 mg, 90%) as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.73-0.94 (4H, m), 1.42 (4H, s), 1.83-1.97 (1H, m), 7.13 (1H, d, J = 9.6 Hz) , 7.34-7.47 (2H, m), 7.76-7.84 (1H, m), 7.90 (1H, s), 8.05 (1H, d, J = 9.6 Hz), 10.81 (1H, s), 11.05 (1H, s ), 13.09 (1H, brs).
実施例３１
1-{[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-2-フルオロフェニル]カルバモイル}シクロプロパンカルボン酸の製造 Example 31
Preparation of 1-{[4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -2-fluorophenyl] carbamoyl} cyclopropanecarboxylic acid
Figure JPOXMLDOC01-appb-C000096
Figure JPOXMLDOC01-appb-C000096
　シクロプロパン-1,1-ジカルボン酸（95 mg, 0.73 mmol）のテトラヒドロフラン（1.0 mL）溶液に、氷冷下トリエチルアミン（0.102 mL, 0.73 mmol）を加え、1時間撹拌した。反応液に、塩化チオニル（54 μL， 0.73 mmol）を加えて0℃にて2時間撹拌した。得られた反応混合物に、N-[6-(4-アミノ-3-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（100 mg, 0.306 mmol）のN,N-ジメチルアセトアミド（0.5 mL）溶液を加え、室温にて15分間撹拌した。得られた反応液に酢酸エチルを加え、1Ｎ水酸化ナトリウムにて2回抽出した後、抽出物に1Ｎ塩酸を加え、酸性とし、酢酸エチルを用いて3回抽出した。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後、ろ過し、減圧下溶媒を留去した。得られた残渣を、ジエチルエーテルにて洗浄し、表題化合物（101 mg, 75%）を薄赤色固体として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.73 - 0.91 (4H, m), 1.49 - 1.63 (4H, m), 1.83 - 2.00 (1H, m), 6.97 - 7.14 (2H, m), 7.38 (1H, dd, J = 11.7, 2.6 Hz), 7.96 (1H, s), 8.04 (1H, d, J = 10.0 Hz), 8.15 (1H, t, J = 9.0 Hz), 11.07 (1H, s), 11.34 (1H, br s), 13.38 (1 H, s). To a solution of cyclopropane-1,1-dicarboxylic acid (95 mg, 0.73 mmol) in tetrahydrofuran (1.0 mL) was added triethylamine (0.102 mL, 0.73 mmol) under ice cooling, and the mixture was stirred for 1 hour. To the reaction solution was added thionyl chloride (54 μL, 0.73 mmol), and the mixture was stirred at 0 ° C. for 2 hours. To the resulting reaction mixture, N- [6- (4-amino-3-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (100 mg, 0.306 mmol) N, N -A dimethylacetamide (0.5 mL) solution was added, and it stirred at room temperature for 15 minutes. Ethyl acetate was added to the resulting reaction solution, and the mixture was extracted twice with 1N sodium hydroxide. The extract was acidified with 1N hydrochloric acid, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was washed with diethyl ether to give the title compound (101 mg, 75%) as a pale red solid.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.73-0.91 (4H, m), 1.49-1.63 (4H, m), 1.83-2.00 (1H, m), 6.97-7.14 (2H, m), 7.38 (1H, dd, J = 11.7, 2.6 Hz), 7.96 (1H, s), 8.04 (1H, d, J = 10.0 Hz), 8.15 (1H, t, J = 9.0 Hz), 11.07 (1H, s ), 11.34 (1H, br s), 13.38 (1 H, s).
実施例３２
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-2-フルオロフェニル]-N'-(3-フルオロフェニル)シクロプロパン-1,1-ジカルボキサミドの製造 Example 32
N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -2-fluorophenyl] -N '-(3-fluorophenyl) cyclo Production of propane-1,1-dicarboxamide
Figure JPOXMLDOC01-appb-C000097
Figure JPOXMLDOC01-appb-C000097
　1-{[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-2-フルオロフェニル]カルバモイル}シクロプロパンカルボン酸（100 mg, 0.228 mmol）、3-フルオロアニリン（52.8 μL, 0.274 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（104 mg, 0.274 mmol）、N,N-ジイソプロピルエチルアミン（58.9 μL, 0.456 mmol）、N,N-ジメチルアセトアミド（1 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（74.9 mg, 62%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.70 - 0.85 (4H, m), 1.45 - 1.63 (4H, m), 1.85 - 1.98 (1H, m), 6.83 - 6.97 (1H, m), 7.01 - 7.16 (2H, m), 7.26 - 7.46 (3H, m), 7.54 - 7.69 (1H, m), 7.76 - 7.88 (1H, m), 7.96 (1H, s), 8.04 (1H, d, J = 10.0 Hz), 10.24 (2H, brs), 11.07 (1H, s). 1-{[4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -2-fluorophenyl] carbamoyl} cyclopropanecarboxylic acid (100 mg, 0.228 mmol), 3-fluoroaniline (52.8 μL, 0.274 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (104 mg, 0.274 mmol), N, N-diisopropylethylamine (58.9 μL, 0.456 mmol), N, N-dimethylacetamide (1 mL), and the same operation as in Example 28 was carried out to give the title compound (74.9 mg, 62% ) Was obtained as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.70-0.85 (4H, m), 1.45-1.63 (4H, m), 1.85-1.98 (1H, m), 6.83-6.97 (1H, m), 7.01-7.16 (2H, m), 7.26-7.46 (3H, m), 7.54-7.69 (1H, m), 7.76-7.88 (1H, m), 7.96 (1H, s), 8.04 (1H, d, J = 10.0 Hz), 10.24 (2H, brs), 11.07 (1H, s).
実施例３３
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-2-フルオロフェニル]-N'-(4-フルオロフェニル)シクロプロパン-1,1-ジカルボキサミドの製造 Example 33
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -2-fluorophenyl] -N '-(4-fluorophenyl) cyclo Production of propane-1,1-dicarboxamide
Figure JPOXMLDOC01-appb-C000098
Figure JPOXMLDOC01-appb-C000098
　N-[6-(4-アミノ-3-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.611 mmol）、1-[(4-フルオロフェニル)カルバモイル]シクロプロパンカルボン酸（177 mg, 0.794 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（302 mg, 0.794 mmol）、N,N-ジイソプロピルエチルアミン（210 μL, 1.22 mmol）、N,N-ジメチルホルムアミド（1 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（73.3 mg, 23%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.73 - 0.83 (4H, m), 1.46 - 1.64 (4H, m), 1.83 - 1.97 (1H, m), 7.02 - 7.22 (4H, m), 7.34 (1H, dd, J = 11.5, 2.5 Hz), 7.55 - 7.67 (2H, m), 7.84 - 7.97 (2H, m), 8.04 (1H, d, J = 9.6 Hz), 9.98 (1H, brs), 10.51 (1H, brs), 11.07 (1H, s). N- [6- (4-Amino-3-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.611 mmol), 1-[(4-fluorophenyl) carbamoyl ] Cyclopropanecarboxylic acid (177 mg, 0.794 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (302 mg, 0.794 mmol) , N, N-diisopropylethylamine (210 μL, 1.22 mmol) and N, N-dimethylformamide (1 mL) were used in the same manner as in Example 28 to give the title compound (73.3 mg, 23%) in white Obtained as a powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.73-0.83 (4H, m), 1.46-1.64 (4H, m), 1.83-1.97 (1H, m), 7.02-7.22 (4H, m), 7.34 (1H, dd, J = 11.5, 2.5 Hz), 7.55-7.67 (2H, m), 7.84-7.97 (2H, m), 8.04 (1H, d, J = 9.6 Hz), 9.98 (1H, brs) , 10.51 (1H, brs), 11.07 (1H, s).
実施例３４
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-メチルフェニル]-N'-フェニルシクロプロパン-1,1-ジカルボキサミドの製造 Example 34
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-methylphenyl] -N'-phenylcyclopropane-1,1 -Production of dicarboxamide
Figure JPOXMLDOC01-appb-C000099
Figure JPOXMLDOC01-appb-C000099
　N-[6-(4-アミノ-2-メチルフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.611 mmol）、1-(フェニルカルバモイル)シクロプロパンカルボン酸（152 mg, 0.743 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（282 mg, 0.743 mmol）、N,N-ジイソプロピルエチルアミン（213 μL, 1.24 mmol）、N,N-ジメチルホルムアミド（1.4 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（231 mg, 73%）を、白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.70 - 0.86 (4H, m), 1.48 (4H, s), 1.84 - 1.97 (1H, m), 2.13 (3H, s), 6.96 - 7.18 (3H, m), 7.25 - 7.37 (2H, m), 7.51 (1H, dd, J = 8.7, 2.5 Hz), 7.56 - 7.67 (3H, m), 7.88 (1H, s), 8.01 (1H, d, J = 9.6 Hz), 10.05 (1H, brs), 10.06 (1H, s), 11.03 (1H, s). N- [6- (4-Amino-2-methylphenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.611 mmol), 1- (phenylcarbamoyl) cyclopropanecarboxylic acid (152 mg, 0.743 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (282 mg, 0.743 mmol), N, N- The same operation as in Example 28 was carried out using diisopropylethylamine (213 μL, 1.24 mmol) and N, N-dimethylformamide (1.4 mL) to obtain the title compound (231 mg, 73%) as a white powder. .
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.70-0.86 (4H, m), 1.48 (4H, s), 1.84-1.97 (1H, m), 2.13 (3H, s), 6.96-7.18 ( 3H, m), 7.25-7.37 (2H, m), 7.51 (1H, dd, J = 8.7, 2.5 Hz), 7.56-7.67 (3H, m), 7.88 (1H, s), 8.01 (1H, d, J = 9.6 Hz), 10.05 (1H, brs), 10.06 (1H, s), 11.03 (1H, s).
実施例３５
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-N'-フェニルシクロプロパン-1,1-ジカルボキサミドの製造 Example 35
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -N'-phenylcyclopropane-1,1 -Production of dicarboxamide
Figure JPOXMLDOC01-appb-C000100
Figure JPOXMLDOC01-appb-C000100
　1-(フェニルカルバモイル)シクロプロパンカルボン酸（150 mg, 0.73 mmol）のテトラヒドロフラン（2 mL）溶液に、N,N-ジメチルホルムアミド（2 滴）とオキザリルクロライド（126 μl, 1.46 mmol）を加え、室温にて 4 時間撹拌した。反応溶液を、減圧下濃縮し溶媒を留去した。残渣のN,N-ジメチルアセトアミド（2 mL）溶液に、N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.611 mmol）を加え、室温にて4時間撹拌した。反応液にテトラヒドロフランと酢酸エチル、そして、1Ｎ水酸化ナトリウム（5 mL）を加え、酢酸エチルを用いて3回抽出後、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、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝70／30→100／0）にて精製し、白色粉末を得た。得られた白色粉末を、酢酸エチルを用いて洗浄し、表題化合物（175 mg, 73%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.78 - 0.79 (4H, m), 1.41 - 1.54 (4H, m), 1.86 - 1.98 (1H, m), 6.99 - 7.18 (2H, m), 7.23 - 7.51 (4H, m), 7.63 (2H, m), 7.82 (1H, dd, J = 13.3, 2.2 Hz), 7.89 (1H, s), 8.05 (1H, d, J = 10.2 Hz), 10.00 (1H, brs), 10.30 (1H, s), 11.06 (1H, s). To a solution of 1- (phenylcarbamoyl) cyclopropanecarboxylic acid (150 mg, 0.73 mmol) in tetrahydrofuran (2 mL) is added N, N-dimethylformamide (2 drops) and oxalyl chloride (126 μl, 1.46 mmol). Stir at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure and the solvent was distilled off. To the N, N-dimethylacetamide (2 mL) solution of the residue, N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg , 0.611 mmol) and stirred at room temperature for 4 hours. Tetrahydrofuran, ethyl acetate and 1N sodium hydroxide (5 mL) were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 70/30 → 100/0) to obtain a white powder. The obtained white powder was washed with ethyl acetate to give the title compound (175 mg, 73%) as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.78-0.79 (4H, m), 1.41-1.54 (4H, m), 1.86-1.98 (1H, m), 6.99-7.18 (2H, m), 7.23-7.51 (4H, m), 7.63 (2H, m), 7.82 (1H, dd, J = 13.3, 2.2 Hz), 7.89 (1H, s), 8.05 (1H, d, J = 10.2 Hz), 10.00 (1H, brs), 10.30 (1H, s), 11.06 (1H, s).
実施例３６
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-2-メチルフェニル]-N'-フェニルシクロプロパン-1,1-ジカルボキサミドの製造 Example 36
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -2-methylphenyl] -N'-phenylcyclopropane-1,1 -Production of dicarboxamide
Figure JPOXMLDOC01-appb-C000101
Figure JPOXMLDOC01-appb-C000101
　N-[6-(4-アミノ-3-メチルフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.619 mmol）と 1-(フェニルカルバモイル)シクロプロパンカルボン酸（152 mg, 0.74 mmol）のN,N-ジメチルホルムアミド（2.0 mL）溶液に、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（282 mg, 0.743 mmol）とN,N-ジイソプロピルエチルアミン（213 μL, 1.24 mmol）を加え、室温にて4時間撹拌した。反応液に酢酸エチルと水を加え、酢酸エチルを用いて3回抽出後、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、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝95／5→100／0）にて精製した。得られた白色結粉末に酢酸エチルを加え、ろ過し、表題化合物（218.2 mg, 69%）を白色結晶として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.73 - 0.87 (4H, m), 1.56 (4H, s), 1.80 - 1.98 (1H, m), 2.22 (3H, s), 6.96 - 7.18 (4H, m), 7.25 - 7.37 (2H, m), 7.52 - 7.66 (3H, m), 7.94 (1H, s), 8.02 (1H, d, J = 9.6 Hz), 9.97 (1H, brs), 10.23 (1H, brs), 11.06 (1H, s). N- [6- (4-Amino-3-methylphenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.619 mmol) and 1- (phenylcarbamoyl) cyclopropanecarboxylic acid (152 mg, 0.74 mmol) in a solution of N, N-dimethylformamide (2.0 mL) and O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophos Fart (282 mg, 0.743 mmol) and N, N-diisopropylethylamine (213 μL, 1.24 mmol) were added, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 95/5 → 100/0). Ethyl acetate was added to the obtained white powder, followed by filtration to obtain the title compound (218.2 mg, 69%) as white crystals.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.73-0.87 (4H, m), 1.56 (4H, s), 1.80-1.98 (1H, m), 2.22 (3H, s), 6.96-7.18 ( 4H, m), 7.25-7.37 (2H, m), 7.52-7.66 (3H, m), 7.94 (1H, s), 8.02 (1H, d, J = 9.6 Hz), 9.97 (1H, brs), 10.23 (1H, brs), 11.06 (1H, s).
実施例３７
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-N'-(4-フルオロフェニル)シクロプロパン-1,1-ジカルボキサミドの製造 Example 37
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -N '-(4-fluorophenyl) cyclo Production of propane-1,1-dicarboxamide
Figure JPOXMLDOC01-appb-C000102
Figure JPOXMLDOC01-appb-C000102
　N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.61 mmol）、1-[(4-フルオロフェニル)カルバモイル]シクロプロパンカルボン酸（177 mg, 0.79 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（372 mg, 0.978 mmol）、N,N-ジイソプロピルエチルアミン（210 μL, 1.22 mmol）、N,N-ジメチルホルムアミド（1.0 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（113 mg, 35%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.73 - 0.87 (4H, m), 1.45 (4H, s), 1.82 - 2.00 (1H, m), 7.07 - 7.22 (3H, m), 7.32 - 7.49 (2H, m), 7.57 - 7.71 (2H, m), 7.82 (1H, dd, J = 13.2, 2.3 Hz), 7.88 (1H, s), 8.05 (1H, d, J = 9.6 Hz), 10.01 (1H, brs), 10.33 (1H, brs), 11.06 (1H, s). N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.61 mmol), 1-[(4-fluorophenyl) carbamoyl ] Cyclopropanecarboxylic acid (177 mg, 0.79 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (372 mg, 0.978 mmol) , N, N-diisopropylethylamine (210 μL, 1.22 mmol) and N, N-dimethylformamide (1.0 mL) were used in the same manner as in Example 28 to give the title compound (113 mg, 35%) in white Obtained as a powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.73-0.87 (4H, m), 1.45 (4H, s), 1.82-2.00 (1H, m), 7.07-7.22 (3H, m), 7.32- 7.49 (2H, m), 7.57-7.71 (2H, m), 7.82 (1H, dd, J = 13.2, 2.3 Hz), 7.88 (1H, s), 8.05 (1H, d, J = 9.6 Hz), 10.01 (1H, brs), 10.33 (1H, brs), 11.06 (1H, s).
実施例３８
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-N'-(3-フルオロフェニル)シクロプロパン-1,1-ジカルボキサミドの製造 Example 38
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -N '-(3-fluorophenyl) cyclo Production of propane-1,1-dicarboxamide
Figure JPOXMLDOC01-appb-C000103
Figure JPOXMLDOC01-appb-C000103
　1-{[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]カルバモイル}シクロプロパンカルボン酸（100 mg, 0.228 mmol）、3-フルオロアニリン（52.8 μL, 0.274 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（104 mg, 0.274 mmol）、N,N-ジイソプロピルエチルアミン（78.4 μL, 0.456 mmol）、N,N-ジメチルホルムアミド（1 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（67.5 mg, 56%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.68 - 0.85 (4H, m), 1.47 (4H, s), 1.82 - 1.97 (1H, m), 6.78 - 6.96 (1H, m), 7.13 (1H, d, J= 9.8 Hz), 7.25 - 7.50 (4H, m), 7.57 - 7.69 (1H, m), 7.82 (1H, dd, J = 13.1, 2.2 Hz), 7.89 (1H, s), 8.05 (1H, d, J = 9.8 Hz), 10.24 (2H, brs), 11.06 (1H, s). 1-{[4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] carbamoyl} cyclopropanecarboxylic acid (100 mg, 0.228 mmol), 3-fluoroaniline (52.8 μL, 0.274 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (104 mg, 0.274 mmol), N, N-diisopropylethylamine (78.4 μL, 0.456 mmol), N, N-dimethylformamide (1 mL), and the same operation as in Example 28 was carried out to give the title compound (67.5 mg, 56% ) Was obtained as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.68-0.85 (4H, m), 1.47 (4H, s), 1.82-1.97 (1H, m), 6.78-6.96 (1H, m), 7.13 ( 1H, d, J = 9.8 Hz), 7.25-7.50 (4H, m), 7.57-7.69 (1H, m), 7.82 (1H, dd, J = 13.1, 2.2 Hz), 7.89 (1H, s), 8.05 (1H, d, J = 9.8 Hz), 10.24 (2H, brs), 11.06 (1H, s).
実施例３９
N-[3-クロロ-4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-N'-フェニルシクロプロパン-1,1-ジカルボキサミドの製造 Example 39
N- [3-Chloro-4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -N'-phenylcyclopropane-1,1 -Production of dicarboxamide
Figure JPOXMLDOC01-appb-C000104
Figure JPOXMLDOC01-appb-C000104
　N-[6-(4-アミノ-2-クロロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.582 mmol）、1-(フェニルカルバモイル)シクロプロパンカルボン酸（143 mg, 0.698 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（265 mg, 0.698 mmol）、N,N-ジイソプロピルエチルアミン（201 μL, 1.4 mmol）、N,N-ジメチルホルムアミド（2.0 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（210 mg, 68%）を、白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.67 - 0.89 (4H, m), 1.47 (4H, s), 1.81 - 1.98 (1H, m), 6.95 - 7.15 (2H, m), 7.22 - 7.45 (3H, m), 7.54 - 7.69 (3H, m), 7.89 (1H, s), 7.96 - 8.11 (2H, m), 10.04 (1H, brs), 10.27 (1H, brs), 11.06 (1H, s). N- [6- (4-Amino-2-chlorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.582 mmol), 1- (phenylcarbamoyl) cyclopropanecarboxylic acid (143 mg, 0.698 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (265 mg, 0.698 mmol), N, N- The same operation as in Example 28 was carried out using diisopropylethylamine (201 μL, 1.4 mmol) and N, N-dimethylformamide (2.0 mL) to obtain the title compound (210 mg, 68%) as a white powder. .
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.67-0.89 (4H, m), 1.47 (4H, s), 1.81-1.98 (1H, m), 6.95-7.15 (2H, m), 7.22- 7.45 (3H, m), 7.54-7.69 (3H, m), 7.89 (1H, s), 7.96-8.11 (2H, m), 10.04 (1H, brs), 10.27 (1H, brs), 11.06 (1H, s).
実施例４０
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-2-オキソ-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 40
N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -2-oxo-1,2-dihydropyridine- 3-Carboxamide production
Figure JPOXMLDOC01-appb-C000105
Figure JPOXMLDOC01-appb-C000105
　N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（100 mg, 0.306 mmol）、2-オキソ-1,2-ジヒドロピリジン-3-カルボン酸（51 mg, 0.367 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（140 mg, 0.368 mmol）、N,N-ジイソプロピルエチルアミン（105 μL, 0.612 mmol）、N,N-ジメチルホルムアミド（1.0 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（52.7 mg, 38%）を、白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.67 - 0.88 (4H, m), 1.23 (1H, s), 1.86 - 1.98 (1H, m), 6.48 (1H, dd, J = 7.2, 5.8 Hz), 7.14 (1H, d, J = 9.6 Hz), 7.27 - 7.49 (2H, m), 7.77 - 8.12 (4H, m), 8.32 (1H, dd, J = 7.2, 2.3 Hz), 11.06 (1H, s), 13.31 (1H, brs). N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (100 mg, 0.306 mmol), 2-oxo-1,2-dihydropyridine- 3-carboxylic acid (51 mg, 0.367 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (140 mg, 0.368 mmol), The same operation as in Example 28 was carried out using N, N-diisopropylethylamine (105 μL, 0.612 mmol) and N, N-dimethylformamide (1.0 mL) to give the title compound (52.7 mg, 38%) as white Obtained as a powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.67-0.88 (4H, m), 1.23 (1H, s), 1.86-1.98 (1H, m), 6.48 (1H, dd, J = 7.2, 5.8 Hz), 7.14 (1H, d, J = 9.6 Hz), 7.27-7.49 (2H, m), 7.77-8.12 (4H, m), 8.32 (1H, dd, J = 7.2, 2.3 Hz), 11.06 (1H , s), 13.31 (1H, brs).
実施例４１
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-1-メチル-2-オキソ-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 41
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -1-methyl-2-oxo-1, Preparation of 2-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000106
Figure JPOXMLDOC01-appb-C000106
　N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.611 mmol）、1-メチル-2-オキソ-1,2-ジヒドロピリジン-3-カルボン酸（112 mg, 0.733 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（279 mg, 0.733 mmol）、N,N-ジイソプロピルエチルアミン（211 μL, 1.22 mmol）、N,N-ジメチルホルムアミド（2.0 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（204 mg, 72%）を、白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.71 - 0.85 (4H, m), 1.85 - 1.98 (1H, m), 3.65 (3H, s), 6.62 (1H, dd, J = 7.4, 6.5 Hz), 7.15 (1H, d, J = 9.7 Hz), 7.39 - 7.52 (2H, m), 7.91 (1H, s), 7.96 - 8.03 (1H, m), 8.06 (1H, d, J = 9.7 Hz), 8.19 (1H, dd, J = 6.5, 2.3 Hz), 8.47 (1H, dd, J = 7.4, 2.3 Hz), 11.06 (1H, s), 12.37 (1H, s). N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.611 mmol), 1-methyl-2-oxo-1, 2-dihydropyridine-3-carboxylic acid (112 mg, 0.733 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (279 mg, 0.733 mmol), N, N-diisopropylethylamine (211 μL, 1.22 mmol), N, N-dimethylformamide (2.0 mL), and the same operation as in Example 28 was carried out to give the title compound (204 mg, 72% ) Was obtained as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.71-0.85 (4H, m), 1.85-1.98 (1H, m), 3.65 (3H, s), 6.62 (1H, dd, J = 7.4, 6.5 Hz), 7.15 (1H, d, J = 9.7 Hz), 7.39-7.52 (2H, m), 7.91 (1H, s), 7.96-8.03 (1H, m), 8.06 (1H, d, J = 9.7 Hz ), 8.19 (1H, dd, J = 6.5, 2.3 Hz), 8.47 (1H, dd, J = 7.4, 2.3 Hz), 11.06 (1H, s), 12.37 (1H, s).
実施例４２
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-メチルフェニル]-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 42
N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-methylphenyl] -2-oxo-1-phenyl-1, Preparation of 2-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000107
Figure JPOXMLDOC01-appb-C000107
　N-[6-(4-アミノ-2-メチルフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（80 mg, 0.247 mmol）、2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボン酸（69 mg, 0.321 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（122 mg, 0.320 mmol）、N,N-ジイソプロピルエチルアミン（85 μL, 0.494 mmol）、N,N-ジメチルホルムアミド（1.0 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（90 mg, 70%）を、白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.69 - 0.87 (4H, m), 1.85 - 1.94 (1H, m), 2.14 (3H, s), 6.65 - 6.79 (1H, m), 7.04 (1H, d, J = 9.6 Hz), 7.13 - 7.23 (1H, m), 7.45 - 7.71 (7H, m), 7.88 (1H, s), 8.01 (1H, d, J = 9.6 Hz), 8.12 (1H, dd, J = 6.5, 2.2 Hz), 8.59 (1H, dd, J = 7.3, 2.2 Hz), 11.03 (1H, s), 12.00 (1H, s). N- [6- (4-Amino-2-methylphenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (80 mg, 0.247 mmol), 2-oxo-1-phenyl-1, 2-dihydropyridine-3-carboxylic acid (69 mg, 0.321 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (122 mg, 0.320 mmol), N, N-diisopropylethylamine (85 μL, 0.494 mmol), N, N-dimethylformamide (1.0 mL), and the same operation as in Example 28 was carried out to give the title compound (90 mg, 70% ) Was obtained as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.69-0.87 (4H, m), 1.85-1.94 (1H, m), 2.14 (3H, s), 6.65-6.79 (1H, m), 7.04 ( 1H, d, J = 9.6 Hz), 7.13-7.23 (1H, m), 7.45-7.71 (7H, m), 7.88 (1H, s), 8.01 (1H, d, J = 9.6 Hz), 8.12 (1H , dd, J = 6.5, 2.2 Hz), 8.59 (1H, dd, J = 7.3, 2.2 Hz), 11.03 (1H, s), 12.00 (1H, s).
実施例４３
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-2-メチルフェニル]-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 43
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -2-methylphenyl] -2-oxo-1-phenyl-1, Preparation of 2-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000108
Figure JPOXMLDOC01-appb-C000108
　N-[6-(4-アミノ-3-メチルフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（80 mg, 0.247 mmol）、2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボン酸（69 mg, 0.321 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（122 mg, 0.320 mmol）、N,N-ジイソプロピルエチルアミン（85 μL, 0.494 mmol）、N,N-ジメチルホルムアミド（1.0 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（78.6 mg, 61%）を、淡黄色結晶として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.68 - 0.86 (4H, m), 1.84 - 1.97 (1H, m), 2.27 (3H, s), 6.64 - 6.79 (1H, m), 7.02 (1H, d, J = 9.6 Hz), 7.07 - 7.24 (2H, m), 7.42 - 7.68 (5H, m), 7.94 (1H, s), 8.01 (1H, d, J = 9.6 Hz), 8.11 (1H, dd, J = 6.6, 2.2 Hz), 8.35 (1H, d, J = 8.9 Hz), 8.63 (1H, dd, J = 7.4, 2.2 Hz), 11.05 (1H, s), 11.87 (1H, s). N- [6- (4-Amino-3-methylphenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (80 mg, 0.247 mmol), 2-oxo-1-phenyl-1, 2-dihydropyridine-3-carboxylic acid (69 mg, 0.321 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (122 mg, 0.320 mmol), N, N-diisopropylethylamine (85 μL, 0.494 mmol), N, N-dimethylformamide (1.0 mL), and the same operation as in Example 28 was carried out to give the title compound (78.6 mg, 61% ) Was obtained as pale yellow crystals.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.68-0.86 (4H, m), 1.84-1.97 (1H, m), 2.27 (3H, s), 6.64-6.79 (1H, m), 7.02 ( 1H, d, J = 9.6 Hz), 7.07-7.24 (2H, m), 7.42-7.68 (5H, m), 7.94 (1H, s), 8.01 (1H, d, J = 9.6 Hz), 8.11 (1H , dd, J = 6.6, 2.2 Hz), 8.35 (1H, d, J = 8.9 Hz), 8.63 (1H, dd, J = 7.4, 2.2 Hz), 11.05 (1H, s), 11.87 (1H, s) .
実施例４４
N-{6-[2-フルオロ-4-(4-オキソキナゾリン-3(4H)-イル)フェノキシ]イミダゾ[1,2-b]ピリダジン-2-イル}シクロプロパンカルボキサミドの製造 Example 44
Preparation of N- {6- [2-fluoro-4- (4-oxoquinazolin-3 (4H) -yl) phenoxy] imidazo [1,2-b] pyridazin-2-yl} cyclopropanecarboxamide
Figure JPOXMLDOC01-appb-C000109
Figure JPOXMLDOC01-appb-C000109
　2-アミノ安息香酸（251 mg, 1.83 mmol）、N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（500 mg, 1.53 mmol）の N,N-ジメチルホルムアミド（5 mL）溶液に、N,N-ジイソプロピルエチルアミン（527 μL, 3.06 mmol）とO-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（698 mg, 0.320 mmol）を加え、70℃にて1日間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルを用いて3回抽出後、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後、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル／ヘキサン＝95／5→100／0）にて精製し、得られた白色粉末のエタノール（2 mL）／テトラヒドロフラン（2 mL）溶液に、酢酸（20 μL）とオルトぎ酸トリエチル（0.7 mL, 4.21 mmol）を加え、75℃にて26時間撹拌した。反応溶液を濃縮後、残渣をろ過し、N,N-ジメチルホルムアミド、テトラヒドロフラン、そして、酢酸エチルにて洗浄し、表題化合物（49.4 mg, 7%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.63 - 1.01 (4H, m), 1.64 - 2.22 (1H, m), 7.23 (1H, d, J = 9.6 Hz), 7.45 - 8.00 (7H, m), 8.05 - 8.17 (1H, m), 8.24 (1H, dd, J = 7.9, 1.1 Hz), 8.45 (1H, s), 11.10 (1H, s). 2-aminobenzoic acid (251 mg, 1.83 mmol), N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (500 mg, 1.53 mmol) in N, N-dimethylformamide (5 mL), N, N-diisopropylethylamine (527 μL, 3.06 mmol) and O- (7-azabenzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate (698 mg, 0.320 mmol) was added, and the mixture was stirred at 70 ° C. for 1 day. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 95/5 → 100/0), and the resulting white powder was added to an ethanol (2 mL) / tetrahydrofuran (2 mL) solution. , Acetic acid (20 μL) and triethyl orthoformate (0.7 mL, 4.21 mmol) were added, and the mixture was stirred at 75 ° C. for 26 hours. After the reaction solution was concentrated, the residue was filtered and washed with N, N-dimethylformamide, tetrahydrofuran and ethyl acetate to obtain the title compound (49.4 mg, 7%) as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.63-1.01 (4H, m), 1.64-2.22 (1H, m), 7.23 (1H, d, J = 9.6 Hz), 7.45-8.00 (7H, m), 8.05-8.17 (1H, m), 8.24 (1H, dd, J = 7.9, 1.1 Hz), 8.45 (1H, s), 11.10 (1H, s).
実施例４５
N-(1-{[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]カルバモイル}シクロプロピル)ベンズアミドの製造 Example 45
N- (1-{[4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] carbamoyl} cyclopropyl) benzamide Manufacturing
Figure JPOXMLDOC01-appb-C000110
Figure JPOXMLDOC01-appb-C000110
　N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.611 mmol）、1-[(フェニルカルボニル)アミノ]シクロプロパンカルボン酸（150 mg, 0.733 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（279 mg, 0.733 mmol）、N,N-ジイソプロピルエチルアミン（211 μL, 1.22 mmol）、N,N-ジメチルホルムアミド（2.0 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（132.8 mg, 42%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.72 - 0.86 (4H, m), 1.09 - 1.19 (2H, m), 1.47 - 1.54 (2H, m), 1.83 - 1.96 (1H, m), 7.12 (1H, d, J = 9.6 Hz), 7.37 (1H, t, J = 8.9 Hz), 7.44 - 7.61 (4H, m), 7.78 (1H, dd, J = 13.3, 2.4 Hz), 7.89 (1H, s), 7.94 - 8.08 (3H, m), 9.06 (1H, s), 9.88 (1H, s), 11.05 (1H, s). N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.611 mmol), 1-[(phenylcarbonyl) amino] cyclo Propanecarboxylic acid (150 mg, 0.733 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (279 mg, 0.733 mmol), N , N-diisopropylethylamine (211 μL, 1.22 mmol) and N, N-dimethylformamide (2.0 mL) were used in the same manner as in Example 28 to give the title compound (132.8 mg, 42%) as a white powder. Obtained.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.72-0.86 (4H, m), 1.09-1.19 (2H, m), 1.47-1.54 (2H, m), 1.83-1.96 (1H, m), 7.12 (1H, d, J = 9.6 Hz), 7.37 (1H, t, J = 8.9 Hz), 7.44-7.61 (4H, m), 7.78 (1H, dd, J = 13.3, 2.4 Hz), 7.89 (1H , s), 7.94-8.08 (3H, m), 9.06 (1H, s), 9.88 (1H, s), 11.05 (1H, s).
実施例４６
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-1-(4-フルオロフェニル)-2-オキソ-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 46
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -1- (4-fluorophenyl) -2 Of 2-oxo-1,2-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000111
Figure JPOXMLDOC01-appb-C000111
　N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.611 mmol）と1-(4-フルオロフェニル)-2-オキソ-1,2-ジヒドロピリジン-3-カルボン酸（171 mg, 0.733 mmol）のN,N-ジメチルホルムアミド（2.0 mL）溶液に、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（279 mg, 0.733 mmol）とN,N-ジイソプロピルエチルアミン（211 μL, 1.22 mmol）を加え、室温にて8時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルを用いて3回抽出後、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後、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル／ヘキサン＝95／5→100／0）にて精製し、白色粉末を得た。得られた白色粉末を酢酸エチルを用いて洗浄し、表題化合物（205 mg, 62%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.54 - 0.92 (4H, m), 1.84 - 1.98 (1H, m), 6.67 - 6.77 (1H, m), 7.14 (1H, d, J = 9.6 Hz), 7.34 - 7.50 (4H, m), 7.56 - 7.66 (2H, m), 7.90 (1H, s), 7.94 - 8.08 (2H, m), 8.13 (1H, dd, J = 6.7, 2.2 Hz), 8.59 (1H, dd, J = 7.3, 2.2 Hz), 11.06 (1H, s), 12.09 (1H, s). N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.611 mmol) and 1- (4-fluorophenyl) -2 To a solution of 2-oxo-1,2-dihydropyridine-3-carboxylic acid (171 mg, 0.733 mmol) in N, N-dimethylformamide (2.0 mL), O- (7-azabenzotriazol-1-yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate (279 mg, 0.733 mmol) and N, N-diisopropylethylamine (211 μL, 1.22 mmol) were added, and the mixture was stirred at room temperature for 8 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 95/5 → 100/0) to obtain a white powder. The obtained white powder was washed with ethyl acetate to give the title compound (205 mg, 62%) as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.54-0.92 (4H, m), 1.84-1.98 (1H, m), 6.67-6.77 (1H, m), 7.14 (1H, d, J = 9.6 Hz), 7.34-7.50 (4H, m), 7.56-7.66 (2H, m), 7.90 (1H, s), 7.94-8.08 (2H, m), 8.13 (1H, dd, J = 6.7, 2.2 Hz) , 8.59 (1H, dd, J = 7.3, 2.2 Hz), 11.06 (1H, s), 12.09 (1H, s).
実施例４７
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 47
N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -2-oxo-1-phenyl-1, Preparation of 2-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000112
Figure JPOXMLDOC01-appb-C000112
　2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボン酸（43 mg, 0.199 mmol）、N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（50 mg, 0.153 mmol）のN,N-ジメチルホルムアミド（1 mL）溶液に、N,N-ジイソプロピルエチルアミン（53 μL, 0.305 mmol）とO-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（87 mg, 0.229 mmol）を加え、室温にて6時間撹拌した。反応液に水を加え、酢酸エチルを用いて3回抽出後、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、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル／ヘキサン＝70／30→100／0）にて精製し、白色粉末を得た。得られた白色粉末を酢酸エチルにて洗浄、ろ過し、表題化合物（63.3 mg, 79%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.69 - 0.88 (4H, m), 1.83 - 1.97 (1H, m), 6.64 - 6.81 (1H, m), 7.14 (1H, d, J = 9.6 Hz), 7.33 - 7.69 (7H, m), 7.79 - 8.23 (4H, m), 8.60 (1H, dd, J = 7.3, 2.2 Hz), 11.06 (1H, s), 12.13 (1H, s). 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (43 mg, 0.199 mmol), N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2-b] pyridazine -2-yl] cyclopropanecarboxamide (50 mg, 0.153 mmol) in N, N-dimethylformamide (1 mL) was mixed with N, N-diisopropylethylamine (53 μL, 0.305 mmol) and O- (7-azabenzo Triazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (87 mg, 0.229 mmol) was added, and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / hexane = 70/30 → 100/0) to obtain a white powder. The obtained white powder was washed with ethyl acetate and filtered to give the title compound (63.3 mg, 79%) as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.69-0.88 (4H, m), 1.83-1.97 (1H, m), 6.64-6.81 (1H, m), 7.14 (1H, d, J = 9.6 Hz), 7.33-7.69 (7H, m), 7.79-8.23 (4H, m), 8.60 (1H, dd, J = 7.3, 2.2 Hz), 11.06 (1H, s), 12.13 (1H, s).
実施例４８
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-N'-(3-メチルフェニル)シクロプロパン-1,1-ジカルボキサミドの製造 Example 48
N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -N '-(3-methylphenyl) cyclo Production of propane-1,1-dicarboxamide
Figure JPOXMLDOC01-appb-C000113
Figure JPOXMLDOC01-appb-C000113
　1-{[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]カルバモイル}シクロプロパンカルボン酸（200 mg, 0.455 mmol）、m-アニソール（58.5 mL, 0.546 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（207 mg, 0.544 mmol）、N,N-ジイソプロピルエチルアミン（146 μL, 0.91 mmol）、N,N-ジメチルホルムアミド（2 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（20 mg, 8%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.72 - 0.85 (4H, m), 1.47 (4H, s), 1.86 - 1.97 (1H, m), 2.28 (3H, s), 6.89 (1H, d, J = 7.4 Hz), 7.08 - 7.26 (2H, m), 7.27 - 7.53 (4H, m), 7.82 (1H, dd, J = 13.3, 2.2 Hz), 7.89 (1H, s), 8.05 (1H, d, J = 9.6 Hz), 9.94 (1H, brs), 10.29 (1H, brs), 11.07 (1H, s). 1-{[4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] carbamoyl} cyclopropanecarboxylic acid (200 mg, 0.455 mmol), m-anisole (58.5 mL, 0.546 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (207 mg, 0.544 mmol), N, N-diisopropylethylamine (146 μL, 0.91 mmol), N, N-dimethylformamide (2 mL), and the same operation as in Example 28 was carried out, and the title compound (20 mg, 8%) Was obtained as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.72-0.85 (4H, m), 1.47 (4H, s), 1.86-1.97 (1H, m), 2.28 (3H, s), 6.89 (1H, d, J = 7.4 Hz), 7.08-7.26 (2H, m), 7.27-7.53 (4H, m), 7.82 (1H, dd, J = 13.3, 2.2 Hz), 7.89 (1H, s), 8.05 (1H , d, J = 9.6 Hz), 9.94 (1H, brs), 10.29 (1H, brs), 11.07 (1H, s).
実施例４９
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-4-メチル-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 49
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -4-methyl-2-oxo-1- Preparation of phenyl-1,2-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000114
Figure JPOXMLDOC01-appb-C000114
　4-メチル-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボン酸（84.1 mg, 0.367 mmol）、N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（100 mg, 0.306 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（140 mg, 0.367 mmol）、N,N-ジイソプロピルエチルアミン（98.1 μL, 0.612 mmol）、N,N-ジメチルホルムアミド（1 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（130 mg, 79%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.63 - 0.92 (4H, m), 1.85 - 1.96 (1H, m), 2.31 (3H, s), 6.37 (1H, d, J = 7.2 Hz), 7.14 (1H, d, J = 9.8 Hz), 7.34 - 7.61 (7H, m), 7.74 (1H, d, J = 7.2 Hz), 7.84 - 7.90 (1H, m), 7.91 (1H, s), 8.05 (1H, d, J = 9.8 Hz), 10.88 (1H, s), 11.06 (1H, s). 4-Methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (84.1 mg, 0.367 mmol), N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2 -b] pyridazin-2-yl] cyclopropanecarboxamide (100 mg, 0.306 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (140 mg, 0.367 mmol), N, N-diisopropylethylamine (98.1 μL, 0.612 mmol) and N, N-dimethylformamide (1 mL) were used in the same manner as in Example 28 to obtain the title compound (130 mg, 79%) was obtained as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.63-0.92 (4H, m), 1.85-1.96 (1H, m), 2.31 (3H, s), 6.37 (1H, d, J = 7.2 Hz) , 7.14 (1H, d, J = 9.8 Hz), 7.34-7.61 (7H, m), 7.74 (1H, d, J = 7.2 Hz), 7.84-7.90 (1H, m), 7.91 (1H, s), 8.05 (1H, d, J = 9.8 Hz), 10.88 (1H, s), 11.06 (1H, s).
実施例５０
N-[2-クロロ-4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-N'-フェニルシクロプロパン-1,1-ジカルボキサミドの製造 Example 50
N- [2-Chloro-4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -N'-phenylcyclopropane-1,1 -Production of dicarboxamide
Figure JPOXMLDOC01-appb-C000115
Figure JPOXMLDOC01-appb-C000115
　N-[6-(4-アミノ-3-クロロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.582 mmol）、1-(フェニルカルバモイル)シクロプロパンカルボン酸（143 mg, 0.698 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（331 mg, 0.871 mmol）、N,N-ジイソプロピルエチルアミン（200 μL, 1.16 mmol）、N,N-ジメチルホルムアミド（2 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（41 mg, 10%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.62 - 0.94 (4H, m), 1.47 - 1.76 (4H, m), 1.84 - 1.97 (1H, m), 7.02 - 7.17 (2H, m), 7.21 - 7.42 (3H, m), 7.51 - 7.64 (3H, m), 7.95 (1H, s), 8.04 (2H, dd, J = 9.2, 2.7 Hz), 9.94 (1H, brs), 10.77 (1H, brs), 11.08 (1H, s). N- [6- (4-Amino-3-chlorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.582 mmol), 1- (phenylcarbamoyl) cyclopropanecarboxylic acid (143 mg, 0.698 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (331 mg, 0.871 mmol), N, N- The same operation as in Example 28 was carried out using diisopropylethylamine (200 μL, 1.16 mmol) and N, N-dimethylformamide (2 mL) to obtain the title compound (41 mg, 10%) as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.62-0.94 (4H, m), 1.47-1.76 (4H, m), 1.84-1.97 (1H, m), 7.02-7.17 (2H, m), 7.21-7.42 (3H, m), 7.51-7.64 (3H, m), 7.95 (1H, s), 8.04 (2H, dd, J = 9.2, 2.7 Hz), 9.94 (1H, brs), 10.77 (1H, brs), 11.08 (1H, s).
実施例５１
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-2-オキソ-1-フェニルピペリジン-3-カルボキサミドの製造 Example 51
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -2-oxo-1-phenylpiperidine-3 -Production of carboxamide
Figure JPOXMLDOC01-appb-C000116
Figure JPOXMLDOC01-appb-C000116
　N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（187 mg, 0.544 mmol）、2-オキソ-1-フェニルピペリジン-3-カルボン酸（143 mg, 0.652 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（310 mg, 0.815 mmol）、N,N-ジイソプロピルエチルアミン（187 μL, 1.09 mmol）、N,N-ジメチルホルムアミド（2 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（150 mg, 52%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.67 - 0.86 (4H, m), 1.79 - 2.27 (5H, m), 3.51 - 3.80 (3H, m), 7.13 (1H, d, J = 9.9 Hz), 7.21 - 7.48 (7H, m), 7.78 - 7.86 (1H, m), 7.90 (1H, s), 8.05 (1H, d, J = 9.9 Hz), 10.48 (1H, s), 11.06 (1H, s). N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (187 mg, 0.544 mmol), 2-oxo-1-phenylpiperidine-3 -Carboxylic acid (143 mg, 0.652 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (310 mg, 0.815 mmol), N , N-Diisopropylethylamine (187 μL, 1.09 mmol) and N, N-dimethylformamide (2 mL) were used in the same manner as in Example 28 to give the title compound (150 mg, 52%) as a white powder. Obtained.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.67-0.86 (4H, m), 1.79-2.27 (5H, m), 3.51-3.80 (3H, m), 7.13 (1H, d, J = 9.9 Hz), 7.21-7.48 (7H, m), 7.78-7.86 (1H, m), 7.90 (1H, s), 8.05 (1H, d, J = 9.9 Hz), 10.48 (1H, s), 11.06 (1H , s).
実施例５２
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-1-(3-メチルフェニル)-2-オキソ-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 52
N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -1- (3-methylphenyl) -2 Of 2-oxo-1,2-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000117
Figure JPOXMLDOC01-appb-C000117
　N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.611 mmol）、1-(3-メチルフェニル)-2-オキソ-1,2-ジヒドロピリジン-3-カルボン酸（143 mg, 0.698 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（279 mg, 0.733 mmol）、N,N-ジイソプロピルエチルアミン（211 μL, 1.22 mmol）、N,N-ジメチルホルムアミド（2 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（276 mg, 84%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.72 - 0.86 (4H, m), 1.86 - 1.96 (1H, m), 2.40 (3H, s), 6.63 - 6.78 (1H, m), 7.14 (1H, d, J = 9.8 Hz), 7.24 - 7.39 (3H, m), 7.40 - 7.51 (3H, m), 7.90 (1H, s), 7.95 - 8.02 (1H, m), 8.05 (1H, d, J = 9.8 Hz), 8.12 (1H, dd, J = 6.6, 2.2 Hz), 8.59 (1H, dd, J = 7.3, 2.2 Hz), 11.06 (1H, s), 12.14 (1H, s). N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.611 mmol), 1- (3-methylphenyl) -2 -Oxo-1,2-dihydropyridine-3-carboxylic acid (143 mg, 0.698 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophos The same operation as in Example 28 was carried out using furt (279 mg, 0.733 mmol), N, N-diisopropylethylamine (211 μL, 1.22 mmol), N, N-dimethylformamide (2 mL), and the title compound ( 276 mg, 84%) was obtained as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.72-0.86 (4H, m), 1.86-1.96 (1H, m), 2.40 (3H, s), 6.63-6.78 (1H, m), 7.14 ( 1H, d, J = 9.8 Hz), 7.24-7.39 (3H, m), 7.40-7.51 (3H, m), 7.90 (1H, s), 7.95-8.02 (1H, m), 8.05 (1H, d, J = 9.8 Hz), 8.12 (1H, dd, J = 6.6, 2.2 Hz), 8.59 (1H, dd, J = 7.3, 2.2 Hz), 11.06 (1H, s), 12.14 (1H, s).
実施例５３
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-1-(4-メチル-1,3-チアゾール-2-イル)-2-オキソ-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 53
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -1- (4-methyl-1,3 -Thiazol-2-yl) -2-oxo-1,2-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000118
Figure JPOXMLDOC01-appb-C000118
　N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（200 mg, 0.611 mmol）、1-(4-メチル-1,3-チアゾール-2-イル)-2-オキソ-1,2-ジヒドロピリジン-3-カルボン酸（173 mg, 0.733 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（279 mg, 0.733 mmol）、N,N-ジイソプロピルエチルアミン（211 μL, 1.22 mmol）、N,N-ジメチルホルムアミド（2 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（66.6 mg, 20%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.70 - 0.90 (4H, m), 1.85 - 1.97 (1H, m), 2.43 (3H, s), 6.86 - 6.97 (1H, m), 7.16 (1H, d, J = 9.6 Hz), 7.37 (1H, s), 7.42 - 7.58 (2H, m), 7.91 (1H, s), 7.96 - 8.10 (2H, m), 8.56 (1H, d, J = 7.0 Hz), 9.10 (1H, d, J = 7.0 Hz), 11.07 (1H, s), 11.48 (1H, s). N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (200 mg, 0.611 mmol), 1- (4-methyl-1,3 -Thiazol-2-yl) -2-oxo-1,2-dihydropyridine-3-carboxylic acid (173 mg, 0.733 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3, Example 28 with 3-tetramethyluronium hexafluorophosphate (279 mg, 0.733 mmol), N, N-diisopropylethylamine (211 μL, 1.22 mmol), N, N-dimethylformamide (2 mL) The same operation was performed to obtain the title compound (66.6 mg, 20%) as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.70-0.90 (4H, m), 1.85-1.97 (1H, m), 2.43 (3H, s), 6.86-6.97 (1H, m), 7.16 ( 1H, d, J = 9.6 Hz), 7.37 (1H, s), 7.42-7.58 (2H, m), 7.91 (1H, s), 7.96-8.10 (2H, m), 8.56 (1H, d, J = 7.0 Hz), 9.10 (1H, d, J = 7.0 Hz), 11.07 (1H, s), 11.48 (1H, s).
実施例５４
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-6-メチル-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 54
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -6-methyl-2-oxo-1- Preparation of phenyl-1,2-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000119
Figure JPOXMLDOC01-appb-C000119
　6-メチル-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボン酸（84 mg, 0.367 mmol）、N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（100 mg, 0.306 mmol）のN,N-ジメチルホルムアミド（1 mL）溶液に、N,N-ジイソプロピルエチルアミン（105 μL, 0.612 mmol）とO-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（140 mg, 0.368 mmol）を加え、室温にて6時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液とテトラヒドロフランを加え、酢酸エチルを用いて3回抽出後、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後、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチルのみ）にて精製し、表題化合物（126 mg, 76%）を淡黄色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.73 - 0.84 (4H, m), 1.83 - 1.96 (1H, m), 2.07 (3H, s), 6.71 (1H, d, J = 7.9 Hz), 7.14 (1H, d, J = 9.7 Hz), 7.36 - 7.67 (7H, m), 7.89 (1H, s), 7.98 (1H, dd, J = 13.1, 2.0 Hz), 8.05 (1H, d, J = 9.7 Hz), 8.50 (1H, d, J = 7.9 Hz), 11.07 (1H, s), 12.09 (1H, s). 6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (84 mg, 0.367 mmol), N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2 -b] pyridazin-2-yl] cyclopropanecarboxamide (100 mg, 0.306 mmol) in N, N-dimethylformamide (1 mL) and N, N-diisopropylethylamine (105 μL, 0.612 mmol) and O- ( 7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (140 mg, 0.368 mmol) was added, and the mixture was stirred at room temperature for 6 hours. Saturated aqueous sodium hydrogen carbonate solution and tetrahydrofuran were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. . The obtained residue was purified by silica gel column chromatography (ethyl acetate alone) to give the title compound (126 mg, 76%) as a pale yellow powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.73-0.84 (4H, m), 1.83-1.96 (1H, m), 2.07 (3H, s), 6.71 (1H, d, J = 7.9 Hz) , 7.14 (1H, d, J = 9.7 Hz), 7.36-7.67 (7H, m), 7.89 (1H, s), 7.98 (1H, dd, J = 13.1, 2.0 Hz), 8.05 (1H, d, J = 9.7 Hz), 8.50 (1H, d, J = 7.9 Hz), 11.07 (1H, s), 12.09 (1H, s).
実施例５５
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-6-フェニルピリジン-2-カルボキサミド 1-オキシドの製造 Example 55
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -6-phenylpyridine-2-carboxamide 1- Oxide production
Figure JPOXMLDOC01-appb-C000120
Figure JPOXMLDOC01-appb-C000120
　6-フェニルピリジン-2-カルボン酸 1-オキシド（79 mg, 0.367 mmol）、N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（100 mg, 0.306 mmol）のN,N-ジメチルホルムアミド（1 mL）溶液に、N,N-ジイソプロピルエチルアミン（105 μL, 0.612 mmol）とO-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（140 mg, 0.368 mmol）を加え、室温にて17時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液とテトラヒドロフランを加え、酢酸エチルを用いて3回抽出後、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後、ろ過し、減圧下溶媒を留去した。得られた残渣をテトラヒドロフランを用いて洗浄、ろ過し表題化合物（120 mg, 75%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.66 - 0.88 (4H, m), 1.87 - 1.96 (1H, m), 7.16 (1H, d, J = 9.9 Hz), 7.42 - 7.60 (5H, m), 7.69 - 7.82 (3H, m), 7.87 (1H, dd, J = 7.8, 2.2 Hz), 7.91 (1H, s), 8.00 (1H, dd, J = 12.7, 2.4 Hz), 8.06 (1H, d, J = 9.9 Hz), 8.33 (1H, dd, J = 8.0, 2.2 Hz), 11.07 (1H, s), 13.62 (1H, s). 6-Phenylpyridine-2-carboxylic acid 1-oxide (79 mg, 0.367 mmol), N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclo To a solution of propanecarboxamide (100 mg, 0.306 mmol) in N, N-dimethylformamide (1 mL), N, N-diisopropylethylamine (105 μL, 0.612 mmol) and O- (7-azabenzotriazol-1-yl) -1,1,3,3-Tetramethyluronium hexafluorophosphate (140 mg, 0.368 mmol) was added, and the mixture was stirred at room temperature for 17 hours. Saturated aqueous sodium hydrogen carbonate solution and tetrahydrofuran were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. . The obtained residue was washed with tetrahydrofuran and filtered to give the title compound (120 mg, 75%) as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.66-0.88 (4H, m), 1.87-1.96 (1H, m), 7.16 (1H, d, J = 9.9 Hz), 7.42-7.60 (5H, m), 7.69-7.82 (3H, m), 7.87 (1H, dd, J = 7.8, 2.2 Hz), 7.91 (1H, s), 8.00 (1H, dd, J = 12.7, 2.4 Hz), 8.06 (1H , d, J = 9.9 Hz), 8.33 (1H, dd, J = 8.0, 2.2 Hz), 11.07 (1H, s), 13.62 (1H, s).
実施例５６
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-2-オキソ-3-フェニル-7-オキサ-3-アザビシクロ[4.1.0]ヘプタン-1-カルボキサミドの製造 Example 56
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -2-oxo-3-phenyl-7- Preparation of oxa-3-azabicyclo [4.1.0] heptane-1-carboxamide
Figure JPOXMLDOC01-appb-C000121
Figure JPOXMLDOC01-appb-C000121
　N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（77 mg, 0.235 mmol）、2-オキソ-3-フェニル-7-オキサ-3-アザビシクロ[4.1.0]ヘプタン-1-カルボン酸（61.5 mg, 0.263 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（107 mg, 0.281 mmol）、N,N-ジイソプロピルエチルアミン（81 μL, 0.47 mmol）、N,N-ジメチルホルムアミド（1 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（107.9 mg, 85%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.66 - 0.88 (4H, m), 1.80 - 2.01 (1H, m), 2.39 - 2.47 (2H, m), 3.36 - 3.51 (1H, m), 3.66 - 3.87 (1H, m), 4.07 - 4.18 (1H, m), 7.14 (1H, d, J = 9.8 Hz), 7.24 - 7.37 (3H, m), 7.39 - 7.54 (4H, m), 7.82 (1H, dd, J = 12.9, 2.2 Hz), 7.90 (1H, s), 8.05 (1H, d, J = 9.8 Hz), 10.68 (1H, s), 11.06 (1H, s). N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (77 mg, 0.235 mmol), 2-oxo-3-phenyl-7- Oxa-3-azabicyclo [4.1.0] heptane-1-carboxylic acid (61.5 mg, 0.263 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium The same operation as in Example 28 was performed using hexafluorophosphate (107 mg, 0.281 mmol), N, N-diisopropylethylamine (81 μL, 0.47 mmol), N, N-dimethylformamide (1 mL), The title compound (107.9 mg, 85%) was obtained as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.66-0.88 (4H, m), 1.80-2.01 (1H, m), 2.39-2.47 (2H, m), 3.36-3.51 (1H, m), 3.66-3.87 (1H, m), 4.07-4.18 (1H, m), 7.14 (1H, d, J = 9.8 Hz), 7.24-7.37 (3H, m), 7.39-7.54 (4H, m), 7.82 ( 1H, dd, J = 12.9, 2.2 Hz), 7.90 (1H, s), 8.05 (1H, d, J = 9.8 Hz), 10.68 (1H, s), 11.06 (1H, s).
実施例５７
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-2,5-ジフルオロフェニル]-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 57
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -2,5-difluorophenyl] -2-oxo-1-phenyl- Production of 1,2-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000122
Figure JPOXMLDOC01-appb-C000122
　N-(6-クロロイミダゾ[1,2-b]ピリダジン-2-イル)シクロプロパンカルボキサミド（1 g, 4.23 mmol）と4-アミノ-2,5-ジフルオロフェノール（736 mg，5.07 mmol）のジメチルスルフォキシド（10 mL）溶液に、炭酸セシウム（2.76 g, 8.47 mmol）を加え、110℃にて6時間撹拌した。反応液をセライトを用いてろ過し、ろ液に水を加え、酢酸エチルにて3回抽出した。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後、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチルのみ）に付し、薄茶色粉末（600 mg）を得た。
　得られた薄茶色粉末（600 mg）と2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボン酸（486 mg, 2.26 mmol）のN,N-ジメチルホルムアミド（6 mL）溶液に、N,N-ジイソプロピルエチルアミン（0.6 mL, 3.48 mmol）とO-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（860 mg, 2.26 mmol）を加え、室温にて4時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルを用いて抽出後、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後、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチル／メタノール＝100／0→90／10）にて精製し、淡黄色粉末を得た。得られた淡黄色粉末を、酢酸エチルにて洗浄、ろ過し、表題化合物（150 mg, 7%）を淡黄色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.67 - 0.89 (4H, m), 1.86 - 1.96 (1H, m), 6.76 (1H, t, J = 7.0 Hz), 7.17 (1H, d, J= 9.6 Hz), 7.43 - 7.74 (6H, m), 7.93 (1H, s), 8.08 (1H, d, J = 9.6 Hz), 8.17 (1H, dd, J = 7.0, 2.1 Hz), 8.54 (1H, dd, J = 12.6, 7.3 Hz), 8.62 (1H, dd, J = 7.0, 2.1 Hz), 11.09 (1H, s), 12.45 (1H, s). N- (6-Chloroimidazo [1,2-b] pyridazin-2-yl) cyclopropanecarboxamide (1 g, 4.23 mmol) and 4-amino-2,5-difluorophenol (736 mg, 5.07 mmol) in dimethyl Cesium carbonate (2.76 g, 8.47 mmol) was added to the sulfoxide (10 mL) solution, and the mixture was stirred at 110 ° C. for 6 hours. The reaction mixture was filtered through celite, water was added to the filtrate, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate alone) to obtain a light brown powder (600 mg).
To a solution of the obtained light brown powder (600 mg) and 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (486 mg, 2.26 mmol) in N, N-dimethylformamide (6 mL), N, N-diisopropylethylamine (0.6 mL, 3.48 mmol) and O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (860 mg, 2.26 mmol) ) And stirred at room temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate / methanol = 100/0 → 90/10) to obtain a pale yellow powder. The obtained pale yellow powder was washed with ethyl acetate and filtered to give the title compound (150 mg, 7%) as a pale yellow powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.67-0.89 (4H, m), 1.86-1.96 (1H, m), 6.76 (1H, t, J = 7.0 Hz), 7.17 (1H, d, J = 9.6 Hz), 7.43-7.74 (6H, m), 7.93 (1H, s), 8.08 (1H, d, J = 9.6 Hz), 8.17 (1H, dd, J = 7.0, 2.1 Hz), 8.54 ( 1H, dd, J = 12.6, 7.3 Hz), 8.62 (1H, dd, J = 7.0, 2.1 Hz), 11.09 (1H, s), 12.45 (1H, s).
実施例５８
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3,5-ジフルオロフェニル]-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 58
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3,5-difluorophenyl] -2-oxo-1-phenyl- Production of 1,2-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000123
Figure JPOXMLDOC01-appb-C000123
　N-[6-(4-アミノ-2,6-ジフルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（78 mg, 0.226 mmol）、2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボン酸（63 mg, 0.293 mmol）、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（112 mg, 0.295 mmol）、N,N-ジイソプロピルエチルアミン（78 μL, 0.452 mmol）、N,N-ジメチルホルムアミド（1 mL）を用いて、実施例２８と同様の操作を行い、表題化合物（80 mg, 65%）を白色粉末として得た。
1H-NMR (DMSO-d6, 300 MHz) δ 0.67 - 0.89 (4H, m), 1.85 - 1.97 (1H, m), 6.68 - 6.82 (1H, m), 7.24 (1H, d, J = 9.9 Hz), 7.46 - 7.66 (5H, m), 7.71 - 7.83 (2H, m), 7.92 (1H, s), 8.10 (1H, d, J = 9.9 Hz), 8.16 (1H, dd, J = 6.6, 2.1 Hz), 8.60 (1H, dd, J = 7.3, 2.1 Hz), 11.09 (1H, s), 12.22 (1H, s). N- [6- (4-Amino-2,6-difluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (78 mg, 0.226 mmol), 2-oxo-1-phenyl- 1,2-dihydropyridine-3-carboxylic acid (63 mg, 0.293 mmol), O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (112 mg, 0.295 mmol), N, N-diisopropylethylamine (78 μL, 0.452 mmol), N, N-dimethylformamide (1 mL), and the same operation as in Example 28 was carried out to obtain the title compound (80 mg, 65%) was obtained as a white powder.
1 H-NMR (DMSO-d 6 , 300 MHz) δ 0.67-0.89 (4H, m), 1.85-1.97 (1H, m), 6.68-6.82 (1H, m), 7.24 (1H, d, J = 9.9 Hz), 7.46-7.66 (5H, m), 7.71-7.83 (2H, m), 7.92 (1H, s), 8.10 (1H, d, J = 9.9 Hz), 8.16 (1H, dd, J = 6.6, 2.1 Hz), 8.60 (1H, dd, J = 7.3, 2.1 Hz), 11.09 (1H, s), 12.22 (1H, s).
実施例５９
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-N'-(2-フルオロフェニル)シクロプロパン-1,1-ジカルボキサミドの製造 Example 59
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -N '-(2-fluorophenyl) cyclo Production of propane-1,1-dicarboxamide
Figure JPOXMLDOC01-appb-C000124
Figure JPOXMLDOC01-appb-C000124
　0.144 mol/Lの2-フルオロアニリンのN,N-ジメチルホルムアミド溶液（500 μL, 72 μmol）と0.144 mol/LのN-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミドのN,N-ジメチルホルムアミド溶液（500 μL, 72 μmol）の混合溶液に、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート（5.47 g, 14.4 mmol）とN,N-ジイソプロピルエチルアミン(1.86 g, 14.4 mmol)をN,N-ジメチルホルムアミド(100 mL)に溶解して調製した溶液を500 μL(O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロフォスファート : 72 μmol, N,N-ジイソプロピルエチルアミン：72 μmol)加え、50℃にて6時間撹拌し、さらに80℃にて18時間撹拌した。反応液に酢酸エチルと10％炭酸水素ナトリウム水溶液を加え、分離した有機層をろ過し、溶媒を留去した。残渣を分取HPLCにて精製し、表題化合物（6.4 mg, 17%）を得た。
MS（m/z）：533(M＋H) 0.144 mol / L 2-fluoroaniline in N, N-dimethylformamide solution (500 μL, 72 μmol) and 0.144 mol / L N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2 -b] pyridazin-2-yl] cyclopropanecarboxamide in N, N-dimethylformamide solution (500 μL, 72 μmol) was added to O- (7-azabenzotriazol-1-yl) -1,1, Prepared by dissolving 3,3-tetramethyluronium hexafluorophosphate (5.47 g, 14.4 mmol) and N, N-diisopropylethylamine (1.86 g, 14.4 mmol) in N, N-dimethylformamide (100 mL) Add 500 μL of the solution (O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate: 72 μmol, N, N-diisopropylethylamine: 72 μmol) The mixture was stirred at 50 ° C. for 6 hours and further stirred at 80 ° C. for 18 hours. Ethyl acetate and 10% aqueous sodium hydrogen carbonate solution were added to the reaction solution, the separated organic layer was filtered, and the solvent was distilled off. The residue was purified by preparative HPLC to give the title compound (6.4 mg, 17%).
MS (m / z): 533 (M + H)
　表１～８に示す実施例６０～１２３は、実施例５９と同様の方法にて製造した。 Examples 60 to 123 shown in Tables 1 to 8 were produced in the same manner as in Example 59.
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000128
Figure JPOXMLDOC01-appb-T000128
Figure JPOXMLDOC01-appb-T000129
  
Figure JPOXMLDOC01-appb-T000129
  
Figure JPOXMLDOC01-appb-T000130
Figure JPOXMLDOC01-appb-T000130
Figure JPOXMLDOC01-appb-T000131
Figure JPOXMLDOC01-appb-T000131
Figure JPOXMLDOC01-appb-T000132
Figure JPOXMLDOC01-appb-T000132
実施例１２４
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-3-メチル-2-オキソ-1-フェニルピペリジン-3-カルボキサミドの製造 Example 124
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -3-methyl-2-oxo-1- Preparation of phenylpiperidine-3-carboxamide
Figure JPOXMLDOC01-appb-C000133
Figure JPOXMLDOC01-appb-C000133
　3-メチル-2-オキソ-1-フェニルピペリジン-3-カルボン酸（86 mg, 0.369 mmol）、N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（100 mg, 0.306 mmol）のN,N-ジメチルホルムアミド（1 mL）溶液に、N,N-ジイソプロピルエチルアミン（105 μL, 0.612 mmol）とO-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスファート（140 mg, 0.368 mmol）を加え、室温にて1時間攪拌した。反応液に酢酸エチルと飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルを用いて３回抽出後、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ＮＨシリカゲル、酢酸エチルのみ）にて精製し、白色固体を得た。得られた固体を、酢酸エチルにて洗浄し、ろ過して表題化合物（42 mg, 25%）を白色固体として得た。
1H-NMR (300 MHz, DMSO-d6) δ 0.47 - 1.04 (4.5H, m), 1.58 (3H, s), 1.75 - 2.15 (4.5H, m), 3.39 - 3.96 (2H, m), 7.14 (1H, d, J = 9.6 Hz), 7.20 - 7.57 (7H, m), 7.77 - 7.95 (2H, m), 8.05 (1H, d, J = 9.4 Hz), 9.82 (1H, s), 11.06 (1H, s). 3-methyl-2-oxo-1-phenylpiperidine-3-carboxylic acid (86 mg, 0.369 mmol), N- [6- (4-amino-2-fluorophenoxy) imidazo [1,2-b] pyridazine- 2-yl] cyclopropanecarboxamide (100 mg, 0.306 mmol) in N, N-dimethylformamide (1 mL) and N, N-diisopropylethylamine (105 μL, 0.612 mmol) and O- (7-azabenzotriazole -1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (140 mg, 0.368 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the mixture was filtered and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate only) to obtain a white solid. The obtained solid was washed with ethyl acetate and filtered to give the title compound (42 mg, 25%) as a white solid.
1 H-NMR (300 MHz, DMSO-d 6 ) δ 0.47-1.04 (4.5H, m), 1.58 (3H, s), 1.75-2.15 (4.5H, m), 3.39-3.96 (2H, m), 7.14 (1H, d, J = 9.6 Hz), 7.20-7.57 (7H, m), 7.77-7.95 (2H, m), 8.05 (1H, d, J = 9.4 Hz), 9.82 (1H, s), 11.06 (1H, s).
実施例１２５
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-6-エチル-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 125
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -6-ethyl-2-oxo-1- Preparation of phenyl-1,2-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000134
Figure JPOXMLDOC01-appb-C000134
　N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（100 mg, 0.306 mmol）、1-フェニル-6-エチル-2-オキソ-1,2-ジヒドロピリジン-3-カルボン酸（89 mg, 0.366 mmol）のN,N-ジメチルホルムアミド（1.0 mL）溶液に、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスファート（151 mg, 0.397 mmol）、N,N-ジイソプロピルエチルアミン（105 μL, 0.612 mmol）を加え、室温にて17時間攪拌した。反応液に酢酸エチルと飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルを用いて抽出後、有機層を飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチルのみ）にて精製し、白色固体を得た。得られた白色固体を、酢酸エチルを用いて洗浄し、ろ過して表題化合物（100 mg, 59%）を白色固体として得た。
1H-NMR (300 MHz, DMSO-d6) δ 0.72 - 0.87 (4H, m), 1.06 (3H, t, J = 7.4 Hz), 1.82 - 1.96 (1H, m), 2.31 (2H, q, J = 7.4 Hz), 6.69 (1H, d, J = 7.7 Hz), 7.14 (1H, d, J = 9.9 Hz), 7.36 - 7.49 (4H, m), 7.50 - 7.67 (3H, m), 7.89 (1H, s), 7.98 (1H, dd, J = 13.0, 2.1 Hz), 8.05 (1H, d, J = 9.9 Hz), 8.55 (1H, d, J = 7.7 Hz), 11.06 (1H, s), 12.09 (1H, s). N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (100 mg, 0.306 mmol), 1-phenyl-6-ethyl-2- To a solution of oxo-1,2-dihydropyridine-3-carboxylic acid (89 mg, 0.366 mmol) in N, N-dimethylformamide (1.0 mL) was added O- (7-azabenzotriazol-1-yl) -1,1. , 3,3-Tetramethyluronium hexafluorophosphate (151 mg, 0.397 mmol) and N, N-diisopropylethylamine (105 μL, 0.612 mmol) were added, and the mixture was stirred at room temperature for 17 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate only) to obtain a white solid. The resulting white solid was washed with ethyl acetate and filtered to give the title compound (100 mg, 59%) as a white solid.
1 H-NMR (300 MHz, DMSO-d 6 ) δ 0.72-0.87 (4H, m), 1.06 (3H, t, J = 7.4 Hz), 1.82-1.96 (1H, m), 2.31 (2H, q, J = 7.4 Hz), 6.69 (1H, d, J = 7.7 Hz), 7.14 (1H, d, J = 9.9 Hz), 7.36-7.49 (4H, m), 7.50-7.67 (3H, m), 7.89 ( 1H, s), 7.98 (1H, dd, J = 13.0, 2.1 Hz), 8.05 (1H, d, J = 9.9 Hz), 8.55 (1H, d, J = 7.7 Hz), 11.06 (1H, s), 12.09 (1H, s).
実施例１２６
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-1-(4-フルオロフェニル)-6-メチル-2-オキソ-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 126
N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -1- (4-fluorophenyl) -6 Of 2-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000135
Figure JPOXMLDOC01-appb-C000135
　N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（100 mg, 0.306 mmol）、1-(4-フルオロフェニル)-6-メチル-2-オキソ-1,2-ジヒドロピリジン-3-カルボン酸(98 mg, 0.397 mmol)、N,N-ジメチルホルムアミド (1 mL)、N,N-ジイソプロピルエチルアミン(105 μL, 0.612 mmol)、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスファート(151 mg, 0.398 mmol)を用いて実施例１２４と同様の操作を行い、表題化合物（125 mg, 74%）を白色固体として得た。
1H-NMR (300 MHz, DMSO-d6) δ 0.75 - 0.87 (4H, m), 1.85 - 1.96 (1H, m), 2.08 (3H, s), 6.72 (1H, d, J = 8.1 Hz), 7.14 (1H, d, J = 9.6 Hz), 7.36 - 7.56 (6H, m), 7.89 (1H, s), 7.98 (1H, dd, J = 13.0, 2.1 Hz), 8.05 (1H, d, J = 10.2 Hz), 8.50 (1H, d, J = 7.6 Hz), 11.06 (1H, s), 12.05 (1H, s). N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (100 mg, 0.306 mmol), 1- (4-fluorophenyl) -6 -Methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (98 mg, 0.397 mmol), N, N-dimethylformamide (1 mL), N, N-diisopropylethylamine (105 μL, 0.612 mmol), The same operation as in Example 124 was performed using O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (151 mg, 0.398 mmol), The title compound (125 mg, 74%) was obtained as a white solid.
1 H-NMR (300 MHz, DMSO-d 6 ) δ 0.75-0.87 (4H, m), 1.85-1.96 (1H, m), 2.08 (3H, s), 6.72 (1H, d, J = 8.1 Hz) , 7.14 (1H, d, J = 9.6 Hz), 7.36-7.56 (6H, m), 7.89 (1H, s), 7.98 (1H, dd, J = 13.0, 2.1 Hz), 8.05 (1H, d, J = 10.2 Hz), 8.50 (1H, d, J = 7.6 Hz), 11.06 (1H, s), 12.05 (1H, s).
実施例１２７
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-1-(2-メチルフェニル)-2-オキソ-1,2-ジヒドロピリジン-3-カルボキサミドの製造 Example 127
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -1- (2-methylphenyl) -2 Of 2-oxo-1,2-dihydropyridine-3-carboxamide
Figure JPOXMLDOC01-appb-C000136
Figure JPOXMLDOC01-appb-C000136
　N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（100 mg, 0.306 mmol）、1-(2-メチルフェニル)-2-オキソ-1,2-ジヒドロピリジン-3-カルボン酸 (84 mg, 0.367 mmol)、N,N-ジメチルホルムアミド (1 mL)、N,N-ジイソプロピルエチルアミン(105 μL, 0.612 mmol)、O-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスファート(151 mg, 0.398 mmol)を用いて実施例１２４と同様の操作を行い、表題化合物（134 mg, 81%）を白色固体として得た。
1H-NMR (300 MHz, DMSO-d6) δ0.65 - 0.91 (4H, m), 1.86 - 1.95 (1H, m), 2.09 (3H, s), 6.69 - 6.83 (1H, m), 7.14 (1H, d, J = 9.4 Hz), 7.34 - 7.51 (6H, m), 7.89 (1H, s), 7.94 - 8.10 (3H, m), 8.63 (1H, dd, J = 7.3, 2.2 Hz), 11.07 (1H, s), 12.14 (1H, s). N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (100 mg, 0.306 mmol), 1- (2-methylphenyl) -2 -Oxo-1,2-dihydropyridine-3-carboxylic acid (84 mg, 0.367 mmol), N, N-dimethylformamide (1 mL), N, N-diisopropylethylamine (105 μL, 0.612 mmol), O- (7 -Azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (151 mg, 0.398 mmol) was used for the same operation as in Example 124, and the title compound (134 mg, 81%) was obtained as a white solid.
1 H-NMR (300 MHz, DMSO-d 6 ) δ0.65-0.91 (4H, m), 1.86-1.95 (1H, m), 2.09 (3H, s), 6.69-6.83 (1H, m), 7.14 (1H, d, J = 9.4 Hz), 7.34-7.51 (6H, m), 7.89 (1H, s), 7.94-8.10 (3H, m), 8.63 (1H, dd, J = 7.3, 2.2 Hz), 11.07 (1H, s), 12.14 (1H, s).
実施例１２８
N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-6-(4-フルオロフェニル)-5-メチルピリジン-2-カルボキサミド 1-オキシドの製造 Example 128
N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -6- (4-fluorophenyl) -5 Of 2-methylpyridine-2-carboxamide 1-oxide
Figure JPOXMLDOC01-appb-C000137
Figure JPOXMLDOC01-appb-C000137
　N-[6-(4-アミノ-2-フルオロフェノキシ)イミダゾ[1,2-b]ピリダジン-2-イル]シクロプロパンカルボキサミド（1.0 g, 3.05 mmol）、5-メチル-6-(4-フルオロフェニル)ピリジン-2-カルボン酸 1-オキシド(906 mg, 3.66 mmol)のN,N-ジメチルホルムアミド(10 mL)溶液に、N,N-ジイソプロピルエチルアミン(1.05 mL, 6.12 mmol)とO-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム ヘキサフルオロホスファート(1.51 g, 3.97 mmol)を加え、室温にて4時間攪拌した。反応液に酢酸エチルと飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルを用いて３回抽出後、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、ろ過し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチルのみ）にて精製し、白色固体を得た。得られた白色固体を、酢酸エチルを用いて洗浄し、ろ過した。得られた残渣をメチルエチルケトン（90 mL）と水（10 mL）を用いて再結晶を行い、表題化合物(570 mg, 33%)を白色固体として得た。
1H-NMR (300 MHz, DMSO-d6) δ 0.70 - 0.89 (4H, m), 1.82 - 2.00 (1H, m), 2.13 (3H, s), 7.15 (1H, d, J = 9.6 Hz), 7.32 - 7.61 (6H, m), 7.70 (1H, d, J = 8.9 Hz), 7.90 (1H, s), 8.00 (1 H, dd, J = 12.8, 2.3 Hz), 8.06 (1H, d, J = 10.0 Hz), 8.32 (1H, d, J = 8.3 Hz), 11.06 (1H, s), 13.79 (1H, s). N- [6- (4-Amino-2-fluorophenoxy) imidazo [1,2-b] pyridazin-2-yl] cyclopropanecarboxamide (1.0 g, 3.05 mmol), 5-methyl-6- (4-fluoro To a solution of (phenyl) pyridine-2-carboxylic acid 1-oxide (906 mg, 3.66 mmol) in N, N-dimethylformamide (10 mL), N, N-diisopropylethylamine (1.05 mL, 6.12 mmol) and O- (7 -Azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (1.51 g, 3.97 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure. . The obtained residue was purified by silica gel column chromatography (ethyl acetate only) to obtain a white solid. The resulting white solid was washed with ethyl acetate and filtered. The obtained residue was recrystallized from methyl ethyl ketone (90 mL) and water (10 mL) to give the title compound (570 mg, 33%) as a white solid.
1 H-NMR (300 MHz, DMSO-d 6 ) δ 0.70-0.89 (4H, m), 1.82-2.00 (1H, m), 2.13 (3H, s), 7.15 (1H, d, J = 9.6 Hz) , 7.32-7.61 (6H, m), 7.70 (1H, d, J = 8.9 Hz), 7.90 (1H, s), 8.00 (1 H, dd, J = 12.8, 2.3 Hz), 8.06 (1H, d, J = 10.0 Hz), 8.32 (1H, d, J = 8.3 Hz), 11.06 (1H, s), 13.79 (1H, s).
製剤例１
　本発明の化合物を有効成分として含有する医薬は、例えば、次のような処方によって製造することができる。
１．カプセル剤
（１）実施例１で得られた化合物 　４０ｍｇ
（２）ラクトース 　　　　　　　　　　　　７０ｍｇ
（３）微結晶セルロース 　　　　　　　　９ｍｇ
（４）ステアリン酸マグネシウム 　　　　１ｍｇ
１カプセル 　　　　　　　　　　　　　　１２０ｍｇ
　（１）、（２）、（３）および（４）の１／２を混和した後、顆粒化する。これに残りの（４）を加えて全体をゼラチンカプセルに封入する。 Formulation Example 1
A medicament containing the compound of the present invention as an active ingredient can be produced, for example, according to the following formulation.
1. Capsule (1) 40 mg of the compound obtained in Example 1
(2) Lactose 70mg
(3) Microcrystalline cellulose 9mg
(4) Magnesium stearate 1mg
1 capsule 120mg
After mixing 1/2 of (1), (2), (3) and (4), granulate. The remaining (4) is added to this and the whole is enclosed in a gelatin capsule.
２．錠剤
（１）実施例１で得られた化合物 　４０ｍｇ
（２）ラクトース 　　　　　　　　　　　　５８ｍｇ
（３）コーンスターチ 　　　　　　　　　１８ｍｇ
（４）微結晶セルロース 　　　　　　３．５ｍｇ
（５）ステアリン酸マグネシウム　 　０．５ｍｇ
１錠 　　　　　　　　　　　　　　　　　　１２０ｍｇ
（１）、（２）、（３）、（４）の２／３および（５）の１／２を混和した後、顆粒化する。残りの（４）および（５）をこの顆粒に加えて錠剤に加圧成型する。 2. Tablet (1) Compound obtained in Example 1 40 mg
(2) Lactose 58mg
(3) Corn starch 18mg
(4) Microcrystalline cellulose 3.5mg
(5) Magnesium stearate 0.5mg
1 tablet 120mg
After mixing 2/3 of (1), (2), (3), (4) and 1/2 of (5), granulate. The remaining (4) and (5) are added to the granules and pressed into tablets.
製剤例２
　日局注射用蒸留水５０ｍＬに実施例１で得られた化合物５０ｍｇを溶解した後、日局注射用蒸留水を加えて１００ｍＬとする。この溶液を滅菌条件下でろ過し、次にこの溶液１ｍＬずつを取り、滅菌条件下、注射用バイアルに充填し、凍結乾燥して密閉する。 Formulation Example 2
After dissolving 50 mg of the compound obtained in Example 1 in 50 mL of JP injection distilled water, JP JP distilled water is added to make 100 mL. The solution is filtered under sterile conditions, then 1 mL of this solution is taken and filled into injection vials under sterile conditions, lyophilized and sealed.
実験例１　ヒト血管内皮増殖因子受容体２（ＶＥＧＦＲ２）遺伝子のクローニングと組換えバキュロウイルスの調製
　ヒト血管内皮増殖因子受容体２（以下ＶＥＧＦＲ２と略する）遺伝子のクローニングは、ｃＤＮＡ　Ｌｉｂｒａｒｉｅｓ　Ｈｕｍａｎ　Ｐｌａｃｅｎｔａ（Ｃｌｏｎｔｅｃｈ社製）を鋳型としたＰＣＲを行って実施した。ＰＣＲに使用したプライマーは、ＶＥＧＦＲ２遺伝子の塩基配列（Ｇｅｎｂａｎｋ　Ａｃｃｅｓｓｉｏｎ　ＡＦ０３５１２１）情報より、ＶＥＧＦＲ２細胞内ドメイン部分をコードする塩基配列（Ｇｅｎｂａｎｋ　Ａｃｃｅｓｓｉｏｎ　ＡＦ０３５１２１における２６７１－４３７４）に、タンパクのＮ末にｆｌａｇ　ｔａｇが付加するように、ｆｌａｇペプチドをコードする塩基配列および制限酵素認識配列を加えて作製した。プライマー塩基配列を以下に示す。
ＶＥＧＦＲ２－Ｕ：
5'-AATTAAGTCGACATGGACTACAAGGATGACGATGACAAGAAGCGGGCCAATGGAGGGGAACTGAAGACA-3’（配列番号：１）
および
ＶＥＧＦＲ２－Ｌ：
5'-AATTAAGCATGCTTAAACAGGAGGAGAGCTCAGTGTGGTCCC-3'（配列番号：２）
プライマーＶＥＧＦＲ２－Ｕの塩基配列を配列表配列番号１に、プライマーＶＥＧＦＲ２－Ｌの塩基配列を配列表配列番号２に示す。
　ＰＣＲ反応はＫＯＤ－ｐｌｕｓキット（ＴＯＹＯＢＯ製）を用いて実施した。得られたＰＣＲ産物をアガロースゲル（１％）で電気泳動し、ＰＣＲによって増幅されたＤＮＡ断片をゲルから回収した後、制限酵素Ｓａｌ　ＩおよびＳｐｈ　Ｉで消化した。制限酵素処理したＤＮＡをアガロースゲル（１％）で電気泳動し、得られたＤＮＡ断片を回収し、制限酵素Ｓａｌ　ＩおよびＳｐｈ　Ｉで消化したプラスミドｐＦＡＳＴＢＡＣ１（インビトロジェン製）へライゲーションし、発現プラスミドｐＦＢ－ＶＥＧＦＲ２を作製した。挿入断片の塩基配列を確認したところ、ＶＥＧＦＲ２細胞内ドメインの塩基配列（Ｇｅｎｂａｎｋ　Ａｃｃｅｓｓｉｏｎ　ＡＦ０３５１２１における２６７１－４３７４）と一致した。さらに、ＢＡＣ－ＴＯ－ＢＡＣ　Ｂａｃｕｌｏｖｉｒｕｓ　Ｅｘｐｒｅｓｓｉｏｎ　Ｓｙｓｔｅｍ（インビトロジェン製）を用いて、組換えバキュロウイルスのウイルスストックＢＡＣ－ＶＥＧＦＲ２を調製した。 Experimental Example 1 Cloning of Human Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Gene and Preparation of Recombinant Baculovirus Cloning of Human Vascular Endothelial Growth Factor Receptor 2 (hereinafter abbreviated as VEGFR2) gene is performed using cDNA Library Human Humana (Clontech). PCR was carried out using as a template. The primer used for PCR is based on the VEGFR2 gene base sequence (Genbank Accession AF035121) information, and the flag tag is added to the base sequence encoding the VEGFR2 intracellular domain (2671-4374 in Genbank Access AF035121) at the N-terminus of the protein. Thus, a nucleotide sequence encoding a flag peptide and a restriction enzyme recognition sequence were added. The primer base sequence is shown below.
VEGFR2-U:
5'-AATTAAGTCGACATGGACTACAAGGATGACGATGACAAGAAGCGGGCCAATGGAGGGGAACTGAAGACA-3 '(SEQ ID NO: 1)
And VEGFR2-L:
5'-AATTAAGCATGCTTAAACAGGAGGAGAGCTCAGTGTGGTCCC-3 '(SEQ ID NO: 2)
The base sequence of primer VEGFR2-U is shown in SEQ ID NO: 1 in the sequence listing, and the base sequence of primer VEGFR2-L is shown in SEQ ID NO: 2 in the sequence listing.
The PCR reaction was performed using a KOD-plus kit (manufactured by TOYOBO). The obtained PCR product was electrophoresed on an agarose gel (1%), and a DNA fragment amplified by PCR was recovered from the gel and then digested with restriction enzymes Sal I and Sph I. The restriction enzyme-treated DNA was electrophoresed on an agarose gel (1%), and the resulting DNA fragment was recovered, ligated to the plasmid pFASTBAC1 (manufactured by Invitrogen) digested with restriction enzymes Sal I and Sph I, and the expression plasmid pFB- VEGFR2 was produced. When the nucleotide sequence of the inserted fragment was confirmed, it matched with the nucleotide sequence of the VEGFR2 intracellular domain (2671-4374 in Genbank Access AF035121). Further, a recombinant baculovirus virus stock BAC-VEGFR2 was prepared using a BAC-TO-BAC Baculovirus Expression System (manufactured by Invitrogen).
実験例２　血管内皮増殖因子受容体２（ＶＥＧＦＲ２）細胞内ドメインタンパクの調製
　ＳＦ－２１細胞を１０％ウシ胎児血清（トレース）、５０ｍｇ／Ｌ　Ｇｅｎｔａｍｉｃｉｎ（インビトロジェン）、０．１％　Ｐｌｕｒｏｎｉｃ　Ｆ－６８（インビトロジェン）を含むＳｆ－９００ＩＩＳＦＭ培地（インビトロジェン）１Ｌに１×１０６　ｃｅｌｌｓ／ｍＬで播種し、２Ｌ容エルレンマイヤーフラスコを用いて２７℃、１００ｒｐｍで振盪培養を行った。培養２４時間後に組換えバキュロウイルスＢＡＣ－ＶＥＧＦＲ２を１３．４ｍＬ添加し、さらに３日間の培養を行った。培養液を２，０００ｒｐｍで５分間遠心分離し、ウイルス感染細胞を得た。感染細胞をリン酸生理緩衝液（インビトロジェン製）で洗浄して同条件で遠心分離を行い、細胞を－８０℃で保存した。凍結保存した細胞を氷中で融解し、Ｃｏｍｐｌｅｔｅ　Ｐｒｏｔｅａｓｅ　Ｉｎｈｉｂｉｔｏｒ（ベーリンガー製）を添加した緩衝液Ａ（２０％　Ｇｌｙｃｅｒｏｌ、０．１５Ｍ　ＮａＣｌを含む５０ｍＭ　トリス緩衝液（ｐＨ７．４））３０ｍＬに懸濁した後、ポリトロンホモジナイザー（キネマティカ製）を用いて２０，０００ｒｐｍ、３０秒の条件で３回破砕を行った。破砕液を４０，０００ｒｐｍ、３０分間の遠心分離により清澄化し、さらに０．４５μｍフィルターを用いたろ過を行った。ろ過液をＡｎｔｉ－ＦＬＡＧ　Ｍ２　Ａｆｆｉｎｉｔｙ　Ｇｅｌ（シグマ社製）４ｍＬを詰めたカラムに流速約０．５ｍＬ／ｍｉｎで通した。カラムを緩衝液Ａで洗浄した後、１００μｇ／ｍＬのＦＬＡＧペプチドを含む緩衝液Ａで溶出した。溶出液を分画分子量３０Ｋのビバスピン２０（ビバサイエンス製）で濃縮した。この濃縮液を緩衝液Ａで平衡化したＮＡＰＴＭ　２５　カラム（アマシャムバイオサイエンス製）により緩衝液交換を行った。ＶＥＧＦＲ２細胞内ドメインタンパクを含むフラクションを集め、終濃度５０％になるようにグリセロールを添加し－８０℃で凍結保存した。 Experimental Example 2 Preparation of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Intracellular Domain Protein SF-21 cells were treated with 10% fetal bovine serum (trace), 50 mg / L Gentamin (Invitrogen), 0.1% Pluronic F-68 ( Inoculated at 1 × 10 6 cells / mL in 1 L of Sf-900IISFM medium (Invitrogen) containing Invitrogen), and cultured with shaking at 27 ° C. and 100 rpm using a 2 L Erlenmeyer flask. After 24 hours of culture, 13.4 mL of recombinant baculovirus BAC-VEGFR2 was added, and further cultured for 3 days. The culture solution was centrifuged at 2,000 rpm for 5 minutes to obtain virus-infected cells. The infected cells were washed with phosphate physiological buffer (Invitrogen), centrifuged under the same conditions, and the cells were stored at -80 ° C. The cryopreserved cells were thawed in ice and suspended in 30 mL of buffer A (20% Glycerol, 50 mM Tris buffer (pH 7.4) containing 0.15 M NaCl) supplemented with Complete Protease Inhibitor (manufactured by Boehringer). Thereafter, crushing was performed three times using a Polytron homogenizer (manufactured by Kinematica) under the conditions of 20,000 rpm and 30 seconds. The crushed liquid was clarified by centrifugation at 40,000 rpm for 30 minutes, and further filtered using a 0.45 μm filter. The filtrate was passed through a column packed with 4 mL of Anti-FLAG M2 Affinity Gel (manufactured by Sigma) at a flow rate of about 0.5 mL / min. The column was washed with buffer A and then eluted with buffer A containing 100 μg / mL FLAG peptide. The eluate was concentrated with Vivaspin 20 (manufactured by Viva Science) having a molecular weight cut off of 30K. The buffer solution was exchanged with a NAP ™ 25 column (manufactured by Amersham Bioscience) in which the concentrated solution was equilibrated with buffer A. Fractions containing the VEGFR2 intracellular domain protein were collected, added with glycerol to a final concentration of 50%, and stored frozen at −80 ° C.
試験例１　血管内皮増殖因子受容体２（ＶＥＧＦＲ２）キナーゼ阻害活性の測定
　ジメチルスルホキシド（ＤＭＳＯ）に溶解した試験化合物を緩衝液（５０ｍＭ　Ｔｒｉｓ－ＨＣｌ（ｐＨ７．５）、５ｍＭ　ＭｇＣｌ２、５ｍＭ　ＭｎＣｌ２、２ｍＭ　ジチオスレイトール（Ｄｉｔｈｉｏｔｈｒｅｉｔｏｌ）、０．０１％　Ｔｗｅｅｎ－２０）で希釈した。この化合物溶液5μＬに50ｎｇ／ｍＬのＶＥＧＦＲ２細胞内ドメインタンパクと２５０ｎｇ／ｍＬのビオチン標識ポリペプチドｂｉｏｔｉｎｙｌ－ｐｏｌｙ－Ｇｌｕ：Ｔｙｒ（４：１）（ＣＩＳ　ｂｉｏ　Ｉｎｔｅｒｎａｔｉｏｎａｌ）を含む緩衝液を１０μＬ加えた。得られた混合液に２５μＭ　ＡＴＰを含む緩衝液を１０μＬ添加し、２５℃で５分間反応させた後、２５μＬの停止液（１００ｍＭ　ＥＤＴＡ・２ナトリウム塩、６２．５ｍＭ　ＨＥＰＥＳ緩衝液（ｐＨ７．４）、２５０ｍＭ　ＮａＣｌ、０．１％　牛血清アルブミン、１０μｇ／ｍＬ　アルファスクリーンアッセイ用ストレプトアビジンドナービーズ（Ｓｔｒｅｐｔａｖｉｄｉｎ　Ｄｏｎｏｒ　ｂｅａｄｓ：パーキンエルマー製）、１０μｇ／ｍＬ　アルファスクリーンアッセイ用抗チロシンリン酸化認識抗体ＰＹ－１００結合アクセプタービーズ（Ａｎｔｉ－ｐｈｏｓｐｈｏｔｙｒｏｓｉｎｅ（Ｐ－Ｔｙｒ－１００）　Ａｃｃｅｐｔｏｒ　ｂｅａｄｓ：パーキンエルマー製））を加え、反応を停止させた。反応溶液を２５℃で１６時間放置した後、プレートリーダー・フュージョン（ＦｕｓｉｏｎＴＭ）（パーキンエルマー製）を使用してカウントを測定した。試験化合物のキナーゼ阻害率（％）は以下の式で計算した。
　阻害率（％）＝（１－（試験化合物のカウント－ブランク）÷（対照－ブランク））×１００
　ここで、化合物を添加せずに反応させた溶液のカウントを「対照」とし、化合物とＡＴＰを添加しなかった溶液のカウントを「ブランク」とした。
　表９に示すように、実施例６、２７、３５、３６、４７、５４、５５、１２６および１２８の化合物の１μＭにおける阻害率は８０％以上であった。 Test Example 1 Measurement of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Kinase Inhibitory Activity Test compounds dissolved in dimethyl sulfoxide (DMSO) were mixed with a buffer solution (50 mM Tris-HCl (pH 7.5), 5 mM MgCl 2 , 5 mM MnCl 2 , Diluted with 2 mM dithiothreitol, 0.01% Tween-20). To 5 μL of this compound solution, 10 μL of a buffer containing 50 ng / mL VEGFR2 intracellular domain protein and 250 ng / mL biotin-labeled polypeptide biotinyl-poly-Glu: Tyr (4: 1) (CIS bio International) was added. After adding 10 μL of a buffer solution containing 25 μM ATP to the obtained mixture and reacting at 25 ° C. for 5 minutes, 25 μL of a stop solution (100 mM EDTA · 2 sodium salt, 62.5 mM HEPES buffer (pH 7.4)) , 250 mM NaCl, 0.1% bovine serum albumin, 10 μg / mL streptavidin donor beads for alpha screen assay (Streptavidin Donor beads: manufactured by Perkin Elmer), 10 μg / mL anti-tyrosine phosphorylation recognition antibody PY-100 binding for alpha screen assay Acceptor beads (Anti-phosphotyrosine (P-Tyr-100) Acceptor beads: manufactured by Perkin Elmer)) were added to stop the reaction. The reaction solution was left for 16 hours at 25 ° C., were counted using a plate reader Fusion (Fusion TM) (Perkin Elmer). The kinase inhibition rate (%) of the test compound was calculated by the following formula.
Inhibition rate (%) = (1− (count of test compound−blank) ÷ (control−blank)) × 100
Here, the count of the solution reacted without adding the compound was taken as “control”, and the count of the solution without adding the compound and ATP was taken as “blank”.
As shown in Table 9, the inhibition rate at 1 μM of the compounds of Examples 6, 27, 35, 36, 47, 54, 55, 126 and 128 was 80% or more.
Figure JPOXMLDOC01-appb-T000138
Figure JPOXMLDOC01-appb-T000138
試験例２　血管内皮細胞の増殖阻害試験
　ヒト臍帯静脈由来血管内皮細胞（ＨＵＶＥＣ、クラボウより購入）は３７℃、５％炭酸ガスインキュベーター内において、３％ウシ胎仔血清および２．５ｎｇ／ｍＬ塩基性繊維芽細胞増殖因子を含む血管内皮細胞用培地（インビトロジェン製）で培養した。詳細には、前記３％ウシ胎仔血清を含む血管内皮細胞用培地に懸濁したＨＵＶＥＣを、９６ウエル平底プレートに各ウエル５０μＬ（３０００個）播種した。一晩培養後、種々の濃度の被験物質ならびに１２０ｎｇ／ｍＬの血管内皮増殖因子（ＶＥＧＦ）を、３％ウシ胎仔血清を含む血管内皮細胞用培地に溶解し、各ウエル５０μＬ添加した。５日間培養後、Ｃｅｌｌ　ｃｏｕｎｔｉｎｇ　ｋｉｔ－８試薬（同仁化学製）を各ウエル１０μＬ添加し、３７℃、５％炭酸ガスインキュベーター内において２－３時間反応させた。４５０ｎｍの吸光度を、マイクロタイタープレートリーダーにより測定し、細胞増殖阻害活性を測定した。被験物質各濃度添加時の吸光度値を用いてSAS system NLIN procedure のロジスティック曲線を用いた非線形最小二乗法により、被験物質無添加時の５０％を示す被験物質濃度（ＩＣ５０値）を算出した。また、試験化合物の血管内皮細胞の増殖阻害率（％）を以下の式で計算した。陽性対照（１００％増殖）には、被験物質の代わりのジメチルスルホキシドをＶＥＧＦとともに添加した。
　阻害率（％）＝（１－(試験化合物添加時の吸光度÷陽性対照の吸光度)）×１００
　表１０に示すように、実施例６、２７、３５、３６、４７、５４、５５、１２６および１２８の化合物の１μＭにおける阻害率は８０％以上であった。
　また、実施例６、２７、３５、３６、４７、５４、５５、１２６および１２８の化合物のＩＣ５０値は１μＭ以下であった。 Test Example 2 Growth Inhibition Test of Vascular Endothelial Cells Human umbilical vein-derived vascular endothelial cells (HUVEC, purchased from Kurabo Industries) were obtained at 37 ° C. in a 5% carbon dioxide incubator with 3% fetal calf serum and 2.5 ng / mL basic fiber. The cells were cultured in a vascular endothelial cell medium (manufactured by Invitrogen) containing blast growth factor. Specifically, HUVEC suspended in the vascular endothelial cell medium containing 3% fetal bovine serum was seeded in a 96-well flat-bottom plate at 50 μL (3,000 cells). After overnight culture, various concentrations of the test substance and 120 ng / mL vascular endothelial growth factor (VEGF) were dissolved in vascular endothelial cell medium containing 3% fetal calf serum, and 50 μL of each well was added. After culturing for 5 days, 10 μL of Cell counting kit-8 reagent (manufactured by Dojin Chemical) was added to each well and reacted in a 37 ° C., 5% carbon dioxide incubator for 2-3 hours. Absorbance at 450 nm was measured with a microtiter plate reader to measure cell growth inhibitory activity. The test substance concentration (IC 50 value) indicating 50% when no test substance was added was calculated by the nonlinear least square method using the logistic curve of the SAS system NLIN procedure, using the absorbance value when each test substance concentration was added. Further, the growth inhibition rate (%) of vascular endothelial cells of the test compound was calculated by the following formula. As a positive control (100% growth), dimethyl sulfoxide instead of the test substance was added together with VEGF.
Inhibition rate (%) = (1− (absorbance when test compound is added ÷ absorbance of positive control)) × 100
As shown in Table 10, the inhibition rate at 1 μM of the compounds of Examples 6, 27, 35, 36, 47, 54, 55, 126 and 128 was 80% or more.
In addition, the IC 50 values of the compounds of Examples 6, 27, 35, 36, 47, 54, 55, 126 and 128 were 1 μM or less.
Figure JPOXMLDOC01-appb-T000139
Figure JPOXMLDOC01-appb-T000139
試験例３　肝細胞増殖因子受容体（ｃ－Ｍｅｔ）キナーゼ阻害活性の測定
　ジメチルスルホキシド（ＤＭＳＯ）に溶解した試験化合物を緩衝液（５０ｍＭ　Ｔｒｉｓ－ＨＣｌ（ｐＨ７．５）、５ｍＭ　ＭｇＣｌ２、５ｍＭ　ＭｎＣｌ２、２ｍＭ　ジチオスレイトール（Ｄｉｔｈｉｏｔｈｒｅｉｔｏｌ）、０．０１％　Ｔｗｅｅｎ－２０）で希釈した。この化合物溶液５μＬに２．５ｎｇ／ｍＬのｃ－Ｍｅｔ細胞内ドメインタンパク（Ｍｉｌｌｉｐｏｒｅ社）と２５０ｎｇ／ｍＬのビオチン標識ポリペプチドｂｉｏｔｉｎｙｌ－ｐｏｌｙ－Ｇｌｕ：Ｔｙｒ（４：１）（ＣＩＳ　ｂｉｏ　Ｉｎｔｅｒｎａｔｉｏｎａｌ）を含む緩衝液を１０μＬ加えた。キナーゼ酵素と化合物とビオチン標識ポリペプチドを混合した５分後に、５μＭ　ＡＴＰを含む緩衝液を１０μＬ添加し、２５℃で１０分間反応させた後、２５μＬの停止液（１００ｍＭ　ＥＤＴＡ・２ナトリウム塩、６２．５ｍＭ　ＨＥＰＥＳ緩衝液（ｐＨ７．４）、２５０ｍＭ　ＮａＣｌ、０．１％　牛血清アルブミン、１０μｇ／ｍＬ　アルファスクリーンアッセイ用ストレプトアビジンドナービーズ（Ｓｔｒｅｐｔａｖｉｄｉｎ　Ｄｏｎｏｒ　ｂｅａｄｓ：パーキンエルマー製）、１０μｇ／ｍＬ　アルファスクリーンアッセイ用抗チロシンリン酸化認識抗体ＰＴ－６６結合アクセプタービーズ（Ａｎｔｉ－ｐｈｏｓｐｈｏｔｙｒｏｓｉｎｅ（Ｐ－Ｔｙｒ－６６）　Ａｃｃｅｐｔｏｒ　ｂｅａｄｓ：パーキンエルマー製））を加え、反応を停止させた。反応溶液を２５℃で１６時間放置した後、プレートリーダー・フュージョン（ＦｕｓｉｏｎＴＭ）（パーキンエルマー製）を使用してカウントを測定した。試験化合物のキナーゼ阻害率（％）は以下の式で計算した。
　阻害率（％）＝（１－（試験化合物のカウント－ブランク）÷（対照－ブランク））×１００
　ここで、化合物を添加せずに反応させた溶液のカウントを「対照」とし、化合物とＡＴＰを添加しなかった溶液のカウントを「ブランク」とした。
　表１１に示すように、実施例６、２７、３５、３６、４７、５４、５５、１２６および１２８の化合物の１μＭにおける阻害率は８０％以上であった。 Test Example 3 Measurement of Hepatocyte Growth Factor Receptor (c-Met) Kinase Inhibitory Activity A test compound dissolved in dimethyl sulfoxide (DMSO) was buffered (50 mM Tris-HCl (pH 7.5), 5 mM MgCl 2 , 5 mM MnCl 2 Diluted with 2 mM dithiothreitol (0.01% Tween-20). 5 μL of this compound solution contains 2.5 ng / mL c-Met intracellular domain protein (Millipore) and 250 ng / mL biotinylated polypeptide biotinyl-poly-Glu: Tyr (4: 1) (CIS bio International). 10 μL of buffer was added. Five minutes after mixing the kinase enzyme, the compound and the biotin-labeled polypeptide, 10 μL of a buffer solution containing 5 μM ATP was added and reacted at 25 ° C. for 10 minutes, and then 25 μL of stop solution (100 mM EDTA · disodium salt, 62 .5 mM HEPES buffer (pH 7.4), 250 mM NaCl, 0.1% bovine serum albumin, 10 μg / mL Streptavidin donor beads for alpha screen assay (Streptavidin Donor beads: manufactured by PerkinElmer), 10 μg / mL for alpha screen assay Anti-tyrosine phosphorylation recognition antibody PT-66 binding acceptor beads (Anti-phosphotyrosine (P-Tyr-66) Acceptor beads: manufactured by Perkin Elmer)) were added to stop the reaction. The reaction solution was left for 16 hours at 25 ° C., were counted using a plate reader Fusion (Fusion TM) (Perkin Elmer). The kinase inhibition rate (%) of the test compound was calculated by the following formula.
Inhibition rate (%) = (1− (count of test compound−blank) ÷ (control−blank)) × 100
Here, the count of the solution reacted without adding the compound was taken as “control”, and the count of the solution without adding the compound and ATP was taken as “blank”.
As shown in Table 11, the inhibition rate at 1 μM of the compounds of Examples 6, 27, 35, 36, 47, 54, 55, 126 and 128 was 80% or more.
Figure JPOXMLDOC01-appb-T000140
Figure JPOXMLDOC01-appb-T000140
試験例４　ヒト胃癌細胞株ＭＫＮ４５増殖阻害試験
　ヒト胃癌細胞株ＭＫＮ４５（理化学研究所 バイオリソースセンター）は３７℃、５％炭酸ガスインキュベーター内において、１０％ウシ胎仔血清を含むＲＰＭＩ１６４０（インビトロジェン製）で培養した。ＭＫＮ４５細胞はトリプシン／ＥＤＴＡ処理して回収し、０．３％ウシ胎仔血清を含むＲＰＭＩ１６４０に懸濁し、９６ウェル平底プレートに各ウェルあたり３０００個／５０μＬの細胞密度で播種した。一晩培養後、種々の濃度の被験物質を、０．３％ウシ胎仔血清を含むＲＰＭＩ１６４０に溶解し、各ウェル５０μＬ添加した。３日間培養後、Ｃｅｌｌ　ｃｏｕｎｔｉｎｇ　ｋｉｔ－８試薬（同仁化学製）を各ウェル１０μＬ添加し、３７℃、５％炭酸ガスインキュベーター内において２－３時間反応させた。反応後、各ウェルの４５０ｎｍの吸光度を、マイクロタイタープレートリーダーにより測定した。被験物質各濃度添加時の細胞増殖活性値を用いて、ＧｒａｐｈＰａｄ　Ｐｒｉｓｍの非線形回帰解析［Ｓｉｇｍｏｉｄａｌ ｄｏｓｅ ｒｅｓｐｏｎｓｅ　（ｖａｒｉａｂｌｅ ｓｌｏｐｅ）］により、増殖が５０％阻害される被験物質濃度（ＩＣ５０値）を算出した。また、試験化合物のヒト胃癌細胞株ＭＫＮ４５増殖阻害率（％）を以下の式で計算した。陽性対照（１００％増殖）には被験物質の代わりにジメチルスルホキシドを添加した。陰性対照（０％増殖）には被験物質の代わりに既知のｃ-Ｍｅｔ阻害剤である参考例５２（ＷＯ２００５／０３０１４０のＥｎｔｒｙ　１０４記載の化合物）を大過剰量（１０μＭ）添加した。
　阻害率（％）＝（１－(試験化合物添加時の吸光度－陰性対照の吸光度）÷ (陽性対照の吸光度－陰性対照の吸光度）)×１００
　表１２に示すように、実施例６、２７、３５、３６、４７、５４、５５、１２６および１２８の化合物の１μＭにおける阻害率は８０％以上であった。
　また、実施例６、２７、３５、３６、４７、５４、５５、１２６および１２８の化合物のＩＣ５０値は１μＭ以下であった。 Test Example 4 Human Gastric Cancer Cell Line MKN45 Growth Inhibition Test Human gastric cancer cell line MKN45 (RIKEN BioResource Center) was cultured in RPMI 1640 (manufactured by Invitrogen) containing 10% fetal calf serum in a 37%, 5% carbon dioxide incubator. . MKN45 cells were collected by trypsin / EDTA treatment, suspended in RPMI 1640 containing 0.3% fetal calf serum, and seeded in a 96-well flat bottom plate at a cell density of 3000 cells / 50 μL per well. After overnight culture, various concentrations of the test substance were dissolved in RPMI 1640 containing 0.3% fetal calf serum, and 50 μL of each well was added. After culturing for 3 days, 10 μL of Cell counting kit-8 reagent (manufactured by Dojin Chemical) was added to each well and allowed to react for 2-3 hours in a 37 ° C., 5% carbon dioxide incubator. After the reaction, the absorbance at 450 nm of each well was measured with a microtiter plate reader. Using the cell growth activity value when each test substance concentration was added, the test substance concentration (IC 50 value) at which growth was inhibited by 50% was calculated by GraphPad Prism non-linear regression analysis [Sigma dose response (variable slope)]. . Moreover, the human gastric cancer cell line MKN45 growth inhibition rate (%) of the test compound was calculated by the following formula. Dimethyl sulfoxide was added to the positive control (100% growth) instead of the test substance. A large excess (10 μM) of Reference Example 52 (compound described in Entry 104 of WO2005 / 030140), which is a known c-Met inhibitor, was added to the negative control (0% growth) instead of the test substance.
Inhibition rate (%) = (1− (absorbance when test compound is added−absorbance of negative control) ÷ (absorbance of positive control−absorbance of negative control)) × 100
As shown in Table 12, the inhibition rate at 1 μM of the compounds of Examples 6, 27, 35, 36, 47, 54, 55, 126 and 128 was 80% or more.
In addition, the IC 50 values of the compounds of Examples 6, 27, 35, 36, 47, 54, 55, 126 and 128 were 1 μM or less.
Figure JPOXMLDOC01-appb-T000141
Figure JPOXMLDOC01-appb-T000141
試験例５　抗腫瘍試験
　癌細胞は３７℃、５％炭酸ガスインキュベーター内において、１０％ウシ胎仔血清を含む培養液で培養する。細胞をトリプシン／ＥＤＴＡ処理して単離し、ＨＢＳＳ（ＨＡＮＫ’ｓ　Ｂａｌａｎｃｅｄ　Ｓａｌｉｎｅ　Ｓｏｌｕｔｉｏｎ）で洗浄後、ＨＢＳＳで５ｘ１０7　ｃｅｌｌｓ／ｍＬの細胞密度に調製する。本細胞懸濁液０．１ｍＬ（５ｘ１０6　ｃｅｌｌｓ）を６週齢の雌性ヌードマウス（ＢＡＬＢ／ｃ　ｎｕ／ｎｕ，日本クレア製）の腹部皮下に注射して移植する。腫瘍体積が１００－２００ｍｍ３に達した時点で群分けを行い、翌日より種々の用量の被験物質を経口で連日１４日間投与する。腫瘍体積は腫瘍の長径および短径を経時的に測定することにより、腫瘍体積＝長径×短径×短径×０．５により算出する。 Test Example 5 Antitumor Test Cancer cells are cultured in a culture solution containing 10% fetal bovine serum in a 37 ° C., 5% carbon dioxide incubator. The cells are isolated by trypsin / EDTA treatment, washed with HBSS (HANK's Balanced Solution), and then adjusted to a cell density of 5 × 10 7 cells / mL with HBSS. 0.1 mL (5 × 10 6 cells) of this cell suspension is injected subcutaneously into the abdomen of a 6-week-old female nude mouse (BALB / c nu / nu, manufactured by CLEA Japan) and transplanted. When the tumor volume reaches 100-200 mm 3 , grouping is performed, and various doses of the test substance are orally administered for 14 consecutive days from the next day. Tumor volume is calculated by measuring tumor major axis and minor axis with time, and tumor volume = major axis × minor axis × minor axis × 0.5.
配列表フリーテキスト
〔配列番号：１〕
ヒトＶＥＧＦＲ２をコードするＤＮＡを増幅するために設計されたオリゴヌクレオチドプライマー
〔配列番号：２〕
ヒトＶＥＧＦＲ２をコードするＤＮＡを増幅するために設計されたオリゴヌクレオチドプライマー Sequence Listing Free Text [SEQ ID NO: 1]
Oligonucleotide primer designed to amplify DNA encoding human VEGFR2 [SEQ ID NO: 2]
Oligonucleotide primers designed to amplify DNA encoding human VEGFR2
　本発明の化合物は、血管内皮増殖因子受容体、肝細胞増殖因子受容体等のキナーゼに対して優れた阻害作用を示すので、生体内における血管内皮増殖因子、肝細胞増殖因子の作用と関連した疾患（例えば、癌等）の臨床上有用な予防・治療剤を提供することができる。また、本発明の化合物は、薬効発現、薬物動態、溶解性、他の医薬品との相互作用、安全性、安定性の点でも優れているので、医薬として有用である。 Since the compound of the present invention exhibits an excellent inhibitory action on kinases such as vascular endothelial growth factor receptor and hepatocyte growth factor receptor, it is related to the action of vascular endothelial growth factor and hepatocyte growth factor in vivo. A clinically useful prophylactic / therapeutic agent for a disease (for example, cancer) can be provided. The compound of the present invention is also useful as a pharmaceutical because it is excellent in terms of drug efficacy, pharmacokinetics, solubility, interaction with other pharmaceuticals, safety, and stability.
　本出願は、日本で出願された特願２００８－０１８３６７および特願２００８－２７６３５４を基礎としており、それらの内容は本明細書にすべて包含されるものである。 This application is based on Japanese Patent Application No. 2008-018367 and Japanese Patent Application No. 2008-276354 filed in Japan, the contents of which are incorporated in full herein.

Claims (18)

  1. 　式（Ｉａ）
    Figure JPOXMLDOC01-appb-C000001
    〔式中、
    Ｘは、ＮまたはＣＲ１（Ｒ１は、水素原子、ハロゲン原子またはＣ１－６アルキルを示す）を示し；
    Ｙは、ＮまたはＣＲ２（Ｒ２は、水素原子、ハロゲン原子またはＣ１－６アルキルを示す）を示し；
    Ｒ３は、水素原子、ハロゲン原子またはＣ１－６アルキルを示し；
    Ｒ４は、水素原子、ハロゲン原子またはＣ１－６アルキルを示し；
    Ｒ５は、水素原子を示し；
    Ｒ６０は、
    (1) １ないし３個のハロゲン原子で置換されていてもよい、Ｃ１－６アルキルを有していてもよいＣ６－１０アリールアミノ、
    (2) Ｃ７－１２アラルキル－カルボニルアミノ、
    (3) Ｃ７－１２アラルキルオキシ、
    (4)(a)(i) Ｃ１－６アルコキシ、および
    　　　(ii)Ｃ１－６アルキル－カルボニル
    から選ばれる置換基を有していてもよいＣ１－６アルキル、
    　 (b) Ｃ６－１０アリール、
    　 (c) オキソ、
    　 (d) ヒドロキシ、および
    　 (e) Ｃ１－６アルコキシ
    から選ばれる１ないし４個の置換基を有していてもよい含窒素５員環基、
    (5)(a) Ｃ１－６アルキル、
    　 (b) ハロゲン原子またはＣ１－６アルキルを１ないし３個有していてもよい、Ｃ６－１０アリール、
    　 (c) オキソ、
    　 (d) Ｃ１－６アルキルを１ないし３個有していてもよい、５員の芳香族複素環基、および
    　 (e) エポキシ
    から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい含窒素６員環基、
    (6) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル、
    (7) Ｃ７－１２アラルキル、または
    (8)(a) Ｃ６－１０アリール－カルボニル、
    　 (b) Ｃ６－１０アリール－カルボニルアミノ、
    　 (c) カルボキシル、または
    　 (d) 式－ＣＯＮＲ７Ｒ８
    （式中、Ｒ７は、
    　　　　(a) ５員の芳香族複素環基を有していてもよいＣ１－６アルキル、
    　　　　(b) Ｃ１－６アルキルを有していてもよいＣ３－６シクロアルキル、
    　　　　(c) ハロゲン原子を有していてもよいＣ７－１２アラルキル、
    　　　　(d)(i) ハロゲン原子、
    　　　　　 (ii) シアノ、
    　　　　　 (iii) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルキル、
    　　　　　 (iv) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルコキシ、
    　　　　　 (v) Ｃ１－６アルキル－カルボニル、
    　　　　　 (vi) Ｃ１－６アルキルチオ、および
    　　　　　 (vii) Ｃ１－６アルコキシ－カルボニル
    から選ばれる１または２個の置換基を有していてもよいＣ６－１０アリール、または、
    　　　　(e)(i) ハロゲン原子、
    　　　　　 (ii) Ｃ１－６アルキル、
    　　　　　 (iii) Ｃ３－６シクロアルキル、および
    　　　　　 (iv) Ｃ１－６アルコキシ
    から選ばれる１または２個の置換基を有していてもよい芳香族複素環基を示し；
    　　　　Ｒ８は、水素原子またはＣ１－６アルキルを示すか；
    　　　　あるいは、Ｒ７とＲ８が一緒になって、－ＮＲ７Ｒ８で、６員の複素環を形成してもよい）
    で表される基を有するＣ３－６シクロアルキルを示すか；
    あるいは、Ｒ５とＲ６０は一緒になって縮合複素環を形成してもよく；
    Ｚは、ＯまたはＳを示す。
    但し、下記４化合物を除く：
    (1) N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-5-メチル-1-フェニル-1H-ピラゾール-3-カルボキサミド；
    (2) N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-3-メチル-1-フェニル-1H-ピラゾール-5-カルボキサミド；
    (3) N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-1,3-ジメチル-1H-ピラゾール-5-カルボキサミド；および
    (4) N-{6-[4-({[(フェニルアセチル)アミノ]チオカルボニル}アミノ)フェノキシ]イミダゾ[1,2-b]ピリダジン-2-イル}シクロプロパンカルボキサミド〕
    で表される化合物またはその塩。     Formula (Ia)
    Figure JPOXMLDOC01-appb-C000001
    [Where,
    X represents N or CR 1 (R 1 represents a hydrogen atom, a halogen atom or C 1-6 alkyl);
    Y represents N or CR 2 (R 2 represents a hydrogen atom, a halogen atom or C 1-6 alkyl);
    R 3 represents a hydrogen atom, a halogen atom or C 1-6 alkyl;
    R 4 represents a hydrogen atom, a halogen atom or C 1-6 alkyl;
    R 5 represents a hydrogen atom;
    R 60 is
    (1) a C 6-10 arylamino optionally having C 1-6 alkyl, optionally substituted by 1 to 3 halogen atoms,
    (2) C 7-12 aralkyl-carbonylamino,
    (3) C 7-12 aralkyloxy,
    (4) (a) (i ) C 1-6 alkoxy, and (ii) C 1-6 alkyl - which may have a substituent group selected from a carbonyl C 1-6 alkyl,
    (b) C 6-10 aryl,
    (c) oxo,
    (d) hydroxy, and (e) a nitrogen-containing 5-membered cyclic group optionally having 1 to 4 substituents selected from C 1-6 alkoxy,
    (5) (a) C 1-6 alkyl,
    (b) a C 6-10 aryl optionally having 1 to 3 halogen atoms or C 1-6 alkyl,
    (c) oxo,
    (d) 1 to 3 C 1-6 alkyl optionally having 5 membered aromatic heterocyclic group, and (e) 1 to 3 substituents selected from epoxy Well, a nitrogen-containing 6-membered cyclic group that may be oxidized,
    (6) C 6-10 aryl-carbamoyl-C 1-6 alkyl,
    (7) C 7-12 aralkyl, or
    (8) (a) C 6-10 aryl-carbonyl,
    (b) C 6-10 aryl-carbonylamino,
    (c) Carboxyl, or (d) Formula —CONR 7 R 8
    (Wherein R 7 is
    (a) C 1-6 alkyl optionally having a 5-membered aromatic heterocyclic group,
    (b) C 3-6 cycloalkyl optionally having C 1-6 alkyl,
    (c) a C 7-12 aralkyl optionally having a halogen atom,
    (d) (i) a halogen atom,
    (ii) cyano,
    (iii) C 1-6 alkyl optionally having 1 to 3 halogen atoms,
    (iv) C 1-6 alkoxy optionally having 1 to 3 halogen atoms,
    (v) C 1-6 alkyl-carbonyl,
    (vi) C 1-6 alkylthio, and (vii) C 6-10 aryl optionally having 1 or 2 substituents selected from C 1-6 alkoxy-carbonyl, or
    (e) (i) a halogen atom,
    (ii) C 1-6 alkyl,
    (iii) C 3-6 cycloalkyl, and (iv) an aromatic heterocyclic group optionally having 1 or 2 substituents selected from C 1-6 alkoxy;
    R 8 represents a hydrogen atom or C 1-6 alkyl;
    Alternatively, R 7 and R 8 may be combined to form a 6-membered heterocyclic ring with —NR 7 R 8.
    C 3-6 cycloalkyl having a group represented by:
    Alternatively, R 5 and R 60 may together form a fused heterocycle;
    Z represents O or S.
    However, the following 4 compounds are excluded:
    (1) N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -5-methyl-1-phenyl-1H-pyrazole -3-carboxamide;
    (2) N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -3-methyl-1-phenyl-1H-pyrazole -5-carboxamide;
    (3) N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -1,3-dimethyl-1H-pyrazole-5 -Carboxamide; and
    (4) N- {6- [4-({[(Phenylacetyl) amino] thiocarbonyl} amino) phenoxy] imidazo [1,2-b] pyridazin-2-yl} cyclopropanecarboxamide]
    Or a salt thereof.
  2. 　式（Ｉｂ）
    Figure JPOXMLDOC01-appb-C000002
    〔式中、
    Ｘは、ＮまたはＣＲ１（Ｒ１は、水素原子、ハロゲン原子またはＣ１－６アルキルを示す）を示し；
    Ｙは、ＮまたはＣＲ２（Ｒ２は、水素原子、ハロゲン原子またはＣ１－６アルキルを示す）を示し；
    Ｒ３は、水素原子、ハロゲン原子またはＣ１－６アルキルを示し；
    Ｒ４は、水素原子、ハロゲン原子またはＣ１－６アルキルを示し；
    Ｒ５は、水素原子を示し；
    Ｒ６は、
    (1) １ないし３個のハロゲン原子で置換されていてもよい、Ｃ１－６アルキルを有していてもよいＣ６－１０アリールアミノ、
    (2) Ｃ７－１２アラルキル－カルボニルアミノ、
    (3) Ｃ７－１２アラルキルオキシ、
    (4)(a)(i) Ｃ１－６アルコキシ、および
    　　　(ii)Ｃ１－６アルキル－カルボニル
    から選ばれる置換基を有していてもよいＣ１－６アルキル、
    　 (b) Ｃ６－１０アリール、
    　 (c) オキソ、
    　 (d) ヒドロキシ、および
    　 (e) Ｃ１－６アルコキシ
    から選ばれる１ないし３個の置換基を有していてもよい含窒素５員環基、
    (5)(a) Ｃ１－６アルキル、
    　 (b) ハロゲン原子またはＣ１－６アルキルを１ないし３個有していてもよい、Ｃ６－１０アリール、
    　 (c) オキソ、
    　 (d) Ｃ１－６アルキルを１ないし３個有していてもよい、５員の芳香族複素環基、および
    　 (e) エポキシ
    から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい含窒素６員環基、
    (6) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル、
    (7) Ｃ７－１２アラルキル、または
    (8)(a) Ｃ６－１０アリール－カルボニル、
    　 (b) Ｃ６－１０アリール－カルボニルアミノ、
    　 (c) カルボキシル、または
    　 (d) 式－ＣＯＮＲ７Ｒ８
    （式中、Ｒ７は、
    　　　　(a) ５員の芳香族複素環基を有していてもよいＣ１－６アルキル、
    　　　　(b) Ｃ１－６アルキルを有していてもよいＣ３－６シクロアルキル、
    　　　　(c) ハロゲン原子を有していてもよいＣ７－１２アラルキル、
    　　　　(d)(i) ハロゲン原子、
    　　　　　 (ii) シアノ、
    　　　　　 (iii) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルキル、
    　　　　　 (iv) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルコキシ、
    　　　　　 (v) Ｃ１－６アルキル－カルボニル、
    　　　　　 (vi) Ｃ１－６アルキルチオ、および
    　　　　　 (vii) Ｃ１－６アルコキシ－カルボニル
    から選ばれる１または２個の置換基を有していてもよいＣ６－１０アリール、または、
    　　　　(e)(i) ハロゲン原子、
    　　　　　 (ii) Ｃ１－６アルキル、および
    　　　　　 (iii) Ｃ３－６シクロアルキル
    から選ばれる１または２個の置換基を有していてもよい芳香族複素環基を示し；
    　　　　Ｒ８は、水素原子またはＣ１－６アルキルを示すか；
    　　　　あるいは、Ｒ７とＲ８が一緒になって、－ＮＲ７Ｒ８で、６員の複素環を形成してもよい）
    で表される基を有するＣ３－６シクロアルキルを示すか；
    あるいは、Ｒ５とＲ６は一緒になって縮合複素環を形成してもよく；
    Ｚは、ＯまたはＳを示す。
    但し、下記４化合物を除く：
    (1) N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-5-メチル-1-フェニル-1H-ピラゾール-3-カルボキサミド；
    (2) N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-3-メチル-1-フェニル-1H-ピラゾール-5-カルボキサミド；
    (3) N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)フェニル]-1,3-ジメチル-1H-ピラゾール-5-カルボキサミド；および
    (4) N-{6-[4-({[(フェニルアセチル)アミノ]チオカルボニル}アミノ)フェノキシ]イミダゾ[1,2-b]ピリダジン-2-イル}シクロプロパンカルボキサミド〕
    で表される化合物またはその塩。     Formula (Ib)
    Figure JPOXMLDOC01-appb-C000002
    [Where,
    X represents N or CR 1 (R 1 represents a hydrogen atom, a halogen atom or C 1-6 alkyl);
    Y represents N or CR 2 (R 2 represents a hydrogen atom, a halogen atom or C 1-6 alkyl);
    R 3 represents a hydrogen atom, a halogen atom or C 1-6 alkyl;
    R 4 represents a hydrogen atom, a halogen atom or C 1-6 alkyl;
    R 5 represents a hydrogen atom;
    R 6 is
    (1) a C 6-10 arylamino optionally having C 1-6 alkyl, optionally substituted by 1 to 3 halogen atoms,
    (2) C 7-12 aralkyl-carbonylamino,
    (3) C 7-12 aralkyloxy,
    (4) (a) (i ) C 1-6 alkoxy, and (ii) C 1-6 alkyl - which may have a substituent group selected from a carbonyl C 1-6 alkyl,
    (b) C 6-10 aryl,
    (c) oxo,
    (d) hydroxy, and (e) a nitrogen-containing 5-membered cyclic group optionally having 1 to 3 substituents selected from C 1-6 alkoxy,
    (5) (a) C 1-6 alkyl,
    (b) a C 6-10 aryl optionally having 1 to 3 halogen atoms or C 1-6 alkyl,
    (c) oxo,
    (d) 1 to 3 C 1-6 alkyl optionally having 5 membered aromatic heterocyclic group, and (e) 1 to 3 substituents selected from epoxy Well, a nitrogen-containing 6-membered cyclic group that may be oxidized,
    (6) C 6-10 aryl-carbamoyl-C 1-6 alkyl,
    (7) C 7-12 aralkyl, or
    (8) (a) C 6-10 aryl-carbonyl,
    (b) C 6-10 aryl-carbonylamino,
    (c) Carboxyl, or (d) Formula —CONR 7 R 8
    (Wherein R 7 is
    (a) C 1-6 alkyl optionally having a 5-membered aromatic heterocyclic group,
    (b) C 3-6 cycloalkyl optionally having C 1-6 alkyl,
    (c) a C 7-12 aralkyl optionally having a halogen atom,
    (d) (i) a halogen atom,
    (ii) cyano,
    (iii) C 1-6 alkyl optionally having 1 to 3 halogen atoms,
    (iv) C 1-6 alkoxy optionally having 1 to 3 halogen atoms,
    (v) C 1-6 alkyl-carbonyl,
    (vi) C 1-6 alkylthio, and (vii) C 6-10 aryl optionally having 1 or 2 substituents selected from C 1-6 alkoxy-carbonyl, or
    (e) (i) a halogen atom,
    an aromatic heterocyclic group optionally having 1 or 2 substituents selected from (ii) C 1-6 alkyl, and (iii) C 3-6 cycloalkyl;
    R 8 represents a hydrogen atom or C 1-6 alkyl;
    Alternatively, R 7 and R 8 may be combined to form a 6-membered heterocyclic ring with —NR 7 R 8.
    C 3-6 cycloalkyl having a group represented by:
    Alternatively, R 5 and R 6 may be taken together to form a fused heterocycle;
    Z represents O or S.
    However, the following 4 compounds are excluded:
    (1) N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -5-methyl-1-phenyl-1H-pyrazole -3-carboxamide;
    (2) N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -3-methyl-1-phenyl-1H-pyrazole -5-carboxamide;
    (3) N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) phenyl] -1,3-dimethyl-1H-pyrazole-5 -Carboxamide; and
    (4) N- {6- [4-({[(Phenylacetyl) amino] thiocarbonyl} amino) phenoxy] imidazo [1,2-b] pyridazin-2-yl} cyclopropanecarboxamide]
    Or a salt thereof.
  3. 　Ｒ１およびＲ２が、独立して、水素原子、フッ素原子、塩素原子またはメチルである、請求項２記載の化合物。 The compound according to claim 2, wherein R 1 and R 2 are independently a hydrogen atom, a fluorine atom, a chlorine atom or methyl.
  4. 　Ｒ３が、水素原子またはハロゲン原子である、請求項２記載の化合物。 The compound according to claim 2, wherein R 3 is a hydrogen atom or a halogen atom.
  5. 　Ｒ４が、水素原子またはハロゲン原子である、請求項２記載の化合物。 The compound according to claim 2, wherein R 4 is a hydrogen atom or a halogen atom.
  6. 　Ｒ５が、水素原子であり；
    Ｒ６が、
    (1) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルキルを有していてもよい、Ｃ６－１０アリールアミノ、
    (2) Ｃ７－１２アラルキルオキシ、
    (3)(a) Ｃ１－６アルキル、
    　 (b) ハロゲン原子またはＣ１－６アルキルを１ないし３個有していてもよい、Ｃ６－１０アリール、
    　 (c) オキソ、
    　 (d) Ｃ１－６アルキルを１ないし３個有していてもよい、５員の芳香族複素環基、および
    　 (e) エポキシ
    から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい含窒素６員環基、
    (4) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル、
    (5) Ｃ７－１２アラルキル、または
    (6) Ｃ６－１０アリール－カルボニル、Ｃ６－１０アリール－カルボニルアミノ、カルボキシルまたは式－ＣＯＮＲ７Ｒ８
    （式中、Ｒ７が、
    　　　　(a) ５員の芳香族複素環基を有していてもよいＣ１－６アルキル、
    　　　　(b) Ｃ１－６アルキルを有していてもよいＣ３－６シクロアルキル、
    　　　　(c) ハロゲン原子を有していてもよいＣ７－１２アラルキル、
    　　　　(d)(i) ハロゲン原子、
    　　　　　 (ii) シアノ、
    　　　　　 (iii) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルキル、
    　　　　　 (iv) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルコキシ、
    　　　　　 (v) Ｃ１－６アルキル－カルボニル、
    　　　　　 (vi) Ｃ１－６アルキルチオ、および
    　　　　　 (vii) Ｃ１－６アルコキシ－カルボニル
    から選ばれる１または２個の置換基を有していてもよいＣ６－１０アリール、または、
    　　　　(e)(i) ハロゲン原子、
    　　　　　 (ii) Ｃ１－６アルキル、および
    　　　　　 (iii) Ｃ３－６シクロアルキル
    から選ばれる１または２個の置換基を有していてもよい芳香族複素環基であり；
    　　　　Ｒ８が水素原子またはＣ１－６アルキルであるか；
    　　　　あるいは、Ｒ７とＲ８が一緒になって、－ＮＲ７Ｒ８で、６員の複素環を形成してもよい）
    で表される基を有するＣ３－６シクロアルキルであるか；
    あるいは、Ｒ５とＲ６が一緒になって縮合複素環を形成してもよい、請求項２記載の化合物。     R 5 is a hydrogen atom;
    R 6 is
    (1) C 6-10 arylamino optionally having C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms,
    (2) C 7-12 aralkyloxy,
    (3) (a) C 1-6 alkyl,
    (b) a C 6-10 aryl optionally having 1 to 3 halogen atoms or C 1-6 alkyl,
    (c) oxo,
    (d) 1 to 3 C 1-6 alkyl optionally having 5 membered aromatic heterocyclic group, and (e) 1 to 3 substituents selected from epoxy Well, a nitrogen-containing 6-membered cyclic group that may be oxidized,
    (4) C 6-10 aryl-carbamoyl-C 1-6 alkyl,
    (5) C 7-12 aralkyl, or
    (6) C 6-10 aryl-carbonyl, C 6-10 aryl-carbonylamino, carboxyl or formula —CONR 7 R 8
    (Wherein R 7 is
    (a) C 1-6 alkyl optionally having a 5-membered aromatic heterocyclic group,
    (b) C 3-6 cycloalkyl optionally having C 1-6 alkyl,
    (c) a C 7-12 aralkyl optionally having a halogen atom,
    (d) (i) a halogen atom,
    (ii) cyano,
    (iii) C 1-6 alkyl optionally having 1 to 3 halogen atoms,
    (iv) C 1-6 alkoxy optionally having 1 to 3 halogen atoms,
    (v) C 1-6 alkyl-carbonyl,
    (vi) C 1-6 alkylthio, and (vii) C 6-10 aryl optionally having 1 or 2 substituents selected from C 1-6 alkoxy-carbonyl, or
    (e) (i) a halogen atom,
    an aromatic heterocyclic group optionally having 1 or 2 substituents selected from (ii) C 1-6 alkyl, and (iii) C 3-6 cycloalkyl;
    Whether R 8 is a hydrogen atom or C 1-6 alkyl;
    Alternatively, R 7 and R 8 may be combined to form a 6-membered heterocyclic ring with —NR 7 R 8.
    Or C 3-6 cycloalkyl having a group represented by:
    Alternatively, the compound according to claim 2, wherein R 5 and R 6 may form a condensed heterocyclic ring together.
  7. 　Ｘが、ＮまたはＣＲ１’（Ｒ１’は、水素原子、フッ素原子、塩素原子またはメチルを示す）であり；
    Ｙが、ＮまたはＣＲ２’（Ｒ２’は、水素原子、フッ素原子、塩素原子またはメチルを示す）であり；
    Ｒ３が、水素原子またはハロゲン原子であり；
    Ｒ４が、水素原子またはハロゲン原子であり；
    Ｒ５が、水素原子であり；
    Ｒ６が、
    (1) １ないし３個のハロゲン原子で置換されていてもよいＣ１－６アルキルを有していてもよい、Ｃ６－１０アリールアミノ、
    (2) Ｃ７－１２アラルキルオキシ、
    (3)(a) Ｃ１－６アルキル、
    　 (b) ハロゲン原子またはＣ１－６アルキルを１ないし３個有していてもよい、Ｃ６－１０アリール、
    　 (c) オキソ、
    　 (d) Ｃ１－６アルキルを１ないし３個有していてもよい、５員の芳香族複素環基、および
    　 (e) エポキシ
    から選ばれる１ないし３個の置換基を有していてもよく、酸化されていてもよい含窒素６員環基、
    (4) Ｃ６－１０アリール－カルバモイル－Ｃ１－６アルキル、
    (5) Ｃ７－１２アラルキル、または
    (6)(a) Ｃ６－１０アリール－カルボニル、
    　 (b) Ｃ６－１０アリール－カルボニルアミノ、
    　 (c) カルボキシル、または
    　 (d) 式－ＣＯＮＲ７Ｒ８
    （式中、Ｒ７が、
    　　　　(a) ５員の芳香族複素環基を有していてもよいＣ１－６アルキル、
    　　　　(b) Ｃ１－６アルキルを有していてもよいＣ３－６シクロアルキル、
    　　　　(c) ハロゲン原子を有していてもよいＣ７－１２アラルキル、
    　　　　(d)(i) ハロゲン原子、
    　　　　　 (ii) シアノ、
    　　　　　 (iii) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルキル、
    　　　　　 (iv) １ないし３個のハロゲン原子を有していてもよいＣ１－６アルコキシ、
    　　　　　 (v) Ｃ１－６アルキル－カルボニル、
    　　　　　 (vi) Ｃ１－６アルキルチオ、および
    　　　　　 (vi) Ｃ１－６アルコキシ－カルボニル
    から選ばれる１または２個の置換基を有していてもよいＣ６－１０アリール、または、
    　　　　(e)(i) ハロゲン原子、
    　　　　　 (ii) Ｃ１－６アルキル、および
    　　　　　 (iii) Ｃ３－６シクロアルキル
    から選ばれる１または２個の置換基を有していてもよい芳香族複素環基であり；
    　　　　Ｒ８は水素原子またはＣ１－６アルキルであるか；
    　　　　あるいは、Ｒ７とＲ８が一緒になって－ＮＲ７Ｒ８で、６員の複素環を形成してもよい）
    で表される基を有するＣ３－６シクロアルキルであるか；
    あるいは、Ｒ５とＲ６が一緒になって縮合複素環を形成してもよく；
    Ｚが、ＯまたはＳである、請求項２記載の化合物。     X is N or CR 1 ′ (R 1 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
    Y is N or CR 2 ′ (R 2 ′ represents a hydrogen atom, a fluorine atom, a chlorine atom or methyl);
    R 3 is a hydrogen atom or a halogen atom;
    R 4 is a hydrogen atom or a halogen atom;
    R 5 is a hydrogen atom;
    R 6 is
    (1) C 6-10 arylamino optionally having C 1-6 alkyl optionally substituted with 1 to 3 halogen atoms,
    (2) C 7-12 aralkyloxy,
    (3) (a) C 1-6 alkyl,
    (b) a C 6-10 aryl optionally having 1 to 3 halogen atoms or C 1-6 alkyl,
    (c) oxo,
    (d) 1 to 3 C 1-6 alkyl optionally having 5 membered aromatic heterocyclic group, and (e) 1 to 3 substituents selected from epoxy Well, a nitrogen-containing 6-membered cyclic group that may be oxidized,
    (4) C 6-10 aryl-carbamoyl-C 1-6 alkyl,
    (5) C 7-12 aralkyl, or
    (6) (a) C 6-10 aryl-carbonyl,
    (b) C 6-10 aryl-carbonylamino,
    (c) Carboxyl, or (d) Formula —CONR 7 R 8
    (Wherein R 7 is
    (a) C 1-6 alkyl optionally having a 5-membered aromatic heterocyclic group,
    (b) C 3-6 cycloalkyl optionally having C 1-6 alkyl,
    (c) a C 7-12 aralkyl optionally having a halogen atom,
    (d) (i) a halogen atom,
    (ii) cyano,
    (iii) C 1-6 alkyl optionally having 1 to 3 halogen atoms,
    (iv) C 1-6 alkoxy optionally having 1 to 3 halogen atoms,
    (v) C 1-6 alkyl-carbonyl,
    (vi) C 1-6 alkylthio, and (vi) C 6-10 aryl optionally having 1 or 2 substituents selected from C 1-6 alkoxy-carbonyl, or
    (e) (i) a halogen atom,
    an aromatic heterocyclic group optionally having 1 or 2 substituents selected from (ii) C 1-6 alkyl, and (iii) C 3-6 cycloalkyl;
    R 8 is a hydrogen atom or C 1-6 alkyl;
    Alternatively, R 7 and R 8 may be taken together as —NR 7 R 8 to form a 6-membered heterocycle)
    Or C 3-6 cycloalkyl having a group represented by:
    Alternatively, R 5 and R 6 may be taken together to form a fused heterocyclic ring;
    The compound according to claim 2, wherein Z is O or S.
  8. 　N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-N'-フェニルシクロプロパン-1,1-ジカルボキサミドまたはその塩。 N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -N'-phenylcyclopropane-1,1 -Dicarboxamide or a salt thereof.
  9. 　N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボキサミドまたはその塩。 N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -2-oxo-1-phenyl-1, 2-dihydropyridine-3-carboxamide or a salt thereof.
  10. 　N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-6-メチル-2-オキソ-1-フェニル-1,2-ジヒドロピリジン-3-カルボキサミドまたはその塩。 N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -6-methyl-2-oxo-1- Phenyl-1,2-dihydropyridine-3-carboxamide or a salt thereof.
  11. 　N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-6-フェニルピリジン-2-カルボキサミド 1-オキシドまたはその塩。 N- [4-({2-[(cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -6-phenylpyridine-2-carboxamide 1- Oxide or its salt.
  12. 　N-[4-({2-[(シクロプロピルカルボニル)アミノ]イミダゾ[1,2-b]ピリダジン-6-イル}オキシ)-3-フルオロフェニル]-6-(4-フルオロフェニル)-5-メチルピリジン-2-カルボキサミド 1-オキシドまたはその塩。 N- [4-({2-[(Cyclopropylcarbonyl) amino] imidazo [1,2-b] pyridazin-6-yl} oxy) -3-fluorophenyl] -6- (4-fluorophenyl) -5 -Methylpyridine-2-carboxamide 1-oxide or a salt thereof.
  13. 　請求項１または２記載の化合物のプロドラッグ。 A prodrug of the compound according to claim 1 or 2.
  14. 　請求項１または２記載の化合物またはそのプロドラッグを含有してなる医薬。 A pharmaceutical comprising the compound according to claim 1 or 2 or a prodrug thereof.
  15. 　キナーゼ阻害剤である請求項１４記載の医薬。 The medicament according to claim 14, which is a kinase inhibitor.
  16. 　癌の予防治療剤である請求項１４記載の医薬。 The medicament according to claim 14, which is a preventive or therapeutic agent for cancer.
  17. 　哺乳動物に対して請求項１または２記載の化合物またはそのプロドラッグの有効量を投与することを特徴とする癌の予防・治療方法。 A method for preventing or treating cancer, comprising administering an effective amount of the compound or prodrug thereof according to claim 1 or 2 to a mammal.
  18. 　癌の予防・治療剤を製造するための、請求項１または２記載の化合物またはそのプロドラッグの使用。 Use of the compound according to claim 1 or 2 or a prodrug thereof for producing a preventive / therapeutic agent for cancer.
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US20110046169A1 (en) * 2008-05-08 2011-02-24 Takeda Pharmaceutical Company Limited Fused heterocyclic derivatives and use thereof
US8445509B2 (en) * 2008-05-08 2013-05-21 Takeda Pharmaceutical Company Limited Fused heterocyclic derivatives and use thereof
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JP2016520617A (en) * 2013-05-30 2016-07-14 カラ ファーマシューティカルズ インコーポレイテッド Novel compounds and uses thereof
CN109879827A (en) * 2019-03-30 2019-06-14 陕西理工大学 A kind of novel indazole analog derivative and its application
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CN110467616A (en) * 2019-07-01 2019-11-19 江西科技师范大学 Replace the preparation and application of the Triazolopyrazine class compound of pyridazinone structure containing heteroaryl
EP4005637A4 (en) * 2019-07-29 2023-07-19 Takeda Pharmaceutical Company Limited Heterocyclic compound
WO2023125803A1 (en) * 2021-12-29 2023-07-06 北京鞍石生物科技有限责任公司 Heteroaromatic nitrogen-oxide compound, preparation method therefor, and use thereof

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