WO2018221433A1 - Heteroaryl amine derivative - Google Patents

Heteroaryl amine derivative Download PDF

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WO2018221433A1
WO2018221433A1 PCT/JP2018/020268 JP2018020268W WO2018221433A1 WO 2018221433 A1 WO2018221433 A1 WO 2018221433A1 JP 2018020268 W JP2018020268 W JP 2018020268W WO 2018221433 A1 WO2018221433 A1 WO 2018221433A1
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mmol
group
compound
amino
added
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PCT/JP2018/020268
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French (fr)
Japanese (ja)
Inventor
充洋 山口
貴司 辻
貴之 馬場
純市 黒柳
正治 乾
聡 小森谷
哲義 松藤
信二 古薗
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第一三共株式会社
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Publication of WO2018221433A1 publication Critical patent/WO2018221433A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/80—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel compound having an action such as lowering blood sugar and useful as a therapeutic and / or prophylactic agent for diabetes and the like and a pharmaceutically acceptable salt thereof.
  • the present invention includes diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia, impaired glucose tolerance, diabetic neuropathy, diabetes containing the above compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • diabetes type 1 diabetes, type 2 diabetes, gestational diabetes, etc.
  • postprandial hyperglycemia impaired glucose tolerance
  • diabetic neuropathy diabetes containing the above compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a composition for the prevention or treatment of the above-mentioned diseases containing the above-mentioned compound as an active ingredient, the use of the above-mentioned compound for producing a medicament for the prevention or treatment of the above-mentioned diseases,
  • the present invention relates to a method for preventing or treating the above diseases, wherein a pharmacologically effective amount is administered to a mammal (preferably a human).
  • Diabetes is a disease whose main feature is chronic hyperglycemia, and develops due to an absolute or relative lack of insulin action. In clinical practice, it is roughly divided into insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes).
  • diabetes treatment is basically diet therapy and exercise therapy.
  • a drug is administered. Therefore, there is a demand for safer and more effective drugs.
  • a compound having a partial structure partially in common with the compound of the present invention has been reported in a plurality of reports for kinase inhibitors (Patent Documents 1-4, Non-Patent Document 1) or other uses (Patent Documents 5-10, Non-Patent Documents). 2-5).
  • the present inventors have found that the compound represented by the following formula (I) has an excellent action such as hypoglycemia, based on its specific chemical structure, and has hyperglycemia, diabetes and It has been found that the drug is useful as a preventive / therapeutic agent for a disease state or a disease related to those diseases, and the present invention has been completed based on these findings.
  • the compound of the present invention has a hypoglycemic action and the like, such as diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetes Prevention, treatment for diseases such as retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia, especially type 2 diabetes Useful as an agent.
  • diabetes type 1 diabetes, type 2 diabetes, gestational diabetes, etc.
  • postprandial hyperglycemia impaired glucose tolerance
  • diabetic neuropathy diabetic nephropathy
  • diabetes Prevention treatment for diseases such as retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia, especially type 2 diabetes Useful as an agent.
  • Ring A represents a benzene ring or a bicyclic benzoheterocycle
  • Ring B represents a unitary or bicyclic ring containing two nitrogen atoms in the ring
  • the bicyclic ring may further contain one or more atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in the ring
  • Ring C represents a benzene ring or a 4- to 6-membered saturated nitrogen-containing heterocycle
  • R 1 represents a hydrogen atom or a halogen atom
  • R 2 is a substituent which the ring A is bonded to the position of the 2-position in the case of a benzene ring, one or more of which may be substituted by a group C 1 independently selected from the following group Z - C 6 alkyl group, C 1 -C 6 alkoxy group optionally substituted by one or more groups independently selected from the following group Z, substituted by one or more groups independently selected from the following group Z which may be mono-C
  • Group Z C 1 -C 6 alkoxy group, mono C 1 -C 6 alkylamino group, di C 1 -C 6 alkylamino group, phenyl group (the phenyl group is a halogen atom, a carboxy group, and C 1 -C 6 An optionally substituted 1 or 2 group selected from the group consisting of alkyl groups), and a 4-6 membered saturated or unsaturated heterocyclic group (the heterocyclic group is a halogen atom, a carboxy group) And optionally substituted by 1 or 2 groups independently selected from the group consisting of C 1 -C 6 alkyl groups).
  • Group Y an oxo group, a C 1 -C 6 alkoxy group, and a carbamoyl group.
  • Ring D represents a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, a cyclopentene ring, or a dihydrofuran ring
  • R 3 represents a hydrogen atom or a halogen atom.
  • Ring E represents a benzene ring, a pyrrole ring, or a thiophene ring
  • R 3 represents a hydrogen atom or a halogen atom.
  • the partial structural formula (I-2) in the formula (I) is Following group
  • a hypoglycemic agent comprising the compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • a pharmaceutical comprising the compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Diabetes, postprandial hyperglycemia, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance The medicament according to (9) for the treatment or prevention of sexual, unstable diabetes, insulinoma, hyperinsulinemia and the like.
  • the “C 1 -C 6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms.
  • Examples of the “C 1 -C 6 alkyl group” include methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group and the like.
  • the “C 1 -C 6 alkoxy group” means an alkoxy group having a linear or branched alkyl group having 1 to 6 carbon atoms.
  • Examples of the “C 1 -C 6 alkoxy group” include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group and the like.
  • examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the “mono C 1 -C 6 alkylamino group” means an amino group substituted with one C 1 -C 6 alkyl group
  • the “di C 1 -C 6 alkylamino group” means Means an amino group substituted with two C 1 -C 6 alkyl groups, such as a methylamino group, an ethylamino group, a propylamino group, or an isopropylamino group, or a dimethylamino group or a diethylamino group, respectively.
  • a methylamino group such as a methylamino group, an ethylamino group, a propylamino group, or an isopropylamino group, or a dimethylamino group or a diethylamino group, respectively.
  • the “C 1 -C 6 alkylsulfonyl group” means a sulfonyl group substituted by the above C 1 -C 6 alkyl group, and includes a methanesulfonyl group, an ethanesulfonyl group, an n-propanesulfonyl group, and isopropane.
  • a sulfonyl group etc. can be mentioned.
  • the “4- to 6-membered saturated nitrogen-containing heterocyclic group” is a 4- to 6-membered saturated ring group containing 1 to 4 nitrogen atoms in the ring, and includes an azetidinyl group, a pyrrolidinyl group, an imidazolidinyl group. , Pyrazolidinyl group, piperidinyl group, piperazinyl group and the like.
  • the “4- to 6-membered unsaturated nitrogen-containing heterocyclic group” is a 4- to 6-membered unsaturated ring group containing 1 to 4 nitrogen atoms in the ring, and includes a pyrrolyl group, a pyrazolyl group, Examples include imidazolyl group, triazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, tetrazinyl group and the like.
  • the “bicyclic benzoheterocycle” is a bicyclic ring in which a saturated or unsaturated heterocycle containing 1 to 4 nitrogen, oxygen or sulfur is condensed to a benzene ring, and is condensed.
  • the heterocycle is preferably a 4-6 membered ring.
  • Examples of the “bicyclic benzoheterocycle” include benzofuran, isobenzofuran, indole, isoindole, chromene, isochromene, quinoline, isoquinoline, benzimidazole, indazole, quinoxaline, quinazoline, phthalazine, indoline, isoindoline, chroman, isochroman.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof has the general formula (I)
  • Ring A represents a benzene ring or a bicyclic benzoheterocycle. Ring A is preferably a benzene ring, a benzofuran ring or a benzothiophene ring.
  • R 1 is a group on the ring A and is a hydrogen atom or a halogen atom.
  • R 1 is preferably a hydrogen atom, a fluorine atom or a chlorine atom.
  • R 2 is a substituent bonded to the 2-position when ring A is a benzene ring, and C 1 -C optionally substituted by one or more groups independently selected from the above Z group 6 alkyl group, C 1 -C 6 alkoxy group optionally substituted by one or more groups independently selected from the above Z group, substituted by one or more groups independently selected from the above Z group
  • An optionally mono C 1 -C 6 alkylamino group, — [O— (CH 2 ) 2 ] mXQ or —O— (CH 2 ) nXQ (where m represents an integer of 1 or 2, n represents an integer of 1, 2, 3 or 4, X represents O, NH or NHC O, Q represents a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group or a mono C 1 -C 6 Represents an alkylamino group).
  • R 2 is a C 1 -C 3 alkoxy group (the C 1 -C 3 alkoxy group is a C 1 -C 3 alkoxy group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group which may be substituted with one halogen atom) group, pyrazinyl group, thiazolyl group, tetrahydropyranyl group, dioxanyl group, may be substituted with a morpholyl group or carboxyphenyl group), C 1 -C 3 optionally substituted by an alkoxy group C 1 -C 3 It is more preferably an alkylamino group, — [O— (CH 2 ) 2 ] mXQ, or —O— (CH 2 ) nXQ.
  • Ring B represents a unitary or bicyclic ring containing two nitrogen atoms in the ring, and the bicyclic ring is further one or more selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom May be included in the ring.
  • R 3 is a group on ring B and represents a hydrogen atom or a halogen atom.
  • R 3 is preferably a hydrogen atom or a fluorine atom.
  • Ring B represents “a monocyclic or bicyclic ring containing two nitrogen atoms, and the bicyclic ring further includes one or more selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom.
  • the ring represented by ⁇ may contain an atom in the ring '', when ring B is a unitary ring, ring B is preferably a 6-membered unsaturated nitrogen-containing ring, and pyrazine, pyrimidine And pyridazine, and pyridazine is particularly preferable.
  • ring B is a bicyclic ring, it is preferably a fused ring of a 6-membered unsaturated nitrogen-containing ring and a saturated or unsaturated 5-membered or 6-membered ring, and a 6-membered unsaturated ring
  • nitrogen-containing ring examples include pyrazine, pyrimidine, pyridazine, and triazine.
  • saturated or unsaturated 5-membered or 6-membered ring condensed with the 6-membered unsaturated nitrogen-containing ring include cyclopentene, benzene, furan, Dihydrofuran, thiophene, pyrrole, pyridine, imidazole, pyrazole and the like can be mentioned.
  • ring D represents a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, a cyclopentene ring, or a dihydrofuran ring
  • R 3 represents a hydrogen atom or a halogen atom. It is preferable that it is group represented by these.
  • the partial structural formula (I-2) is The following formula (III)
  • ring E represents a benzene ring, a pyrrole ring, or a thiophene ring
  • R 3 represents a hydrogen atom or a halogen atom. It is preferable that it is group represented by this.
  • Ring C represents a benzene ring or a 4- to 6-membered saturated nitrogen-containing heterocycle.
  • “4- to 6-membered saturated nitrogen-containing heterocycle” is a 4- to 6-membered saturated ring containing 1 to 4 nitrogen atoms in the ring, and examples thereof include azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine. It is done.
  • Ring C is more preferably benzene, azetidine, pyrrolidine, or piperidine.
  • R 4 , R 5 and R 6 are groups on the ring C, each independently a hydrogen atom, a halogen atom, or C which may be substituted by one or more groups independently selected from the following group Y 1 -C 6 alkyl group, one or more substituted C 1 optionally -C 6 alkoxy group by group, one or more groups independently selected from the following group Y is individually selected from the following group Y A mono C 1 -C 6 alkylamino group, a C 1 -C 6 alkylsulfonyl group, which may be substituted by:
  • Group Y oxo group, C 1 -C 6 alkoxy group, and carbamoyl group.
  • R 4 , R 5 and R 6 are C 1 -C 3 alkyl group or a fluorine atom.
  • R 4 , R 5 and R 6 are hydrogen atoms, and the other group is a C 1 -C 6 alkylsulfonyl group, or a carbamoyl group And a C 1 -C 3 alkyl group substituted with one or more groups independently selected from the group consisting of oxo groups.
  • the term “pharmaceutically acceptable salt” refers to an acid group such as a carboxyl group by reacting with an acid when the compound of the present invention has a basic group such as an amino group. In the case of having a salt, it can be converted into a salt by reacting with a base.
  • the salt based on the basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid.
  • Inorganic acid salts such as salts and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salt, acetate salt, malate salt, fumarate salt, succinate salt, citrate salt, ascorbate salt, tartrate salt, succinate salt, maleate salt, etc .; and glycine salt, lysine salt And amino acid salts such as arginine salt, ornithine salt, glutamate and aspartate.
  • the salt is preferably an inorganic acid salt,
  • the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, potassium salt or lithium salt, an alkaline earth metal salt such as a calcium salt or magnesium salt, an aluminum salt or an iron salt.
  • Metal salt; inorganic salt such as ammonium salt; 2-methylpropan-2-amine salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methyl Glucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethyl Ammonium salt, tris (hydroxymethyl) amino Amine salts such as organic salts such as me
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof includes all isomers (keto-enol isomer, stereoisomer, etc.).
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has various isomers when an asymmetric carbon atom is present in the molecule.
  • these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.
  • stereoisomers as described above can be obtained by isolating the synthesized compound according to the present invention using a conventional optical resolution method or separation method, if desired.
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof may contain an unnatural proportion of atomic isotopes at one or more of atoms constituting such a compound.
  • atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like.
  • the compound may also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be left in the atmosphere or recrystallized to absorb moisture and adsorb water. It may become a hydrate, and such a hydrate is also encompassed in the compound or salt of the present invention.
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof may absorb a certain other solvent and become a solvate, and such a solvate is also present in the present invention. Included in the compounds or salts of the invention.
  • the compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has an excellent hypoglycemic action, such as diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia. , Glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, It is useful as a medicament used in a therapeutic agent / treatment method for diseases such as hyperinsulinemia or a prophylactic agent / prevention method.
  • diseases such as hyperinsulinemia or a prophylactic agent / prevention method.
  • solvent used in the reaction of each step of the production method shown below is not particularly limited as long as it does not inhibit the reaction and partially dissolves the starting material, and is selected from the following solvent group, for example.
  • Solvent groups include aliphatic hydrocarbons such as hexane, pentane, heptane, petroleum ether, cyclohexane; aromatic hydrocarbons such as toluene, benzene, xylene; dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, di- Halogenated hydrocarbons such as chlorobenzene; ethers such as diethyl ether, diisopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetone, methyl ethyl ketone
  • the acid used in the reaction in each step of the production method shown below is not particularly limited as long as it does not inhibit the reaction, and is selected from the following acid group.
  • the acid group includes inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid; organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, pentafluoropropionic acid; and , Methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and organic sulfonic acids such as camphorsulfonic acid.
  • Base groups include alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; lithium hydroxide and sodium hydroxide Alkali metal hydroxides such as potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; alkali metal phosphates such as sodium phosphate and potassium phosphate; lithium hydride Alkali metal hydrides such as sodium hydride, potassium hydride; Alkali metal amides such as lithium amide, sodium amide, potassium amide; Lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium metal tert-butoxide Lithium oxide such as lithium diisopropylamide (LDA),
  • LDA lithium diisopropylamide
  • reaction temperature varies depending on the solvent, starting material, reagent and the like
  • reaction time varies depending on the solvent, starting material, reagent and the like.
  • the target compound in each step is isolated from the reaction mixture according to a conventional method.
  • the target compound is, for example, (i) removing insoluble matters such as a catalyst if necessary, and (ii) water and a solvent immiscible with water (for example, dichloromethane, chloroform, diethyl ether, ethyl acetate, toluene) And (iii) the organic layer is washed with water and dried using a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and (iv) the solvent is distilled off. can get.
  • a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate
  • the obtained target product can be further purified by a conventional method, for example, recrystallization, reprecipitation, silica gel column chromatography or the like, if necessary.
  • the target compound in each step can be directly used in the next reaction without purification.
  • Production method 1 is a method for synthesizing a compound having a partial structure represented by formula (II). The process of synthesizing compound (5) from compound (1) is shown. In addition, also when the ring B in general formula (I) is unity, it can manufacture by the same method (it is the same also in the following other methods).
  • Y 1 represents a substituent necessary for bonding the compound (1) and the A ring, and represents, for example, boronic acid, boronic acid ester, magnesium halide, zinc halide and the like.
  • Step A-1 is a step for producing compound (3) by conducting a coupling reaction between compound (1) and compound (2) in the presence of a transition metal catalyst.
  • Compound (1) is commercially available or can be easily prepared from known compounds.
  • Compound (2) represents various organometallic compounds used for coupling with aryl halides, and preferably Y 1 is a boronic acid or boronic ester.
  • the synthesis method used in this step is not particularly limited as long as it does not affect other parts of the compound, but generally known methods in the art of organic synthetic chemistry, such as Palladium Reagents and Catalysts (2004, Johns). Wiley & Sons Ltd.).
  • the metal catalyst used is preferably tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), dichloromethane complex.
  • the base used is preferably an alkali metal carbonate, alkali metal phosphate or alkali metal alkoxide, but more preferably cesium carbonate or potassium phosphate n-hydrate.
  • the solvent used is preferably an ether, water or a mixture thereof, but more preferably a mixed solvent of 1,4-dioxane and water, or a mixture of 1,2-dimethoxyethane and water. It is a solvent.
  • the reaction temperature is preferably from room temperature to 120 ° C., more preferably from 80 ° C. to 100 ° C.
  • Step A-2 is a step of heating compound (3) and compound (4) obtained in step A-1 to produce compound (5) by an aromatic substitution reaction.
  • Compound (4) is commercially available or can be easily prepared from known compounds. Examples of the solvent used include alcohols, amides and sulfoxides, and ethanol, 1-butanol or dimethyl sulfoxide is preferable. Alternatively, it can be carried out without solvent. If necessary, the reaction can be promoted by adding a catalytic amount of an organic acid such as trifluoroacetic acid.
  • the reaction temperature is from room temperature to 140 ° C, preferably from 90 ° C to 140 ° C.
  • Step A-3 is a step of producing compound (6) by reacting compound (1) with compound (4). This step can be performed in the same manner as the step A-2.
  • Step A-4 is a step for producing compound (5) by conducting a coupling reaction between compound (6) obtained in step A-3 and compound (2) in the presence of a transition metal catalyst. This step can be performed in the same manner as the step A-1.
  • Production method 2 is a method different from [Production method 1] for obtaining compound (3).
  • Step B-1 is a step of synthesizing compound (8) by activating compound (7) and reacting compound (7a).
  • Compound (7) and compound (7a) are commercially available or can be easily prepared from known compounds.
  • the activator for the compound (7) include lithium amide, alkali metal silylamide, alkyllithium, and alkylmagnesium halide, and preferably n-butyllithium.
  • the solvent used include aliphatic hydrocarbons, aromatic hydrocarbons, and ethers, and tetrahydrofuran is preferred.
  • the reaction temperature is from -78 ° C to room temperature.
  • Step B-2 is a step of synthesizing compound (9) by cyclizing compound (8) obtained from step B-1 using hydrazine.
  • the hydrazine used in the reaction can be its hydrochloride or hydrate.
  • the solvent to be used include alcohols, amides, and sulfoxides, and alcohols such as ethanol and 1-butanol are preferable.
  • the reaction temperature is preferably from room temperature to 140 ° C, more preferably from 80 ° C to 120 ° C.
  • Step B-3 is a step of synthesizing compound (3) by allowing a chlorinating agent to act on compound (9) obtained from step B-2.
  • the chlorinating agent to be used is not particularly limited as long as it does not affect other parts of the compound, and examples thereof include sulfonyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus oxychloride and the like. Preferred is phosphorus oxychloride.
  • the solvent used is preferably aliphatic hydrocarbons, aromatic hydrocarbons, or no solvent, but more preferably no solvent.
  • the reaction temperature is preferably from room temperature to 150 ° C, more preferably from 80 ° C to 120 ° C.
  • Production method 3 is a synthesis method of compound (8) different from [Production method 2].
  • A, D, R 1 , R 2 , and R 3 are the same as those in the general formulas (I), (II) and the above production method, and Alkyl is C 1 —C 6 represents an alkyl group.
  • Y 2 is a substituent necessary for bonding the compound (12) and the A ring, and represents a halogen group, a triflate group, or the like.
  • Step C-1 is a step of converting compound (10) into silyl ether compound (11) by the action of trimethylsilyl cyanide under basic conditions.
  • the compound (10) used is commercially available or can be easily prepared from known compounds.
  • the base used is preferably an organic amine, more preferably triethylamine.
  • Examples of the solvent used include aliphatic hydrocarbons, aromatic hydrocarbons, and ethers, and chloroform is preferred.
  • the reaction temperature is 0 ° C to 70 ° C, preferably 50 ° C.
  • Step C-2 is a step of synthesizing compound (8) by activating compound (11) obtained in step C-1 with a base and then reacting with compound (12).
  • the compound (12) used is commercially available or can be easily prepared from known compounds.
  • the base used include alkali metal hydrides, alkali metal amides, metal alkoxides, lithium amides, alkali metal silylamides, and alkyllithiums, and alkali metal silylamides such as potassium bistrimethylsilylamide are preferred.
  • the solvent used include aliphatic hydrocarbons, aromatic hydrocarbons, and ethers, and tetrahydrofuran is preferred.
  • the reaction temperature is -78 ° C to 0 ° C.
  • Compound (8) can be obtained by hydrolyzing the ester group of the obtained compound (8) ′.
  • Production method 4 is a synthesis method of compound (5) different from [Production method 1].
  • Step D-1 is a step of synthesizing compound (14) by intramolecular cyclization of compound (13) with hydrazine.
  • Compound (13) is commercially available or can be easily prepared from known compounds. This step can be performed in the same manner as the step B-2.
  • step D-2 compound (5) is synthesized by coupling reaction with aryl halide (15) in the presence of a transition metal catalyst using compound (14) obtained in step D-1. It is.
  • the compound (15) used is commercially available or can be easily prepared from known compounds.
  • the reagents and reaction conditions used in this step can be the same as those used in step A-1.
  • Production method 5 is a synthesis method of compound (5) different from [Production method 1] and [Production method 4].
  • A, D, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are the same as those in the general formulas (I), (II), and the above production method. Show significance.
  • Y 3 represents a C 1 -C 6 alkyl group or an alkoxycarbonylmethylene group.
  • Step E-1 is a step of synthesizing compound (16) from compound (9) obtained in [Production Method 2] using a sulfurizing agent.
  • the sulfurating agent used include 2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawson reagent) and pentasulfide. Examples thereof include 2-phosphorus, and 2-phosphorus pentasulfide is preferable.
  • the solvent used is aromatic hydrocarbons or solvent-free, but is preferably solvent-free.
  • the reaction temperature is preferably from 100 ° C. to 180 ° C., but more preferably, the reaction is performed at 150 ° C. using a microwave reactor.
  • Step E-2 is a step of synthesizing compound (17) by reacting compound (16) obtained in step E-1 with an alkylating agent in the presence of a base.
  • the alkylating agent to be used is preferably an alkyl halide or a haloacetic acid ester, and more preferably iodoethane or ethyl bromoacetate.
  • the solvent used include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, nitriles, amides, and sulfoxides. Is an ether such as tetrahydrofuran.
  • the reaction temperature is 0 ° C. to 60 ° C., preferably room temperature.
  • Step E-3 is a step of synthesizing compound (5) by adding compound (4) to compound (17) obtained from step E-2.
  • the solvent used is preferably an organic acid, more preferably acetic acid.
  • the reaction temperature is from room temperature to 150 ° C, preferably 130 ° C.
  • Production method 6 is a method for synthesizing a compound having a partial structure represented by formula (III).
  • Step H-1 is a method in which either compound (26) or compound (27) is led to isocyanate and the remaining compound is reacted to obtain compound (28).
  • Preferred is a method in which the compound (27) is led to the corresponding isocyanate compound and then reacted with the compound (26).
  • Compound (26) and compound (27) are commercially available or can be easily prepared from known compounds.
  • the method for converting compound (27) into isocyanate is not particularly limited as long as it does not affect other parts of the compound, but a method well known in the art of synthetic organic chemistry, for example, The forth series of It can be performed according to the method described in experimental chemistry (1992, the chemical society of japan, pp. 473-483).
  • Preferred examples of the reactant used include phosgene, triphosgene, oxalyl chloride, and the like, and more preferred is oxalyl chloride.
  • the solvent used include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, and nitriles, and dichloroethane is preferable.
  • the reaction temperature is preferably from room temperature to 120 ° C., more preferably 90 ° C. (Step H-1b).
  • the solvent used include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, nitriles, amides, and sulfoxides. Is 1,4-dioxane.
  • the reaction temperature is preferably room temperature to 60 ° C., more preferably room temperature.
  • Step H-2 is a step of synthesizing compound (29) by intramolecular cyclization of compound (28) obtained from step H-1 in the presence of a base.
  • a base examples include alkali metal silylamide, alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal phosphate, and alkali metal hydride, and preferably sodium hydride.
  • the solvent used include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, amides, and sulfoxides. N, N-dimethylformamide is preferable. is there.
  • the reaction temperature is preferably from room temperature to 100 ° C, more preferably 70 ° C.
  • Step H-3 is a step of synthesizing compound (30) by reacting compound (29) obtained in step H-2 with a sulfurizing agent. This step can be performed in the same manner as the step E-1.
  • Step H-4 is a step of synthesizing compound (31) by reacting compound (30) obtained in step H-3 with an alkylating agent in the presence of a base. This step can be performed in the same manner as the step E-2.
  • Step H-5 is a step of synthesizing compound (32) by substituting compound (4) for compound (31) obtained from step H-4. This step can be performed in the same manner as the step E-3.
  • Production method 7 is an intermediate synthesis method different from [Production method 6] in the synthesis of a compound having a partial structure represented by formula (III).
  • Step I-1 is a step derived from compound (33) for compound (29) shown in production method 6. This step is a step of synthesizing compound (29) by allowing an activator to act on compound (33) and then performing intramolecular cyclization in the presence of a base.
  • Compound (33) is commercially available or can be easily prepared from known compounds.
  • the activator used is, for example, N-chlorocarbonyl isocyanate, sulfa isocyanatoyl chloride, but is preferably sulfa isocyanatoyl chloride.
  • the solvent used include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, nitriles, amides, sulfoxides or mixtures thereof. Is preferably a mixed solvent of tetrahydrofuran and ethyl acetate.
  • the base used is an aqueous solution of an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the reaction temperature is from -40 ° C to room temperature, preferably from -15 ° C to room temperature.
  • the target compound is collected from the reaction mixture according to a conventional method.
  • the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, washed with water, and the target compound is then contained.
  • the organic layer is separated, dried over anhydrous magnesium sulfate and the like, and then the solvent is distilled off.
  • the obtained target product can be obtained by a conventional method such as recrystallization, reprecipitation, or a method commonly used for separation and purification of organic compounds, such as adsorption column chromatography, distribution column chromatography, etc. Separation and purification by eluting with a suitable eluent by combining a method using a synthetic adsorbent, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel. can do.
  • optically active substance can be separated and purified by a chiral column as necessary.
  • the compound having the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is administered in various forms.
  • the administration form is not particularly limited, and is determined according to various preparation forms, patient age, sex and other conditions, the degree of disease, and the like.
  • it is orally administered in the case of tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules and capsules.
  • a normal fluid such as glucose or amino acid
  • it is administered intramuscularly, intradermally, subcutaneously or intraperitoneally as needed.
  • a suppository it is administered intrarectally. Oral administration is preferred.
  • auxiliaries that can be generally used in the field of known pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, solubilizers, flavoring agents, and coating agents in accordance with conventional methods. Can be formulated.
  • conventionally known carriers can be widely used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like.
  • carriers such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like.
  • binder such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder Sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and other disintegrants, sucrose, stearin, cacao butter, hydrogenated oil and other disintegration inhibitors, Class Ammoni Absorption accelerators such as mud base, sodium lauryl sul
  • the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.
  • those conventionally known in this field can be widely used as carriers, for example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and other excipients, gum arabic powder, Examples thereof include binders such as tragacanth powder, gelatin and ethanol, and disintegrants such as lamina lankanten.
  • conventionally known carriers can be widely used as carriers, such as polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like. it can.
  • the solutions and suspensions are preferably sterilized and isotonic with blood, and in the form of these solutions, emulsions and suspensions, this is used as a diluent.
  • Any of those commonly used in the field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters.
  • a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation.
  • Ordinary solubilizers, buffers, soothing agents, etc. may be added. It may be added.
  • colorants may be included.
  • preservatives may be included.
  • fragrances may be included.
  • flavoring agents may be included.
  • sweetening agents may be included.
  • the amount of the active ingredient compound contained in the pharmaceutical preparation is not particularly limited and is appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 30% by weight in the total composition. Is appropriate.
  • the dose varies depending on symptoms, age, body weight, administration method, dosage form, etc., but is usually 0.001 mg / kg (preferably 0.01 mg / kg, more preferably 0.1 mg as a lower limit for adults per day) / mg), and 200 mg / kg (preferably 20 mg / kg, more preferably 10 mg / kg) as the upper limit can be administered once to several times.
  • the compound of the present invention can be used in combination with various therapeutic or prophylactic agents for the diseases for which the present invention is considered to be effective.
  • the combination may be administered simultaneously or separately in succession or at desired time intervals.
  • the simultaneous administration preparation may be a compounding agent or may be separately formulated.
  • the compound of the present invention and a pharmaceutically acceptable salt thereof have an excellent hypoglycemic action, such as diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia, impaired glucose tolerance, diabetic nerves Disorders, such as diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia, etc.
  • diabetes type 1 diabetes, type 2 diabetes, gestational diabetes, etc.
  • postprandial hyperglycemia impaired glucose tolerance
  • diabetic nerves Disorders such as diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia, etc.
  • Useful as a therapeutic or prophylactic agent since it is low in toxicity and excellent in safety, it can be said
  • Reference Example R1 The compound (9.4 g, 36 mmol) and ethyl 4-aminophenyl acetate (6.4 g, 36 mmol) were dissolved in n-butanol (150 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred at 135 ° C. for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure.
  • the compound obtained in a) (10.3 g, 26 mmol) was dissolved in ethanol (70 mL) and tetrahydrofuran (70 mL), 5N aqueous sodium hydroxide solution (10.4 mL) was added, and the mixture was stirred at room temperature for 3 days.
  • the reaction mixture was concentrated under reduced pressure, 5N hydrochloric acid (10.4 mL) was added to the residue, and the insoluble material was collected by filtration.
  • the compound of Reference Example R4 200 mg, 0.83 mmol was dissolved in 1,4-dioxane (10 mL), methyl (4-bromo-3-fluorophenyl) acetate (250 mg, 1.01 mmol), 2-dicyclohexylphosphino-3 , 6-Dimethoxy-2 ', 4', 6'-triisopropyl-1,1'-biphenyl (174 mg, 0.32 mmol), palladium (II) acetate (30 mg, 0.13 mmol), cesium carbonate (354 mg, 1.09 mmol) ) was added and stirred with heating at 150 ° C.
  • the compound (169 mg, 0.42 mmol) obtained in production step 2 (a) is dissolved in a mixed solvent of tetrahydrofuran (9 mL) and methanol (9 mL), and 5N aqueous sodium hydroxide solution (0.87 mL) is added at room temperature for 18.5 hours. Stir. The reaction mixture was neutralized with 2N hydrochloric acid (0.5 mL), and the reaction mixture was concentrated under reduced pressure.
  • Step 3 (a): Production of 1-chloro-4- [2- (pyridin-2-ylmethoxy) phenyl] -6,7-dihydro-5H-cyclopenta [d] pyridazine
  • Compound of Reference Example 1 300 mg, 1.22 mmol ) was dissolved in N, N-dimethylformamide (10 mL), 2- (bromomethyl) pyridine ⁇ hydrobromide (460 mg, 1.82 mmol) was added, and the mixture was cooled to 0 ° C. Thereafter, sodium hydride (80 mg, 1.8 mmol) was added, followed by stirring at room temperature for 5 hours.
  • Compound (230 mg, 0.70 mmol) obtained in Step 3 (a) was dissolved in 1,4-dioxane (5.0 mL) and ethyl (4-amino-3-fluorophenyl) acetate (140 mg , 0.71 mmol), 2-dicyclohexylphosphino-3,6-dimethoxy-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl (75 mg, 0.14 mmol), palladium (II) acetate (16 mg, 0.070 mmol) and cesium carbonate (0.68 g, 2.10 mmol) were added, and the
  • the compound (60 mg, 0.12 mmol) obtained in Step 3 (b) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and methanol (5 mL), and 1N aqueous sodium hydroxide solution (1.0 mL) was added and stirred for 1 hour. The reaction mixture was neutralized with 2N hydrochloric acid (0.5 mL), and the reaction mixture was concentrated under reduced pressure.
  • Compound (350 mg, 1.15 mmol) obtained in Step 4 (a) was suspended in n-butanol (15 ml), and ethyl (4-amino-3-fluorophenyl) acetate (300 mg, 1.5 mmol) was suspended.
  • trifluoroacetic acid (0.23 mL, 3.5 mmol) were added, and the mixture was stirred at 140 ° C. for 10 hours.
  • 1,4-dichloro-6,7-dihydro-5H-cyclopenta [d] pyridazine 500 mg, 2.64 mmol
  • tert-butyl 3-aminoazetidine-1-carboxylate 600 mg, 3.48 mmol
  • 1-carboxylate Compound (110 mg, 0.339 mmol) obtained in Step 5 (a) was dissolved in 1,2-dimethoxyethane (15 ml) and water (0.5 mL), and (4-fluorobenzofuran-7 -Yl) boronic acid (91 mg, 0.51 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane complex (28 mg, 0.034 mmol), potassium phosphate (234 mg, 1.02 mmol) And stirred at 90 ° C.
  • Step 5 (b) 130 mg, 0.306 mmol
  • dichloromethane 5 ml
  • trifluoroacetic acid 3 mL
  • Oxalamide 54 mg, 0.61 mmol was dissolved in N, N-dimethylformamide (5 mL) and (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b ] Pyridin-3-yloxy) methaniminium hexafluorophosphate (232 mg, 1.23 mmol) was added and stirred at room temperature for 15 minutes, and then the crude N- (azetidin-3-yl) -4- (4- Fluoro-1-benzofuran-7-yl) -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-amine dissolved in N, N-dimethylformamide (5 mL) was added dropwise at room temperature.
  • Step 6 (a): tert-butyl 3-( ⁇ 4- [2- (2-methoxyethoxy) phenyl] -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl ⁇ amino) azetidine-1 -Carboxylate Preparation
  • the compound (0.088 g, 0.27 mmol) obtained in Step 5 (a) was dissolved in 1,2-dimethoxyethane (2 mL) and water (0.5 mL), and 2- (2- Methoxyethoxy) phenylboronic acid (0.069 g, 0.35 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (0.044 g, 0.054 mmol) and tripotassium phosphate (0.115 g, 0.542 mmol) was added, followed by stirring at 100 ° C.
  • the compound obtained in Step 6 (a) (0.085 g, 0.19 mmol), trifluoroacetic acid (1.5 mL), oxamic acid (0.017 g, 0.19 mmol), O- (7-aza-1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (0.081 g, 0.21 mmol) and triethylamine (0.081 mL, 0.58 mmol) was used to give the title compound (0.024 g, 0.058 mmol, 30%) as a solid.
  • 1,4-Dichloro-6,7-dihydro-5H-cyclopenta [d] pyridazine (575 mg, 3.00 mmol) was suspended in n-butanol (15 ml) and ethyl (4-amino-3-fluorophenyl) acetate ( 720 mg, 3.65 mmol) was added, and the mixture was stirred at 140 ° C. for 4 hours.
  • the compound obtained in step 7 (a) (75 mg, 0.21 mmol), N- (2-methoxyethyl) -2- (4,4 , 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (400 mg, 1.44 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane complex (80 mg, 0.10 mmol), potassium phosphate (800 mg, 2.83 mmol), 1,2-dimethoxyethane (20 ml) and water
  • the compound obtained in step 7 (b) (18 mg, 0.039 mmol), 1N aqueous sodium hydroxide solution (1.0 mL), methanol ( 5mL), 2N ammonia / isopropanol solution (0.036 mL, 0.072 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy )
  • methanium hexafluorophosphate (30 mg, 0.080 mmol)
  • N, N-diisopropylethylamine 0.0
  • the compound obtained in step 5 (a) (0.350 g, 1.08 mmol) was dissolved in 1,2-dimethoxyethane (10 mL) and water (1 mL), and the mixture was brought to room temperature.
  • Compound (0.249 g, 0.525 mmol) obtained in Step 8 (a) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) at room temperature. And then stirred at room temperature for 4 hours.
  • the compound (0.154 g, 0.325 mmol) obtained in Step 8 (b) was dissolved in ethanol (3 mL), and 1N hydroxylated under ice cooling. An aqueous sodium solution (0.390 mL, 0.390 mmol) was added, and the mixture was stirred for 30 minutes.
  • the compound obtained in Step 9 (a) (42 mg, 0.13 mmol), 2-methoxyphenylboronic acid (30 mg, 0.20 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium
  • the title compound (36 mg, 70%) was obtained as a solid using II), dichloromethane complex (14 mg, 0.017 mmol), and potassium phosphate n-hydrate (105 mg, 0.40 mmol).
  • Step 9 (c) Step 3 (c) for producing 2- (3-fluoro-4- ⁇ [6- (2-methoxyphenyl) -4,5-dimethylpyridazin-3-yl] amino ⁇ phenyl) acetamide; Similarly, the title compound (24 mg, 78%) was obtained as a solid from the compound (32 mg, 0.081 mmol) obtained in Step 9 (b).
  • Step 10 (a): Preparation of ethyl ⁇ 4-[(7-chlorothieno [2,3-d] pyridazin-4-yl) amino] -3-fluorophenyl ⁇ acetate 4,7-dichlorothieno [2,3-d] pyridazine (300 mg, 1.46 mmol) was dissolved in ethanol (50 mL), and ethyl (4-amino-3-fluorophenyl) acetate / hydrobromide (487 mg, 1.75 mmol) was added and the mixture was stirred at 100 ° C. for 3 hours. Insoluble material was filtered off using ethanol, and the filtrate was concentrated under reduced pressure.
  • the compound obtained in Step 10 (a) 300 mg, 0.82 mmol
  • 2-methoxyphenylboronic acid 300 mg, 1.14 mmol
  • [1,1′-bis (diphenylphosphino) ferrocene] dichloro Using palladium (II), dichloromethane complex (80 mg, 0.10 mmol), potassium phosphate n-hydrate (750 mg, 2.81 mmol), 1,2-dimethoxyethane (15 ml), water (1 mL), the title compound ( 162 mg, 0.37 mmol, 45%) was obtained as a solid.
  • Step 10 (c) for producing 2- (3-fluoro-4- ⁇ [7- (2-methoxyphenyl) thieno [2,3-d] pyridazin-4-yl] amino ⁇ phenyl) acetamide ),
  • the compound obtained in step 10 (b) (130 mg, 0.297 mmol), 1N aqueous sodium hydroxide solution (2.0 mL), tetrahydrofuran (3 mL), methanol (3 mL), 2N ammonia / isopropanol solution (0.300 mL, 0.600 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methaninium hexafluorophosphate (230 mg , 0.61 mmol), N, N-diisopropylethylamine (0.100 mL, 0.60 mmol) and N, N-d
  • the compound obtained in Step 10 (a) (300 mg, 0.82 mmol), 2-methoxyethoxyphenylboronic acid (300 mg, 1.53 mmol), [1,1′-bis (diphenyl) Phosphino) ferrocene] dichloropalladium (II), dichloromethane complex (80 mg, 0.10 mmol), potassium phosphate n-hydrate (750 mg, 2.81 mmol), 1,2-dimethoxyethane (15 ml), water (1 mL) Used to give the title compound (150 mg, 0.311 mmol, 38%) as a solid.
  • the compound obtained in step 11 (a) (150 mg, 0.311 mmol), 1N aqueous sodium hydroxide solution (2.0 mL), tetrahydrofuran (3 mL), methanol (3 mL), 2 Normal ammonia / isopropanol solution (0.300 mL, 0.600 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methaniminium Using hexafluorophosphate (230 mg, 0.61 mmol), N, N-diisopropylethylamine (0.100 hexafluorophosphate (230
  • the compound obtained in Step 12 (a) (300 mg, 0.83 mmol), 2-methoxyethoxyphenylboronic acid (300 mg, 1.5 mmol), [1,1′-bis (diphenyl) Phosphino) ferrocene] dichloropalladium (II) -dichloromethane complex (80 mg, 0.10 mmol), potassium phosphate n-hydrate (800 mg, 3.0 mmol), 1,2-dimethoxyethane (20 ml), water (0.5 mL) To give the title compound (125 mg, 0.26 mmol, 31%) as a solid.
  • the compound obtained in Example 12 (b) (125 mg, 0.26 mmol), 1N aqueous sodium hydroxide solution (2.0 mL), methanol (3 mL), 2N ammonia / isopropanol Solution (0.26 mL, 0.52 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (200 mg, 0.53 mmol), N, N -The title compound (50 mg, 0.11 mmol, 43%) was obtained as a solid using -
  • the compound obtained in step 13 (a) (390 mg, 1.0 mmol), ethyl (4-amino-3-fluorophenyl) acetate / hydrobromide (400 mg, 1.5 mmol), trifluoroacetic acid (0.23 mL, 3.0 mmol), and n-butanol (5 mL) were used to give the title compound (482 mg, 0.92 mmol, 92%) as an oil.
  • the compound obtained in step 13 (b) (482 mg, 0.92 mmol), 1N aqueous sodium hydroxide solution (2.0 mL), methanol (5 mL), 2N ammonia Isopropanol solution (0.700 mL, 1.40 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (530 mg, 1.4 mmol), N, The title compound (100 mg, 0.20 mmol, 22%) was obtained as a solid using N-diisopropylethylamine (0.24 m
  • the compound obtained in Step 10 (a) (220 mg, 0.60 mmol), 4-chloro-2-methoxyphenylboronic acid (200 mg, 1.0 mmol), [1,1′- Bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane complex (50 mg, 0.060 mmol), potassium phosphate n-hydrate (520 mg, 1.95 mmol), 1,2-dimethoxyethane (20 ml), water ( 0.5 mL) was used to give the title compound (190 mg, 0.40 mmol, 67%) as a solid.
  • Step 3 (c) ethyl (3-fluoro-4- ⁇ [7- (2-methoxyphenyl) thieno [2,3-d] pyridazin-4-yl] obtained in Example 14 (a) was used.
  • Amino ⁇ phenyl) carboxylate (190 mg, 0.40 mmol), 1 N aqueous sodium hydroxide (2.0 mL), methanol (10 mL), 2 N ammonia / isopropanol solution (0.40 mL, 0.80 mmol), O- (7- Azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (300 mg, 0.80 mmol), N, N-diisopropylethylamine (0.14 mL, 0.80 mmol), N, N -Dimethylformamide (10 mL) was used to obtain the title compound (110 mg, 0.25 mmol, 62%) as a solid.
  • Compound of Reference Example R3 (0.94 g, 4.8 mmol) was dissolved in N, N-dimethylformamide (25 mL), potassium carbonate (1.1 g, 7.7 mmol) was added, and the mixture was stirred at 70 ° C. for 10 hr. Water and ethyl acetate were added to the reaction solution, and after liquid separation, the organic layer was dried over anhydrous sodium sulfate.
  • Compound (210mg, 0.58mmol) obtained in Production Process 15 (a) and compound obtained in Reference Example R5 (110mg, 0.48mmol) were dissolved in dimethyl sulfoxide (25mL) And stirred at 120 ° C. for 6 hours.
  • the title compound 60 mg, 0.12 mmol, 49%) was obtained from the compound (87 mg, 0.16 mmol) obtained in Step 15 (b).
  • Step 15 (b) was obtained as a solid.
  • the compound obtained in step 16 (a) (135 mg, 0.37 mmol), n-butanol (15 mL), butyl (4-amino-3 Using -fluorophenyl) acetate (110 mg, 0.48 mmol) and trifluoroacetic acid (0.085 mL, 1.1 mmol), the title compound (87 mg, 0.16 mmol, 42%) was obtained as an oily substance.
  • the compound obtained in step 16 (b) (87 mg, 0.16 mmol), 1N aqueous sodium hydroxide solution (1.0 mL), methanol (5 mL), 2 Normal ammonia / isopropanol solution (0.16mL, 0.32mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (130mg, 0.32mmol) , N, N-diisopropylethylamine (0.060 mL, 0.032 mmol) and N, N-dimethylformamide (10 mL
  • Compound of Reference Example R3 100 mg, 0.38 mmol
  • 2- (bromomethyl) -1,3-thiazole reference: Inorganic Chemistry, 2016, vol. 55, 619-632; 88 mg, 0.49 mmol
  • potassium carbonate 100 mg, 0.76 mmol
  • the compound (98 mg, 0.27 mmol) obtained in step 17 (a) and ethyl (4-amino-3-fluorophenyl) acetate / hydrobromide 75 mg, 0.27 mmol
  • trifluoroacetic acid 0.1 mL
  • n-butanol 3 mL
  • Reference Example R3 Of the title compound (300 mg, 1.14 mmol), methyl 2- (bromomethyl) phenyl acetate (314 mg, 1.4 mmol), sodium hydride (70 mg, 1.7 mmol), N, N-dimethylformamide (10 mL). 200 mg, 0.49 mmol, 43%) was obtained as a solid.
  • compound (200 mg, 0.49 mmol) was dissolved in ethanol (15 mL), and 2- (4-amino-3-fluorophenyl) acetamide (220 mg, 1.3 mmol) was dissolved. In addition, the mixture was stirred at 100 ° C. for 2 hours.
  • Compound (50 mg, 0.092 mmol) obtained in Step 18 (b) was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL), and 1N aqueous sodium hydroxide solution (1 mL) was added. The mixture was stirred for 1 hour at 45 ° C.
  • 2-iodophenol 1.5 g, 6.8 mmol
  • Tetrahydrofuran 20 mL
  • tert-butyl [2- (2-hydroxyethoxy) ethyl] carbamate reference: Journal of Medicinal Chemistry, 2000, vol. 43, p.
  • the compound (1.4 g, 3.4 mmol) obtained in production step 19 (a) was dissolved in toluene (25 mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 g, 10 mmol), tetrakis (triphenylphosphine) palladium (200 mg, 0.17 mmol), and triethylamine (1.9 mL, 13 mmol) were added, and the mixture was stirred at 120 ° C.
  • the compound obtained in Step 19 (b) (143 mg, 0.36 mmol), tert-butyl (2- ⁇ 2 -[2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] ethoxy ⁇ ethyl) carbamate (300 mg, 0.72 mmol), [1,1′-bis ( Diphenylphosphino) ferrocene] dichloropalladium (II) / dichloromethane complex (40 mg, 0.050 mmol), potassium phosphate / n-hydrate (400 mg
  • the compound obtained in Step 19 (c) (164 mg, 0.26 mmol), 1N aqueous sodium hydroxide solution (2.0 mL), methanol (10 mL), 2N ammonia / isopropanol solution (0.26 mL, 0.52 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium Hexafluorophosphate (200 mg, 0.52 mmol), N, N-diisopropylethylamine (0.088 mL, 0.52 mmol), N
  • 2-iodophenol 1.5 g, 6.8 mmol
  • tetrahydrofuran (20 mL
  • tert-butyl [2- (2-hydroxyethoxy) ethyl] carbamate reference: Bioorganic and Medicinal Chemistry, 2009, vol. 17, p. 2536-2543; 1.9 g, 10 mmol
  • (tributylphosphoranylidene) acetonitrile 2.7 mL, 10 mmol
  • the compound obtained in Step 20 (a) (3.1 g, 8.0 mmol), toluene (30 mL), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane ( The title compound (1.0 g, 2.5 mmol, 31%) was obtained as an oily substance using 1.8 g, 14 mmol), tetrakis (triphenylphosphine) palladium (470 mg, 0.40 mmol), and triethylamine (4.5 mL, 32 mmol).
  • the compound obtained in Step 10 (a) 350 mg, 0.96 mmol
  • the compound obtained in Example 20 (b) 1.0 g, 2.5 mmol
  • [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) ⁇ dichloromethane complex 250 mg, 0.31 mmol
  • potassium phosphate ⁇ n-hydrate 2.5 g, 3.0 mmol
  • the title compound (330 mg, 0.55 mmol, 57%) was obtained as an oily substance using 1,2-dimethoxyethane (30 ml) and water (0.5 mL).
  • the compound obtained in Step 20 (c) (100 mg, 0.17 mmol), 1N aqueous sodium hydroxide solution (1.0 mL), methanol ( 5 mL), 2 N ammonia / isopropanol solution (0.20 mL, 0.40 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (150 mg , 0.39 mmol), N, N-diisopropylethylamine (0.070 mL, 0.39 mmol) and N,
  • the compound of Reference Example 3 11.6 g, 44.2 mmol
  • 1-bromo-2-methoxyethane 9.22 g, 66.4 mmol
  • sodium hydride 1.95 g, 48.7 mmol
  • N, N-dimethylformamide 140 mL
  • the title compound 9.24 g, 28.8 mmol, 65%
  • the compound obtained in Step 21 (b) (0.050 g, 0.11 mmol), 4N hydrochloric acid-1,4-dioxane solution (0.5 mL), oxamic acid ( 0.0098g, 0.11mmol), O- (7-aza-1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (0.046g, 0.12mmol) and triethylamine (0.046 mL, 0.33 mmol) was used to obtain the title compound (0.007 g, 0.016 mmol, 15%) as a solid.
  • the compound (200 mg, 0.50 mmol) obtained in step 19 (b) the compound of Reference Example 2 (280 mg, 1.0 mmol), [1,1′- Bis (diphenylphosphino) ferrocene] dichloropalladium (II) / dichloromethane complex (40 mg, 0.050 mmol), potassium phosphate / n-hydrate (400 mg, 1.5 mmol), 1,2-dimethoxyethane (20 ml), water (0.5 mL) was used to give the title compound (120 mg, 0.24 mmol, 47%) as a solid.
  • the compound obtained in step 22 (a) (164 mg, 0.26 mmol), 1 N aqueous sodium hydroxide (2.0 mL), methanol (10 mL), 2 N ammonia Isopropanol solution (0.26 mL, 0.52 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (200 mg, 0.52 mmol), N , N-diisopropylethylamine (0.088 mL, 0.52 mmol) and N, N-dimethylformamide (10 m
  • the compound obtained in Step 10 (a) 500 mg, 1.37 mmol
  • the compound obtained in Step 23 (a) 707 mg, 2.56 mmol
  • [1,1′- Bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex 110 mg, 0.137 mmol
  • potassium phosphate n-hydrate 1.1 g, 1.37 mmol
  • 1,2-dimethoxyethane (20 mL) Water (1 mL) was used to give the title compound (100 mg, 0.209 mmol, 15%) as an oil.
  • the compound obtained in step 23 (b) (100 mg, 0.21 mmol), 1N aqueous sodium hydroxide solution (1.0 mL), methanol (10 mL), 2N ammonia / isopropanol solution (0.420 mL, 0.84 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methaninium hexafluorophosphate (160 mg , 0.42 mmol) and N, N-dimethylformamide (10 mL) to give the title compound (30 mg, 0.067 mmol, 32%) as a
  • Step 24 (a): Production of tert-butyl (3aRS, 6aRS) -5- [amino (oxo) acetyl] hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -carboxylate 5 (c) Tert-butyl (3aRS, 6aRS) -hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -carboxylate hydrochloride (0.302 g, 1.21 mmol), oxamic acid (0.119 g, 1.34) mol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methaniminium hexafluorophosphate (0.508 g, 1.34 mmol) And triethylamine (0.508 mL, 3.64 mmol) was used to give the title compound (0.145 g
  • ethanol 1 mL
  • Aqueous hydrochloric acid solution 0.55 mL
  • the compound obtained in step 25 (b) (170 mg, 0.37 mmol), 1N aqueous sodium hydroxide solution (2.0 mL), methanol (10 mL), 2N Ammonia / isopropanol solution (0.73 mL, 1.46 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methaniminium hexa
  • the title compound (50 mg, 0.115 mmol, 31%) was obtained as a solid using fluorophosphate (280 mg, 0.73 mmol) and N, N-d
  • the reaction mixture was concentrated under reduced pressure, the residue was neutralized with 5N hydrochloric acid (96 mL), and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (500 mL), and oxalyl chloride (32.5 mL) was added dropwise while stirring at room temperature. Further N, N-dimethylformamide (0.5 mL) was added. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure and further azeotroped once with toluene.
  • N, O-dimethylhydroxylamine hydrochloride 31.2 g
  • dichloromethane 400 mL
  • N, N-diisopropylethylamine 121 mL
  • the adjusted acid chloride in dichloromethane 100 mL
  • the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was poured into water and separated.
  • the aqueous layer was further extracted twice with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Furan-3-carboxylic acid (14.5 g) was dissolved in tetrahydrofuran (300 mL) and dried ice-acetone While cooling in a bath, n-butyllithium (2.6M, 97.6 mL) was added dropwise. After stirring for 10 minutes, the mixture was stirred for 30 minutes in an ice bath. The reaction solution was cooled again in a dry ice-acetone bath, and a solution of the compound (22.1 g) obtained in Example 26 (a) in tetrahydrofuran (80 mL) was added dropwise.
  • Compound obtained in Step 26 (b) (34.1 g) was suspended in butanol (400 mL), hydrazine monohydrate (12.5 mL) was added, and the mixture was stirred at 140 ° C. for 6.5 hours. The reaction mixture was cooled and concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitate was collected by filtration to give the title compound (24.7 g) as a solid.
  • the compound (24.7 g) obtained in Step 26 (c) was converted to 1, The mixture was suspended in 2-dichloroethane (30 mL), phosphorus oxychloride (21.7 mL) was added, and the mixture was stirred at 90 ° C. for 4 hours. The reaction was cooled and poured onto ice. The mixture was neutralized with 5N aqueous sodium hydroxide solution, and extracted three times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the compound (23.2 g) obtained in Step 26 (d) was dissolved in dichloromethane (200 mL). And a solution of boron tribromide (25 g) in dichloromethane (50 mL) was added dropwise while stirring in an ice bath. After completion of the dropwise addition, the mixture was stirred at room temperature for 4 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours and allowed to stand overnight.
  • the obtained compound (22.0 g) was suspended in dichloromethane (200 mL) -toluene (200 mL), and ethylene glycol monoisopropyl ether (13.0 g) and triphenylphosphine (24.0 g) were added.
  • -Butyl azodicarboxylate (21.1 g) was added slowly. After completion of the addition, the mixture was stirred at room temperature for 15 hours.
  • Compound (12.0 g) obtained in Step 26 (f) ethyl 2- (4-amino-3-fluorophenyl) acetate (7.08 g) dissolved in ethanol (100 mL) Trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at 120 ° C. for 8 hours. The reaction mixture was cooled and concentrated under reduced pressure.
  • Compound (5.46 g) obtained in Step 26 (g) was dissolved in ethanol (100 mL) and acetic acid (50 mL), and 10% palladium-carbon (4.98 g) was added, and the mixture was stirred at 50 ° C. for 6 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • the compound (9.0 g) obtained in Step 26 (h) was dissolved in ethanol (50 mL) and tetrahydrofuran (50 mL), and 5N sodium hydroxide ( 5.3 mL) was added and stirred at room temperature for 3 days. 5N Hydrochloric acid (5.3 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure.
  • the compound obtained in Step 27 (a) (300 mg, 1.95 mmol) was dissolved in tetrahydrofuran (10 mL), and -78 After cooling to 0 ° C., 2-methoxyphenylmagnesium bromide / tetrahydrofuran solution (1.0 M, 2.33 mL, 2.33 mmol) was added dropwise and stirred for 1 hour.
  • 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was used for the next reaction without purification.
  • the compound (610 mg, 2.33 mmol) obtained in Step 27 (b) was treated with ethanol. (5 mL), hydrazine monohydrate (150 mg, 3.0 mmol) was added, and the mixture was stirred at 100 ° C. for 5 hr.
  • the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with a mixed solvent of dichloromethane / methanol (10/1), and the organic layer was dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the resulting residue was used for the next reaction without purification.
  • the compound obtained in Step 27 (c) The title compound (510 mg, 1.85 mmol, 93%) was obtained as an oily substance using 510 mg, 2.0 mmol) and phosphoric trichloride (2.0 mL).
  • the compound obtained in Step 27 (d) (510 mg, 1.85 mmol) was added to dichloromethane (6 mL).
  • tribromoborane / dichloromethane solution (1.0 M, 3.0 mL, 3.0 mmol) was added at room temperature, and the mixture was stirred for 3 hours.
  • the reaction mixture was cooled to 0 ° C., saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane.
  • the organic layer was dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the resulting residue was used for the next reaction without purification.
  • Step 27 (e) Using the obtained compound (227 mg, 0.74 mmol), sodium hydride (40 mg, 2.8 mmol), 1-bromo-2-methoxyethane (0.20 mL, 2.2 mmol), N, N-dimethylformamide (10 mL), The title compound (29 mg, 0.0794 mmol, 11%) was obtained as an oily substance.
  • the compound obtained in Step 27 (f) (29 mg, 0.0794 mmol), ethyl (4-amino-3-fluorophenyl) acetate (0.140 g, 0.71 mmol), ethanol (8 mL )
  • ethanol 8 mL
  • the compound obtained in step 27 (g) (20 mg, 0.0415 mmol), 1N aqueous sodium hydroxide solution (2 mL), methanol (5 mL), 2N ammonia / isopropanol solution ( 0.073 mL, 0.146 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methaninium hexafluorophosphate (28 mg, 0.073 mmol) and N, N-dimethylformamide (4 mL) were used to obtain the title compound (15 mg, 0.033 mmol, 80%
  • Step 28 (a): Production of 4-fluoro-2- (2-methoxybenzoyl) benzoic acid 2-Bromo-4-fluorobenzoic acid (4.24 g, 19.4 mmol) is dissolved in tetrahydrofuran (50 mL), cooled to ⁇ 78 ° C., and then n-butyllithyl-hexane solution (f 2.69, 15 mL, 40.7 mmol) is added. The solution was added dropwise and stirred for 1 hour.
  • the compound (2.75 g, 10 mmol), n-butanol (20 mL), and hydrazine monohydrate (1.45 mL, 30 mmol) were used to obtain the title compound (1.8 g, 6.7 mmol, 67%) as a solid.
  • the compound (1.8 g, 6.66) obtained in Step 28 (b) was used.
  • mmol) and phosphoric trichloride (2.5 mL) to give the title compound (820 mg, 2.84 mmol, 43%) as a solid.
  • the compound obtained in Step 28 (c) (320 mg, 1.10 mmol) was dissolved in dichloromethane (4 mL).
  • a tribromoborane / dichloromethane solution (1.0 M, 2.0 mL, 2.0 mmol) was added at room temperature, and the mixture was stirred for 3 hours.
  • the reaction mixture was cooled to 0 ° C., saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane.
  • the organic layer was dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the resulting residue was used for the next reaction without purification.
  • the compound (ca 1.1 mmol) obtained in (d), (3-chloropyridin-2-yl) methyl methanesulfonate (366 mg, 1.65 mmol), cesium carbonate (780 mg, 2.4 mmol), N, N-dimethylformamide ( 15 mL) was used to give the title compound (280 mg, 0.700 mmol, 64%) as a solid.
  • the compound obtained in step 28 (e) (100 mg, 0.25 mmol), ethyl (4-amino-3-fluorophenyl) acetate (0.140 g, 0.71 mmol) , Trifluoroacetic acid (0.020 mL) and ethanol (5 mL) were used to obtain the title compound (127 mg, 0.226 mmol, 90%) as a solid.
  • the compound obtained in Step 28 (f) (127 mmol, 0.226 mmol), 1N aqueous sodium hydroxide solution (2 mL), methanol (5 mL), 2N ammonia ⁇ Isopropanol solution (0.500 mL, 1.00 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methaninium hexafluoro
  • the title compound (85 mg, 0.160 mmol, 71%) was obtained as a solid using phosphate (180 mg, 0.500 mmol) and N
  • the compound obtained in Step 29 (a) ( 620 mg, 2.16 mmol) was dissolved in N, N-dimethylformamide (10 mL), sodium hydride (100 mg, 2.6 mmol) was added, and the mixture was stirred at 100 ° C. for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate.
  • the compound obtained in Step 29 (b) 230 mg, 0.953 mmol was dissolved in pyridine (5 mL), diphosphorus pentasulfide (233 mg, 1.05 mmol) was added, and the mixture was stirred at 110 ° C. for 5 hours. Thereafter, diphosphorus pentasulfide (270 mg, 1.21 mmol) was added to the reaction solution, and the mixture was stirred at 150 ° C. for 5 hours.
  • Acetamide production step 29 (d) compound (90 mg, 0.26 mmol) was dissolved in acetic acid (5 mL), 2- (4-amino-3-fluorophenyl) acetamide (100 mg, 0.595 mmol) was added, Stir at 130 ° C. for 5 hours.
  • the compound obtained in Step 29 (c) ( To 8.3 mmol), potassium carbonate (5.7 g, 42 mmol), tetrahydrofuran (10 mL) and water (5 mL) were added. Thereafter, iodoethane (1.94 g, 12.4 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate.
  • the compound obtained in Step 30 (a) ( 600 mg, 2.1 mmol) was dissolved in dichloromethane (4 mL).
  • the reaction solution was cooled to 0 ° C., boron tribromide (17% dichloromethane solution, 3.2 mL, 3.2 mmol) was added, and the mixture was stirred for 2 hours.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane and ethyl acetate.
  • the organic layer was dried over magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the resulting residue was used for the next reaction without purification.
  • the compound (1.0 mmol) obtained in Step 30 (b) 2- (bromomethyl) -1,4-dioxane (0.26 mL, 2.0 mmol), cesium carbonate (1.0 g, 3.0 mmol) and N, N-dimethylformamide (10 mL) were used to give the title compound (160 mg, 0.43 mmol, 43%) as an oil.
  • the compound obtained in Step 30 (d) (75 mg, 0.15 mmol), 1N aqueous sodium hydroxide solution (1.0 mL) , Methanol (5 mL), 2N ammonia, isopropanol solution (0.300 mL, 0.60 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridine-
  • the title compound (56 mg, 0.12 mmol, 81%) was obtained as a solid using 3-yloxy) methaniminium hexafluorophosphate (100 mg, 0.30 mmol) and N, N-
  • Step 31 (a): tert-butyl 3-[(7-chlorothieno [2,3-d] pyridazin-4-yl) amino] azetidine-1-carboxylate and tert-butyl 3-[(4-chlorothieno [2 , 3-d] pyridazin-7-yl) amino] azetidine-1-carboxylate Mixture of 4,7-dichlorothieno [2,3-d] pyridazine (1.00 g, 4.88 mmol) and tert-butyl 3-aminoazetidine-1-carboxylate (1.26 g, 7.31 mmol) at 100 ° C. for 4 hours Stir.
  • the mixture (0.300 g, 0.880 mmol) obtained in production step 31 (a) was dissolved in 1,2-dimethoxyethane (10 mL) and water (1 mL), and 4-chloro-2- (2-methoxy) was obtained at room temperature.
  • Step 32 (a): Production step R2 of N- [2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] tetrahydro-2H-pyran-4-carboxamide
  • 2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline 2.0 g, 9.0 mmol
  • acetonitrile 20 mL
  • potassium carbonate (1.45 g, 10.5 mmol
  • tetrahydro-2H-pyran-4-carbonyl chloride reference: WO2008 / 71948, 10 mmol
  • Step 32 (a) Step of producing N- (tetrahydro-2H-pyran-4-ylmethyl) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline
  • the compound obtained in step 31 (a) 100 mg, 0.293 mmol
  • the compound obtained in step 32 (b) 280 mg, 0.88 mmol
  • [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane complex 47 mg, 0.059 mmol
  • potassium phosphate n-hydrate (405 mg, 1.76 mmol
  • 1,2 -Dimethoxyethane 15 ml was used to give the title compound (100 mg, 0.202 mmol, 69%) as an oil.
  • the compound obtained in Step 32 (c) (260 mg, 0.525 mmol), dichloromethane (6 ml), trifluoroacetic acid (1.5 mL), oxamic acid (186 mg, 0.186 mmol), N, N-dimethylformamide (5 mL), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] Pyridin-3-yloxy) methaniminium hexafluorophosphate (780 mg, 2.10 mmol), N, N-diisopropylamine (0.36
  • the compound (0.296 g, 0.615 mmol) obtained in production step 33 (b) is dissolved in ethanol (9 mL), 1N aqueous sodium hydroxide solution (0.922 mL, 0.922 mmol) is added at room temperature, and 2 at room temperature. Stir for hours. A 1N aqueous hydrochloric acid solution (0.922 mL, 0.922 mmol) was added to the reaction mixture, and the mixture was concentrated under reduced pressure.
  • the compound obtained in Step 34 (a) (3.52 g, 11.9 mmol) was dissolved in n-butanol (50 mL), hydrazine monohydrate (1.15 mL, 23.7 mmol) was added, and the mixture was stirred with heating at 140 ° C. for 3 hr.
  • the reaction solution was allowed to cool to room temperature, and diethyl ether was added to form a suspension.
  • the compound obtained in Step 34 (b) (1.86 g, 6.34 mmol) was dissolved in phosphoryl chloride (12.8 mL, 140 mmol), and the mixture was heated and stirred at 100 ° C. for 2.5 hours.
  • the reaction solution was placed in an ice bath, and saturated aqueous sodium hydrogen carbonate solution was gradually added to stop the reaction. Ethyl acetate was added thereto, and the organic layer was extracted, washed with saturated brine, and dried over anhydrous magnesium sulfate.
  • tert-butyl 3-aminoazetidine-1-carboxylate 4.00 mL, 23.2 mmol
  • the compound (1.51 g, 3.37 mmol) obtained in the oxoacetamide production step 34 (d) was dissolved in dichloromethane (12 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 2 hours.
  • Step 35 (a): Preparation of 5-chloro-2- (7-chlorothieno [2,3-d] pyridazin-4-yl) -N- (2-methoxyethyl) aniline as in Step 5 (b) 4,7-dichlorothieno [2,3-d] pyridazine (800 mg, 3.9 mmol), compound of Reference Example 6 (1.2 g, 3.9 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloro Using the palladium (II) -dichloromethane complex (320 mg, 0.39 mmol), potassium phosphate n hydrate (2.7 g, 12 mmol), 1,2-dimethoxyethane (20 mL), water (0.5 mL), the title compound ( 320 mg, 0.90 mmol, 23%) was obtained as an oily substance.
  • azetidine Preparation of -1-carboxylate
  • tert-butyl 3-aminoazetidine carboxylate 466 mg, 2.71 mmol
  • the compound obtained in Step 35 (b) (180 mg, 0.367 mmol), dichloromethane (4 mL), trifluoroacetic acid (2 mL), Oxamic acid (65 mg, 0.735 mmol), N, N-dimethylformamide (5 mL), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridine-3
  • the title compound (100 mg, 0.217 mmol, 59%) was obtained as a solid using -yloxy) methaniminium hexafluorophosphate (279 mg,
  • reaction mixture was poured into dilute hydrochloric acid and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (300 mL) -methanol (50 mL), and trimethylsilyldiazomethane solution (2M, 82 mL, 0.16 mol) was added dropwise while stirring in an ice bath. After stirring for 30 minutes, the mixture was allowed to stand at room temperature. Acetic acid (5 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure.
  • Compound obtained in Step 36 (b) (15 g, 53 mmol) was dissolved in 1,4-dioxane (150 mL), 2-methoxyethylamine (12 mL, 0.13 mol) and triethylamine (18 mL, 0.13 mol) were added, and the mixture was stirred at 85 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was poured into an aqueous sodium hydrogen carbonate solution and extracted three times with dichloromethane.
  • the obtained compound (10 g, 30 mmol) was dissolved in ethanol (70 mL) and tetrahydrofuran (70 mL), 5N sodium hydroxide (12 mL, 60 mmol) was added, and the mixture was stirred at room temperature for 4 hours and allowed to stand.
  • 5N Hydrochloric acid 13 mL, 65 mmol was added to the reaction mixture, and the mixture was concentrated under reduced pressure.
  • phosphorus oxychloride 15 mL, 0.16 mol
  • the reaction mixture was poured onto ice, neutralized with 5N aqueous sodium hydroxide, hydrochloric acid and sulfuric acid, and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • [2,3-d] pyridazin-7-yl) amino] -3-methylpiperidine-1-carboxylate Compound (0.200 g, 0.592 mmol) obtained in Step 36 (e) and tert-butyl (3R , 4S) -4-amino-3-methylpiperidine-1-carboxylate and tert-butyl (3R, 4R) -4-amino-3-methyl
  • Step 36 (g): 2- ⁇ (3R, 4S) -4-[(4- ⁇ 4-fluoro-2-[(2-methoxyethyl) amino] phenyl ⁇ thieno [2,3-d] pyridazine-7 -Yl) amino] -3-methylpiperidin-1-yl ⁇ -2-oxoacetamide in the same manner as in Step 5 (c), tert-butyl (3R, 4S) -4 obtained in Step 36 (f) -[(4- ⁇ 4-Fluoro-2-[(2-methoxyethyl) amino] phenyl ⁇ thieno [2,3-d] pyridazin-7-yl) amino] -3-methylpiperidine-1-carboxylate ( 0.073 g, 0.14 mmol), 4N hydrochloric acid-1,4-dioxane solution (2 mL), oxamic acid (0.015 g, 0.17 mmol), O
  • the compound (49 g, 0.27 mol) obtained in Step 37 (a) was dissolved in methanol (500 mL), and 5N water was added.
  • Sodium oxide (80 mL, 0.40 mol) was added, and the mixture was allowed to stand at room temperature for 6 days.
  • Concentrated hydrochloric acid (35 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure.
  • Dichloromethane was added to the residue, poured into water, and extracted with dichloromethane three times. The organic layer was concentrated under reduced pressure and dried.
  • Thiophene-2-carboxylic acid 22 g, 0.17 mol
  • tetrahydrofuran 300 mL
  • n-butyllithium-hexane solution 2.65 mol / L, 130 mL, 0.35 mol
  • the compound obtained in Step 37 (c) (44 g, 0.16 mol) was dissolved in n-butanol (400 mL), hydrazine hydrate (15 mL, 0.31 mol) was added, and the mixture was stirred at 140 ° C. for 5 hours.
  • the reaction solution was cooled to room temperature and concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitate was collected by filtration to give the title compound (5.5 g, 20 mmol, 13%) as a solid.
  • the compound obtained in Step 37 (d) (7.0 g, 25 mmol) Phosphorus oxychloride (15 mL, 0.16 mol) was added, and the mixture was stirred at 90 ° C. for 3 hr.
  • the reaction mixture was poured onto ice and neutralized with 5N sodium hydroxide. Dichloromethane was added for liquid separation, and the aqueous layer was further extracted twice with dichloromethane.
  • the compound obtained in Step 37 (e) (7.1 g, 24 mmol) was dissolved in dichloromethane.
  • a solution of boron tribromide (25 g, 0.10 mol) in dichloromethane (80 mL) was added dropwise while stirring in an ice bath. After completion of the dropwise addition, the mixture was stirred at room temperature for 1.5 hours, and the reaction solution was gradually added to an ice-cooled saturated aqueous sodium bicarbonate solution.
  • the compound (3.62 g, 10.7 mmol) obtained in the carboxylate production step 37 (g) and tert-butyl 4-aminopiperidine-1-carboxylate (6.42 g, 32.0 mmol) were stirred at 150 ° C. for 13 hours.
  • the compound (2.33 g, 4.64 mmol) obtained in step 37 (h) was dissolved in 1,4-dioxane (10 mL), 4N hydrochloric acid-dioxane solution (10 mL) was added, and the mixture was stirred at room temperature for 1 hr.
  • the reaction mixture was concentrated under reduced pressure and azeotroped with 1,4-dioxane. The obtained residue was used for the next reaction without purification.
  • the compound obtained in the amine production step 37 (i) (100 mg, 0.228 mmol) was dissolved in N, N-dimethylformamide (3 mL), triethylamine (0.089 mL, 1.21 mmol), methanesulfonyl chloride (0.018 mL, 0.232 mmol).
  • the compound obtained in Step 34 (c) (18 g, 59 mmol) was dissolved in dichloromethane ( The solution was suspended in 300 mL), and a solution of boron tribromide (50 g, 0.20 mol) in dichloromethane (150 mL) was added dropwise while stirring in an ice bath. After stirring at room temperature for 2 hours, the reaction solution was poured into an aqueous sodium hydrogen carbonate solution in an ice bath and stirred for 1.5 hours. The mixture was transferred to a separatory funnel and extracted three times with dichloromethane-methanol.
  • Compound (17g) obtained in Step 38 (a) 58 mmol) was dissolved in N, N-dimethylformamide (150 mL), 2-bromoethyl methyl ether (3.5 mL, 64 mmol) and potassium carbonate (6.8 g, 87 mmol) were added, and the mixture was stirred at 70 ° C. for 8 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate.
  • pyrrolidine-1-carboxylate 38 mg, 0.704 mmol
  • (3S) -1- (tert-butoxycarbonyl) -3-aminopyrrolidine (0.38 mL, 1.98 mmol) was stirred at 150 ° C. for 9 hours.
  • the compound (267 mg, 0.528 mmol) obtained in Step 38 (c) was dissolved in 1,4-dioxane (2 mL). 4N hydrochloric acid-dioxane solution (2 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • the compound obtained in Step 39 (a) (0.021 g, 0.039 mmol), 4N hydrochloric acid- 1,4-dioxane solution (0.5 mL), oxamic acid (0.004 g, 0.05 mmol), O- (7-aza-1H-benzotriazol-1-yl) -N, N, N ′, N′-tetramethyl
  • the title compound (0.012 g, 0.02 mmol, 60%) was obtained as a solid using uronium hexafluorophosphate (0.016 g, 0.043 mmol) and trieth
  • Compound (2.1 g) obtained in Step 40 (a) was suspended in N, N-dimethylformamide (15 mL), sodium hydride (0.57 g, 14 mmol) was added, and the mixture was stirred at 70 ° C. for 5 hr. 1N Hydrochloric acid was added to the reaction mixture, and the precipitated solid was collected by filtration and washed with water. The obtained solid was dried under reduced pressure at 50 ° C. to obtain a crude product (2.23 g) of the title compound. The obtained solid was used for the next reaction without purification.
  • Compound obtained in Step 40 (b) Pyridine (20 mL) and 1,3-dithioxodiphosphatian 1,3-disulfide (4.3 g, 19 mmol) were added to 2.23 g), and the mixture was stirred at 110 ° C. for 10 hours.
  • the reaction mixture was cooled to room temperature, 1N hydrochloric acid was added, the precipitated solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure at 50 ° C.
  • the compound obtained in Step 40 (c) 75 mg, 0.22 mmol
  • 2- (4-amino-3-methylphenyl) acetamide 106 mg, 0.65 mmol
  • acetic acid 3 mL
  • the compound obtained in Step 41 (a) (3.546 g, 8.931 mmol) was dissolved in a tetrahydrofuran / ethyl acetate mixed solvent (30 mL / 30 mL), cooled to -15 ° C, and N- (oxomethylene) sulfanyl chloride (1.90 g, 13.4 mmol) was added dropwise over 10 minutes. Stir at warm for 20 minutes. Water (10 mL) was added to the reaction solution to stop the reaction, and the temperature was gradually returned to room temperature.
  • Compound obtained in Step 41 (b) ( 2.02 g, 6.29 mmol) was dissolved in pyridine (30 mL), diphosphorus pentasulfide (1.68 g, 7.54 mmol) was added, and the mixture was heated with stirring at 120 ° C. for 5 hours.
  • the reaction solution was evaporated under reduced pressure to dilute the residue obtained by adding ethyl acetate, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Compound (100 mg, 0.274 mmol) obtained in Step 41 (c) was dissolved in acetic acid (2 mL) to give 2- (4-amino-3-methyl-phenyl) acetamide (50 mg, 0.30 mmol) And stirred at 135 ° C. for 1.5 hours.
  • the compound obtained in Step 42 (a) (7.91 g, 27.0 mmol) was dissolved in a tetrahydrofuran / ethyl acetate mixed solvent (60 mL / 60 mL), cooled to -15 ° C, and N- (oxomethylene) sulfanyl chloride (4.10 g, 29.0 mmol) was added dropwise over 10 minutes at the same temperature. For 40 minutes. Water (10 mL) was added to the reaction solution to stop the reaction, and the temperature was gradually returned to room temperature.
  • the compound obtained in Step 42 (b) ( 8.25 g, 27.1 mmol) was dissolved in pyridine (60 mL), diphosphorus pentasulfide (7.23 g, 32.5 mmol) was added, and the mixture was heated with stirring at 120 ° C. for 5 hours.
  • reaction solution was evaporated under reduced pressure to dilute the residue obtained by adding ethyl acetate, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • a crude product thiocarbonyl (7.2 g) was obtained. This was dissolved in a tetrahydrofuran / water mixed solvent (60 mL / 30 mL), iodoethane (12.7 g, 81.3 mmol) and potassium carbonate (18.7 g, 135 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Compound obtained in Step 42 (c) ( 0.833 g, 2.39 mmol) was dissolved in dichloroethane (30 mL), cooled to 0 ° C., boron tribromide / dichloromethane solution (1.0 M, 3.00 mL, 3.00 mmol) was added dropwise, and the mixture was heated to reflux with stirring for 1.5 hours.
  • the compound (90 mg, 0.27 mmol) obtained in 1 was dissolved in toluene (5 mL), 2-pyridylmethanol (59 mg, 0.54 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (135 mg, 0.54 mmol), and Tri-n-butylphosphine (0.134 mL, 0.54 mmol) was added and stirred overnight.
  • the compound obtained in Step 42 (e) (111 mg, 0.26 mmol), 2- (4-amino-3-methyl
  • the title compound (90 mg, 0.17 mmol, 65%) was obtained as a solid using -phenyl) acetamide (50 mg, 0.30 mmol) and acetic acid (2 mL).
  • the compound obtained in Step 41 (c) ( 8.51 g, 23.3 mmol) was dissolved in 1,2-dichloroethane (85.1 ml), and a boron tribromide / dichloromethane solution (1.0 M dichloromethane, 28.0 ml, 28.0 mmol) was added in portions at room temperature. Stir for hours.
  • the compound obtained in Step 43 (a) ( 1.89 g, 5.39 mmol) was dissolved in N, N-dimethylformamide (37.8 ml), potassium carbonate (2.23 g, 16.2 mmol) and iodoethane (0.646 ml, 8.08 mmol) were added, and the mixture was stirred at room temperature overnight.
  • Step 43 (b) (100 mg, 0.264 mmol), 1- (3-amino-2-methylphenyl) imidazolidin-2-one (50 mg, 0.264 mmol)
  • the acetic acid (3.00 ml) solution was stirred at 120 ° C. for 1 hour.
  • the compound (13.1 g, 45.0 mmol) obtained in Step 44 (a) Dissolved in tetrahydrofuran (100 mL) and ethyl acetate (50 mL).
  • the reaction solution was cooled to ⁇ 15 ° C., sulfa isocyanatoyl chloride (9.55 g, 67.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction was cooled to 0 ° C. and water (50 mL) was added.
  • the compound obtained in step 44 (b) (15.0 g, 49.6 mmol), pyridine (200 mL) and diphosphorus pentasulfide (11.0 g, 49.6 mmol), tetrahydrofuran (200 mL), water (100 mL), potassium carbonate ( 20.7 g, 150 mmol) and iodoethane (8.0 mL, 100 mmol) were used to obtain the title compound (12.6 g, 36.4 mmol, 73%) as a solid.
  • the obtained compound (12.6 g, 36.4 mmol) was dissolved in dichloroethane (100 mL), boron tribromide / dichloromethane solution (1.0 M, 50 mL, 50 mmol) was added, and the mixture was stirred at 80 ° C. for 5 hr. Boron tribromide / dichloromethane solution (1.0 M, 50 mL, 50 mmol) was added to the reaction solution, and the mixture was further stirred for 5 hours.
  • the reaction solution was added to a saturated aqueous sodium hydrogen carbonate solution cooled to 0 ° C., and the precipitated solid was collected by filtration and washed with ethyl acetate and hexane to obtain the title compound (8.0 g, 24 mmol, 66%).
  • the mother liquor was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (3.0 g, 9.0 mmol, 25%) as a solid.
  • Step 44 (d) the compound obtained in Step 44 (d) (1.00 g, 3.00 mmol), cesium carbonate (2.94 g, 9.01 mmol), N, N-dimethylformamide (15 mL) were added, and the mixture was stirred at 80 ° C. for 30 minutes. The mixture was stirred for 3 minutes, and then further stirred at room temperature for 3 hours.
  • the compound (250 mg, 0.566 mmol) obtained in Step 44 (e) 2- (4-amino-3-
  • the title compound (100 mg, 0.184 mmol, 32%) was obtained as a solid using methylphenyl) acetamide (111 mg, 0.679 mmol) and acetic acid (2 mL).
  • the compound obtained in Step 45 (a) (23.3 g, 138 mmol) was converted to 1,4- Dissolved in dioxane (400 mL), 2-bromo-5-fluoroanisole (28.3 g, 138 mmol), palladium (II) acetate (1.55 g, 6.89 mmol), dicyclohexyl [3,6-dimethoxy-2 ′, 4 ′, 6'-Tri (propan-2-yl) biphenyl-2-yl] phosphane (7.40 g, 13.8 mmol) and cesium carbonate (112 g, 345 mmol) were added, and the mixture was stirred for 13 hours under heating to reflux.
  • the compound obtained in Step 45 (b) (45.3 g, 154 mmol) was dissolved in a mixed solvent of tetrahydrofuran (500 mL) and ethyl acetate (250 mL), chlorosulfonyl isocyanate (20.0 mL, 231 mmol) was added at -15 ° C, and the mixture was stirred at -15 ° C for 1 hour. Water (100 mL) was added, and the mixture was stirred at 0 ° C.
  • Compound obtained in Step 45 (c) ( 50.9 g, 167 mmol) was dissolved in pyridine (850 mL), diphosphorus pentasulfide (39.0 g, 176 mmol) was added, and the mixture was stirred with heating under reflux for 8 hours. The solvent was distilled off under reduced pressure, and water was added. The solid was collected by filtration, and the filtrate was extracted three times with ethyl acetate.
  • the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure and combined with the solid collected earlier. This solid was dissolved in a mixed solvent of tetrahydrofuran (600 mL) and water (300 mL), potassium carbonate (69.3 g, 502 mmol) and iodoethane (26.8 mL, 335 mmol) were added, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Compound obtained in Step 45 (d) ( 31.5 g, 90.5 mmol) was dissolved in 1,2-dichloroethane (450 mL), boron tribromide / dichloromethane solution (1.0 M, 113 mL, 113 mmol) was added, and the mixture was stirred at 80 ° C. for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added at 0 ° C., and the mixture was extracted with ethyl acetate.
  • Compound (200 mg, 0.598 mmol) obtained in 45 (e) was dissolved in N, N-dimethylformamide (10 mL), and 2- (chloromethyl) -1,3-thiazole (95.9 mg, 0.718 mmol) was obtained.
  • Potassium carbonate 124 mg, 0.897 mmol
  • Bretphos dicyclohexyl -[
  • the compound obtained in Step 46 (c) (100 mg, 0.283 mmol)
  • 2- (4-amino-3-methyl-phenyl) acetamide The reaction was carried out using (56 mg, 0.34 mmol) to obtain the title compound (23 mg, 0.051 mmol, 18%) as a solid.
  • the reaction was carried out using the compound obtained in step 46 (c) (4.50 g, 12.8 mmol) and boron tribromide / dichloromethane solution (1.0 M, 15.3 mL, 15.3 mmol) to give the title compound ( 3.91 g, 11.5 mmol, 90.5%) was obtained as a solid.
  • the compound obtained in Step 47 (b) (9.27 g, 27.4 mmol)
  • the compound obtained in Step 47 (a) (8.42 g, 41.0 mmol)
  • the compound (158 mg, 0.353 mmol) obtained in Step 47 (c) 2- Reaction was carried out using (4-amino-3-methyl-phenyl) acetamide (64 mg, 0.39 mmol) to obtain the title compound (138 mg, 0.251 mmol, 71.1%) as a solid.
  • the compound obtained in Step 48 (a) (0.762 g, 3.01 mmol) was dissolved in ethanol (15 mL). 10% Palladium-carbon (0.25 g) was added, and the mixture was stirred at room temperature for 2.5 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.635 g, 2.84 mmol, 94.5%) as a solid.
  • the compound obtained in Step 47 (c) 130 mg, 0.290 mmol
  • the title compound (176 mg, 0.289 mmol, 99.6%) was obtained as a solid by performing a reaction using the compound (80 mg, 0.358 mmol) obtained in Step 48 (b).
  • the compound (0.176 g, 0.289 mmol) obtained in step 48 (c) was dissolved in methanol (1 mL), and 5N Aqueous sodium oxide (2 mL) was added and stirred overnight at room temperature.
  • the reaction solution was neutralized with 1N hydrochloric acid, and a 10% methanol / dichloromethane mixed solvent was added to the reaction solution.
  • the obtained compound (10.0 g, 29.5 mmol) was dissolved in N, N-dimethylformamide (200 mL), potassium carbonate (8.16 g, 59.0 mmol) and iodoethane (3.54 ml, 44.3 mmol) were added, and the mixture was stirred at room temperature overnight. did.
  • the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (400 ml) and washed with saturated aqueous ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained concentrated residue was washed with hexane and concentrated under reduced pressure to obtain the title compound (10.8 g, 99.9%) as a solid.
  • Step 50 (a): tert-butyl (2S, 4S) -4-[(1- ⁇ 4-chloro-2-[(5-fluoropyridin-2-yl) methoxy] phenyl ⁇ -2-oxo-1, 2-Dihydrothieno [3,2-d] pyrimidin-4-yl) amino] -2-methylpiperidine-1-carboxylate
  • Compound (194 mg) obtained in Step 47 (c) tert-butyl (2S, 4S) -4-Amino-2-methylpiperidine-1-carboxylate (278 mg) was stirred at 150 ° C. Stirring was stopped after 8 hours and allowed to stand at room temperature.
  • reaction solution was concentrated under reduced pressure, and the residue was azeotroped with 1,4-dioxane. This was dissolved in N, N-dimethylformamide (3 mL), triethylamine (0.21 mL) and methanesulfonyl chloride (0.026 mL) were added, and the mixture was stirred at room temperature for 10 hours and allowed to stand. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • step 49 (c) 1- (3-amino-2-methylphenyl) imidazolidin-2-one (52.1 mg, 0.273) was used instead of methyl N- (3-amino-2-methylphenyl) carbamate. mmol) to give the title compound (48.9 mg, 0.0986 mmol, 36%) as a solid.
  • step 49 (c) instead of methyl N- (3-amino-2-methylphenyl) carbamate, 3- (3-amino-6-fluoro-2-methylphenyl) imidazolidine-2,4- Dione (60.8 mg, 0.273 mmol) was used to obtain the title compound (96.7 mg, 0.183 mmol, 67%) as a solid.
  • step 49 (c) instead of methyl N- (3-amino-2-methylphenyl) carbamate, 4- (3-amino-2-methylphenyl) -2,4-dihydro-3H-1, The title compound (91.0 mg, 0.184 mmol, 67%) was obtained as a solid using 2,4-triazol-3-one (51.8 mg, 0.273 mmol).
  • Step 55 (a): Preparation of methyl 2-[(4-fluoro-2-methoxyphenyl) amino] thiophene-3-carboxylate Methyl 2-aminothiophene-3-carboxylate (3.00 g, 19.1 mmol) Dissolved in 4-dioxane (100 mL), 1-bromo-4-fluoro-2-methoxybenzene (3.91 g, 19.1 mmol), palladium (II) acetate (214 mg, 0.954 mmol), (9,9-dimethyl-9H -Xanthene-4,5-diyl) bis (diphenylphosphane) (1.10 g, 1.91 mmol) and cesium carbonate (12.4 g, 38.2 mmol) were added, and the mixture was stirred with heating under reflux for 8 hours.
  • the compound (4.64 g, 16.5 mmol) was dissolved in a mixed solvent of tetrahydrofuran (100 mL) and ethyl acetate (50.0 mL), chlorosulfonyl isocyanate (2.14 mL, 24.8 mmol) was added at -15 ° C, and -15 ° C For 30 minutes.
  • the compound (50.0 mg, 0.149 mmol) obtained in step 55 (b) was dissolved in a mixed solvent of acetic acid (2.00 mL) and 1,2-dimethoxyethane (4.00 mL).
  • 2- (4-amino-3-methylphenyl) acetamide 26.9 mg, 0.164 mmol
  • ON Thiourea (16.1 g, 212 mmol) was suspended in ethanol (120 mL), iodoethane (43.2 g, 277 mmol) was added, and the mixture was stirred at 65 ° C. for 5 hours to prepare ethyl carbamidimide thioate.
  • step 56 (b) The compound (59.0 g, 163 mmol) obtained in step 56 (b) was dissolved in ethanol (400 mL), cooled to 0 ° C., and ethyl carbamimidothioate prepared earlier was added. The reaction mixture was brought to room temperature, triethylamine (56.5 mL, 408 mmol) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with dichloromethane.
  • the compound obtained in step 56 (c) (5.41 g, 13.5 mmol) is dissolved in dichloromethane (40.0 mL), cooled to 0 ° C., and then mixed with trifluoroacetic acid (10.0 mL) / water (10.0 mL). The solution was added dropwise and stirred for 5 hours. Extraction was performed using dichloromethane, and the organic layer was neutralized by adding a saturated aqueous sodium hydrogen carbonate solution.
  • the compound (105 mg, 0.312 mmol) obtained in Step 56 (d) was dissolved in acetic acid (1.00 mL) to give 2- (4-amino -3-Methylphenyl) acetamide (77.0 mg, 0.469 mmol) was added, and the mixture was stirred at 135 ° C. for 4 hours.
  • 4-fluoro-1-isothiocyanato-2-methoxybenzene (64.8 g, 354 mmol)
  • 3-bromo-1,1-dimethoxypropane 90.7 g, 496 mmol
  • magnesium (13.8 g, 566 mmol
  • tetrahydrofuran 900 mL
  • the compound obtained in step 57 (a) (57.3 g, 199 mmol), sodium hydride (11.4 g, 299 mmol), methyl chloroformate ( 37.7 g, 399 mmol), tetrahydrofuran (500 mL), ethyl carbamidimide thioate (48.4 g, 208 mmol), triethylamine (27.5 mL, 198 mmol), dichloromethane (300 mL), trifluoroacetic acid (10 mL) / water (10 mL), 3 , 3,3-triethyl-1- (methoxycarbonyl) diazathian-3-ium
  • the compound obtained in Step 57 (b) (3.20 g, 10.0 mmol), boron tribromide / 17% dichloromethane solution (1.90 mL, 20.0 mmol), dichloromethane (100 mL) were added. Used to give the title compound (1.90 g, 6.20 mmol, 62%) as a solid.
  • Step 16 (a) the compound (100 mg, 0.328 mmol) obtained in Step 57 (c) and 2- (bromomethyl) tetrahydro-2H-pyran (117 mg, 0.655 mmol), cesium carbonate (320 mg, 0.983 mmol) and N, N-dimethylformamide (1.50 mL) were used to obtain the title compound (14.0 mg, 0.0347 mmol, 11%) as an oily substance.
  • the compound (14.0 mg, 0.0347 mmol) obtained in Step 57 (d) was converted to dimethyl sulfoxide (0.300 mL). ), 2- (4-amino-3-methylphenyl) acetamide (8.00 mg, 0.0520 mmol) was added, and the mixture was stirred at 120 ° C. for 5 hours.
  • Manufacture of triazine-2 (1H) -one (3-Fluoropyridin-2-yl) methanol (200 mg, 1.57 mmol) was dissolved in dichloromethane (25.0 mL), and triethylamine (0.454 mL, 3.28 mmol) was added.
  • the compound obtained in Step 58 (a) ( 119 mg, 0.369 mmol), 2- (4-amino-3-methylphenyl) acetamide (90.0 mg, 0.554 mmol), dimethyl sulfoxide (0.300 mL), and the title compound (80.0 mg, 0.150 mmol, 41%) Obtained as a solid.
  • Step R1 (a): Preparation of methyl 2- ⁇ [(trifluoromethyl) sulfonyl] oxy ⁇ cyclopent-1-ene-1-carboxylate
  • Methyl 2-oxocyclopentanecarboxylate (50 g, 352 mmol) was dissolved in dichloromethane (450 mL), N, N-diisopropylethylamine (250 mL, 1.41 mol) was added, and the mixture was cooled to -78 ° C.
  • Trifluoromethanesulfonic anhydride (65 mL, 390 mmol) was added dropwise to the reaction solution, and then the mixture was heated to 0 ° C. and stirred for 2 hours.
  • 2-Methoxybenzaldehyde 25.9 g, 190 mmol
  • chloroform 500 mL
  • trimethylsilylcyanide 18.9 g, 190 mmol
  • triethylamine 29.0 mL, 207 mmol
  • Compound (40) obtained in Step R1 (b) 2 g, 154 mmol) was dissolved in ethanol (350 mL), hydrazine dihydrochloride (45 g, 334 mmol) was added, and the mixture was stirred with heating at 110 ° C. for 14 hr. The reaction mixture was concentrated, extracted with water and dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, ethyl acetate and dichloromethane were added to the resulting residue, and the precipitated solid was collected by filtration. The obtained solid was dried by heating at 50 ° C. under reduced pressure to obtain the title compound (16 g, 63 mmol, 44%).
  • Phosphorus oxychloride 50 mL was added, and the mixture was stirred with heating at 80 ° C. for 2 hr.
  • the reaction solution was added to ice water and then neutralized with 5N aqueous sodium hydroxide solution.
  • Dichloromethane was added for extraction, and the organic layer was dried over anhydrous magnesium sulfate.
  • the compound obtained in Step R1 (d) (3.1 g, 11.9 mmol) ) was dissolved in dichloromethane (30 mL), borane tribromide (17% dichloromethane solution, 15 mL, 15 mmol) was added, and the mixture was stirred at room temperature for 5 hours. A small amount of methanol was added to the reaction solution, and then a saturated aqueous sodium hydrogen carbonate solution was added.
  • Step R2 (a): Preparation of 2-methoxy-N- [2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] acetamide 2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.15 g, 5.25 mmol) was dissolved in acetonitrile (20 mL) and potassium carbonate (1.45 g, 10.5 mmol) and methoxyacetyl chloride (600 mg, 5.51 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the crude title compound as an oil. The obtained compound was used for the next reaction without purification.
  • the obtained compound was diluted with tetrahydrofuran (50 mL), 1N borane / tetrahydrofuran solution (36.8 mL, 36.8 mmol) was added, and the mixture was heated to reflux for 7 hr. After cooling the reaction solution to room temperature, a small amount of methanol was added.
  • Step R3 (a): Preparation of 2- (2-methoxybenzoyl) thiophene-3-carboxylic acid 2-Chlorothiophene-3-carboxylic acid (21.5 g, 168 mmol) was dissolved in tetrahydrofuran (230 mL), cooled to ⁇ 78 ° C., and then n-butyllithyl hexane solution (2.69 mol / L, 137 mL, 369 mmol) was added to 30 Added dropwise over a period of minutes.
  • the compound (43 g, 164 mmol) obtained in Step R3 (a) was converted to butanol ( 250 ml), hydrazine monohydrate (20 mL, 412 mmol) was added, and the reaction solution stirred at 140 ° C. for 2 hours was cooled to room temperature and concentrated under reduced pressure. Diethyl ether was added to the obtained residue, and the insoluble material was collected by filtration. The mother liquor was concentrated under reduced pressure, poured into dilute hydrochloric acid, and extracted three times with dichloromethane.
  • the compound obtained in Step R3 (b) (20.2 g, 78.4 mmol) was added to phosphorus oxychloride. (20 mL) was added and stirred at 100 ° C. After 4 hours, the reaction was cooled to room temperature and poured onto ice. A 5N aqueous sodium hydroxide solution was gradually added to neutralize, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the compound (15 g) obtained in Step R3 (c) The title compound (14.2 g, 54.2 mmol, 100%) was obtained as a solid using dichloromethane (15 mL), tribromoborane / dichloromethane solution (1N, 100 mL, 100 mmol).
  • Step R4 (a): Preparation of 2- (2-methoxybenzoyl) cyclopentene-1-carbonitrile Triethylamine (30 mL, 0.22 mol) was added to chloroform (180 mL), and 2-methoxybenzoyl chloride (16 mL) was stirred in an ice bath. , 0.11 mol) in chloroform (20 mL) was added dropwise. After stirring in an ice bath for 1 hour, trimethylsilylcyanide (22 mL, 0.16 mol) was added, stirred in an ice bath for 30 minutes, and then stirred at room temperature for 2 hours.
  • Trifluoroacetic acid (32.5 mL, 0.44 mol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour.
  • the compound (18 g, 78 mmol) obtained in Step R4 (a) was prepared. After dissolving in ethanol (200 mL), hydrazine hydrate (7.6 mL, 0.16 mol) and 5N hydrochloric acid (40 mL, 0.20 mol) were added, and the mixture was heated to reflux. After 1.5 hours, hydrazine dihydrochloride (8.2 g, 78 mmol) was added, and the mixture was further heated to reflux for 5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure.
  • Step R5 (a): Preparation of dimethyl 2- (2,3-difluoro-4-nitrophenyl) propanedioate Dimethyl 2-chloropropanedioate (7.2 mL, 56 mmol), 1,2,3-trifluoro-4- Nitrobenzene (5.0 g, 28 mmol) was dissolved in tetrahydrofuran (80 mL), and 1,8-diazabicyclo [5.4.0] undecene (8.4 mL, 56 mmol) was added while stirring in an ice bath. After completion of dropping, the mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted three times with ethyl acetate.
  • the compound (3.2 g, 11 mmol) obtained in Step R5 (a) was dissolved in ethanol (100 mL).
  • 10% palladium-carbon (0.60 g) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere.
  • the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure.
  • the compound obtained in Step R5 (b) (2.4 g, 9.3 mmol) was dissolved in ethanol (30 mL).
  • 5N Aqueous sodium hydroxide solution (2.4 mL, 12 mmol) was added, and the mixture was stirred at 90 ° C. for 3.5 hr.
  • the reaction mixture was cooled to room temperature, 5N hydrochloric acid (2.4 mL, 12 mmol) was added, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted 3 times with ethyl acetate.
  • Step R6 (a): Preparation of 5-chloro-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline 2-Bromo-5-chloroaniline (3.0 g, 14.5 mmol) dissolved in 1,4-dioxane (50 mL), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) / dichloromethane complex (590 mg, 0.73 mmol), triethylamine (8.0 mL, 58 mmol) and pinacol borane (5.6 g, 44 mmol) were added, and the mixture was stirred at 100 ° C. for 5 hours.
  • the title compound (1.2 g, 3.9 mmol, 100%) was obtained as an oily substance using the compound (1.0 g, 3.9 mmol) obtained in Step R6 (a).
  • the title compound (1.9 g, 6.3 mmol, 27%) was obtained as an oily substance using the compound (5.4 g, 23 mmol) obtained in Step R7 (a).
  • ⁇ Test Example 1 Oral glucose tolerance test using Zucker diabetic fatty rats Male Zucker diabetic fatty rats (ZDF rats, 10 weeks old) are allowed to freely ingest feed (FR-2, Funabashi Farm Co., Ltd.) for 1 week or longer. And then fasted overnight and used for oral glucose tolerance test.
  • As an administration solution to ZDF rats 0.5% methylcellulose (Wako Pure Chemical Industries, Ltd.) solution (0.5% MC) with a test compound concentration of 2.5 mg / ml, or 92 mg / mL CAPTISOL (CYDEX) solution (SBE- ⁇ -CyD) was prepared.
  • the adjusted administration solution was forcibly orally administered at a dose of 4 ml / kg so that the test compound dose was 10 mg / kg.
  • the control group was orally administered with a 4 ml / kg dose of 0.5% methylcellulose solution or SBE- ⁇ -CyD.
  • a glucose solution (Otsuka sugar solution 50%: Otsuka Pharmaceutical Co., Ltd.) was forcibly orally administered at a dose of 2 g / kg 30 minutes after administration of the test compound.
  • T5 Immediately before test compound administration (T0), 25 minutes after test compound administration (T1), 30 minutes after oral glucose load (T2), 60 minutes (T3), 120 minutes (T4) and 180 minutes (T5), Blood was collected from the tail vein of the rat, and the blood glucose level was measured with a blood glucose meter (Accucheck Aviva: Roche Diagnostics). The T1 blood glucose level was analyzed as the value immediately before glucose load 30 minutes after compound administration. The area under the blood glucose level curve was determined from the following formula, and the blood glucose lowering rate (%) from the control group was calculated and shown in Table 1.
  • the adjusted administration solution was forcibly orally administered at a dose of 10 ml / kg so that the test compound dose was 10 mg / kg or 30 mg / kg.
  • 0.5% methylcellulose solution was orally administered by gavage at a dose of 10 ml / kg.
  • test compound administration 30 minutes after test compound administration (T1), 60 minutes (T2), 120 minutes (T3), and 240 minutes (T4), blood is collected from the tail vein of the mouse, The blood glucose level was measured with a blood glucose meter (Accu Check Aviva: Roche Diagnostics). From the following formula, the area under the blood glucose level curve was obtained, and the blood glucose lowering rate (%) from the control group was calculated and shown in Tables 2-1 and 2-2.

Abstract

Provided is a novel compound, and a pharmaceutically acceptable salt thereof, that has an action of reducing blood sugar and the like, and that is useful as a therapeutic and/or preventive medicine for diseases such as diabetes. Provided is a heteroaryl amine derivative represented by formula (I), or a salt thereof, or a crystal thereof, the formula having various substituents (here, the meanings of A, B, C, R1, R2, R3, R4, R5, and R6 in formula (I) are as defined in the specification).

Description

ヘテロアリールアミン誘導体Heteroarylamine derivatives
　本発明は、血糖低下等の作用を有し、糖尿病等の治療薬及び／または予防薬として有用な新規な化合物及びその薬学上許容される塩に関する。 The present invention relates to a novel compound having an action such as lowering blood sugar and useful as a therapeutic and / or prophylactic agent for diabetes and the like and a pharmaceutically acceptable salt thereof.
　本発明は、上記化合物またはその薬学上許容される塩を有効成分として含有する糖尿病（1型糖尿病、2型糖尿病、妊娠糖尿病等）、食後過血糖症、耐糖能障害、糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、高脂血症、動脈硬化症、血栓性疾患、肥満、高血圧、浮腫、インスリン抵抗性、不安定糖尿病、インスリノーマ、高インスリン血症等の治療薬及び／または予防薬（好適には糖尿病の治療薬及び／または予防薬である）に関する。 The present invention includes diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia, impaired glucose tolerance, diabetic neuropathy, diabetes containing the above compound or a pharmaceutically acceptable salt thereof as an active ingredient. Therapeutic and / or prevention for diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia, etc. It relates to a drug (preferably a therapeutic and / or prophylactic drug for diabetes).
　さらに、本発明は、上記化合物を有効成分として含有する上記疾病の予防若しくは治療のための組成物、上記疾病の予防若しくは治療のための医薬を製造するための上記化合物の使用、または上記化合物の薬理的な有効量を哺乳動物（好適には人間である）に投与する上記疾病の予防若しくは治療方法に関する。 Furthermore, the present invention provides a composition for the prevention or treatment of the above-mentioned diseases containing the above-mentioned compound as an active ingredient, the use of the above-mentioned compound for producing a medicament for the prevention or treatment of the above-mentioned diseases, The present invention relates to a method for preventing or treating the above diseases, wherein a pharmacologically effective amount is administered to a mammal (preferably a human).
　糖尿病は、慢性的な高血糖を主徴とする疾患であり、インスリン作用の絶対的または相対的な不足により発症する。臨床においてはその特徴からインスリン依存性糖尿病（1型糖尿病）とインスリン非依存性糖尿病（2型糖尿病）に大別される。 Diabetes is a disease whose main feature is chronic hyperglycemia, and develops due to an absolute or relative lack of insulin action. In clinical practice, it is roughly divided into insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes).
　現在、糖尿病の治療は基本的に食事療法と運動療法である。しかし、これらだけで血糖値をコントロールできなくなった場合、薬物が投与される。そこで、より安全で効果の高い薬剤が求められている。 Currently, diabetes treatment is basically diet therapy and exercise therapy. However, if the blood sugar level cannot be controlled by these alone, a drug is administered. Therefore, there is a demand for safer and more effective drugs.
　本発明の化合物と一部共通する部分構造を有する化合物は、キナーゼ阻害剤（特許文献1-4、非特許文献1）またはその他の用途で複数報告がある（特許文献5-10、非特許文献2-5）。 A compound having a partial structure partially in common with the compound of the present invention has been reported in a plurality of reports for kinase inhibitors (Patent Documents 1-4, Non-Patent Document 1) or other uses (Patent Documents 5-10, Non-Patent Documents). 2-5).
国際公開第2007/024754号パンフレットInternational Publication No. 2007/024754 Pamphlet 国際公開第2008/124083号パンフレットInternational Publication No. 2008/124083 Pamphlet 米国特許公開第2014/0336182号U.S. Patent Publication No. 2014/0336182 米国特許第7560551号U.S. Pat.No. 7,560,551 国際公開第2016/123796号パンフレットInternational Publication No. 2016/123796 Pamphlet 国際公開第2012/167133号パンフレットInternational Publication No. 2012/167133 Pamphlet 米国特許公開第2007/0099895号US Patent Publication No. 2007/0099895 米国特許公開第2009/0163545号US Patent Publication No. 2009/0163545 国際公開第2009/012242号パンフレットInternational Publication No. 2009/012242 Pamphlet 国際公開第98/46574号パンフレットInternational Publication No. 98/46574 Pamphlet
　本発明者らは、鋭意研究を重ねた結果、後記式(I)で表わされる化合物がその特異的な化学構造に基づいて、優れた血糖低下等の作用を有し、高血糖症、糖尿病及びそれら疾病に関連する病態または疾患の予防・治療薬として有用な医薬となることを見出し、これらの知見に基づいて本発明を完成した。 As a result of intensive studies, the present inventors have found that the compound represented by the following formula (I) has an excellent action such as hypoglycemia, based on its specific chemical structure, and has hyperglycemia, diabetes and It has been found that the drug is useful as a preventive / therapeutic agent for a disease state or a disease related to those diseases, and the present invention has been completed based on these findings.
　即ち、本発明の化合物は、血糖降下作用等を有し糖尿病（1型糖尿病、2型糖尿病、妊娠糖尿病等）、食後過血糖症、耐糖能障害、糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、高脂血症、動脈硬化症、血栓性疾患、肥満、高血圧、浮腫、インスリン抵抗性、不安定糖尿病、インスリノーマ、高インスリン血症などの疾患、特に、2型糖尿病に対する予防・治療剤として有用である。 That is, the compound of the present invention has a hypoglycemic action and the like, such as diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetes Prevention, treatment for diseases such as retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia, especially type 2 diabetes Useful as an agent.
　本発明は、
(1)一般式(I) The present invention
(1) General formula (I)
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
［式中、
環Aは、ベンゼン環または二環性ベンゾ複素環を示し、
環Bは、環内に窒素原子を2つ含む一環性または二環性の環を示し、
該二環性の環はさらに、窒素原子、酸素原子及び硫黄原子からなる群から選ばれる1または2以上の原子を環内に含んでいてもよく、
環Cは、ベンゼン環または4～6員の飽和含窒素複素環を示し、
R1は、水素原子またはハロゲン原子を示し、
R2は、環Aがベンゼン環である場合に2位の位置に結合する置換基であって、下記Z群より独立に選ばれる1または2以上の基によって置換されていてもよいC1-C6アルキル基、下記Z群より独立に選ばれる1または2以上の基によって置換されていてもよいC1-C6アルコキシ基、下記Z群より独立に選ばれる1または2以上の基によって置換されていてもよいモノC1-C6アルキルアミノ基、-[O-(CH2)2]m-X-Qまたは-O-(CH2)n-X-Qを示し、
mは1または2の整数を示し、
nは1、2、3または4の整数を示し、
XはO、NHまたはNHC=Oを示し、
QはC1-C6アルキル基、C1-C6アルコキシ基またはモノC1-C6アルキルアミノ基を示し、
R3は、水素原子またはハロゲン原子を示し、
R4、R5およびR6は、それぞれ独立に、水素原子、ハロゲン原子、下記Y群より独立に選ばれる1または2以上の基によって置換されていてもよいC1-C6アルキル基、下記Y群より独立に選ばれる1または2以上の基によって置換されていてもよいC1-C6アルコキシ基、下記Y群より独立に選ばれる1または2以上の基によって置換されていてもよいモノC1-C6アルキルアミノ基、C1-C6アルキルスルホニル基、または下記のいずれかの基 [Where:
Ring A represents a benzene ring or a bicyclic benzoheterocycle,
Ring B represents a unitary or bicyclic ring containing two nitrogen atoms in the ring,
The bicyclic ring may further contain one or more atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in the ring,
Ring C represents a benzene ring or a 4- to 6-membered saturated nitrogen-containing heterocycle,
R 1 represents a hydrogen atom or a halogen atom,
R 2 is a substituent which the ring A is bonded to the position of the 2-position in the case of a benzene ring, one or more of which may be substituted by a group C 1 independently selected from the following group Z - C 6 alkyl group, C 1 -C 6 alkoxy group optionally substituted by one or more groups independently selected from the following group Z, substituted by one or more groups independently selected from the following group Z which may be mono-C 1 -C 6 alkylamino group, - [O- (CH 2) 2] mXQ or -O- (CH 2) shows the NXQ,
m represents an integer of 1 or 2,
n represents an integer of 1, 2, 3 or 4,
X represents O, NH or NHC = O;
Q represents a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group or a mono C 1 -C 6 alkylamino group,
R 3 represents a hydrogen atom or a halogen atom,
R 4 , R 5 and R 6 are each independently a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group optionally substituted by one or more groups independently selected from the following group Y, A C 1 -C 6 alkoxy group optionally substituted by one or more groups independently selected from the Y group, a mono group optionally substituted by one or more groups independently selected from the following Y group C 1 -C 6 alkylamino group, C 1 -C 6 alkylsulfonyl group, or any of the following groups
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
を示す。］
で表される化合物またはその薬学上許容される塩。
Z群：C1-C6アルコキシ基、モノC1-C6アルキルアミノ基、ジC1-C6アルキルアミノ基、フェニル基（該フェニル基は、ハロゲン原子、カルボキシ基及びC1-C6アルキル基からなる群より独立に選ばれる１または２の基で置換されていてもよい）、及び4～6員の飽和もしくは不飽和の複素環基（該複素環基は、ハロゲン原子、カルボキシ基及びC1-C6アルキル基からなる群より独立に選ばれる1または2の基で置換されていてもよい）。
Y群：オキソ基、C1-C6アルコキシ基、及びカルバモイル基。
(2)前記式(I)において、下記の部分構造式(I-1) Indicates. ]
Or a pharmaceutically acceptable salt thereof.
Group Z: C 1 -C 6 alkoxy group, mono C 1 -C 6 alkylamino group, di C 1 -C 6 alkylamino group, phenyl group (the phenyl group is a halogen atom, a carboxy group, and C 1 -C 6 An optionally substituted 1 or 2 group selected from the group consisting of alkyl groups), and a 4-6 membered saturated or unsaturated heterocyclic group (the heterocyclic group is a halogen atom, a carboxy group) And optionally substituted by 1 or 2 groups independently selected from the group consisting of C 1 -C 6 alkyl groups).
Group Y: an oxo group, a C 1 -C 6 alkoxy group, and a carbamoyl group.
(2) In the above formula (I), the following partial structural formula (I-1)
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
が、下記群 But the following group
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-I000017
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-I000017
のいずれかである(1)に記載の化合物またはその薬学上許容される塩。
(3)前記式(I)において、下記の部分構造式(I-2) Or the pharmaceutically acceptable salt thereof.
(3) In the above formula (I), the following partial structural formula (I-2)
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
が、下記式(II) Is represented by the following formula (II)
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
［式中、
環Dは、ベンゼン環、ピロール環、フラン環、チオフェン環、シクロペンテン環、またはジヒドロフラン環を示し、
R3は、水素原子またはハロゲン原子を示す。］
で表される基である(1)または(2)に記載の化合物またはその薬学上許容される塩。
(4)前記式(I)中の部分構造式(I-2)が、
下記群 [Where:
Ring D represents a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, a cyclopentene ring, or a dihydrofuran ring,
R 3 represents a hydrogen atom or a halogen atom. ]
The compound or its pharmaceutically acceptable salt as described in (1) or (2) which is group represented by these.
(4) The partial structural formula (I-2) in the formula (I) is
Following group
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
のいずれかである(1)または(2)に記載の化合物またはその薬学上許容される塩。
(5)前記式(I)中の部分構造式(I-2)が、
下記式(III) Or the pharmaceutically acceptable salt thereof, or (1) or (2).
(5) The partial structural formula (I-2) in the formula (I) is
The following formula (III)
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
［式中、
環Eは、ベンゼン環、ピロール環、またはチオフェン環を示し、
R3は、水素原子またはハロゲン原子を示す。］
で表される基である(1)または(2)に記載の化合物またはその薬学上許容される塩。
(6)前記式(I)中の部分構造式(I-2)が、
下記群 [Where:
Ring E represents a benzene ring, a pyrrole ring, or a thiophene ring,
R 3 represents a hydrogen atom or a halogen atom. ]
The compound or its pharmaceutically acceptable salt as described in (1) or (2) which is group represented by these.
(6) The partial structural formula (I-2) in the formula (I) is
Following group
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
のいずれかである(1)または(2)に記載の化合物またはその薬学上許容される塩。
(7)前記式(I)において、下記の部分構造式(I-3) Or the pharmaceutically acceptable salt thereof, or (1) or (2).
(7) In the above formula (I), the following partial structural formula (I-3)
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
が、下記群 But the following group
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
のいずれかである(1)から(6)のいずれか1に記載の化合物またはその薬学上許容される塩。
(8)(1)から(7)のいずれか1に記載の化合物またはその薬学上許容される塩を有効成分として含有する血糖降下剤。
(9)(1)から(7)のいずれか1に記載の化合物またはその薬学上許容される塩を有効成分として含有する医薬。
(10)糖尿病、食後過血糖症、耐糖能障害、糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、高脂血症、動脈硬化症、血栓性疾患、肥満、高血圧、浮腫、インスリン抵抗性、不安定糖尿病、インスリノーマまたは高インスリン血症などの治療若しくは予防のための、(9)に記載の医薬。
(11)医薬組成物を製造するための、(1)から(7)のいずれか1に記載の化合物またはその薬学上許容される塩の使用。
(12)(1)から(7)のいずれか1に記載の化合物またはその薬学上許容される塩の薬理的な有効量を哺乳動物に投与することを特徴とする糖尿病の治療方法。 Any one of (1) to (6), or a pharmaceutically acceptable salt thereof.
(8) A hypoglycemic agent comprising the compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof as an active ingredient.
(9) A pharmaceutical comprising the compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof as an active ingredient.
(10) Diabetes, postprandial hyperglycemia, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance The medicament according to (9) for the treatment or prevention of sexual, unstable diabetes, insulinoma, hyperinsulinemia and the like.
(11) Use of the compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition.
(12) A method for treating diabetes, which comprises administering to a mammal a pharmacologically effective amount of the compound according to any one of (1) to (7) or a pharmaceutically acceptable salt thereof.
　本発明において、「C1-C6アルキル基」とは、炭素数1～6の直鎖、分岐鎖のアルキル基を意味する。「C1-C6アルキル基」としては、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、tert-ブチル基などが挙げられる。 In the present invention, the “C 1 -C 6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms. Examples of the “C 1 -C 6 alkyl group” include methyl group, ethyl group, propyl group, isopropyl group, butyl group, tert-butyl group and the like.
　本発明において、「C1-C6アルコキシ基」とは、炭素数1～6の直鎖、分岐鎖のアルキル基を有するアルコキシ基を意味する。「C1-C6アルコキシ基」としては、例えば、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基などが挙げられる。 In the present invention, the “C 1 -C 6 alkoxy group” means an alkoxy group having a linear or branched alkyl group having 1 to 6 carbon atoms. Examples of the “C 1 -C 6 alkoxy group” include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group and the like.
　本発明において、「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子等が挙げられる。 In the present invention, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
　本発明において、「モノC1-C6アルキルアミノ基」とは、上記C1-C6アルキル基が1つ置換したアミノ基を意味し、「ジC1-C6アルキルアミノ基」とは、上記C1-C6アルキル基が2つ置換したアミノ基を意味し、それぞれメチルアミノ基、エチルアミノ基、プロピルアミノ基、もしくはイソプロピルアミノ基など、またはジメチルアミノ基、もしくはジエチルアミノ基など等が挙げられる。 In the present invention, the “mono C 1 -C 6 alkylamino group” means an amino group substituted with one C 1 -C 6 alkyl group, and the “di C 1 -C 6 alkylamino group” means Means an amino group substituted with two C 1 -C 6 alkyl groups, such as a methylamino group, an ethylamino group, a propylamino group, or an isopropylamino group, or a dimethylamino group or a diethylamino group, respectively. Can be mentioned.
　本発明において、「C1-C6アルキルスルホニル基」とは、上記C1-C6アルキル基が置換したスルホニル基を意味し、メタンスルホニル基、エタンスルホニル基、n-プロパンスルホニル基、イソプロパンスルホニル基等を挙げることができる。 In the present invention, the “C 1 -C 6 alkylsulfonyl group” means a sulfonyl group substituted by the above C 1 -C 6 alkyl group, and includes a methanesulfonyl group, an ethanesulfonyl group, an n-propanesulfonyl group, and isopropane. A sulfonyl group etc. can be mentioned.
　本発明において、「4～6員の飽和含窒素複素環基」とは、環内に窒素原子を1～4個含む4～6員の飽和環基であり、アゼチジニル基、ピロリジニル基、イミダゾリジニル基、ピラゾリジニル基、ピペリジニル基、ピペラジニル基等が挙げられる。 In the present invention, the “4- to 6-membered saturated nitrogen-containing heterocyclic group” is a 4- to 6-membered saturated ring group containing 1 to 4 nitrogen atoms in the ring, and includes an azetidinyl group, a pyrrolidinyl group, an imidazolidinyl group. , Pyrazolidinyl group, piperidinyl group, piperazinyl group and the like.
　本発明において、「4～6員の不飽和含窒素複素環基」とは、環内に窒素原子を1～4個含む4～6員の不飽和環基であり、ピロリル基、ピラゾリル基、イミダゾリル基、トリアゾリル基、ピリジル基、ピリダジニル基、ピリミジニル基、ピラジニル基、トリアジニル基、テトラジニル基等が挙げられる。 In the present invention, the “4- to 6-membered unsaturated nitrogen-containing heterocyclic group” is a 4- to 6-membered unsaturated ring group containing 1 to 4 nitrogen atoms in the ring, and includes a pyrrolyl group, a pyrazolyl group, Examples include imidazolyl group, triazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, tetrazinyl group and the like.
　本発明において、「二環性ベンゾ複素環」とは、ベンゼン環に、窒素、酸素もしくは硫黄を1～4個含む飽和または不飽和の複素環が縮合した二環性の環であり、縮合する複素環は4～6員の環であることが好ましい。「二環性ベンゾ複素環」としては、例えば、ベンゾフラン、イソベンゾフラン、インドール、イソインドール、クロメン、イソクロメン、キノリン、イソキノリン、ベンズイミダゾール、インダゾール、キノキサリン、キナゾリン、フタラジン、インドリン、イソインドリン、クロマン、イソクロマン、2,3-ジヒドロベンゾフラン、3,4-ジヒドロイソクロメン、1,2,3,4-テトラヒドロキノリン、1,2,3,4-テトラヒドロイソキノリン、ベンゾチオフェン、ベンゾチアゾールなどが挙げられる。 In the present invention, the “bicyclic benzoheterocycle” is a bicyclic ring in which a saturated or unsaturated heterocycle containing 1 to 4 nitrogen, oxygen or sulfur is condensed to a benzene ring, and is condensed. The heterocycle is preferably a 4-6 membered ring. Examples of the “bicyclic benzoheterocycle” include benzofuran, isobenzofuran, indole, isoindole, chromene, isochromene, quinoline, isoquinoline, benzimidazole, indazole, quinoxaline, quinazoline, phthalazine, indoline, isoindoline, chroman, isochroman. 2,3-dihydrobenzofuran, 3,4-dihydroisochromene, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, benzothiophene, benzothiazole and the like.
　本発明の化合物またはその薬学的に許容される塩は、一般式(I) The compound of the present invention or a pharmaceutically acceptable salt thereof has the general formula (I)
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
で表される化合物またはその薬学的に許容される塩である。 Or a pharmaceutically acceptable salt thereof.
　環Aは、ベンゼン環または二環性ベンゾ複素環を示す。環Aはベンゼン環、ベンゾフラン環またはベンゾチオフェン環であることが好ましい。 Ring A represents a benzene ring or a bicyclic benzoheterocycle. Ring A is preferably a benzene ring, a benzofuran ring or a benzothiophene ring.
　R1は、環A上の基であり、水素原子またはハロゲン原子である。R1としては水素原子、フッ素原子または塩素原子が好ましい。 R 1 is a group on the ring A and is a hydrogen atom or a halogen atom. R 1 is preferably a hydrogen atom, a fluorine atom or a chlorine atom.
　R2は、環Aがベンゼン環である場合に2位の位置に結合する置換基であり、上記Z群より独立に選ばれる1または2以上の基によって置換されていてもよいC1-C6アルキル基、上記Z群より独立に選ばれる1または2以上の基によって置換されていてもよいC1-C6アルコキシ基、上記Z群より独立に選ばれる1または2以上の基によって置換されていてもよいモノC1-C6アルキルアミノ基、-[O-(CH2)2]m-X-Qまたは-O-(CH2)n-X-Qを示す（ここで、mは1または2の整数を示し、nは1、2、3または4の整数を示し、XはO、NHまたはNHC=Oを示し、QはC1-C6アルキル基、C1-C6アルコキシ基またはモノC1-C6アルキルアミノ基を示す。）。 R 2 is a substituent bonded to the 2-position when ring A is a benzene ring, and C 1 -C optionally substituted by one or more groups independently selected from the above Z group 6 alkyl group, C 1 -C 6 alkoxy group optionally substituted by one or more groups independently selected from the above Z group, substituted by one or more groups independently selected from the above Z group An optionally mono C 1 -C 6 alkylamino group, — [O— (CH 2 ) 2 ] mXQ or —O— (CH 2 ) nXQ (where m represents an integer of 1 or 2, n represents an integer of 1, 2, 3 or 4, X represents O, NH or NHC = O, Q represents a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group or a mono C 1 -C 6 Represents an alkylamino group).
　R2としては、C1-C3アルコキシ基（該C1-C3アルコキシ
基は、C1-C3アルコキシ基、1個のハロゲン原子で置換されていてもよいピリジル基、ピリミジニル基、ピリダジニル基、ピラジニル基、チアゾリル基、テトラヒドロピラニル基、ジオキサニル基、モルホリル基もしくはカルボキシフェニル基で置換されていてもよい）、C1-C3アルコキシ基で置換されていてもよいC1-C3アルキルアミノ基、-[O-(CH2)2]m-X-Q、または-O-(CH2)n-X-Qであることがより好ましい。 R 2 is a C 1 -C 3 alkoxy group (the C 1 -C 3 alkoxy group is a C 1 -C 3 alkoxy group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group which may be substituted with one halogen atom) group, pyrazinyl group, thiazolyl group, tetrahydropyranyl group, dioxanyl group, may be substituted with a morpholyl group or carboxyphenyl group), C 1 -C 3 optionally substituted by an alkoxy group C 1 -C 3 It is more preferably an alkylamino group, — [O— (CH 2 ) 2 ] mXQ, or —O— (CH 2 ) nXQ.
　さらに、前記式(I)において、下記の部分構造式(I-2) Furthermore, in the above formula (I), the following partial structural formula (I-2)
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
が、下記群 But the following group
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-I000028
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-I000028
のいずれかであることが好ましい。 It is preferable that it is either.
　環Bは環内に窒素原子を2つ含む一環性または二環性の環を示し、該二環性の環はさらに、窒素原子、酸素原子及び硫黄原子からなる群から選ばれる1または2以上の原子を環内に含んでいてもよい。 Ring B represents a unitary or bicyclic ring containing two nitrogen atoms in the ring, and the bicyclic ring is further one or more selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom May be included in the ring.
　R3は、環B上の基であり、水素原子またはハロゲン原子を示す。R3としては、水素原子またはフッ素原子が好ましい。 R 3 is a group on ring B and represents a hydrogen atom or a halogen atom. R 3 is preferably a hydrogen atom or a fluorine atom.
　環Bとして、「窒素原子を2つ含む一環性または二環性の環を示し、該二環性の環はさらに、窒素原子、酸素原子及び硫黄原子からなる群から選ばれる1または2以上の原子を環内に含んでいてもよい」で表される環は、環Bが一環性の環である場合、環Bは6員の不飽和の含窒素環であることが好ましく、ピラジン、ピリミジン、ピリダジンが挙げられ、特に、ピリダジンであることが好ましい。環Bが二環性の環である場合、6員の不飽和の含窒素環と飽和もしくは不飽和の5員または6員の環との縮合環であることが好ましく、6員の不飽和の含窒素環としてはピラジン、ピリミジン、ピリダジン、トリアジンが挙げられ、該6員の不飽和の含窒素環と縮合する飽和もしくは不飽和の5員または6員の環としては、シクロペンテン、ベンゼン、フラン、ジヒドロフラン、チオフェン、ピロール、ピリジン、イミダゾール、ピラゾール等が挙げられる。 Ring B represents “a monocyclic or bicyclic ring containing two nitrogen atoms, and the bicyclic ring further includes one or more selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. The ring represented by `` may contain an atom in the ring '', when ring B is a unitary ring, ring B is preferably a 6-membered unsaturated nitrogen-containing ring, and pyrazine, pyrimidine And pyridazine, and pyridazine is particularly preferable. When ring B is a bicyclic ring, it is preferably a fused ring of a 6-membered unsaturated nitrogen-containing ring and a saturated or unsaturated 5-membered or 6-membered ring, and a 6-membered unsaturated ring Examples of the nitrogen-containing ring include pyrazine, pyrimidine, pyridazine, and triazine. Examples of the saturated or unsaturated 5-membered or 6-membered ring condensed with the 6-membered unsaturated nitrogen-containing ring include cyclopentene, benzene, furan, Dihydrofuran, thiophene, pyrrole, pyridine, imidazole, pyrazole and the like can be mentioned.
　環Bが二環性である場合、前記式(I)中の下記の部分構造式(I-2) When ring B is bicyclic, the following partial structural formula (I-2) in the above formula (I)
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
が、下記式(II) Is represented by the following formula (II)
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
［式中、環Dは、ベンゼン環、ピロール環、フラン環、チオフェン環、シクロペンテン環、またはジヒドロフラン環を示し、R3は、水素原子またはハロゲン原子を示す。］
で表される基であることが好ましい。 [Wherein, ring D represents a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, a cyclopentene ring, or a dihydrofuran ring, and R 3 represents a hydrogen atom or a halogen atom. ]
It is preferable that it is group represented by these.
　この場合、さらに、部分構造式(I-2)が、
下記群 In this case, the partial structural formula (I-2)
Following group
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
のいずれかであることが好ましい。 It is preferable that it is either.
　さらに、別の態様では、部分構造式(I-2)が、
下記式(III) Furthermore, in another aspect, the partial structural formula (I-2) is
The following formula (III)
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
［式中、環Eは、ベンゼン環、ピロール環、またはチオフェン環を示し、R3は、水素原子またはハロゲン原子を示す。］で表される基であることが好ましい。 [Wherein, ring E represents a benzene ring, a pyrrole ring, or a thiophene ring, and R 3 represents a hydrogen atom or a halogen atom. It is preferable that it is group represented by this.
　この場合、さらに、部分構造式(I-2)が、
下記群 In this case, the partial structural formula (I-2)
Following group
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
のいずれかであることが好ましい。 It is preferable that it is either.
　環Cは、ベンゼン環または4～6員の飽和含窒素複素環を示す。「4～6員の飽和含窒素複素環」は、環内に窒素原子を1～4個含む4～6員の飽和環であり、アゼチジジン、ピロリジン、イミダゾリジン、ピラゾリジン、ピペリジン、ピペラジン等が挙げられる。環Cとしては、ベンゼン、アゼチジン、ピロリジン、またはピペリジンがより好ましい。 Ring C represents a benzene ring or a 4- to 6-membered saturated nitrogen-containing heterocycle. “4- to 6-membered saturated nitrogen-containing heterocycle” is a 4- to 6-membered saturated ring containing 1 to 4 nitrogen atoms in the ring, and examples thereof include azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine. It is done. Ring C is more preferably benzene, azetidine, pyrrolidine, or piperidine.
　R4、R5およびR6は、環C上の基であり、それぞれ独立に、水素原子、ハロゲン原子、下記Y群より独立に選ばれる1または2以上の基によって置換されていてもよいC1-C6アルキル基、下記Y群より独立に選ばれる1または2以上の基によって置換されていてもよいC1-C6アルコキシ基、下記Y群より独立に選ばれる1または2以上の基によって置換されていてもよいモノC1-C6アルキルアミノ基、C1-C6アルキルスルホニル基、または下記 R 4 , R 5 and R 6 are groups on the ring C, each independently a hydrogen atom, a halogen atom, or C which may be substituted by one or more groups independently selected from the following group Y 1 -C 6 alkyl group, one or more substituted C 1 optionally -C 6 alkoxy group by group, one or more groups independently selected from the following group Y is individually selected from the following group Y A mono C 1 -C 6 alkylamino group, a C 1 -C 6 alkylsulfonyl group, which may be substituted by:
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
のいずれかの基を示す（Y群：オキソ基、C1-C6アルコキシ基、及びカルバモイル基）。 (Group Y: oxo group, C 1 -C 6 alkoxy group, and carbamoyl group).
　環Cがベンゼン環である場合、R4、R5およびR6は、そのうちの一つの基がC1-C3アルキル基またはフッ素原子であることが好ましい。 When the ring C is a benzene ring, it is preferred that one of R 4 , R 5 and R 6 is a C 1 -C 3 alkyl group or a fluorine atom.
　環Cがアゼチジン、ピロリジンまたはピペリジンである場合、R4、R5およびR6のうちの2つの基は水素原子であり、他の一つの基がC1-C6アルキルスルホニル基、またはカルバモイル基およびオキソ基からなる群から独立に選ばれる1または2以上の基により置換されたC1-C3アルキル基であることが好ましい。 When ring C is azetidine, pyrrolidine or piperidine, two groups out of R 4 , R 5 and R 6 are hydrogen atoms, and the other group is a C 1 -C 6 alkylsulfonyl group, or a carbamoyl group And a C 1 -C 3 alkyl group substituted with one or more groups independently selected from the group consisting of oxo groups.
　さらに、前記式(I)において、下記の部分構造式(I-3) Furthermore, in the above formula (I), the following partial structural formula (I-3)
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
が、下記群 But the following group
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
のいずれかであることが好ましい。 It is preferable that it is either.
　本発明において、「薬学上許容される塩」とは、本発明の化合物がアミノ基のような塩基性の基を有する場合には酸と反応させることにより、また、カルボキシル基のような酸性基を有する場合には塩基と反応させることにより、塩にすることができるので、その塩を示す。 In the present invention, the term “pharmaceutically acceptable salt” refers to an acid group such as a carboxyl group by reacting with an acid when the compound of the present invention has a basic group such as an amino group. In the case of having a salt, it can be converted into a salt by reacting with a base.
　塩基性基に基づく塩としては、好適には、弗化水素酸塩、塩酸塩、臭化水素酸塩、沃化水素酸塩のようなハロゲン化水素酸塩、硝酸塩、過塩素酸塩、硫酸塩、燐酸塩等の無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩のような低級アルカンスルホン酸塩、ベンゼンスルホン酸塩、p-トルエンスルホン酸塩のようなアリールスルホン酸塩、酢酸塩、りんご酸塩、フマ－ル酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩等の有機酸塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩を挙げることができる。当該塩は、好適には、無機酸塩であり、より好適には、ハロゲン化水素酸塩である。 The salt based on the basic group is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, perchlorate, sulfuric acid. Inorganic acid salts such as salts and phosphates; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate, aryl sulfones such as benzene sulfonate and p-toluene sulfonate Acid salt, acetate salt, malate salt, fumarate salt, succinate salt, citrate salt, ascorbate salt, tartrate salt, succinate salt, maleate salt, etc .; and glycine salt, lysine salt And amino acid salts such as arginine salt, ornithine salt, glutamate and aspartate. The salt is preferably an inorganic acid salt, and more preferably a hydrohalide salt.
　一方、酸性基に基づく塩としては、好適には、ナトリウム塩、カリウム塩、リチウム塩のようなアルカリ金属塩、カルシウム塩、マグネシウム塩のようなアルカリ土類金属塩、アルミニウム塩、鉄塩等の金属塩；アンモニウム塩のような無機塩；2-メチルプロパン-2-アミン塩、t-オクチルアミン塩、ジベンジルアミン塩、モルホリン塩、グルコサミン塩、フェニルグリシンアルキルエステル塩、エチレンジアミン塩、N-メチルグルカミン塩、グアニジン塩、ジエチルアミン塩、トリエチルアミン塩、ジシクロヘキシルアミン塩、N,N’-ジベンジルエチレンジアミン塩、クロロプロカイン塩、プロカイン塩、ジエタノ－ルアミン塩、N-ベンジルフェネチルアミン塩、ピペラジン塩、テトラメチルアンモニウム塩、トリス（ヒドロキシメチル）アミノメタン塩のような有機塩等のアミン塩；及び、グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩、アスパラギン酸塩のようなアミノ酸塩を挙げることができる。 On the other hand, the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, potassium salt or lithium salt, an alkaline earth metal salt such as a calcium salt or magnesium salt, an aluminum salt or an iron salt. Metal salt; inorganic salt such as ammonium salt; 2-methylpropan-2-amine salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methyl Glucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethyl Ammonium salt, tris (hydroxymethyl) amino Amine salts such as organic salts such as methane salt; and include glycine salts, lysine salts, arginine salts, ornithine salts, glutamic acid salts, amino acid salts such as aspartate.
　本発明の一般式(I)で表される化合物またはその薬学上許容される塩は、全ての異性体（ケト-エノール異性体、立体異性体等）を包含する。 The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof includes all isomers (keto-enol isomer, stereoisomer, etc.).
　本発明の一般式(I)で表される化合物またはその薬学上許容される塩は、その分子内に不斉炭素原子が存在する場合、種々の異性体を有する。本発明の化合物においては、これらの異性体およびこれらの異性体の混合物がすべて単一の式、即ち一般式(I)で示されている。従って、本発明はこれらの異性体およびこれらの異性体の任意の割合の混合物をもすべて含むものである。 The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has various isomers when an asymmetric carbon atom is present in the molecule. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Therefore, the present invention includes all of these isomers and a mixture of these isomers in an arbitrary ratio.
　上記のような立体異性体は、合成した本発明に係る化合物を所望により通常の光学分割法または分離法を用いて単離することにより得ることができる。 The stereoisomers as described above can be obtained by isolating the synthesized compound according to the present invention using a conventional optical resolution method or separation method, if desired.
　本発明の一般式(I)で表される化合物またはその薬学上許容される塩は、このような化合物を構成する原子の1以上に、非天然割合の原子同位体を含有し得る。原子同位体としては、例えば、重水素(2H)、トリチウム(3H)、ヨウ素－125(125I)または炭素－14(14C)などが挙げられる。また、前記化合物は、例えば、トリチウム(3H)、ヨウ素－125(125I)または炭素－14(14C)などの放射性同位体で放射性標識され得る。放射性標識された化合物は、治療または予防剤、研究試薬、例えば、アッセイ試薬、及び診断剤、例えば、インビボ画像診断剤として有用である。本発明の化合物の全ての同位体変異種は、放射性であると否とを問わず、本発明の範囲に包含されるものとする。 The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof may contain an unnatural proportion of atomic isotopes at one or more of atoms constituting such a compound. Examples of atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like. The compound may also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
　本発明の一般式(I)で表される化合物またはその薬学上許容される塩は、大気中に放置したり、または、再結晶をすることにより、水分を吸収し、吸着水が付いたり、水和物となる場合があり、そのような水和物も本発明の化合物または塩に包含される。 The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof can be left in the atmosphere or recrystallized to absorb moisture and adsorb water. It may become a hydrate, and such a hydrate is also encompassed in the compound or salt of the present invention.
　本発明の一般式(I)で表される化合物またはその薬学上許容される塩は、他のある種の溶媒を吸収し、溶媒和物となる場合があり、そのような溶媒和物も本発明の化合物または塩に包含される。 The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof may absorb a certain other solvent and become a solvate, and such a solvate is also present in the present invention. Included in the compounds or salts of the invention.
　本発明の一般式(I)で表される化合物またはその薬学上許容される塩は、優れた血糖降下作用を有し、糖尿病（1型糖尿病、2型糖尿病、妊娠糖尿病等）、食後過血糖症、耐糖能障害、糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、高脂血症、動脈硬化症、血栓性疾患、肥満、高血圧、浮腫、インスリン抵抗性、不安定糖尿病、インスリノーマ、高インスリン血症などの疾患等の治療薬／治療方法に用いられる医薬、または予防薬／予防方法に用いられる医薬として有用である。 The compound represented by the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof has an excellent hypoglycemic action, such as diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia. , Glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, It is useful as a medicament used in a therapeutic agent / treatment method for diseases such as hyperinsulinemia or a prophylactic agent / prevention method.
　本発明の一般式(I)で表される化合物の代表的な製造法について説明する。 A typical production method of the compound represented by the general formula (I) of the present invention will be described.
　なお、以下に示す製造法の各工程の反応において使用される溶媒は、反応を阻害せず、出発原料を一部溶解するものであれば特に限定なく、例えば、下記溶媒群から選択される。溶媒群は、ヘキサン、ペンタン、ヘプタン、石油エーテル、シクロヘキサンのような脂肪族炭化水素類；トルエン、ベンゼン、キシレンのような芳香族炭化水素類；ジクロロメタン、クロロホルム、四塩化炭素、ジクロロエタン、クロロベンゼン、ジクロロベンゼンのようなハロゲン化炭化水素類；ジエチルエーテル、ジイソプロピルエーテル、シクロペンチルメチルエーテル、t-ブチルメチルエーテル、テトラヒドロフラン、１，４－ジオキサン、ジメトキシエタン、ジエチレングリコールジメチルエーテルのようなエーテル類；アセトン、メチルエチルケトン、メチルイソブチルケトン、シクロヘキサノンのようなケトン類；酢酸メチル、酢酸エチル、酢酸プロピル、酢酸ブチル、炭酸ジエチルのようなエステル類；アセトニトリル、プロピオニトリル、ブチロニトリル、イソブチロニトリルのようなニトリル類；ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、ペンタフルオロプロピオン酸のような有機酸類；メタノール、エタノール、1-プロパノール、2-プロパノール、1-ブタノール、2-ブタノール、2-メチル-1-プロパノール、2-メチル-2-プロパノールのようなアルコール類；ホルムアミド、N,N-ジメチルホルムアミド、N,N-ジメチルアセタミド、N-メチルピロリドン、N,N’-ジメチルプロピレンウレア、ヘキサメチルホスホロトリアミドのようなアミド類；ジメチルスルホキシド、スルホランのようなスルホキシド類；水；および、これらの混合物からなる。 The solvent used in the reaction of each step of the production method shown below is not particularly limited as long as it does not inhibit the reaction and partially dissolves the starting material, and is selected from the following solvent group, for example. Solvent groups include aliphatic hydrocarbons such as hexane, pentane, heptane, petroleum ether, cyclohexane; aromatic hydrocarbons such as toluene, benzene, xylene; dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, di- Halogenated hydrocarbons such as chlorobenzene; ethers such as diethyl ether, diisopropyl ether, cyclopentyl methyl ether, t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetone, methyl ethyl ketone, methyl Ketones such as isobutyl ketone and cyclohexanone; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; acetonitrile, Nitriles such as pionitrile, butyronitrile, isobutyronitrile; organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, pentafluoropropionic acid; methanol, ethanol, 1-propanol, 2-propanol, 1-butanol , 2-butanol, 2-methyl-1-propanol, alcohols such as 2-methyl-2-propanol; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, N , N′-dimethylpropylene urea, amides such as hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane; water; and mixtures thereof.
　以下に示す製造法の各工程の反応において使用される酸は、反応を阻害しないものであれば特に限定はなく、下記酸群より選択される。酸群は、塩酸、臭化水素酸、ヨウ化水素酸、リン酸、硫酸、硝酸のような無機酸；ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、ペンタフルオロプロピオン酸のような有機酸；および、メタンスルホン酸、トリフルオロメタンスルホン酸、p-トルエンスルホン酸、カンファースルホン酸のような有機スルホン酸からなる。 The acid used in the reaction in each step of the production method shown below is not particularly limited as long as it does not inhibit the reaction, and is selected from the following acid group. The acid group includes inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, nitric acid; organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, pentafluoropropionic acid; and , Methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, and organic sulfonic acids such as camphorsulfonic acid.
　以下に示す製造法の各工程の反応において使用される塩基は、反応を阻害しないものであれば特に限定はなく、下記塩基群より選択される。塩基群は、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウムのようなアルカリ金属炭酸塩；炭酸水素リチウム、炭酸水素ナトリウム、炭酸水素カリウムのようなアルカリ金属炭酸水素塩；水酸化リチウム、水酸化ナトリウム、水酸化カリウムのようなアルカリ金属水酸化物；水酸化カルシウム、水酸化バリウムのようなアルカリ土類金属水酸化物；リン酸ナトリウム、リン酸カリウムのようなアルカリ金属リン酸塩;水素化リチウム、水素化ナトリウム、水素化カリウムのようなアルカリ金属水素化物；リチウムアミド、ナトリウムアミド、カリウムアミドのようなアルカリ金属アミド；リチウムメトキシド、ナトリウムメトキシド、ナトリウムエトキシド、ナトリウム-tert-ブトキシド、カリウム-tert-ブトキシドのような金属アルコキシド；リチウムジイソプロピルアミド(LDA)、リチウムシクロヘキシルイソプロピルアミド、リチウムテトラメチルピペラジドのようなリチウムアミド；リチウムビストリメチルシリルアミド、ナトリウムビストリメチルシリルアミド、カリウムビストリメチルシリルアミドのようなアルカリ金属シリルアミド；メチルリチウム、n-ブチルリチウム、sec-ブチルリチウム、tert-ブチルリチウムのようなアルキルリチウム；塩化メチルマグネシウム、臭化メチルマグネシウム、ヨウ化メチルマグネシウム、塩化エチルマグネシウム、臭化エチルマグネシウム、塩化イソプロピルマグネシウム、臭化イソプロピルマグネシウム、塩化イソブチルマグネシウムのようなハロゲン化アルキルマグネシウム；および、トリエチルアミン、トリブチルアミン、ジイソプロピルエチルアミン、ジエチルアミン、ジイソプロピルアミン、N-メチルピペリジン、N-メチルモルホリン、N-エチルモルホリン、ピリジン、ピコリン、2,6-ルチジン、4-(N,N-ジメチルアミノ)ピリジン、N,N-ジメチルアニリン、N,N-ジエチルアニリン、1,5-ジアザビシクロ[4,3,0]ノナ-5-エン、1,4-ジアザビシクロ[2,2,2]オクタン(DABCO)、1,8-ジアザビシクロ[5,4,0]-7-ウンデセン(DBU)のような有機アミンからなる。 The base used in the reaction in each step of the production method shown below is not particularly limited as long as it does not inhibit the reaction, and is selected from the following base group. Base groups include alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate and cesium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; lithium hydroxide and sodium hydroxide Alkali metal hydroxides such as potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide; alkali metal phosphates such as sodium phosphate and potassium phosphate; lithium hydride Alkali metal hydrides such as sodium hydride, potassium hydride; Alkali metal amides such as lithium amide, sodium amide, potassium amide; Lithium methoxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium metal tert-butoxide Lithium oxide such as lithium diisopropylamide (LDA), lithium cyclohexylisopropylamide, lithium tetramethylpiperazide; alkali metal silylamide such as lithium bistrimethylsilylamide, sodium bistrimethylsilylamide, potassium bistrimethylsilylamide; Alkyllithium such as n-butyllithium, sec-butyllithium, tert-butyllithium; methylmagnesium chloride, methylmagnesium bromide, methylmagnesium iodide, ethylmagnesium chloride, ethylmagnesium bromide, isopropylmagnesium chloride, isopropylbromide Magnesium, alkylmagnesium halides such as isobutylmagnesium chloride; and triethylamine, tributylamine , Diisopropylethylamine, diethylamine, diisopropylamine, N-methylpiperidine, N-methylmorpholine, N-ethylmorpholine, pyridine, picoline, 2,6-lutidine, 4- (N, N-dimethylamino) pyridine, N, N- Dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4,3,0] nona-5-ene, 1,4-diazabicyclo [2,2,2] octane (DABCO), 1,8-diazabicyclo It consists of organic amines such as [5,4,0] -7-undecene (DBU).
　以下に示す製造法の各工程の反応において、反応温度は、溶媒、出発原料、試薬等により異なり、反応時間は、溶媒、出発原料、試薬等により異なる。 In the reaction of each step of the production method shown below, the reaction temperature varies depending on the solvent, starting material, reagent and the like, and the reaction time varies depending on the solvent, starting material, reagent and the like.
　以下に示す製造法の各工程の反応において、反応終了後、各工程の目的化合物は、常法にしたがって反応混合物から単離される。目的化合物は、例えば、(i)必要に応じて触媒等の不溶物を濾去し、(ii)反応混合物に水および水と混和しない溶媒（例えば、ジクロロメタン、クロロホルム、ジエチルエーテル、酢酸エチル、トルエン等)を加えて目的化合物を抽出し、(iii)有機層を水洗して、無水硫酸ナトリウム、または、無水硫酸マグネシウム等の乾燥剤を用いて乾燥させ、(iv)溶媒を留去することによって得られる。得られた目的物は、必要に応じて、常法、例えば、再結晶、再沈殿、または、シリカゲルカラムクロマトグラフィー等により、さらに精製することができる。また、各工程の目的化合物は精製することなくそのまま次の反応に使用することもできる。 In the reaction in each step of the production method shown below, after completion of the reaction, the target compound in each step is isolated from the reaction mixture according to a conventional method. The target compound is, for example, (i) removing insoluble matters such as a catalyst if necessary, and (ii) water and a solvent immiscible with water (for example, dichloromethane, chloroform, diethyl ether, ethyl acetate, toluene) And (iii) the organic layer is washed with water and dried using a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, and (iv) the solvent is distilled off. can get. The obtained target product can be further purified by a conventional method, for example, recrystallization, reprecipitation, silica gel column chromatography or the like, if necessary. In addition, the target compound in each step can be directly used in the next reaction without purification.
［製造法１］
製造法1は一般式(II)で示す部分構造を有する化合物の合成方法である。化合物(1)から化合物(5)を合成する工程を示している。尚、一般式（I）中の環Bが一環性である場合も、同様の手法により製造することがでる（以下の別法においても同じ）。 [Production Method 1]
Production method 1 is a method for synthesizing a compound having a partial structure represented by formula (II). The process of synthesizing compound (5) from compound (1) is shown. In addition, also when the ring B in general formula (I) is unity, it can manufacture by the same method (it is the same also in the following other methods).
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
　上記［製造法1]における化合物の構造式において、A、C、D、R1、R2、R3、R4、R5、およびR6は一般式(I)または(II)と同意義を示す。Y1は化合物(1)とA環を結合させるために必要な置換基を示し、例えば、ボロン酸、ボロン酸エステル、マグネシウムハライド、亜鉛ハライドなどを示す。 In the structural formula of the compound in the above [Production Method 1], A, C, D, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 have the same meaning as in the general formula (I) or (II) Indicates. Y 1 represents a substituent necessary for bonding the compound (1) and the A ring, and represents, for example, boronic acid, boronic acid ester, magnesium halide, zinc halide and the like.
　A-1工程は化合物(1)と化合物(2)を遷移金属触媒存在下、カップリング反応を行うことにより、化合物(3)を製造する工程である。 Step A-1 is a step for producing compound (3) by conducting a coupling reaction between compound (1) and compound (2) in the presence of a transition metal catalyst.
　化合物(1)は市販であるか、または公知の化合物から容易に調製できる。化合物(2)はハロゲン化アリールとのカップリングに使用される各種有機金属化合物を示し、好適には、Y1がボロン酸、ボロン酸エステルである化合物である。 Compound (1) is commercially available or can be easily prepared from known compounds. Compound (2) represents various organometallic compounds used for coupling with aryl halides, and preferably Y 1 is a boronic acid or boronic ester.
　本工程に用いられる合成法は、化合物の他の部分に影響を与えないものであれば特に限定はないが、一般に有機合成化学の技術において周知の方法、例えば、Palladium Reagents and Catalysts (2004, John Wiley & Sons Ltd.)に記載された方法等により行うことができる。 The synthesis method used in this step is not particularly limited as long as it does not affect other parts of the compound, but generally known methods in the art of organic synthetic chemistry, such as Palladium Reagents and Catalysts (2004, Johns). Wiley & Sons Ltd.).
使用される金属触媒は、好適には、テトラキス（トリフェニルホスフィン）パラジウム、［1,1’-ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム(II)、ジクロロメタン錯体である。
使用される塩基は、好適には、アルカリ金属炭酸塩、アルカリ金属リン酸塩、または、アルカリ金属アルコキシドであるが、より好適には、炭酸セシウム、リン酸カリウムn-水和物である。
使用される溶媒は、好適には、エーテル類、水またはそれらの混合物であるが、より好適には、1,4-ジオキサンと水の混合溶媒、または、1,2-ジメトキシエタンと水の混合溶媒である。
反応温度は、好適には、室温から120℃であるが、より好適には、80℃から100℃である。 The metal catalyst used is preferably tetrakis (triphenylphosphine) palladium, [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II), dichloromethane complex.
The base used is preferably an alkali metal carbonate, alkali metal phosphate or alkali metal alkoxide, but more preferably cesium carbonate or potassium phosphate n-hydrate.
The solvent used is preferably an ether, water or a mixture thereof, but more preferably a mixed solvent of 1,4-dioxane and water, or a mixture of 1,2-dimethoxyethane and water. It is a solvent.
The reaction temperature is preferably from room temperature to 120 ° C., more preferably from 80 ° C. to 100 ° C.
A-2工程はA-1工程で得られる化合物(3)と化合物(4)を加熱し、芳香族置換反応によって化合物(5)を製造する工程である。化合物(4)は市販であるか、または公知の化合物から容易に調製できる。
使用される溶媒は、例えば、アルコール類、アミド類、スルホキシド類が挙げられるが、好適には、エタノール、1-ブタノールまたはジメチルスルホキシドである。もしくは無溶媒でも行うことも可能である。また、必要に応じて、トリフルオロ酢酸などの有機酸を触媒量加えることで、反応を促進させることが可能である。
反応温度は、室温から140℃であり、好適には90℃から140℃である。 Step A-2 is a step of heating compound (3) and compound (4) obtained in step A-1 to produce compound (5) by an aromatic substitution reaction. Compound (4) is commercially available or can be easily prepared from known compounds.
Examples of the solvent used include alcohols, amides and sulfoxides, and ethanol, 1-butanol or dimethyl sulfoxide is preferable. Alternatively, it can be carried out without solvent. If necessary, the reaction can be promoted by adding a catalytic amount of an organic acid such as trifluoroacetic acid.
The reaction temperature is from room temperature to 140 ° C, preferably from 90 ° C to 140 ° C.
A-3工程は化合物(1)と化合物(4)を反応させることにより化合物(6)を製造する工程である。本工程は、A-2工程と同様にして行うことができる。 Step A-3 is a step of producing compound (6) by reacting compound (1) with compound (4). This step can be performed in the same manner as the step A-2.
A-4工程はA-3工程で得られた化合物(6)と化合物(2)を遷移金属触媒存在下、カップリング反応を行うことにより、化合物(5)を製造する工程である。本工程は、A-1工程と同様にして行うことができる。 Step A-4 is a step for producing compound (5) by conducting a coupling reaction between compound (6) obtained in step A-3 and compound (2) in the presence of a transition metal catalyst. This step can be performed in the same manner as the step A-1.
［製造法２］
製造法2は、化合物(3)を得るための［製造法1］とは異なる方法である。 [Production Method 2]
Production method 2 is a method different from [Production method 1] for obtaining compound (3).
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
上記［製造法2］における化合物の構造式において、A、D、R1、R2、およびR3は一般式(I)または(II)と同意義を示す。 In the structural formula of the compound in the above [Production Method 2], A, D, R 1 , R 2 , and R 3 are as defined in the general formula (I) or (II).
B-1工程は、化合物(7)を活性化し、化合物(7a)を反応させることで化合物(8)を合成する工程である。化合物(7)、および化合物(7a)は、市販であるか、または公知の化合物から容易に調製可能な化合物である。
化合物(7)の活性化剤は、リチウムアミド、アルカリ金属シリルアミド、アルキルリチウム、ハロゲン化アルキルマグネシウムが挙げられるが、好適にはn-ブチルリチウムである。
使用される溶媒は、脂肪族炭化水素類、芳香族炭化水素類、エーテル類が挙げられるが、好適には、テトラヒドロフランである。
反応温度は、-78℃から室温である。 Step B-1 is a step of synthesizing compound (8) by activating compound (7) and reacting compound (7a). Compound (7) and compound (7a) are commercially available or can be easily prepared from known compounds.
Examples of the activator for the compound (7) include lithium amide, alkali metal silylamide, alkyllithium, and alkylmagnesium halide, and preferably n-butyllithium.
Examples of the solvent used include aliphatic hydrocarbons, aromatic hydrocarbons, and ethers, and tetrahydrofuran is preferred.
The reaction temperature is from -78 ° C to room temperature.
B-2工程はB-1工程より得られた化合物(8)をヒドラジンを用いて環化することで化合物(9)を合成する工程である。
反応に使用するヒドラジンは、その塩酸塩や水和物を用いることが可能である。
使用される溶媒は、アルコール類、アミド類、スルホキシド類が挙げられるが、好適には、エタノール、1-ブタノールなどのアルコール類である。
反応温度は、好適には、室温から140℃であるが、さらに好適には80℃から120℃である。 Step B-2 is a step of synthesizing compound (9) by cyclizing compound (8) obtained from step B-1 using hydrazine.
The hydrazine used in the reaction can be its hydrochloride or hydrate.
Examples of the solvent to be used include alcohols, amides, and sulfoxides, and alcohols such as ethanol and 1-butanol are preferable.
The reaction temperature is preferably from room temperature to 140 ° C, more preferably from 80 ° C to 120 ° C.
B-3工程は、B-2工程より得られた化合物(9)にクロロ化剤を作用させ、化合物(3)を合成する工程である。
使用するクロロ化剤としては、化合物の他の部分に影響を与えないものであれば特に限定はないが、例えば、スルホニルクロリド、オキサリルクロリド、5塩化リン、オキシ塩化リンなどが挙げられる。好適にはオキシ塩化リンである。
使用される溶媒は、好適には脂肪族炭化水素類、芳香族炭化水素類、または無溶媒であるが、さらに好適には無溶媒である。
反応温度は、好適には、室温から150℃であるが、さらに好適には80℃から120℃である。 Step B-3 is a step of synthesizing compound (3) by allowing a chlorinating agent to act on compound (9) obtained from step B-2.
The chlorinating agent to be used is not particularly limited as long as it does not affect other parts of the compound, and examples thereof include sulfonyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus oxychloride and the like. Preferred is phosphorus oxychloride.
The solvent used is preferably aliphatic hydrocarbons, aromatic hydrocarbons, or no solvent, but more preferably no solvent.
The reaction temperature is preferably from room temperature to 150 ° C, more preferably from 80 ° C to 120 ° C.
［製造法３］
製造法3は［製造法2］とは異なる化合物(8)の合成方法である。 [Production Method 3]
Production method 3 is a synthesis method of compound (8) different from [Production method 2].
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
上記［製造法3］における化合物の構造式において、A、D、R1、R2、およびR3は一般式(I)、(II)および前記製法と同意義を示し、Alkylは、C1-C6アルキル基を示す。Y2は、化合物(12)とA環を結合するために必要な置換基であり、ハロゲン基、トリフレート基などを示す。 In the structural formula of the compound in the above [Production Method 3], A, D, R 1 , R 2 , and R 3 are the same as those in the general formulas (I), (II) and the above production method, and Alkyl is C 1 —C 6 represents an alkyl group. Y 2 is a substituent necessary for bonding the compound (12) and the A ring, and represents a halogen group, a triflate group, or the like.
C-1工程は、化合物(10)を塩基性条件下、トリメチルシリルシアニドを作用させることでシリルエーテル化合物(11)へと変換する工程である。
用いる化合物(10)は市販であるか、または公知の化合物から容易に調製が可能である。
使用される塩基は、好適には有機アミンであり、さらに好適にはトリエチルアミンである。
使用される溶媒は、脂肪族炭化水素類、芳香族炭化水素類、エーテル類が挙げられるが、好適には、クロロホルムである。
反応温度は、0℃から70℃であり、好適には50℃である。 Step C-1 is a step of converting compound (10) into silyl ether compound (11) by the action of trimethylsilyl cyanide under basic conditions.
The compound (10) used is commercially available or can be easily prepared from known compounds.
The base used is preferably an organic amine, more preferably triethylamine.
Examples of the solvent used include aliphatic hydrocarbons, aromatic hydrocarbons, and ethers, and chloroform is preferred.
The reaction temperature is 0 ° C to 70 ° C, preferably 50 ° C.
C-2工程は、C-1工程より得られた化合物(11)を塩基を用いて活性化した後、化合物(12)と反応させることにより、化合物(8)を合成する工程である。
用いる化合物(12)は市販であるか、または公知の化合物から容易に調製が可能である。
使用される塩基は、アルカリ金属水素化物、アルカリ金属アミド、金属アルコキシド、リチウムアミド、アルカリ金属シリルアミド、アルキルリチウムが挙げられるが、好適には、カリウムビストリメチルシリルアミドのようなアルカリ金属シリルアミドである。
使用される溶媒は、脂肪族炭化水素類、芳香族炭化水素類、エーテル類が挙げられるが、好適には、テトラヒドロフランである。
反応温度は、-78℃から0℃である。 Step C-2 is a step of synthesizing compound (8) by activating compound (11) obtained in step C-1 with a base and then reacting with compound (12).
The compound (12) used is commercially available or can be easily prepared from known compounds.
Examples of the base used include alkali metal hydrides, alkali metal amides, metal alkoxides, lithium amides, alkali metal silylamides, and alkyllithiums, and alkali metal silylamides such as potassium bistrimethylsilylamide are preferred.
Examples of the solvent used include aliphatic hydrocarbons, aromatic hydrocarbons, and ethers, and tetrahydrofuran is preferred.
The reaction temperature is -78 ° C to 0 ° C.
　得られた上記化合物(8)’のエステル基を加水分解することにより化合物(8)を得ることができる。
［製造法４］
製造法4は［製造法1］とは異なる化合物(5)の合成方法である。 Compound (8) can be obtained by hydrolyzing the ester group of the obtained compound (8) ′.
[Production Method 4]
Production method 4 is a synthesis method of compound (5) different from [Production method 1].
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
上記［製造法4］における化合物の構造式において、A、D、R1、R2、R3、R4、R5、R6、およびY2は一般式(I)、(II)および前記製法と同意義を示す。 In the structural formula of the compound in the above [Production Method 4], A, D, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and Y 2 are represented by the general formulas (I), (II) and the above It shows the same significance as the manufacturing method.
D-1工程は、化合物(13)をヒドラジンを用いて分子内環化させることにより、化合物(14)を合成する工程である。
化合物(13)は市販であるか、または公知の化合物から容易に調製が可能である。本工程は、B-2工程と同様にして行うことができる。 Step D-1 is a step of synthesizing compound (14) by intramolecular cyclization of compound (13) with hydrazine.
Compound (13) is commercially available or can be easily prepared from known compounds. This step can be performed in the same manner as the step B-2.
D-2工程は、D-1工程より得られた化合物(14)を用いて、遷移金属触媒存在下、ハロゲン化アリール(15)とカップリング反応させることにより、化合物(5)を合成する工程である。
用いる化合物(15)は市販であるか、または公知の化合物より容易に調製が可能である。
本工程に用いる試薬、反応条件はA-1工程と同様のものを用いることができる。 In step D-2, compound (5) is synthesized by coupling reaction with aryl halide (15) in the presence of a transition metal catalyst using compound (14) obtained in step D-1. It is.
The compound (15) used is commercially available or can be easily prepared from known compounds.
The reagents and reaction conditions used in this step can be the same as those used in step A-1.
［製造法５］
製造法5は［製造法1］、［製造法4］とは異なる化合物(5)の合成法である。 [Production Method 5]
Production method 5 is a synthesis method of compound (5) different from [Production method 1] and [Production method 4].
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
上記［製造法5］における化合物の構造式において、A、D、R1、R2、R3、R4、R5、およびR6は一般式(I)、(II)および前記製法と同意義を示す。Y3は、C1-C6アルキル基または、アルコキシカルボニルメチレン基を示す。 In the structural formula of the compound in the above [Production Method 5], A, D, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are the same as those in the general formulas (I), (II), and the above production method. Show significance. Y 3 represents a C 1 -C 6 alkyl group or an alkoxycarbonylmethylene group.
E-1工程は、［製造法2］で得られる化合物(9)を、硫黄化剤を用いて、化合物(16)を合成する工程である。
使用される硫黄化剤としては、例えば、2,4-ビス（4-メトキシフェニル）-1,3,2,4-ジチアジホスフェタン-2,4-ジスルフィド（ローソン試薬）や、5硫化2リンなどが挙げられるが、好適には、5硫化2リンである。
使用される溶媒は、芳香族炭化水素類、または無溶媒であるが、好適には、無溶媒である。
反応温度は、好適には100℃から180℃であるが、さらに好適には、150℃でマイクロウェーブ反応機を用いて行う手法である。 Step E-1 is a step of synthesizing compound (16) from compound (9) obtained in [Production Method 2] using a sulfurizing agent.
Examples of the sulfurating agent used include 2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawson reagent) and pentasulfide. Examples thereof include 2-phosphorus, and 2-phosphorus pentasulfide is preferable.
The solvent used is aromatic hydrocarbons or solvent-free, but is preferably solvent-free.
The reaction temperature is preferably from 100 ° C. to 180 ° C., but more preferably, the reaction is performed at 150 ° C. using a microwave reactor.
E-2工程は、E-1工程より得られた化合物(16)に塩基存在下、アルキル化剤を反応させ、化合物(17)を合成する工程である。
使用されるアルキル化剤としては、好適には、ハロゲン化アルキル、ハロ酢酸エステルであるが、さらに好適には、ヨードエタン、ブロモ酢酸エチルである。
使用される溶媒は、例えば、脂肪族炭化水素類、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、ケトン類、エステル類、ニトリル類、アミド類、スルホキシド類が挙げられるが、好適には、テトラヒドロフランなどのエーテル類である。
反応温度は、0℃から60℃であるが、好適には、室温である。 Step E-2 is a step of synthesizing compound (17) by reacting compound (16) obtained in step E-1 with an alkylating agent in the presence of a base.
The alkylating agent to be used is preferably an alkyl halide or a haloacetic acid ester, and more preferably iodoethane or ethyl bromoacetate.
Examples of the solvent used include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, nitriles, amides, and sulfoxides. Is an ether such as tetrahydrofuran.
The reaction temperature is 0 ° C. to 60 ° C., preferably room temperature.
E-3工程は、E-2工程より得られた化合物(17)に対し、化合物(4)を付加させることにより化合物(5)を合成する工程である。
使用される溶媒は、好適には有機酸類であり、さらに好適には酢酸である。
反応温度は、室温から150℃であり、好適には、130℃である。 Step E-3 is a step of synthesizing compound (5) by adding compound (4) to compound (17) obtained from step E-2.
The solvent used is preferably an organic acid, more preferably acetic acid.
The reaction temperature is from room temperature to 150 ° C, preferably 130 ° C.
［製造法６］
製造法6は、一般式(III)で示す部分構造を有する化合物の合成方法である。 [Production Method 6]
Production method 6 is a method for synthesizing a compound having a partial structure represented by formula (III).
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
上記［製造法6］における化合物の構造式において、A、C、D、R1、R2、R3、R4、R5、R6、およびY3は一般式(I)、(III)および前記製法と同意義を示し、Halはフルオロ基、クロロ基またはブロモ基を示す。
H-1工程は、化合物(26)もしくは化合物(27)のどちらか一方をイソシアネートへと導いた後、残りの化合物を反応させ、化合物(28)を得る方法である。好適には、化合物(27)を対応するイソシアネート化合物へと導き、その後、化合物(26)と反応させる方法である。化合物(26)および化合物(27)は、市販であるか、または公知の化合物から容易に調製が可能である。
（H-1a工程）
化合物(27)をイソシアネートへと変換する方法としては、化合物の他の部分に影響を与えないものであれば特に限定はないが、有機合成化学の技術において周知の方法、例えば、The forth series of experimental chemistry(1992, the chemical society of japan, pp.473-483)に記載された方法等に準じて行うことができる。
使用される反応剤は、好適には、ホスゲン、トリホスゲン、オキサリルクロリドなどが挙げられるが、さらに好適には、オキサリルクロリドである。
使用される溶媒は、例えば、脂肪族炭化水素類、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、ケトン類、エステル類、ニトリル類が挙げられるが、好適には、ジクロロエタンである。
反応温度は、好適には、室温から120℃であり、さらに好適には、90℃である
（H-1b工程）
使用される溶媒は、例えば、脂肪族炭化水素類、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、ケトン類、エステル類、ニトリル類、アミド類、スルホキシド類が挙げられるが、好適には、1,4-ジオキサンである。
反応温度は、好適には、室温から60℃であるが、さらに好適には、室温である。 In the structural formula of the compound in the above [Production Method 6], A, C, D, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and Y 3 are represented by the general formulas (I) and (III) And the same meaning as in the above production method, wherein Hal represents a fluoro group, a chloro group or a bromo group.
Step H-1 is a method in which either compound (26) or compound (27) is led to isocyanate and the remaining compound is reacted to obtain compound (28). Preferred is a method in which the compound (27) is led to the corresponding isocyanate compound and then reacted with the compound (26). Compound (26) and compound (27) are commercially available or can be easily prepared from known compounds.
(H-1a process)
The method for converting compound (27) into isocyanate is not particularly limited as long as it does not affect other parts of the compound, but a method well known in the art of synthetic organic chemistry, for example, The forth series of It can be performed according to the method described in experimental chemistry (1992, the chemical society of japan, pp. 473-483).
Preferred examples of the reactant used include phosgene, triphosgene, oxalyl chloride, and the like, and more preferred is oxalyl chloride.
Examples of the solvent used include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, and nitriles, and dichloroethane is preferable.
The reaction temperature is preferably from room temperature to 120 ° C., more preferably 90 ° C. (Step H-1b).
Examples of the solvent used include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, nitriles, amides, and sulfoxides. Is 1,4-dioxane.
The reaction temperature is preferably room temperature to 60 ° C., more preferably room temperature.
H-2工程は、H-1工程より得られた化合物(28)を塩基存在下、分子内環化をさせることで、化合物(29)を合成する工程である。
使用される塩基は、例えば、アルカリ金属シリルアミド、アルカリ金属水酸化物、アルカリ土類金属水酸化物、アルカリ金属リン酸塩、アルカリ金属水素化物が挙げられるが、好適には、水素化ナトリウムである。
使用される溶媒は、例えば、脂肪族炭化水素類、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、アミド類、スルホキシド類が挙げられるが、好適には、N,N-ジメチルホルムアミドである。
反応温度は、好適には、室温から100℃であるが、さらに好適には、70℃である。
H-3工程は、H-2工程より得られた化合物(29)に硫黄化剤を反応させ、化合物(30)を合成する工程である。本工程は、E-1工程と同様にして行うことができる。
H-4工程は、H-3工程より得られた化合物(30)を塩基存在下、アルキル化剤を反応させ、化合物(31)を合成する工程である。本工程は、E-2工程と同様にして行うことができる。
H-5工程は、H-4工程より得られた化合物(31)に化合物(4)を置換させることにより化合物(32)を合成する工程である。本工程は、E-3工程と同様にして行うことができる。 Step H-2 is a step of synthesizing compound (29) by intramolecular cyclization of compound (28) obtained from step H-1 in the presence of a base.
Examples of the base used include alkali metal silylamide, alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal phosphate, and alkali metal hydride, and preferably sodium hydride. .
Examples of the solvent used include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, amides, and sulfoxides. N, N-dimethylformamide is preferable. is there.
The reaction temperature is preferably from room temperature to 100 ° C, more preferably 70 ° C.
Step H-3 is a step of synthesizing compound (30) by reacting compound (29) obtained in step H-2 with a sulfurizing agent. This step can be performed in the same manner as the step E-1.
Step H-4 is a step of synthesizing compound (31) by reacting compound (30) obtained in step H-3 with an alkylating agent in the presence of a base. This step can be performed in the same manner as the step E-2.
Step H-5 is a step of synthesizing compound (32) by substituting compound (4) for compound (31) obtained from step H-4. This step can be performed in the same manner as the step E-3.
［製造法７］
製造法7は一般式(III)で示す部分構造を有する化合物合成において、［製造法6］とは異なる中間体合成方法である。 [Production Method 7]
Production method 7 is an intermediate synthesis method different from [Production method 6] in the synthesis of a compound having a partial structure represented by formula (III).
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
上記［製造法7］における化合物の構造式において、A、D、R1、R2、R3、およびAlkylは一般式(I)、(III)および前記製法と同意義を示す。
I-1工程は、製造法6に示した化合物(29)について、化合物(33)から導く工程である。本工程は、化合物(33)に活性化剤を作用させた後、塩基存在下で分子内環化を行うことで、化合物(29)を合成する工程である。
化合物(33)は、市販であるか、または公知の化合物から容易に調製が可能である。
使用される活性化剤は、例えば、N-クロロカルボニルイソシアネート、サルファイソシアナチドイルクロリドであるが、好適には、サルファイソシアナチドイルクロリドである。
使用される溶媒は、例えば、脂肪族炭化水素類、芳香族炭化水素類、ハロゲン化炭化水素類、エーテル類、ケトン類、エステル類、ニトリル類、アミド類、スルホキシド類またはそれらの混合物が挙げられるが、好適には、テトラヒドロフランと酢酸エチルの混合溶媒である。
使用される塩基は、水酸化リチウム、水酸化ナトリウム、水酸化カリウムのようなアルカリ金属水酸化物の水溶液である。
反応温度は、-40℃から室温であり、好適には、-15℃から室温である。 In the structural formula of the compound in the above [Production Method 7], A, D, R 1 , R 2 , R 3 , and Alkyl have the same meanings as in the general formulas (I) and (III) and the above production method.
Step I-1 is a step derived from compound (33) for compound (29) shown in production method 6. This step is a step of synthesizing compound (29) by allowing an activator to act on compound (33) and then performing intramolecular cyclization in the presence of a base.
Compound (33) is commercially available or can be easily prepared from known compounds.
The activator used is, for example, N-chlorocarbonyl isocyanate, sulfa isocyanatoyl chloride, but is preferably sulfa isocyanatoyl chloride.
Examples of the solvent used include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones, esters, nitriles, amides, sulfoxides or mixtures thereof. Is preferably a mixed solvent of tetrahydrofuran and ethyl acetate.
The base used is an aqueous solution of an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide.
The reaction temperature is from -40 ° C to room temperature, preferably from -15 ° C to room temperature.
　上記各工程の反応終了後、目的化合物は常法に従って、反応混合物から採取される。例えば、反応混合物を適宜中和し、又、不溶物が存在する場合には濾過により除去した後、水と酢酸エチルのような混和しない有機溶媒を加え、水等で洗浄後、目的化合物を含む有機層を分離し、無水硫酸マグネシウム等で乾燥後、溶剤を留去することによって得られる。 After completion of each step, the target compound is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insoluble matter is present, it is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, washed with water, and the target compound is then contained. The organic layer is separated, dried over anhydrous magnesium sulfate and the like, and then the solvent is distilled off.
　得られた目的物は必要ならば常法、例えば再結晶、再沈殿、または、通常、有機化合物の分離精製に慣用されている方法、例えば、吸着カラムクロマトグラフィー法、分配カラムクロマトグラフィー法等の合成吸着剤を使用する方法、イオン交換クロマトグラフィーを使用する方法、または、シリカゲル若しくはアルキル化シリカゲルによる順相・逆相カラムクロマトグラフィー法を適宜組み合わせ、適切な溶離剤で溶出することによって分離、精製することができる。 If necessary, the obtained target product can be obtained by a conventional method such as recrystallization, reprecipitation, or a method commonly used for separation and purification of organic compounds, such as adsorption column chromatography, distribution column chromatography, etc. Separation and purification by eluting with a suitable eluent by combining a method using a synthetic adsorbent, a method using ion exchange chromatography, or a normal phase / reverse phase column chromatography method using silica gel or alkylated silica gel. can do.
　さらに、必要に応じて、キラルカラムにより光学活性体の分離、精製を行うこともできる。 Furthermore, the optically active substance can be separated and purified by a chiral column as necessary.
　本発明の前記一般式(I)を有する化合物またはその薬学上許容される塩は、種々の形態で投与される。その投与形態としては特に限定はなく、各種製剤形態、患者の年齢、性別その他の条件、疾患の程度等に応じて決定される。例えば錠剤、丸剤、散剤、顆粒剤、シロップ剤、液剤、懸濁剤、乳剤、顆粒剤およびカプセル剤の場合には経口投与される。また注射剤の場合には単独であるいはぶどう糖、アミノ酸等の通常の補液と混合して静脈内投与され、さらには必要に応じて単独で筋肉内、皮内、皮下もしくは腹腔内投与される。坐剤の場合には直腸内投与される。好適には経口投与である。 The compound having the general formula (I) of the present invention or a pharmaceutically acceptable salt thereof is administered in various forms. The administration form is not particularly limited, and is determined according to various preparation forms, patient age, sex and other conditions, the degree of disease, and the like. For example, it is orally administered in the case of tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules and capsules. In the case of an injection, it is administered intravenously alone or mixed with a normal fluid such as glucose or amino acid, and further administered alone intramuscularly, intradermally, subcutaneously or intraperitoneally as needed. In the case of a suppository, it is administered intrarectally. Oral administration is preferred.
　これらの各種製剤は、常法に従って主薬に賦形剤、結合剤、崩壊剤、潤沢剤、溶解剤、矯味矯臭剤、コーティング剤等既知の医薬製剤分野において通常使用しうる既知の補助剤を用いて製剤化することができる。 These various preparations use known auxiliaries that can be generally used in the field of known pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, solubilizers, flavoring agents, and coating agents in accordance with conventional methods. Can be formulated.
　錠剤の形態に成形するに際しては、担体としてこの分野で従来公知のものを広く使用でき、例えば乳糖、白糖、塩化ナトリウム、ぶどう糖、尿素、澱粉、炭酸カルシウム、カオリン、結晶セルロース、ケイ酸等の賦形剤、水、エタノール、プロパノール、単シロップ、ぶどう糖液、澱粉液、ゼラチン溶液、カルボキシメチルセルロース、セラック、メチルセルロース、リン酸カリウム、ポリビニルピロリドン等の結合剤、乾燥澱粉、アルギン酸ナトリウム、カンテン末、ラミナラン末、炭酸水素ナトリウム、炭酸カルシウム、ポリオキシエチレンソルビタン脂肪酸エステル類、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、澱粉、乳糖等の崩壊剤、白糖、ステアリン、カカオバター、水素添加油等の崩壊抑制剤、第４級アンモニウム塩基、ラウリル硫酸ナトリウム等の吸収促進剤、グリセリン、澱粉等の保湿剤、澱粉、乳糖、カオリン、ベントナイト、コロイド状ケイ酸等の吸着剤、精製タルク、ステアリン酸塩、硼酸末、ポリエチレングリコール等の滑沢剤等が例示できる。さらに錠剤は必要に応じ通常の剤皮を施した錠剤、例えば糖衣錠、ゼラチン被包錠、腸溶被錠、フィルムコーティング錠あるいは二重錠、多層錠とすることができる。 In molding into tablets, conventionally known carriers can be widely used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like. Form, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, binder such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder Sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and other disintegrants, sucrose, stearin, cacao butter, hydrogenated oil and other disintegration inhibitors, Class Ammoni Absorption accelerators such as mud base, sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, purified talc, stearate, boric acid powder, polyethylene glycol, etc. Examples of these lubricants can be given. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.
　丸剤の形態に成形するに際しては、担体としてこの分野で従来公知のものを広く使用でき、例えばぶどう糖、乳糖、澱粉、カカオ脂、硬化植物油、カオリン、タルク等の賦形剤、アラビアゴム末、トラガント末、ゼラチン、エタノール等の結合剤、ラミナランカンテン等の崩壊剤等が例示できる。 In molding into the form of pills, those conventionally known in this field can be widely used as carriers, for example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and other excipients, gum arabic powder, Examples thereof include binders such as tragacanth powder, gelatin and ethanol, and disintegrants such as lamina lankanten.
　坐剤の形態に成形するに際しては、担体としてこの分野で従来公知のものを広く使用でき、例えばポリエチレングリコール、カカオ脂、高級アルコール、高級アルコールのエステル類、ゼラチン、半合成グリセライド等を挙げることができる。 In molding into the form of suppository, conventionally known carriers can be widely used as carriers, such as polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like. it can.
　注射剤として調製される場合には、液剤および懸濁剤は殺菌され、且つ血液と等張であるのが好ましく、これら液剤、乳剤および懸濁剤の形態に成形するに際しては、希釈剤としてこの分野において慣用されているものを全て使用でき、例えば水、エチルアルコール、プロピレングリコール、エトキシ化イソステアリルアルコール、ポリオキシ化イソステアリルアルコール、ポリオキシエチレンソルビタン脂肪酸エステル類等を挙げることができる。なお、この場合、等張性の溶液を調製するに十分な量の食塩、ぶどう糖、あるいはグリセリンを医薬製剤中に含有せしめてもよく、また通常の溶解補助剤、緩衝剤、無痛化剤等を添加してもよい。 When prepared as injections, the solutions and suspensions are preferably sterilized and isotonic with blood, and in the form of these solutions, emulsions and suspensions, this is used as a diluent. Any of those commonly used in the field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation. Ordinary solubilizers, buffers, soothing agents, etc. may be added. It may be added.
　さらに必要に応じて着色剤、保存剤、香料、風味剤、甘味剤等や他の添加剤を含有せしめてもよい。 Furthermore, if necessary, colorants, preservatives, fragrances, flavoring agents, sweetening agents, and other additives and other additives may be included.
　上記医薬製剤中に含まれる有効成分化合物の量は、特に限定されず広範囲に適宜選択されるが、通常全組成物中1～70重量％、好ましくは1～30重量％含まれる量とするのが適当である。 The amount of the active ingredient compound contained in the pharmaceutical preparation is not particularly limited and is appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 30% by weight in the total composition. Is appropriate.
　その投与量は、症状、年令、体重、投与方法および剤型等によって異なるが、通常は成人に対して１日、下限として0.001mg/kg（好ましくは0.01mg/kg、さらに好ましくは0.1mg/kg）であり、上限として200mg/kg（好ましくは20mg/kg、さらに好ましくは10mg/kg）を1回ないし数回投与することができる。 The dose varies depending on symptoms, age, body weight, administration method, dosage form, etc., but is usually 0.001 mg / kg (preferably 0.01 mg / kg, more preferably 0.1 mg as a lower limit for adults per day) / mg), and 200 mg / kg (preferably 20 mg / kg, more preferably 10 mg / kg) as the upper limit can be administered once to several times.
　本発明の化合物は、前述の本発明が有効と考えられる疾患の種々の治療または予防剤と併用することができる。当該併用は、同時投与或いは別個に連続して若しくは所望の時間間隔をおいて投与してもよい。同時投与製剤は、配合剤であっても別個に製剤化されていてもよい。 The compound of the present invention can be used in combination with various therapeutic or prophylactic agents for the diseases for which the present invention is considered to be effective. The combination may be administered simultaneously or separately in succession or at desired time intervals. The simultaneous administration preparation may be a compounding agent or may be separately formulated.
　本発明の化合物及びその薬学上許容される塩は、優れた血糖降下作用を有し、糖尿病（1型糖尿病、2型糖尿病、妊娠糖尿病等）、食後過血糖症、耐糖能障害、糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、高脂血症、動脈硬化症、血栓性疾患、肥満、高血圧、浮腫、インスリン抵抗性、不安定糖尿病、インスリノーマ、高インスリン血症などの疾患等の治療薬または予防薬として有用である。また、毒性が低く、安全性に優れることから、医薬として極めて有用であるといえる。 The compound of the present invention and a pharmaceutically acceptable salt thereof have an excellent hypoglycemic action, such as diabetes (type 1 diabetes, type 2 diabetes, gestational diabetes, etc.), postprandial hyperglycemia, impaired glucose tolerance, diabetic nerves Disorders, such as diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, unstable diabetes, insulinoma, hyperinsulinemia, etc. Useful as a therapeutic or prophylactic agent. In addition, since it is low in toxicity and excellent in safety, it can be said that it is extremely useful as a medicine.
次に実施例等をあげて本発明を更に詳細に説明するが、本発明はこれらに限定されるものではない。 EXAMPLES Next, although an Example etc. are given and this invention is demonstrated further in detail, this invention is not limited to these.
（実施例１）
2-(4-{[4-(2-メトキシフェニル)-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル]アミノ}フェニル)アセタミド Example 1
2- (4-{[4- (2-methoxyphenyl) -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl] amino} phenyl) acetamide
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
工程1(a)：エチル (4-{[4-(2-メトキシフェニル)-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル]アミノ}フェニル)アセテートの製造
参考例R1の化合物(9.4g, 36mmol)、エチル　4-アミノフェニルアセテート(6.4g, 36mmol)をn-ブタノール(150mL)に溶解し、トリフルオロ酢酸(1.0mL)を加え、135℃で4時間撹拌した。反応液を室温に冷却し、減圧下濃縮した。残渣に炭酸水素ナトリウム水溶液を加え、ジクロロメタンで3回抽出した。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後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル=80/20-30/70(v/v)］で精製し、標記化合物(10.5g, 26mmol)を固体として得た。
1H NMR (CDCl3)δ (ppm): 1.26 (3H, t, J=7.3 Hz), 2.13 (2H, quint, J=7.3 Hz), 2.83 (2H, t, J=7.3 Hz), 2.87 (2H, t, J=7.3 Hz), 3.59 (2H, s), 3.81 (3H, s), 4.15 (2H, q, J=7.3 Hz), 6.99 (1H, d, J=7.3 Hz), 7.07 (1H, dd, J=1.0, 7.3 Hz), 7.25 (2H, d, J=8.8 Hz), 7.39-7.43 (1H, m), 7.50 (1H, dd, J=2.0, 7.3 Hz), 7.65 (2H, d, J=8.8 Hz). Step 1 (a): Preparation of ethyl (4-{[4- (2-methoxyphenyl) -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl] amino} phenyl) acetate Reference Example R1 The compound (9.4 g, 36 mmol) and ethyl 4-aminophenyl acetate (6.4 g, 36 mmol) were dissolved in n-butanol (150 mL), trifluoroacetic acid (1.0 mL) was added, and the mixture was stirred at 135 ° C. for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. To the residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 80 / 20-30 / 70 (v / v)] to obtain the title compound (10.5 g, 26 mmol) as a solid.
1H NMR (CDCl 3 ) δ (ppm): 1.26 (3H, t, J = 7.3 Hz), 2.13 (2H, quint, J = 7.3 Hz), 2.83 (2H, t, J = 7.3 Hz), 2.87 (2H , t, J = 7.3 Hz), 3.59 (2H, s), 3.81 (3H, s), 4.15 (2H, q, J = 7.3 Hz), 6.99 (1H, d, J = 7.3 Hz), 7.07 (1H , dd, J = 1.0, 7.3 Hz), 7.25 (2H, d, J = 8.8 Hz), 7.39-7.43 (1H, m), 7.50 (1H, dd, J = 2.0, 7.3 Hz), 7.65 (2H, d, J = 8.8 Hz).
工程1(b)：2-(4-{[4-(2-メトキシフェニル)-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル]アミノ}フェニル)アセタミドの製造
工程1(a)で得られた化合物(10.3g, 26mmol)をエタノール(70mL)、テトラヒドロフラン(70mL)に溶解し、5規定水酸化ナトリウム水溶液(10.4mL)を加え、室温で3日間撹拌した。反応液を減圧下濃縮し、残渣に5規定塩酸(10.4mL)を加えて不溶物をろ取した。これをN,N-ジメチルホルムアミド(200mL)に溶解し、0.5Mアンモニア－ジオキサン溶液(100mL)、O-(7-アザ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ホスフェート(11g, 29 mmol)を加え、室温で一晩撹拌後、塩化アンモニウム(4.2g, 79 mmol)、トリエチルアミン(11mL)、O-(7-アザ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ホスフェート(11g, 29mmol) を加え、室温で一晩撹拌した。反応液を食塩水に注ぎ、酢酸エチル、テトラヒドロフランで6回抽出した。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後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/メタノール=100/0-80/20 (v/v)］で精製し、標記化合物(4.8g, 13mmol)を固体として得た。
LCMS (ES): m/z 375 [M+H]+.
1H NMR (DMSO-D6): 2.04 (2H, quint, J=7.3 Hz), 2.71 (2H, t, J=7.3 Hz), 2.94 (2H, t, J=7.3 Hz), 3.32 (2H, s), 3.77 (3H, s), 6.85 (1H, br s), 7.05 (1H, dd, J=1.0, 7.3 Hz), 7.13 (1H, d, J=7.3 Hz), 7.19 (2H, d, J=8.8 Hz), 7.33 (1H, d, J=7.3 Hz), 7.42-7.49 (2H, m), 7.75 (2H, d, J=8.8 Hz), 8.34 (1H, s). Step 1 (b): Production step 1 of 2- (4-{[4- (2-methoxyphenyl) -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl] amino} phenyl) acetamide ( The compound obtained in a) (10.3 g, 26 mmol) was dissolved in ethanol (70 mL) and tetrahydrofuran (70 mL), 5N aqueous sodium hydroxide solution (10.4 mL) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, 5N hydrochloric acid (10.4 mL) was added to the residue, and the insoluble material was collected by filtration. This was dissolved in N, N-dimethylformamide (200 mL), 0.5 M ammonia-dioxane solution (100 mL), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetra Add methyluronium hexafluorophosphate (11 g, 29 mmol) and stir at room temperature overnight, then ammonium chloride (4.2 g, 79 mmol), triethylamine (11 mL), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-Tetramethyluronium hexafluorophosphate (11 g, 29 mmol) was added and stirred overnight at room temperature. The reaction mixture was poured into brine and extracted six times with ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: ethyl acetate / methanol = 100 / 0-80 / 20 (v / v)] to obtain the title compound (4.8 g, 13 mmol) as a solid.
LCMS (ES): m / z 375 [M + H] + .
1H NMR (DMSO-D 6 ): 2.04 (2H, quint, J = 7.3 Hz), 2.71 (2H, t, J = 7.3 Hz), 2.94 (2H, t, J = 7.3 Hz), 3.32 (2H, s ), 3.77 (3H, s), 6.85 (1H, br s), 7.05 (1H, dd, J = 1.0, 7.3 Hz), 7.13 (1H, d, J = 7.3 Hz), 7.19 (2H, d, J = 8.8 Hz), 7.33 (1H, d, J = 7.3 Hz), 7.42-7.49 (2H, m), 7.75 (2H, d, J = 8.8 Hz), 8.34 (1H, s).
（実施例２）
2-(3-フルオロ-4-{[4-(2-メトキシフェニル)-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル]アミノ}フェニル)アセタミド (Example 2)
2- (3-Fluoro-4-{[4- (2-methoxyphenyl) -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl] amino} phenyl) acetamide
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
工程2(a)：メチル　(3-フルオロ-4-{[4-(2-メトキシフェニル)-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル]アミノ}フェニル)アセテートの製造
参考例R4の化合物(200mg, 0.83mmol)を1,4-ジオキサン(10mL)に溶解し、メチル　(4-ブロモ-3-フルオロフェニル)アセテート(250mg, 1.01mmol)、2-ジシクロヘキシルホスフィノ-3,6-ジメトキシ-2’,4’,6’-トリイソプロピル-1,1’-ビフェニル(174mg, 0.32 mmol)、酢酸パラジウム(II)(30mg, 0.13mmol)、炭酸セシウム(354 mg, 1.09 mmol)を加え、マイクロウェーブ反応機にて150℃で2時間加熱攪拌した。反応液に水、酢酸エチルを加えて分液操作後、有機層を無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝90/10-60/40(V/V)］にて精製し、標記化合物(182mg, 54%) を油状物質として得た。
LCMS (ES): m/z 408 [M+H]+. Step 2 (a): Preparation of methyl (3-fluoro-4-{[4- (2-methoxyphenyl) -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl] amino} phenyl) acetate The compound of Reference Example R4 (200 mg, 0.83 mmol) was dissolved in 1,4-dioxane (10 mL), methyl (4-bromo-3-fluorophenyl) acetate (250 mg, 1.01 mmol), 2-dicyclohexylphosphino-3 , 6-Dimethoxy-2 ', 4', 6'-triisopropyl-1,1'-biphenyl (174 mg, 0.32 mmol), palladium (II) acetate (30 mg, 0.13 mmol), cesium carbonate (354 mg, 1.09 mmol) ) Was added and stirred with heating at 150 ° C. for 2 hours in a microwave reactor. Water and ethyl acetate were added to the reaction solution, and after liquid separation, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-60 / 40 (V / V)] to give the title compound (182 mg, 54%) was obtained as an oil.
LCMS (ES): m / z 408 [M + H] + .
工程2(b)：2-(3-フルオロ-4-{[4-(2-メトキシフェニル)-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル]アミノ}フェニル)アセタミドの製造
工程2(a)で得られた化合物(169mg, 0.42mmol)をテトラヒドロフラン(9mL)とメタノール(9mL)の混合溶媒に溶解し、室温で5規定 水酸化ナトリウム水溶液 (0.87mL)を加え18.5時間撹拌した。反応液に2規定塩酸(0.5mL)を加えて中和した後、反応液を減圧下濃縮した。得られた固体をN,N-ジメチルホルムアミド(15 mL)に溶解し、反応液に塩化アンモニウム(149 mg, 2.79 mmol)、（ジメチルアミノ）-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ）メタンイミニウム　ヘキサフルオロホスフェート(175mg)、N,N-ジイソプロピルエチルアミン(0.66mL)を加え、室温で2日間撹拌した。反応液に水を加え、酢酸エチルを加えて抽出し、有機層を無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ジクロロメタン/メタノール＝100/0-95/5(V/V)］にて精製し、標記化合物 (44mg,27%) を固体として得た。
LCMS (ES): m/z 393 [M+H]+.
1H NMR (CDCl3) δ (ppm): 2.10-2.21 (2H, m), 2.81-2.97 (4H, m), 3.52 (2H, s), 3.78 (3H, s), 5.43 (2H, d, J = 82.5 Hz), 6.38 (1H, br s), 6.94-7.10 (4H, m), 7.37-7.48 (2H, m), 8.74 (1H, t, J = 8.5 Hz). Step 2 (b): 2- (3-Fluoro-4-{[4- (2-methoxyphenyl) -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl] amino} phenyl) acetamide The compound (169 mg, 0.42 mmol) obtained in production step 2 (a) is dissolved in a mixed solvent of tetrahydrofuran (9 mL) and methanol (9 mL), and 5N aqueous sodium hydroxide solution (0.87 mL) is added at room temperature for 18.5 hours. Stir. The reaction mixture was neutralized with 2N hydrochloric acid (0.5 mL), and the reaction mixture was concentrated under reduced pressure. The obtained solid was dissolved in N, N-dimethylformamide (15 mL), and ammonium chloride (149 mg, 2.79 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2, 3] Triazolo [4,5-b] pyridin-3-yloxy) methaniminium hexafluorophosphate (175 mg) and N, N-diisopropylethylamine (0.66 mL) were added, and the mixture was stirred at room temperature for 2 days. Water was added to the reaction solution, ethyl acetate was added for extraction, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: dichloromethane / methanol = 100 / 0-95 / 5 (V / V)] to give the title compound (44 mg, 27 %) As a solid.
LCMS (ES): m / z 393 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 2.10-2.21 (2H, m), 2.81-2.97 (4H, m), 3.52 (2H, s), 3.78 (3H, s), 5.43 (2H, d, J = 82.5 Hz), 6.38 (1H, br s), 6.94-7.10 (4H, m), 7.37-7.48 (2H, m), 8.74 (1H, t, J = 8.5 Hz).
（実施例３）
2-[3-フルオロ-4-({4-[2-(ピリジン-2-イルメトキシ)フェニル]-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル}アミノ)フェニル]アセタミド (Example 3)
2- [3-Fluoro-4-({4- [2- (pyridin-2-ylmethoxy) phenyl] -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl} amino) phenyl] acetamide
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
工程3(a)：1-クロロ-4-[2-(ピリジン-2-イルメトキシ)フェニル]-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジンの製造
参考例１の化合物(300mg, 1.22mmol)をN,N-ジメチルホルムアミド(10mL)に溶解し、2-(ブロモメチル)ピリジン・臭化水素酸塩(460mg, 1.82mmol)を加え、0℃に冷却した。その後、水素化ナトリウム(80mg, 1.8mmol)を加えた後、室温で5時間攪拌した。反応液に飽和塩化アンモニウム水溶液(30mL)を加え、酢酸エチルを加えて抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝50/50-0/100(V/V)］にて精製し、標記化合物(330mg, 0.987mmol, 80%) を油状物質として得た。
LCMS (ES): m/z 378 [M+H]+. Step 3 (a): Production of 1-chloro-4- [2- (pyridin-2-ylmethoxy) phenyl] -6,7-dihydro-5H-cyclopenta [d] pyridazine Compound of Reference Example 1 (300 mg, 1.22 mmol ) Was dissolved in N, N-dimethylformamide (10 mL), 2- (bromomethyl) pyridine · hydrobromide (460 mg, 1.82 mmol) was added, and the mixture was cooled to 0 ° C. Thereafter, sodium hydride (80 mg, 1.8 mmol) was added, followed by stirring at room temperature for 5 hours. Saturated aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, ethyl acetate was added for extraction, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100 (V / V)] to give the title compound (330 mg, 0.987 mmol, 80%) was obtained as an oily substance.
LCMS (ES): m / z 378 [M + H] + .
工程3(b)：エチル　[3-フルオロ-4-({4-[2-(ピリジン-2-イルメトキシ)フェニル]-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル}アミノ)フェニル]アセテートの製造
工程3(a)で得られた化合物(230mg, 0.70mmol)を1,4-ジオキサン(5.0mL)に溶解させ、エチル　(4-アミノ-3-フルオロフェニル)アセテート(140mg, 0.71mmol)、2-ジシクロヘキシルホスフィノ-3,6-ジメトキシ-2’,4’,6’-トリイソプロピル-1,1’-ビフェニル(75mg, 0.14mmol)、酢酸パラジウム(II)(16mg, 0.070mmol)、炭酸セシウム(0.68g, 2.10mmol)を加え、マイクロウェーブ反応機にて150℃で1時間加熱攪拌した。反応液に飽和塩化アンモニウム水溶液(30mL) を加え、酢酸エチルを加えて抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝50/50-0/100(V/V)］にて精製し、標記化合物(60mg, 0.120mmol, 17%) を油状物質として得た。
LCMS (ES): m/z 499 [M+H]+. Step 3 (b): Ethyl [3-fluoro-4-({4- [2- (pyridin-2-ylmethoxy) phenyl] -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl} amino ) Phenyl] acetate Compound (230 mg, 0.70 mmol) obtained in Step 3 (a) was dissolved in 1,4-dioxane (5.0 mL) and ethyl (4-amino-3-fluorophenyl) acetate (140 mg , 0.71 mmol), 2-dicyclohexylphosphino-3,6-dimethoxy-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl (75 mg, 0.14 mmol), palladium (II) acetate (16 mg, 0.070 mmol) and cesium carbonate (0.68 g, 2.10 mmol) were added, and the mixture was heated and stirred at 150 ° C. for 1 hour in a microwave reactor. Saturated aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, ethyl acetate was added for extraction, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100 (V / V)] to give the title compound (60 mg, 0.120 mmol, 17%) was obtained as an oil.
LCMS (ES): m / z 499 [M + H] + .
工程3(c)：2-[3-フルオロ-4-({4-[2-(ピリジン-2-イルメトキシ)フェニル]-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル}アミノ)フェニル]アセタミドの製造
工程3(b)で得られた化合物(60mg, 0.12mmol)をテトラヒドロフラン(5mL)とメタノール(5mL)の混合溶媒に溶解させ、室温で1規定 水酸化ナトリウム水溶液(1.0mL)を加え1時間攪拌した。反応液に2規定 塩酸(0.5 mL)を加えて中和した後、反応液を減圧下濃縮した。得られた固体をN,N-ジメチルホルムアミド(10mL)に溶解し、反応液に2規定アンモニア・イソプロパノール溶液(0.14mL, 0.28mmol)、(ジメチルアミノ)-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ）メタンイミニウム　ヘキサフルオロホスフェート (106mg, 0.28mmol)、N,N-ジイソプロピルエチルアミン(0.050mL, 0.28mmol)を加え、室温で10時間攪拌した。反応液に水を加え、酢酸エチルを加えて抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/メタノール＝100/0-70/30(V/V)］にて精製し、標記化合物 (40mg, 0.085mmol, 71%) を固体として得た。
LCMS (ES): m/z 470 [M+H]+.
1H NMR (CDCl3) δ (ppm): 1.95 (2H, tt, J = 7.3, 7.3 Hz), 2.76 (2H, t, J = 7.3 Hz), 2.86 (2H, t, J = 7.3 Hz), 3.36 (2H, s), 5.18 (2H, s), 6.90 (1H, s), 7.04 (2H, tt, J = 7.8 Hz), 7.12 (1H, dd, J = 11.7, 1.5 Hz), 7.22 (1H, d, J = 8.3 Hz), 7.22 (1H, d, J = 7.8 Hz), 7.28-7.33 (2H, m), 7.36-7.40 (1H, m), 7.47 (1H, s), 7.56 (1H, t, J = 8.3 Hz), 7.75 (1H, td, J = 7.8, 2.0 Hz), 8.14 (1H, s), 8.52-8.54 (1H, m). Step 3 (c): 2- [3-Fluoro-4-({4- [2- (pyridin-2-ylmethoxy) phenyl] -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl} Amino) phenyl] acetamide The compound (60 mg, 0.12 mmol) obtained in Step 3 (b) was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and methanol (5 mL), and 1N aqueous sodium hydroxide solution (1.0 mL) was added and stirred for 1 hour. The reaction mixture was neutralized with 2N hydrochloric acid (0.5 mL), and the reaction mixture was concentrated under reduced pressure. The obtained solid was dissolved in N, N-dimethylformamide (10 mL), and 2N ammonia / isopropanol solution (0.14 mL, 0.28 mmol), (dimethylamino) -N, N-dimethyl (3H- [1 , 2,3] triazolo [4,5-b] pyridin-3-yloxy) methaniminium hexafluorophosphate (106mg, 0.28mmol), N, N-diisopropylethylamine (0.050mL, 0.28mmol) at room temperature Stir for 10 hours. Water was added to the reaction liquid, ethyl acetate was added for extraction, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: ethyl acetate / methanol = 100 / 0-70 / 30 (V / V)] to give the title compound (40 mg, 0.085 mmol, 71%) was obtained as a solid.
LCMS (ES): m / z 470 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.95 (2H, tt, J = 7.3, 7.3 Hz), 2.76 (2H, t, J = 7.3 Hz), 2.86 (2H, t, J = 7.3 Hz), 3.36 (2H, s), 5.18 (2H, s), 6.90 (1H, s), 7.04 (2H, tt, J = 7.8 Hz), 7.12 (1H, dd, J = 11.7, 1.5 Hz), 7.22 (1H , d, J = 8.3 Hz), 7.22 (1H, d, J = 7.8 Hz), 7.28-7.33 (2H, m), 7.36-7.40 (1H, m), 7.47 (1H, s), 7.56 (1H, t, J = 8.3 Hz), 7.75 (1H, td, J = 7.8, 2.0 Hz), 8.14 (1H, s), 8.52-8.54 (1H, m).
（実施例４）
2-[3-フルオロ-4-({4-[2-(2-メトキシエトキシ）フェニル]-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル}アミノ)フェニル]アセタミド Example 4
2- [3-Fluoro-4-({4- [2- (2-methoxyethoxy) phenyl] -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl} amino) phenyl] acetamide
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
工程4(a)：1-クロロ-4-[2-(2-メトキシエトキシ）フェニル]-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジンの製造
工程3(a)と同様にして、参考例１の化合物(300mg, 1.22mmol)、1-ブロモ-2-メトキシエタン(0.232mL, 2.44mmol)、水素化ナトリウム(73mg, 1.8mmol) 、N,N-ジメチルホルムアミド(10mL)を用いて、標記化合物(350mg, 1.15mmol, 94%) を固体として得た。
LCMS (ES): m/z 305 [M+H]+.
1H NMR (CD3OD) δ (ppm): 2.11-2.18 (2H, m), 2.97-3.13 (4H, m), 3.25 (3H, s), 3.56-3.59 (2H, m), 4.12-4.13 (2H, m), 5.18 (2H, s), 7.09 (1H, t, J = 7.8 Hz), 7.13 (1H, d, J = 8.3 Hz), 7.36 (1H, dd, J = 7.6, 1.7 Hz), 7.45-7.49 (1H, m). Step 4 (a): Preparation of 1-chloro-4- [2- (2-methoxyethoxy) phenyl] -6,7-dihydro-5H-cyclopenta [d] pyridazine in the same manner as in Step 3 (a) Using the compound of Example 1 (300 mg, 1.22 mmol), 1-bromo-2-methoxyethane (0.232 mL, 2.44 mmol), sodium hydride (73 mg, 1.8 mmol), N, N-dimethylformamide (10 mL), The title compound (350 mg, 1.15 mmol, 94%) was obtained as a solid.
LCMS (ES): m / z 305 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 2.11-2.18 (2H, m), 2.97-3.13 (4H, m), 3.25 (3H, s), 3.56-3.59 (2H, m), 4.12-4.13 (2H, m), 5.18 (2H, s), 7.09 (1H, t, J = 7.8 Hz), 7.13 (1H, d, J = 8.3 Hz), 7.36 (1H, dd, J = 7.6, 1.7 Hz) , 7.45-7.49 (1H, m).
工程4(b)：エチル　[3-フルオロ-4-({4-[2-(2-メトキシエトキシ)フェニル]-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル}アミノ)フェニル]アセテートの製造
工程4(a)で得られた化合物(350mg, 1.15mmol)をn-ブタノール(15ml)に懸濁させ、エチル　(4-アミノ-3-フルオロフェニル)アセテート(300mg, 1.5mmol)、トリフルオロ酢酸(0.23mL, 3.5mmol)を加え、140℃で10時間攪拌した。反応液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝80/20-30/70(V/V)］にて精製し、標記化合物(160mg, 0.34mmol, 30%) を固体として得た。
LCMS (ES): m/z 466 [M+H]+. Step 4 (b): Ethyl [3-Fluoro-4-({4- [2- (2-methoxyethoxy) phenyl] -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl} amino) Phenyl] acetate Compound (350 mg, 1.15 mmol) obtained in Step 4 (a) was suspended in n-butanol (15 ml), and ethyl (4-amino-3-fluorophenyl) acetate (300 mg, 1.5 mmol) was suspended. ) And trifluoroacetic acid (0.23 mL, 3.5 mmol) were added, and the mixture was stirred at 140 ° C. for 10 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 80 / 20-30 / 70 (V / V)] to give the title compound (160 mg, 0.34 mmol, 30%) as a solid.
LCMS (ES): m / z 466 [M + H] + .
工程4(c): 2-[3-フルオロ-4-({4-[2-(2-メトキシエトキシ)フェニル]-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル}アミノ)フェニル]アセタミドの製造
工程3(c)と同様にして、工程4(b)で得られた化合物(160mg, 0.34mmol)、メタノール(10mL)、1規定水酸化ナトリウム水溶液(2.0mL)、N,N-ジメチルホルムアミド(10mL)、2規定アンモニア・イソプロパノール溶液(0.69mL, 1.4mmol)、（ジメチルアミノ)-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ)メタンイミニウム　ヘキサフルオロホスフェート(260mg, 0.69mmol)を用いて、標記化合物(100mg, 0.229mmol, 67%)を固体として得た。
LCMS (ES): m/z 437 [M+H]+.
1H NMR (CD3OD) δ (ppm): 2.09-2.18 (2H, m), 2.84-2.92 (2H, m), 2.95 (2H, t, J = 7.6 Hz), 3.26 (3H, s), 3.49 (2H, s), 3.60 (2H, t, J = 4.6 Hz), 4.10 (2H, t, J = 4.6 Hz), 7.03-7.14 (4H, m), 7.32 (1H, d, J = 7.3 Hz), 7.40 (1H, t, J = 7.1 Hz), 7.84 (1H, t, J = 8.3 Hz). Step 4 (c): 2- [3-Fluoro-4-({4- [2- (2-methoxyethoxy) phenyl] -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl} amino ) Phenyl] acetamide in the same manner as in production step 3 (c), the compound obtained in step 4 (b) (160 mg, 0.34 mmol), methanol (10 mL), 1 N aqueous sodium hydroxide solution (2.0 mL), N , N-dimethylformamide (10 mL), 2N ammonia / isopropanol solution (0.69 mL, 1.4 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b ] Pyridin-3-yloxy) methaniminium hexafluorophosphate (260 mg, 0.69 mmol) was used to give the title compound (100 mg, 0.229 mmol, 67%) as a solid.
LCMS (ES): m / z 437 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 2.09-2.18 (2H, m), 2.84-2.92 (2H, m), 2.95 (2H, t, J = 7.6 Hz), 3.26 (3H, s), 3.49 (2H, s), 3.60 (2H, t, J = 4.6 Hz), 4.10 (2H, t, J = 4.6 Hz), 7.03-7.14 (4H, m), 7.32 (1H, d, J = 7.3 Hz ), 7.40 (1H, t, J = 7.1 Hz), 7.84 (1H, t, J = 8.3 Hz).
（実施例５）
2-(3-{[4-(4-フルオロ-1-ベンゾフラン-7-イル)-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル]アミノ}アゼチジン-1-イル)-2-オキソアセタミド (Example 5)
2- (3-{[4- (4-Fluoro-1-benzofuran-7-yl) -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl] amino} azetidin-1-yl)- 2-oxoacetamide
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
工程5(a): tert-ブチル　3-[(4-クロロ-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル)アミノ]アゼチジン-1-カルボキシレートの製造
1,4-ジクロロ-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン(500mg, 2.64mmol)にtert-ブチル 3-アミノアゼチジン-1-カルボキシレート(600 mg, 3.48 mmol)を加え、130℃で12時間攪拌した。反応液をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝80/20-0/100(V/V)］にて精製し、標記化合物(410mg, 1.26mmol, 48%)を固体として得た。
LCMS (ES): m/z 325 [M+H]+.
1H NMR (CDCl3) δ (ppm): 1.42 (9H, s), 2.17-2.23 (2H, m), 2.78 (2H, td, J = 7.7, 2.9 Hz), 2.96 (2H, td, J = 6.2, 4.7 Hz), 3.75 (2H, dd, J = 9.3, 4.9 Hz), 4.33-4.40 (2H, m), 4.78-4.82 (1H, m). Step 5 (a): Preparation of tert-butyl 3-[(4-chloro-6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl) amino] azetidine-1-carboxylate
To 1,4-dichloro-6,7-dihydro-5H-cyclopenta [d] pyridazine (500 mg, 2.64 mmol) was added tert-butyl 3-aminoazetidine-1-carboxylate (600 mg, 3.48 mmol), and 130 Stir at 12 ° C. for 12 hours. The reaction solution was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 80 / 20-0 / 100 (V / V)] to obtain the title compound (410 mg, 1.26 mmol, 48%) as a solid. .
LCMS (ES): m / z 325 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.42 (9H, s), 2.17-2.23 (2H, m), 2.78 (2H, td, J = 7.7, 2.9 Hz), 2.96 (2H, td, J = 6.2, 4.7 Hz), 3.75 (2H, dd, J = 9.3, 4.9 Hz), 4.33-4.40 (2H, m), 4.78-4.82 (1H, m).
工程5(b): tert-ブチル　3-{[4-(4-フルオロ-1-ベンゾフラン-7-イル)-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル]アミノ}アゼチジン-1-カルボキシレートの製造
工程5(a)で得られた化合物(110mg, 0.339mmol)を1,2-ジメトキシエタン(15ml)、水(0.5mL)に溶解し、(4-フルオロベンゾフラン-7-イル)ボロン酸(91mg, 0.51mmol)、［1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)・ジクロロメタン錯体(28mg, 0.034mmol)、リン酸カリウム(234mg, 1.02mmol)を加え、90℃で5時間攪拌した。反応液を減圧下濃縮した後、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝50/50-0/100(V/V)］にて精製し、標記化合物(130mg, 0.306mmol, 90%) を固体として得た。
LCMS (ES): m/z 425 [M+H]+.
1H NMR (CDCl3) δ (ppm): 1.42 (9H, s), 2.16 (2H, t, J = 7.6 Hz), 2.81 (2H, t, J = 7.6 Hz), 2.94 (2H, t, J = 7.6 Hz), 3.81 (2H, dd, J = 9.3, 4.9 Hz), 4.41 (2H, dd, J = 9.3, 7.8 Hz), 4.91-4.99 (1H, m), 6.90 (1H, t, J = 1.5 Hz), 7.02 (1H, t, J = 9.8 Hz), 7.49 (1H, dd, J = 8.3, 4.9 Hz), 7.59 (1H, d, J = 2.4 Hz). Step 5 (b): tert-butyl 3-{[4- (4-fluoro-1-benzofuran-7-yl) -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl] amino} azetidine Preparation of 1-carboxylate Compound (110 mg, 0.339 mmol) obtained in Step 5 (a) was dissolved in 1,2-dimethoxyethane (15 ml) and water (0.5 mL), and (4-fluorobenzofuran-7 -Yl) boronic acid (91 mg, 0.51 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane complex (28 mg, 0.034 mmol), potassium phosphate (234 mg, 1.02 mmol) And stirred at 90 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100 (V / V)] to give the title compound (130 mg, 0.306 mmol, 90%) was obtained as a solid.
LCMS (ES): m / z 425 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.42 (9H, s), 2.16 (2H, t, J = 7.6 Hz), 2.81 (2H, t, J = 7.6 Hz), 2.94 (2H, t, J = 7.6 Hz), 3.81 (2H, dd, J = 9.3, 4.9 Hz), 4.41 (2H, dd, J = 9.3, 7.8 Hz), 4.91-4.99 (1H, m), 6.90 (1H, t, J = 1.5 Hz), 7.02 (1H, t, J = 9.8 Hz), 7.49 (1H, dd, J = 8.3, 4.9 Hz), 7.59 (1H, d, J = 2.4 Hz).
工程5(c): 2-(3-{[4-(4-フルオロ-1-ベンゾフラン-7-イル)-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル]アミノ}アゼチジン-1-イル)-2-オキソアセタミドの製造
工程5(b)で得られた化合物(130mg, 0.306mmol)をジクロロメタン(5ml)に溶解し、トリフルオロ酢酸(3mL)を加え、室温で30分間攪拌した。反応液を減圧下濃縮し、粗製のN-(アゼチジン-3-イル)-4-(4-フルオロ-1-ベンゾフラン-7-イル)-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-アミンを油状物質として得た。シュウ酸アミド(54mg, 0.61mmol)をN,N-ジメチルホルムアミド (5mL)に溶解し、(ジメチルアミノ)-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ）メタンイミニウム　ヘキサフルオロホスフェート(232mg, 1.23mmol)を加えて室温で15分間攪拌した後、先ほど調整した粗製のN-(アゼチジン-3-イル)-4-(4-フルオロ-1-ベンゾフラン-7-イル)-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-アミンをN,N-ジメチルホルムアミド(5mL)に溶解させた溶液を滴下し、室温で5時間攪拌した。反応液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/メタノール＝100/0-80/20(V/V)］にて精製し、標記化合物(95mg, 0.24mmol, 78%)を固体として得た。
LCMS (ES): m/z 396 [M+H]+.
1H NMR (CD3OD) δ(ppm): 2.14 (2H, t, J = 7.6 Hz), 2.84-2.93 (4H, m), 4.05-4.08 (1H, m), 4.48-4.57 (2H, m), 4.89-4.99 (2H, m), 7.00 (1H, d, J = 2.0 Hz), 7.08 (1H, dd, J = 9.3, 8.3 Hz), 7.41 (1H, dd, J = 8.3, 4.9 Hz), 7.80 (1H, d, J = 2.0 Hz). Step 5 (c): 2- (3-{[4- (4-Fluoro-1-benzofuran-7-yl) -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl] amino} azetidine Preparation of 1-yl) -2-oxoacetamide Step 5 (b) (130 mg, 0.306 mmol) was dissolved in dichloromethane (5 ml), trifluoroacetic acid (3 mL) was added, and the mixture was stirred at room temperature for 30 minutes. did. The reaction solution was concentrated under reduced pressure to obtain crude N- (azetidin-3-yl) -4- (4-fluoro-1-benzofuran-7-yl) -6,7-dihydro-5H-cyclopenta [d] pyridazine- 1-amine was obtained as an oil. Oxalamide (54 mg, 0.61 mmol) was dissolved in N, N-dimethylformamide (5 mL) and (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b ] Pyridin-3-yloxy) methaniminium hexafluorophosphate (232 mg, 1.23 mmol) was added and stirred at room temperature for 15 minutes, and then the crude N- (azetidin-3-yl) -4- (4- Fluoro-1-benzofuran-7-yl) -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-amine dissolved in N, N-dimethylformamide (5 mL) was added dropwise at room temperature. Stir for hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: ethyl acetate / methanol = 100 / 0-80 / 20 (V / V)] to give the title compound (95 mg, 0.24 mmol, 78%) as a solid.
LCMS (ES): m / z 396 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 2.14 (2H, t, J = 7.6 Hz), 2.84-2.93 (4H, m), 4.05-4.08 (1H, m), 4.48-4.57 (2H, m ), 4.89-4.99 (2H, m), 7.00 (1H, d, J = 2.0 Hz), 7.08 (1H, dd, J = 9.3, 8.3 Hz), 7.41 (1H, dd, J = 8.3, 4.9 Hz) , 7.80 (1H, d, J = 2.0 Hz).
（実施例６）
2-[3-[[4-[2-(メトキシエトキシ)フェニル]-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル]アミノ]アゼチジン-1-イル]-2-オキソアセタミド (Example 6)
2- [3-[[4- [2- (Methoxyethoxy) phenyl] -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl] amino] azetidin-1-yl] -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
工程6(a)：tert-ブチル　3-({4-[2-(2-メトキシエトキシ)フェニル]-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル}アミノ)アゼチジン-1-カルボキシレートの製造
工程5(a)で得られた化合物(0.088g, 0.27mmol)を1,2-ジメトキシエタン(2mL)および水(0.5mL)に溶解し、室温にて2-(2-メトキシエトキシ)フェニルボロン酸(0.069g, 0.35mmol)、［1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド　ジクロロメタン付加物(0.044g, 0.054mmol)およびリン酸三カリウム(0.115g, 0.542mmol)を加えた後、100℃で3時間攪拌した。反応液に酢酸エチルを加え、不溶物を濾別して得られたろ液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝50/50-0/100(V/V)］にて精製し、標記化合物(0.085g, 0.19mmol, 71%)を泡状物質として得た。
1H NMR (CDCl3) δ(ppm): 1.45 (9H, s), 2.08-2.16 (2H, m), 2.77 (2H, t, J = 7.6 Hz), 2.91 (2H, t, J = 7.6 Hz), 3.31 (3H, s), 3.58-3.61 (2H, m), 3.83 (2H, dd, J = 9.3, 4.9 Hz), 4.06-4.10 (2H, m), 4.38 (1H, d, J = 6.3 Hz), 4.40-4.44 (2H, m), 4.91-4.99 (1H, m), 6.96 (1H, d, J = 8.3 Hz), 7.04-7.09 (1H, m), 7.35-7.39 (1H, m), 7.58 (1H, dd, J = 7.6, 1.7 Hz). Step 6 (a): tert-butyl 3-({4- [2- (2-methoxyethoxy) phenyl] -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl} amino) azetidine-1 -Carboxylate Preparation The compound (0.088 g, 0.27 mmol) obtained in Step 5 (a) was dissolved in 1,2-dimethoxyethane (2 mL) and water (0.5 mL), and 2- (2- Methoxyethoxy) phenylboronic acid (0.069 g, 0.35 mmol), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (0.044 g, 0.054 mmol) and tripotassium phosphate (0.115 g, 0.542 mmol) was added, followed by stirring at 100 ° C. for 3 hours. Ethyl acetate was added to the reaction solution, the insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100 (V / V)] to give the title compound (0.085 g, 0.19 mmol, 71%) as a foam.
1 H NMR (CDCl 3 ) δ (ppm): 1.45 (9H, s), 2.08-2.16 (2H, m), 2.77 (2H, t, J = 7.6 Hz), 2.91 (2H, t, J = 7.6 Hz ), 3.31 (3H, s), 3.58-3.61 (2H, m), 3.83 (2H, dd, J = 9.3, 4.9 Hz), 4.06-4.10 (2H, m), 4.38 (1H, d, J = 6.3 Hz), 4.40-4.44 (2H, m), 4.91-4.99 (1H, m), 6.96 (1H, d, J = 8.3 Hz), 7.04-7.09 (1H, m), 7.35-7.39 (1H, m) , 7.58 (1H, dd, J = 7.6, 1.7 Hz).
工程6(b)：2-[3-[[4-[2-(メトキシエトキシ）フェニル]-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル]アミノ]アゼチジン-1-イル]-2-オキソアセタミドの製造
工程5(c)と同様にして、工程6(a)で得られた化合物(0.085g, 0.19mmol)、トリフルオロ酢酸(1.5mL)、オキサミン酸(0.017g, 0.19mmol)、O-(7-アザ-1H-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　ヘキサフルオロホスフェート(0.081g, 0.21mmol) およびトリエチルアミン(0.081mL, 0.58mmol)を用いて、標記化合物(0.024g, 0.058mmol, 30%)を固体として得た。
1H NMR (CDCl3) δ(ppm): 2.08-2.18 (2H, m), 2.78 (2H, t, J = 6.8 Hz), 2.92 (2H, t, J = 6.8 Hz), 3.31 (3H, s), 3.58-3.63 (2H, m), 4.01-4.12 (3H, m), 4.51-4.65 (3H, m), 5.03-5.13 (2H, m), 5.58 (1H, br s), 6.96 (1H, d, J = 7.8 Hz), 7.07 (1H, t, J = 7.3 Hz), 7.37 (1H, t, J = 7.3 Hz), 7.54 (1H, d, J = 7.8 Hz). Step 6 (b): 2- [3-[[4- [2- (methoxyethoxy) phenyl] -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl] amino] azetidin-1-yl In the same manner as in Step 5 (c) for the preparation of 2-oxoacetamide, the compound obtained in Step 6 (a) (0.085 g, 0.19 mmol), trifluoroacetic acid (1.5 mL), oxamic acid (0.017 g, 0.19 mmol), O- (7-aza-1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (0.081 g, 0.21 mmol) and triethylamine (0.081 mL, 0.58 mmol) was used to give the title compound (0.024 g, 0.058 mmol, 30%) as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 2.08-2.18 (2H, m), 2.78 (2H, t, J = 6.8 Hz), 2.92 (2H, t, J = 6.8 Hz), 3.31 (3H, s ), 3.58-3.63 (2H, m), 4.01-4.12 (3H, m), 4.51-4.65 (3H, m), 5.03-5.13 (2H, m), 5.58 (1H, br s), 6.96 (1H, d, J = 7.8 Hz), 7.07 (1H, t, J = 7.3 Hz), 7.37 (1H, t, J = 7.3 Hz), 7.54 (1H, d, J = 7.8 Hz).
（実施例７）
2-{3-フルオロ-4-[(4-{2-[(2-メトキシエチル)アミノ]フェニル}-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル)アミノ]フェニル}アセタミド (Example 7)
2- {3-Fluoro-4-[(4- {2-[(2-methoxyethyl) amino] phenyl} -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl) amino] phenyl} Acetamide
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
工程7(a)：エチル　{4-[(4-クロロ-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル)アミノ]-3-フルオロフェニル}アセテートの製造
1,4-ジクロロ-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン(575mg, 3.00mmol)をn-ブタノール(15ml)に懸濁させ、エチル　(4-アミノ-3-フルオロフェニル)アセテート(720mg, 3.65mmol)を加え、140℃で4時間攪拌した。反応液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝100/0-50/50(V/V)］にて精製し、標記化合物(350mg, 1.00mmol, 33%)を固体として得た。
LCMS (ES): m/z 350 [M+H]+. Step 7 (a): Preparation of ethyl {4-[(4-chloro-6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl) amino] -3-fluorophenyl} acetate
1,4-Dichloro-6,7-dihydro-5H-cyclopenta [d] pyridazine (575 mg, 3.00 mmol) was suspended in n-butanol (15 ml) and ethyl (4-amino-3-fluorophenyl) acetate ( 720 mg, 3.65 mmol) was added, and the mixture was stirred at 140 ° C. for 4 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-50 / 50 (V / V)] to give the title compound (350 mg, 1.00 mmol, 33%) as a solid.
LCMS (ES): m / z 350 [M + H] + .
工程7(b)：エチル　{3-フルオロ-4-[(4-{2-[(2-メトキシエチル)アミノ]フェニル}-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル)アミノ]フェニル}アセテートの製造
工程5(b)と同様にして、工程7(a)で得られた化合物(75mg, 0.21mmol)、N-(2-メトキシエチル)-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン(400mg, 1.44mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)・ジクロロメタン錯体(80mg, 0.10mmol)、リン酸カリウム(800mg, 2.83mmol)、1,2-ジメトキシエタン(20ml)、水(1mL)を用いて、標記化合物(18mg, 0.039mmol, 18%)を固体として得た。
LCMS (ES): m/z 465 [M+H]+. Step 7 (b): ethyl {3-fluoro-4-[(4- {2-[(2-methoxyethyl) amino] phenyl} -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl ) Amino] phenyl} acetate In the same manner as in production step 5 (b), the compound obtained in step 7 (a) (75 mg, 0.21 mmol), N- (2-methoxyethyl) -2- (4,4 , 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (400 mg, 1.44 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane complex (80 mg, 0.10 mmol), potassium phosphate (800 mg, 2.83 mmol), 1,2-dimethoxyethane (20 ml) and water (1 mL) were used to obtain the title compound (18 mg, 0.039 mmol, 18%) as a solid. It was.
LCMS (ES): m / z 465 [M + H] + .
工程7(c)：2-{3-フルオロ-4-[(4-{2-[(2-メトキシエチル)アミノ]フェニル}-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル)アミノ]フェニル}アセタミドの製造
工程3(c)と同様にして、工程7(b)で得られた化合物(18 mg, 0.039 mmol)、1規定水酸化ナトリウム水溶液(1.0mL)、メタノール(5mL)、2規定アンモニア・イソプロパノール溶液(0.036 mL, 0.072 mmol)、(ジメチルアミノ)-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ）メタンイミニウム　ヘキサフルオロホスフェート(30 mg, 0.080 mmol)、N,N-ジイソプロピルエチルアミン(0.012 mL, 0.067 mmol)、N,N-ジメチルホルムアミド(5 mL)を用いて、標記化合物(10mg, 0.023mmol, 59%)を固体として得た。
LCMS (ES): m/z 436 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 2.14 (2H, tt, J = 7.6, 7.3 Hz), 2.91 (2H, t, J = 7.6 Hz), 2.97 (2H, t, J = 7.3 Hz), 3.20-3.29 (2H, m), 3.25 (3H, s), 3.47-3.52 (4H, m), 6.73 (1H, t, J = 7.3 Hz), 6.79 (1H, d, J= 8.3 Hz), 7.07-7.17 (3H, m), 7.23 (1H, t, J = 7.8 Hz), 7.76 (1H, t, J= 8.3 Hz). Step 7 (c): 2- {3-fluoro-4-[(4- {2-[(2-methoxyethyl) amino] phenyl} -6,7-dihydro-5H-cyclopenta [d] pyridazine-1- Yl) amino] phenyl} acetamide In the same manner as in production step 3 (c), the compound obtained in step 7 (b) (18 mg, 0.039 mmol), 1N aqueous sodium hydroxide solution (1.0 mL), methanol ( 5mL), 2N ammonia / isopropanol solution (0.036 mL, 0.072 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy ) Using the methanium hexafluorophosphate (30 mg, 0.080 mmol), N, N-diisopropylethylamine (0.012 mL, 0.067 mmol), N, N-dimethylformamide (5 mL), the title compound (10 mg, 0.023 mmol) , 59%) was obtained as a solid.
LCMS (ES): m / z 436 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 2.14 (2H, tt, J = 7.6, 7.3 Hz), 2.91 (2H, t, J = 7.6 Hz), 2.97 (2H, t, J = 7.3 Hz) , 3.20-3.29 (2H, m), 3.25 (3H, s), 3.47-3.52 (4H, m), 6.73 (1H, t, J = 7.3 Hz), 6.79 (1H, d, J = 8.3 Hz), 7.07-7.17 (3H, m), 7.23 (1H, t, J = 7.8 Hz), 7.76 (1H, t, J = 8.3 Hz).
（実施例８）
2-{3-[(4-{4-クロロ-2-[(2-メトキシエチル)アミノ]フェニル}-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル)アミノ]アゼチジン-1-イル}-2-オキソアセタミド (Example 8)
2- {3-[(4- {4-Chloro-2-[(2-methoxyethyl) amino] phenyl} -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl) amino] azetidine- 1-yl} -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
工程8(a)：tert-ブチル　3-[(4-{4-クロロ-2-[(2-メトキシエチル)アミノ]フェニル}-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル)アミノ]アゼチジン-1-カルボキシレートの製造
工程5(a)で得られた化合物(0.350g, 1.08mmol)を1,2-ジメトキシエタン(10mL)および水(1mL)に溶解し、室温にて5-クロロ-N-(2-メトキシエチル)-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル）アニリン(1.10g, 2.16mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド　ジクロロメタン付加物(0.176g, 0.216mmol)およびリン酸三カリウム(0.458g, 2.16mmol)を加えた後、100℃で4時間攪拌した。反応液に酢酸エチルを加え、無水硫酸ナトリウムで乾燥した。不溶物を濾別して得られたろ液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝90/10-0/100(V/V)］にて精製し、標記化合物(0.249g, 0.525mmol, 49%)を固体として得た。
1H NMR (CDCl3) δ(ppm): 1.45 (9H, s), 2.11-2.18 (2H, m), 2.79 (2H, t, J = 7.4 Hz), 2.98 (2H, t, J = 7.4 Hz), 3.30-3.35 (2H, m), 3.36 (3H, s), 3.59 (2H, t, J = 5.9 Hz), 3.82 (2H, dd, J = 9.4, 4.7 Hz), 4.39-4.48 (3H, m), 4.88-4.98 (1H, m), 6.68 (1H, dd, J = 8.2, 2.0 Hz), 6.72-6.77 (2H, m), 7.10 (1H, d, J = 8.2 Hz). Step 8 (a): tert-butyl 3-[(4- {4-chloro-2-[(2-methoxyethyl) amino] phenyl} -6,7-dihydro-5H-cyclopenta [d] pyridazine-1- Yl) amino] azetidine-1-carboxylate The compound obtained in step 5 (a) (0.350 g, 1.08 mmol) was dissolved in 1,2-dimethoxyethane (10 mL) and water (1 mL), and the mixture was brought to room temperature. 5-chloro-N- (2-methoxyethyl) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.10 g, 2.16 mmol), [ 1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane adduct (0.176 g, 0.216 mmol) and tripotassium phosphate (0.458 g, 2.16 mmol) were added followed by 4 hours at 100 ° C. Stir. Ethyl acetate was added to the reaction solution and dried over anhydrous sodium sulfate. The filtrate obtained by filtering insolubles was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-0 / 100 (V / V)], The title compound (0.249 g, 0.525 mmol, 49%) was obtained as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 1.45 (9H, s), 2.11-2.18 (2H, m), 2.79 (2H, t, J = 7.4 Hz), 2.98 (2H, t, J = 7.4 Hz ), 3.30-3.35 (2H, m), 3.36 (3H, s), 3.59 (2H, t, J = 5.9 Hz), 3.82 (2H, dd, J = 9.4, 4.7 Hz), 4.39-4.48 (3H, m), 4.88-4.98 (1H, m), 6.68 (1H, dd, J = 8.2, 2.0 Hz), 6.72-6.77 (2H, m), 7.10 (1H, d, J = 8.2 Hz).
工程8(b)：エチル　{3-[(4-{4-クロロ-2-[(2-メトキシエチル)アミノ]フェニル}-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル)アミノ]アゼチジン-1-イル}(オキソ)アセテートの製造
工程8(a)で得られた化合物(0.249g, 0.525mmol)をジクロロメタン(4mL)に溶解し、室温にてトリフルオロ酢酸(2mL)を加えた後、室温で4時間攪拌した。反応液を減圧濃縮して得られた油状物質を、ジクロロメタン(4mL)に溶解し、氷冷下、トリエチルアミン(0.437mL, 3.15mmol)およびエチル　オキサリルクロリド(0.0614mL, 0.552mmol)を加え、室温で1時間攪拌した。反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/メタノール＝100/0-90/10(V/V)］にて精製し、標記化合物(0.155g, 0.327mmol, 62%)を固体として得た。
1H NMR (CDCl3) δ(ppm): 1.37 (3H, t, J = 7.0 Hz), 2.13-2.20 (2H, m), 2.81 (2H, t, J = 7.4 Hz), 2.99 (2H, t, J = 7.4 Hz), 3.30-3.36 (3H, m), 3.37 (3H, s), 3.60 (2H, t, J = 5.7 Hz), 4.05 (1H, dd, J = 11.7, 4.7 Hz), 4.32 (2H, q, J = 7.0 Hz), 4.40 (1H, dd, J = 11.7, 4.7 Hz), 4.54 (1H, d, J = 5.5 Hz), 4.59-4.65 (1H, m), 4.95-5.08 (2H, m), 6.69 (1H, dd, J = 8.2, 2.0 Hz), 6.75 (1H, d, J = 2.0 Hz), 7.11 (1H, d, J = 8.2 Hz). Step 8 (b): ethyl {3-[(4- {4-chloro-2-[(2-methoxyethyl) amino] phenyl} -6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl ) Amino] azetidin-1-yl} (oxo) acetate Compound (0.249 g, 0.525 mmol) obtained in Step 8 (a) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (2 mL) at room temperature. And then stirred at room temperature for 4 hours. The oily substance obtained by concentrating the reaction solution under reduced pressure was dissolved in dichloromethane (4 mL), and triethylamine (0.437 mL, 3.15 mmol) and ethyl oxalyl chloride (0.0614 mL, 0.552 mmol) were added under ice-cooling at room temperature. Stir for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: ethyl acetate / methanol = 100 / 0-90 / 10 (V / V)] to give the title compound (0.155 g, 0.327 mmol, 62%) as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 1.37 (3H, t, J = 7.0 Hz), 2.13-2.20 (2H, m), 2.81 (2H, t, J = 7.4 Hz), 2.99 (2H, t , J = 7.4 Hz), 3.30-3.36 (3H, m), 3.37 (3H, s), 3.60 (2H, t, J = 5.7 Hz), 4.05 (1H, dd, J = 11.7, 4.7 Hz), 4.32 (2H, q, J = 7.0 Hz), 4.40 (1H, dd, J = 11.7, 4.7 Hz), 4.54 (1H, d, J = 5.5 Hz), 4.59-4.65 (1H, m), 4.95-5.08 ( 2H, m), 6.69 (1H, dd, J = 8.2, 2.0 Hz), 6.75 (1H, d, J = 2.0 Hz), 7.11 (1H, d, J = 8.2 Hz).
工程8(c)：2-{3-[(4-{4-クロロ-2-[(2-メトキシエチル)アミノ]フェニル}-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル)アミノ]アゼチジン-1-イル}-2-オキソアセタミドの製造
工程8(b)で得られた化合物(0.154g, 0.325mmol)をエタノール(3mL)に溶解し、氷冷下、1規定水酸化ナトリウム水溶液(0.390mL, 0.390mmol)を加え、30 分間攪拌した。反応液に1規定水酸化ナトリウム水溶液(0.390mL, 0.390mmol)を加えた後、減圧濃縮した。得られた固体をN,N-ジメチルホルムアミド(3mL)に溶解し、室温にてO-(7-アザ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　ヘキサフルオロホスフェート(0.173g, 0.455mmol)および 4% アンモニア-イソプロパノール溶液(0.975mL, 1.95mmol) を加え、室温で8時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。不溶物を濾別した後、減圧濃縮して、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/メタノール＝100/0-90/10(V/V)］にて精製し、標記化合物 (0.111g, 0.250mmol, 77%) を固体として得た。
1H NMR (CDCl3) δ(ppm): 2.12-2.19 (2H, m), 2.80 (2H, t, J = 7.4 Hz), 2.99 (2H, t, J = 7.4 Hz), 3.29-3.36 (2H, m), 3.37 (3H, s), 3.59 (2H, t, J = 5.7 Hz), 4.02 (1H, dd, J = 11.3, 4.3 Hz), 4.49-4.58 (2H, m), 4.59-4.65 (1H, m), 5.01-5.15 (2H, m), 5.45 (1H, br s), 6.66-6.76 (2H, m), 7.45 (1H, d, J = 8.2 Hz). Step 8 (c): 2- {3-[(4- {4-chloro-2-[(2-methoxyethyl) amino] phenyl} -6,7-dihydro-5H-cyclopenta [d] pyridazine-1- Yl) amino] azetidin-1-yl} -2-oxoacetamide The compound (0.154 g, 0.325 mmol) obtained in Step 8 (b) was dissolved in ethanol (3 mL), and 1N hydroxylated under ice cooling. An aqueous sodium solution (0.390 mL, 0.390 mmol) was added, and the mixture was stirred for 30 minutes. 1N Aqueous sodium hydroxide solution (0.390 mL, 0.390 mmol) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained solid was dissolved in N, N-dimethylformamide (3 mL), and O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexa Fluorophosphate (0.173 g, 0.455 mmol) and 4% ammonia-isopropanol solution (0.975 mL, 1.95 mmol) were added, and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: ethyl acetate / methanol = 100 / 0-90 / 10 (V / V)] to give the title The compound (0.111g, 0.250mmol, 77%) was obtained as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 2.12-2.19 (2H, m), 2.80 (2H, t, J = 7.4 Hz), 2.99 (2H, t, J = 7.4 Hz), 3.29-3.36 (2H , m), 3.37 (3H, s), 3.59 (2H, t, J = 5.7 Hz), 4.02 (1H, dd, J = 11.3, 4.3 Hz), 4.49-4.58 (2H, m), 4.59-4.65 ( 1H, m), 5.01-5.15 (2H, m), 5.45 (1H, br s), 6.66-6.76 (2H, m), 7.45 (1H, d, J = 8.2 Hz).
（実施例９）
2-(3-フルオロ-4-{[6-(2-メトキシフェニル)-4,5-ジメチルピリダジン-3-イル]アミノ｝フェニル）アセタミド Example 9
2- (3-Fluoro-4-{[6- (2-methoxyphenyl) -4,5-dimethylpyridazin-3-yl] amino} phenyl) acetamide
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
工程9(a)：メチル　{4-[(6-クロロ-4,5-ジメチルピリダジン-3-イル)アミノ]-3-フルオロフェニル}アセテートの製造
6-クロロ-4,5-ジメチルピリダジン-3-アミン(143mg, 0.91mmol)を1,4-ジオキサン(10mL)に溶解し、メチル　(4-ブロモ-3-フルオロフェニル)アセテート(270mg, 1.09mmol)、2-ジシクロヘキシルホスフィノ-3,6-ジメトキシ-2’,4’,6’-トリイソプロピル-1,1’-ビフェニル(190mg, 0.35mmol)、酢酸パラジウム(II) (33mg, 0.15mmol)、炭酸セシウム(393mg, 1.21mmol)を加え、マイクロウェーブ反応機にて150℃で2.5時間加熱攪拌した。反応液に水、酢酸エチルを加えて分液操作後、有機層を無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝90/10-65/35(V/V))］にて精製し、標記化合物(43mg, 15%) を油状物質として得た。
LCMS (ES): m/z 324 [M+H]+. Step 9 (a): Preparation of methyl {4-[(6-chloro-4,5-dimethylpyridazin-3-yl) amino] -3-fluorophenyl} acetate
6-Chloro-4,5-dimethylpyridazin-3-amine (143 mg, 0.91 mmol) was dissolved in 1,4-dioxane (10 mL) and methyl (4-bromo-3-fluorophenyl) acetate (270 mg, 1.09 mmol). ), 2-dicyclohexylphosphino-3,6-dimethoxy-2 ′, 4 ′, 6′-triisopropyl-1,1′-biphenyl (190 mg, 0.35 mmol), palladium (II) acetate (33 mg, 0.15 mmol) Then, cesium carbonate (393 mg, 1.21 mmol) was added, and the mixture was heated and stirred at 150 ° C. for 2.5 hours in a microwave reactor. Water and ethyl acetate were added to the reaction solution, and after liquid separation, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-65 / 35 (V / V)]] to give the title compound (43 mg 15%) as an oil.
LCMS (ES): m / z 324 [M + H] + .
工程9(b)：メチル　(3-フルオロ-4-{[6-(2-メトキシフェニル)-4,5-ジメチルピリダジン-3-イル］アミノ}フェニル)アセテートの製造
工程5(b)と同様にして、工程9(a)で得られた化合物(42mg, 0.13mmol)、2-メトキシフェニルボロン酸(30mg, 0.20mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)、ジクロロメタン錯体(14mg, 0.017mmol)、リン酸カリウムn-水和物(105mg, 0.40mmol)を用いて、標記化合物(36mg, 70%)を固体として得た。
LCMS (ES): m/z 396 [M+H]+. Step 9 (b): Preparation of methyl (3-fluoro-4-{[6- (2-methoxyphenyl) -4,5-dimethylpyridazin-3-yl] amino} phenyl) acetate as in Step 5 (b) Thus, the compound obtained in Step 9 (a) (42 mg, 0.13 mmol), 2-methoxyphenylboronic acid (30 mg, 0.20 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium ( The title compound (36 mg, 70%) was obtained as a solid using II), dichloromethane complex (14 mg, 0.017 mmol), and potassium phosphate n-hydrate (105 mg, 0.40 mmol).
LCMS (ES): m / z 396 [M + H] + .
工程9(c)：2-(3-フルオロ-4-{[6-(2-メトキシフェニル)-4,5-ジメチルピリダジン-3-イル]アミノ}フェニル)アセタミドの製造
工程3(c)と同様にして、工程9(b)で得られた化合物(32mg, 0.081mmol)より、標記化合物(24mg, 78%)を固体として得た。
LCMS (ES): m/z 381 [M+H]+.
1H NMR (CDCl3) δ(ppm): 2.11 (3H, s), 2.28 (3H, s), 3.54 (2H, s), 3.76 (3H, s), 5.31 (1H, br), 5.49 (1H, br), 6.48 (1H, br s), 7.00-7.08 (3H, m), 7.33-7.43 (2H, m), 8.67 (1H, t, J = 8.5 Hz). Step 9 (c): Step 3 (c) for producing 2- (3-fluoro-4-{[6- (2-methoxyphenyl) -4,5-dimethylpyridazin-3-yl] amino} phenyl) acetamide; Similarly, the title compound (24 mg, 78%) was obtained as a solid from the compound (32 mg, 0.081 mmol) obtained in Step 9 (b).
LCMS (ES): m / z 381 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 2.11 (3H, s), 2.28 (3H, s), 3.54 (2H, s), 3.76 (3H, s), 5.31 (1H, br), 5.49 (1H , br), 6.48 (1H, br s), 7.00-7.08 (3H, m), 7.33-7.43 (2H, m), 8.67 (1H, t, J = 8.5 Hz).
（実施例１０）
2-(3-フルオロ-4-{[7-(2-メトキシフェニル)チエノ[2,3-d]ピリダジン-4-イル］アミノ｝フェニル）アセタミド (Example 10)
2- (3-Fluoro-4-{[7- (2-methoxyphenyl) thieno [2,3-d] pyridazin-4-yl] amino} phenyl) acetamide
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
工程10(a)：エチル　{4-[(7-クロロチエノ[2,3-d]ピリダジン-4-イル)アミノ]-3-フルオロフェニル}アセテートの製造
4,7-ジクロロチエノ[2,3-d]ピリダジン(300mg, 1.46mmol)をエタノール(50mL)に溶解し、エチル　(4-アミノ-3-フルオロフェニル)アセテート・臭化水素酸塩(487mg, 1.75mmol)を加え、100℃で3時間攪拌した。エタノールを用いて不溶物をろ別した後、ろ液を減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝80/20-50/50(V/V)］にて精製し、標記化合物(300mg, 0.82mmol, 56%)を固体として得た。
LCMS (ES): m/z 366 [M+H]+. Step 10 (a): Preparation of ethyl {4-[(7-chlorothieno [2,3-d] pyridazin-4-yl) amino] -3-fluorophenyl} acetate
4,7-dichlorothieno [2,3-d] pyridazine (300 mg, 1.46 mmol) was dissolved in ethanol (50 mL), and ethyl (4-amino-3-fluorophenyl) acetate / hydrobromide (487 mg, 1.75 mmol) was added and the mixture was stirred at 100 ° C. for 3 hours. Insoluble material was filtered off using ethanol, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 80 / 20-50 / 50 (V / V)] to give the title compound (300 mg, 0.82 mmol, 56%) as a solid Obtained.
LCMS (ES): m / z 366 [M + H] + .
工程10(b)：エチル　(3-フルオロ-4-{[7-(2-メトキシフェニル)チエノ[2,3-d]ピリダジン-4-イル]アミノ}フェニル)アセテートの製造
工程5(b)と同様にして、工程10(a)で得られた化合物(300mg, 0.82mmol)、2-メトキシフェニルボロン酸(300mg, 1.14mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)、ジクロロメタン錯体(80mg, 0.10mmol)、リン酸カリウムn-水和物(750mg, 2.81mmol)、1,2-ジメトキシエタン(15ml)、水(1mL)を用いて、標記化合物(162mg, 0.37mmol, 45%)を固体として得た。
LCMS (ES): m/z 438 [M+H]+. Step 10 (b): Preparation of ethyl (3-fluoro-4-{[7- (2-methoxyphenyl) thieno [2,3-d] pyridazin-4-yl] amino} phenyl) acetate 5 (b) In the same manner as described above, the compound obtained in Step 10 (a) (300 mg, 0.82 mmol), 2-methoxyphenylboronic acid (300 mg, 1.14 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloro Using palladium (II), dichloromethane complex (80 mg, 0.10 mmol), potassium phosphate n-hydrate (750 mg, 2.81 mmol), 1,2-dimethoxyethane (15 ml), water (1 mL), the title compound ( 162 mg, 0.37 mmol, 45%) was obtained as a solid.
LCMS (ES): m / z 438 [M + H] + .
工程10(c)：2-(3-フルオロ-4-{[7-(2-メトキシフェニル)チエノ[2,3-d]ピリダジン-4-イル]アミノ}フェニル)アセタミドの製造
工程3(c)と同様にして、工程10(b)で得られた化合物(130mg, 0.297mmol)、1規定水酸化ナトリウム水溶液(2.0mL)、テトラヒドロフラン(3mL)、メタノール(3mL)、2規定アンモニア・イソプロパノール溶液(0.300mL, 0.600mmol)、（ジメチルアミノ）-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ）メタンイミニウム　ヘキサフルオロホスフェート(230mg, 0.61mmol)、N,N-ジイソプロピルエチルアミン(0.100mL, 0.60mmol)、N,N-ジメチルホルムアミド(15mL)を用いて、標記化合物(110mg, 0.269mmol, 91%)を固体として得た。
LCMS (ES): m/z 409 [M+H]+.
1H NMR (CD3OD) δ(ppm): 3.52 (2H, s), 3.78 (3H, s), 7.09 (1H, t, J= 7.3 Hz), 7.12-7.21 (3H, m), 7.44 (1H, dd, J = 7.6, 1.7 Hz), 7.51 (1H, td, J = 7.9, 1.5 Hz), 7.81 (1H, t, J = 8.1 Hz), 7.85 (1H, d, J= 5.4 Hz), 8.04 (1H, d, J = 5.4 Hz). Step 10 (c): Step 3 (c) for producing 2- (3-fluoro-4-{[7- (2-methoxyphenyl) thieno [2,3-d] pyridazin-4-yl] amino} phenyl) acetamide ), The compound obtained in step 10 (b) (130 mg, 0.297 mmol), 1N aqueous sodium hydroxide solution (2.0 mL), tetrahydrofuran (3 mL), methanol (3 mL), 2N ammonia / isopropanol solution (0.300 mL, 0.600 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methaninium hexafluorophosphate (230 mg , 0.61 mmol), N, N-diisopropylethylamine (0.100 mL, 0.60 mmol) and N, N-dimethylformamide (15 mL) gave the title compound (110 mg, 0.269 mmol, 91%) as a solid.
LCMS (ES): m / z 409 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 3.52 (2H, s), 3.78 (3H, s), 7.09 (1H, t, J = 7.3 Hz), 7.12-7.21 (3H, m), 7.44 ( 1H, dd, J = 7.6, 1.7 Hz), 7.51 (1H, td, J = 7.9, 1.5 Hz), 7.81 (1H, t, J = 8.1 Hz), 7.85 (1H, d, J = 5.4 Hz), 8.04 (1H, d, J = 5.4 Hz).
（実施例１１）
2-[3-フルオロ-4-({7-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル｝アミノ)フェニル]アセタミド (Example 11)
2- [3-Fluoro-4-({7- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) phenyl] acetamide
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
工程11(a)：エチル　[3-フルオロ-4-({7-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)フェニル]アセテートの製造
工程5(b)と同様にして、工程10(a)で得られた化合物(300mg, 0.82mmol)、2-メトキシエトキシフェニルボロン酸(300mg, 1.53mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)、ジクロロメタン錯体(80mg, 0.10mmol)、リン酸カリウムn-水和物 (750mg, 2.81mmol)、1,2-ジメトキシエタン(15ml)、水(1mL)を用いて、標記化合物(150mg, 0.311mmol, 38%)を固体として得た。
LCMS (ES): m/z 482 [M+H]+. Step 11 (a): Preparation of ethyl [3-fluoro-4-({7- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) phenyl] acetate In the same manner as in Step 5 (b), the compound obtained in Step 10 (a) (300 mg, 0.82 mmol), 2-methoxyethoxyphenylboronic acid (300 mg, 1.53 mmol), [1,1′-bis (diphenyl) Phosphino) ferrocene] dichloropalladium (II), dichloromethane complex (80 mg, 0.10 mmol), potassium phosphate n-hydrate (750 mg, 2.81 mmol), 1,2-dimethoxyethane (15 ml), water (1 mL) Used to give the title compound (150 mg, 0.311 mmol, 38%) as a solid.
LCMS (ES): m / z 482 [M + H] + .
工程11(b)：2-[3-フルオロ-4-({7-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)フェニル]アセタミドの製造
工程3(c)と同様にして、工程11(a)で得られた化合物(150mg, 0.311mmol)、1規定水酸化ナトリウム水溶液(2.0mL)、テトラヒドロフラン(3mL)、メタノール(3mL)、2規定アンモニア・イソプロパノール溶液(0.300mL, 0.600mmol)、（ジメチルアミノ)-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ）メタンイミニウム　ヘキサフルオロホスフェート(230mg, 0.61mmol)、N,N-ジイソプロピルエチルアミン(0.100mL, 0.60mmol)、N,N-ジメチルホルムアミド(15mL)を用いて、標記化合物(110mg, 0.243mmol, 78%)を固体として得た。
LCMS (ES): m/z 453 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 3.08 (3H, s), 3.49-3.54 (4H, m), 4.13 (2H, t, J = 4.9 Hz), 4.14-4.15 (2H, m), 7.09-7.19 (4H, m), 7.45 (1H, dd, J = 7.6, 1.7 Hz), 7.47-7.51 (1H, m), 7.80 (1H, t, J = 8.1 Hz), 7.85 (1H, d, J = 5.4 Hz), 8.05 (1H, d, J = 5.4 Hz). Step 11 (b): 2- [3-Fluoro-4-({7- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) phenyl] acetamide In the same manner as in production step 3 (c), the compound obtained in step 11 (a) (150 mg, 0.311 mmol), 1N aqueous sodium hydroxide solution (2.0 mL), tetrahydrofuran (3 mL), methanol (3 mL), 2 Normal ammonia / isopropanol solution (0.300 mL, 0.600 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methaniminium Using hexafluorophosphate (230 mg, 0.61 mmol), N, N-diisopropylethylamine (0.100 mL, 0.60 mmol) and N, N-dimethylformamide (15 mL), the title compound (110 mg, 0.243 mmol, 78%) was solidified. Got as.
LCMS (ES): m / z 453 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 3.08 (3H, s), 3.49-3.54 (4H, m), 4.13 (2H, t, J = 4.9 Hz), 4.14-4.15 (2H, m), 7.09-7.19 (4H, m), 7.45 (1H, dd, J = 7.6, 1.7 Hz), 7.47-7.51 (1H, m), 7.80 (1H, t, J = 8.1 Hz), 7.85 (1H, d, J = 5.4 Hz), 8.05 (1H, d, J = 5.4 Hz).
（実施例１２）
2-[4-({7-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)-3-メチルフェニル]アセタミド (Example 12)
2- [4-({7- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) -3-methylphenyl] acetamide
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
工程12(a)：エチル　{4-[(7-クロロチエノ[2,3-d]ピリダジン-4-イル)アミノ]-3-メチルフェニル｝アセテートの製造
工程10(a)と同様にして、4,7-ジクロロチエノ[2,3-d]ピリダジン(1.0g, 4.9mmol)、エタノール(40mL)、エチル(4-アミノ-3-メチルフェニル）アセテート(1.13g, 5.84mmol)を用いて、標記化合物(500mg, 1.38mmol, 28%)を固体として得た。
LCMS (ES): m/z 362 [M+H]+. Step 12 (a): Preparation of ethyl {4-[(7-chlorothieno [2,3-d] pyridazin-4-yl) amino] -3-methylphenyl} acetate 4 , 7-dichlorothieno [2,3-d] pyridazine (1.0 g, 4.9 mmol), ethanol (40 mL), ethyl (4-amino-3-methylphenyl) acetate (1.13 g, 5.84 mmol) The compound (500 mg, 1.38 mmol, 28%) was obtained as a solid.
LCMS (ES): m / z 362 [M + H] + .
工程12(b)：エチル　[4-({7-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)-3-メチルフェニル]アセテートの製造
工程5(b)と同様にして、工程12(a)で得られた化合物(300mg, 0.83mmol)、2-メトキシエトキシフェニルボロン酸(300mg, 1.5mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)・ジクロロメタン錯体(80mg, 0.10mmol)、リン酸カリウムn-水和物(800mg, 3.0mmol)、1,2-ジメトキシエタン(20ml)、水(0.5mL)を用いて、標記化合物(125mg, 0.26mmol, 31%)を固体として得た。
LCMS (ES): m/z 478 [M+H]+.
 
工程12(c)：2-[4-({7-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)-3-メチルフェニル]アセタミドの製造
工程3(c)と同様にして、実施例12(b)で得られた化合物(125mg, 0.26mmol)、1規定 水酸化ナトリウム水溶液(2.0mL)、メタノール (3mL)、2規定アンモニア・イソプロパノール溶液 (0.26mL, 0.52mmol)、O-(7-アザ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ホスフェート(200mg, 0.53mmol)、N,N-ジイソプロピルエチルアミン(0.090mL, 0.54 mmol)、N,N-ジメチルホルムアミド(10mL)を用いて、標記化合物(50mg, 0.11mmol, 43%)を固体として得た。
LCMS (ES): m/z 449 [M+H]+.
1H NMR (CD3OD) δ(ppm): 2.26 (3H, s), 3.08 (3H, s), 3.47-3.52 (4H, m), 4.11 (2H, t, J = 4.7 Hz), 7.05-7.10 (1H, m), 7.14-7.17 (2H, m), 7.24 (1H, s), 7.33 (1H, d, J = 8.2 Hz), 7.40-7.48 (2H, m), 7.72 (1H, d, J = 5.5 Hz), 7.97 (1H, d, J = 5.5 Hz). Step 12 (b): Preparation of ethyl [4-({7- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) -3-methylphenyl] acetate In the same manner as in Step 5 (b), the compound obtained in Step 12 (a) (300 mg, 0.83 mmol), 2-methoxyethoxyphenylboronic acid (300 mg, 1.5 mmol), [1,1′-bis (diphenyl) Phosphino) ferrocene] dichloropalladium (II) -dichloromethane complex (80 mg, 0.10 mmol), potassium phosphate n-hydrate (800 mg, 3.0 mmol), 1,2-dimethoxyethane (20 ml), water (0.5 mL) To give the title compound (125 mg, 0.26 mmol, 31%) as a solid.
LCMS (ES): m / z 478 [M + H] + .

Step 12 (c): of 2- [4-({7- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) -3-methylphenyl] acetamide In the same manner as in production step 3 (c), the compound obtained in Example 12 (b) (125 mg, 0.26 mmol), 1N aqueous sodium hydroxide solution (2.0 mL), methanol (3 mL), 2N ammonia / isopropanol Solution (0.26 mL, 0.52 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (200 mg, 0.53 mmol), N, N -The title compound (50 mg, 0.11 mmol, 43%) was obtained as a solid using -diisopropylethylamine (0.090 mL, 0.54 mmol) and N, N-dimethylformamide (10 mL).
LCMS (ES): m / z 449 [M + H] + .
1H NMR (CD 3 OD) δ (ppm): 2.26 (3H, s), 3.08 (3H, s), 3.47-3.52 (4H, m), 4.11 (2H, t, J = 4.7 Hz), 7.05-7.10 (1H, m), 7.14-7.17 (2H, m), 7.24 (1H, s), 7.33 (1H, d, J = 8.2 Hz), 7.40-7.48 (2H, m), 7.72 (1H, d, J = 5.5 Hz), 7.97 (1H, d, J = 5.5 Hz).
（実施例１３）
2-{4-[(7-{2-[2-(ジエチルアミノ）エトキシ]フェニル}チエノ[2,3-d]ピリダジン-4-イル)アミノ]-3-フルオロフェニル}アセタミド (Example 13)
2- {4-[(7- {2- [2- (Diethylamino) ethoxy] phenyl} thieno [2,3-d] pyridazin-4-yl) amino] -3-fluorophenyl} acetamide
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
工程13(a)：2-[2-(4-クロロチエノ[2,3-d]ピリダジン-7-イル)フェノキシ]-N,N-ジエチルエタンアミンの製造
2-(4-クロロチエノ[2,3-d]ピリダジン-7-イル)フェノール(260mg, 1.0mmol)をテトラヒドロフラン(20mL)に溶解し、2-(ジエチルアミノ)エタノール(228mg, 2.0mmol)と（トリブチルホスホラニリデン）アセトニトリル(0.53mL, 2.0mmol)を加え、室温で5時間攪拌した。反応液を減圧下濃縮後、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/メタノール＝100/0-50/50(v/v)］にて精製し、標記化合物 (390mg, 1.0mmol, 100%) を油状物質として得た。
LCMS (ES): m/z 362 [M+H]+.
1H NMR (CDCl3) δ(ppm): 0.85 (6H, t, J = 7.1 Hz), 2.45 (4H, q, J = 7.1 Hz), 2.72 (2H, t, J = 5.9 Hz), 4.14 (2H, t, J = 5.9 Hz), 7.07 (1H, d, J = 7.8 Hz), 7.12 (1H, td, J = 7.6, 1.0 Hz), 7.49 (1H, ddd, J = 8.8, 6.8, 1.5 Hz), 7.56 (1H, dd, J = 7.6, 1.7 Hz), 7.60 (1H, d, J = 5.4 Hz), 7.88 (1H, d, J = 5.9 Hz). Step 13 (a): Preparation of 2- [2- (4-chlorothieno [2,3-d] pyridazin-7-yl) phenoxy] -N, N-diethylethanamine
2- (4-Chlorothieno [2,3-d] pyridazin-7-yl) phenol (260 mg, 1.0 mmol) was dissolved in tetrahydrofuran (20 mL) and 2- (diethylamino) ethanol (228 mg, 2.0 mmol) and (tributyl) were dissolved. Phosphoranilidene) acetonitrile (0.53 mL, 2.0 mmol) was added and stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: ethyl acetate / methanol = 100 / 0-50 / 50 (v / v)] to give the title compound (390 mg, 1.0 mmol, 100%) as an oil.
LCMS (ES): m / z 362 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 0.85 (6H, t, J = 7.1 Hz), 2.45 (4H, q, J = 7.1 Hz), 2.72 (2H, t, J = 5.9 Hz), 4.14 ( 2H, t, J = 5.9 Hz), 7.07 (1H, d, J = 7.8 Hz), 7.12 (1H, td, J = 7.6, 1.0 Hz), 7.49 (1H, ddd, J = 8.8, 6.8, 1.5 Hz ), 7.56 (1H, dd, J = 7.6, 1.7 Hz), 7.60 (1H, d, J = 5.4 Hz), 7.88 (1H, d, J = 5.9 Hz).
工程13(b)：エチル　{4-[(7-{2-[2-(ジエチルアミノ)エトキシ]フェニル}チエノ[2,3-d]ピリダジン-4-イル)アミノ]-3-フルオロフェニル}アセテートの製造
工程4(b)と同様にして、工程13(a)で得られた化合物(390mg, 1.0mmol)、エチル　(4-アミノ-3-フルオロフェニル)アセテート・臭化水素酸塩(400mg, 1.5mmol)、トリフルオロ酢酸(0.23mL, 3.0mmol)、n-ブタノール(5mL)を用いて、標記化合物(482mg, 0.92mmol, 92%)を油状物質として得た。
LCMS (ES): m/z 523 [M+H]+. Step 13 (b): ethyl {4-[(7- {2- [2- (diethylamino) ethoxy] phenyl} thieno [2,3-d] pyridazin-4-yl) amino] -3-fluorophenyl} acetate In the same manner as in production step 4 (b), the compound obtained in step 13 (a) (390 mg, 1.0 mmol), ethyl (4-amino-3-fluorophenyl) acetate / hydrobromide (400 mg, 1.5 mmol), trifluoroacetic acid (0.23 mL, 3.0 mmol), and n-butanol (5 mL) were used to give the title compound (482 mg, 0.92 mmol, 92%) as an oil.
LCMS (ES): m / z 523 [M + H] + .
工程13(c)：2-{4-[(7-{2-[2-(ジエチルアミノ)エトキシ]フェニル}チエノ[2,3-d]ピリダジン-4-イル)アミノ]-3-フルオロフェニル}アセタミドの製造
工程3(c)と同様にして、工程13(b)で得られた化合物(482mg, 0.92mmol)、1規定水酸化ナトリウム水溶液 (2.0mL)、メタノール(5mL)、2規定アンモニア・イソプロパノール溶液(0.700mL, 1.40mmol)、O-(7-アザ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ホスフェート(530mg, 1.4mmol)、N,N-ジイソプロピルエチルアミン(0.24mL, 1.4mmol)、N,N-ジメチルホルムアミド(10mL)を用いて、標記化合物(100mg, 0.20mmol, 22%)を固体として得た。
LCMS (ES): m/z 494 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 1.08 (6H, t, J = 7.3 Hz), 3.08 (4H, q, J = 7.3 Hz), 3.38 (2H, t, J = 4.9 Hz), 3.54 (2H, s), 4.49 (2H, t, J = 4.9 Hz), 7.14-7.26 (3H, m), 7.34 (1H, d, J= 8.3 Hz), 7.54-7.57 (1H, m), 7.62 (1H, t, J = 8.1 Hz), 7.70 (1H, dd, J = 7.6, 1.7 Hz), 7.92 (1H, d, J = 5.4 Hz), 8.13 (1H, d, J= 5.4 Hz). Step 13 (c): 2- {4-[(7- {2- [2- (diethylamino) ethoxy] phenyl} thieno [2,3-d] pyridazin-4-yl) amino] -3-fluorophenyl} In the same manner as in production step 3 (c) of acetamide, the compound obtained in step 13 (b) (482 mg, 0.92 mmol), 1N aqueous sodium hydroxide solution (2.0 mL), methanol (5 mL), 2N ammonia Isopropanol solution (0.700 mL, 1.40 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (530 mg, 1.4 mmol), N, The title compound (100 mg, 0.20 mmol, 22%) was obtained as a solid using N-diisopropylethylamine (0.24 mL, 1.4 mmol) and N, N-dimethylformamide (10 mL).
LCMS (ES): m / z 494 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 1.08 (6H, t, J = 7.3 Hz), 3.08 (4H, q, J = 7.3 Hz), 3.38 (2H, t, J = 4.9 Hz), 3.54 (2H, s), 4.49 (2H, t, J = 4.9 Hz), 7.14-7.26 (3H, m), 7.34 (1H, d, J = 8.3 Hz), 7.54-7.57 (1H, m), 7.62 ( 1H, t, J = 8.1 Hz), 7.70 (1H, dd, J = 7.6, 1.7 Hz), 7.92 (1H, d, J = 5.4 Hz), 8.13 (1H, d, J = 5.4 Hz).
（実施例１４）
2-(3-フルオロ-4-{[7-(4-クロロ-2-メトキシフェニル）チエノ[2,3-d]ピリダジン-4-イル]アミノ}フェニル)アセタミド (Example 14)
2- (3-Fluoro-4-{[7- (4-chloro-2-methoxyphenyl) thieno [2,3-d] pyridazin-4-yl] amino} phenyl) acetamide
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
工程14(a)：エチル　(3-フルオロ-4-{[7-(4-クロロ-2-メトキシフェニル)チエノ[2,3-d]ピリダジン-4-イル]アミノ}フェニル)カルボキシレートの製造
工程5(b)と同様にして、工程10(a)で得られた化合物(220mg, 0.60mmol)、4-クロロ-2-メトキシフェニルボロン酸(200mg, 1.0mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン］ジクロロパラジウム(II)・ジクロロメタン錯体 (50mg, 0.060mmol)、リン酸カリウムn-水和物(520mg, 1.95mmol)、1,2-ジメトキシエタン(20ml)、水(0.5mL)を用いて、標記化合物(190mg, 0.40mmol, 67%)を固体として得た。
LCMS (ES): m/z 472 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 1.25 (3H, t, J = 7.2 Hz), 3.58 (2H, s), 3.80 (3H, s), 4.15 (2H, q, J= 7.2 Hz), 6.96-7.14 (5H, m), 7.44 (1H, t, J = 2.7 Hz), 7.56 (1H, d, J= 8.3 Hz), 7.78 (1H, d, J = 5.4 Hz), 8.73-8.78 (1H, m). Step 14 (a): Preparation of ethyl (3-fluoro-4-{[7- (4-chloro-2-methoxyphenyl) thieno [2,3-d] pyridazin-4-yl] amino} phenyl) carboxylate In the same manner as in Step 5 (b), the compound obtained in Step 10 (a) (220 mg, 0.60 mmol), 4-chloro-2-methoxyphenylboronic acid (200 mg, 1.0 mmol), [1,1′- Bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane complex (50 mg, 0.060 mmol), potassium phosphate n-hydrate (520 mg, 1.95 mmol), 1,2-dimethoxyethane (20 ml), water ( 0.5 mL) was used to give the title compound (190 mg, 0.40 mmol, 67%) as a solid.
LCMS (ES): m / z 472 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.25 (3H, t, J = 7.2 Hz), 3.58 (2H, s), 3.80 (3H, s), 4.15 (2H, q, J = 7.2 Hz), 6.96-7.14 (5H, m), 7.44 (1H, t, J = 2.7 Hz), 7.56 (1H, d, J = 8.3 Hz), 7.78 (1H, d, J = 5.4 Hz), 8.73-8.78 (1H , m).
工程14(b)：2-(3-フルオロ-4-{[7-(4-クロロ-2-メトキシフェニル)チエノ[2,3-d]ピリダジン-4-イル]アミノ}フェニル)アセタミドの製造
工程3(c)と同様にして、実施例14(a)で得たエチル　(3-フルオロ-4-{[7-(2-メトキシフェニル)チエノ[2,3-d]ピリダジン-4-イル]アミノ}フェニル)カルボキシレート(190 mg, 0.40 mmol)、1規定 水酸化ナトリウム水溶液 (2.0mL)、メタノール(10mL)、2規定アンモニア・イソプロパノール溶液(0.40mL, 0.80mmol)、O-(7-アザ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ホスフェート(300mg, 0.80mmol)、N,N-ジイソプロピルエチルアミン(0.14mL, 0.80mmol)、N,N-ジメチルホルムアミド(10mL)を用いて、標記化合物(110mg, 0.25mmol, 62%)を固体として得た。
LCMS (ES): m/z 409 [M+H]+. Step 14 (b): Preparation of 2- (3-fluoro-4-{[7- (4-chloro-2-methoxyphenyl) thieno [2,3-d] pyridazin-4-yl] amino} phenyl) acetamide In the same manner as in Step 3 (c), ethyl (3-fluoro-4-{[7- (2-methoxyphenyl) thieno [2,3-d] pyridazin-4-yl] obtained in Example 14 (a) was used. Amino} phenyl) carboxylate (190 mg, 0.40 mmol), 1 N aqueous sodium hydroxide (2.0 mL), methanol (10 mL), 2 N ammonia / isopropanol solution (0.40 mL, 0.80 mmol), O- (7- Azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (300 mg, 0.80 mmol), N, N-diisopropylethylamine (0.14 mL, 0.80 mmol), N, N -Dimethylformamide (10 mL) was used to obtain the title compound (110 mg, 0.25 mmol, 62%) as a solid.
LCMS (ES): m / z 409 [M + H] + .
（実施例１５）
2-[4-({7-[2-((2S)-1,4-ジオキサン-2-イルメトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)-2,3-フルオロフェニル]アセタミド (Example 15)
2- [4-({7- [2-((2S) -1,4-dioxan-2-ylmethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) -2,3- Fluorophenyl] acetamide
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
工程15(a)：4-クロロ-7-[2-((2S)-1,4-ジオキサン-2-イルメトキシ)フェニル]チエノ[2,3-d]ピリダジンの製造
参考例R3の化合物(0.94g, 4.8mmol) をN,N-ジメチルホルムアミド(25mL)に溶解し、炭酸カリウム(1.1g, 7.7mmol）を加え、70℃で10時間撹拌した。反応液に水、酢酸エチルを加えて分液操作後、有機層を無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝90/10-50/50(v/v)］にて精製し、標記化合物(428mg, 1.2mmol, 43%) を固体として得た。
LCMS (ES): m/z 363 [M+H]+. Step 15 (a): Production of 4-chloro-7- [2-((2S) -1,4-dioxan-2-ylmethoxy) phenyl] thieno [2,3-d] pyridazine Compound of Reference Example R3 (0.94 g, 4.8 mmol) was dissolved in N, N-dimethylformamide (25 mL), potassium carbonate (1.1 g, 7.7 mmol) was added, and the mixture was stirred at 70 ° C. for 10 hr. Water and ethyl acetate were added to the reaction solution, and after liquid separation, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-50 / 50 (v / v)] to give the title compound (428 mg, 1.2 mmol, 43%) as a solid.
LCMS (ES): m / z 363 [M + H] + .
工程15(b)：エチル　{4-[(7-{2-[(2S)-1,4-ジオキサン-2-イルメトキシ]フェニル}チエノ[2,3-d]ピリダジン-4-イル)アミノ]-2,3-ジフルオロフェニル}アセテートの製造
工程15(a)で得られた化合物(210mg, 0.58mmol) および参考例R5で得られた化合物(110mg, 0.48mmol)をジメチルスルホキシド(25mL）に溶解し、120℃で6時間撹拌した。反応液に水、酢酸エチルを加えて分液操作後、有機層を無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ジクロロメタン/メタノール＝100/0-98/2(v/v)］にて精製し、標記化合物 (129mg, 0.24mmol, 41%) を固体として得た。
LCMS (ES): m/z 542 [M+H]+. Step 15 (b): ethyl {4-[(7- {2-[(2S) -1,4-dioxan-2-ylmethoxy] phenyl} thieno [2,3-d] pyridazin-4-yl) amino] -2,3-difluorophenyl} acetate Compound (210mg, 0.58mmol) obtained in Production Process 15 (a) and compound obtained in Reference Example R5 (110mg, 0.48mmol) were dissolved in dimethyl sulfoxide (25mL) And stirred at 120 ° C. for 6 hours. Water and ethyl acetate were added to the reaction solution, and after liquid separation, the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: dichloromethane / methanol = 100 / 0-98 / 2 (v / v)] to give the title compound (129 mg, 0.24 mmol, 41%) as a solid.
LCMS (ES): m / z 542 [M + H] + .
工程15(c)：2-{4-[(7-{2-[(2S)-1,4-ジオキサン-2-イルメトキシ]フェニル}チエノ[2,3-d]ピリダジン-4-イル)アミノ]-2,3-ジフルオロフェニル}アセタミドの製造
工程3(c)と同様にして、工程15(b)で得られた化合物(87mg, 0.16mmol)より、標記化合物(60mg, 0.12mmol, 49%)を固体として得た。
LCMS (ES): m/z 512 [M+H]+.
1H NMR (CDCl3) δ(ppm): 3.05-3.19 (1H, m), 3.34-3.48 (2H, m), 3.56-3.80 (6H, m), 3.87-3.93 (1H, m), 4.02-4.07 (1H, m), 7.03-7.08 (2H, m), 7.13 (1H, t, J = 8.3 Hz), 7.47-7.52 (1H, m), 7.54-7.58 (1H, m), 7.66 (1H, d, J = 4.9 Hz), 7.86 (1H, d, J = 5.4 Hz), 8.08 (1H, br s). Step 15 (c): 2- {4-[(7- {2-[(2S) -1,4-dioxan-2-ylmethoxy] phenyl} thieno [2,3-d] pyridazin-4-yl) amino ] -2,3-difluorophenyl} acetamide In the same manner as in Step 3 (c), the title compound (60 mg, 0.12 mmol, 49%) was obtained from the compound (87 mg, 0.16 mmol) obtained in Step 15 (b). ) Was obtained as a solid.
LCMS (ES): m / z 512 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 3.05-3.19 (1H, m), 3.34-3.48 (2H, m), 3.56-3.80 (6H, m), 3.87-3.93 (1H, m), 4.02- 4.07 (1H, m), 7.03-7.08 (2H, m), 7.13 (1H, t, J = 8.3 Hz), 7.47-7.52 (1H, m), 7.54-7.58 (1H, m), 7.66 (1H, d, J = 4.9 Hz), 7.86 (1H, d, J = 5.4 Hz), 8.08 (1H, br s).
（実施例１６）
2-[4-({7-[2-(1,4-ジオキサン-2-イルメトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)-3-フルオロフェニル]アセタミド (Example 16)
2- [4-({7- [2- (1,4-Dioxane-2-ylmethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) -3-fluorophenyl] acetamide
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
工程16(a)：4-クロロ-7-[2-(1,4-ジオキサン-2-イルメトキシ)フェニル]チエノ[2,3-d]ピリダジンの製造
工程3(a)と同様にして、参考例R3で得られた化合物(400mg, 1.5mmol) 、2-(ブロモメチル)-1,4-ジオキサン(550mg, 3.0mmol) 、水素化ナトリウム(121mg, 3.0mmol)、N,N-ジメチルホルムアミド(20mL)を用いて、標記化合物(250mg, 0.69mmol, 45%) を固体として得た。
LCMS (ES): m/z 363 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 3.12-3.16 (1H, m), 3.42-3.48 (2H, m), 3.57-3.73 (4H, m), 3.88-3.92 (1H, m), 4.02-4.07 (1H, m), 7.07 (1H, d, J= 8.8 Hz), 7.13-7.17 (1H, m), 7.47-7.52 (1H, m), 7.55-7.58 (1H, m), 7.61 (1H, d, J = 5.4 Hz), 7.87 (1H, d, J = 5.4 Hz). Step 16 (a): Preparation of 4-chloro-7- [2- (1,4-dioxane-2-ylmethoxy) phenyl] thieno [2,3-d] pyridazine in the same manner as in Step 3 (a), Compound obtained in Example R3 (400 mg, 1.5 mmol), 2- (bromomethyl) -1,4-dioxane (550 mg, 3.0 mmol), sodium hydride (121 mg, 3.0 mmol), N, N-dimethylformamide (20 mL ) To give the title compound (250 mg, 0.69 mmol, 45%) as a solid.
LCMS (ES): m / z 363 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 3.12-3.16 (1H, m), 3.42-3.48 (2H, m), 3.57-3.73 (4H, m), 3.88-3.92 (1H, m), 4.02- 4.07 (1H, m), 7.07 (1H, d, J = 8.8 Hz), 7.13-7.17 (1H, m), 7.47-7.52 (1H, m), 7.55-7.58 (1H, m), 7.61 (1H, d, J = 5.4 Hz), 7.87 (1H, d, J = 5.4 Hz).
工程16(b)：n-ブチル　[4-({7-[2-(1,4-ジオキサン-2-イルメトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)-3-フルオロフェニル]カルボキシレートの製造
工程4(b)と同様にして、工程16(a)で得られた化合物(135 mg, 0.37 mmol) 、n-ブタノール(15mL)、ブチル(4-アミノ-3-フルオロフェニル)アセテート(110 mg, 0.48 mmol)、トリフルオロ酢酸(0.085 mL, 1.1 mmol)を用いて、標記化合物(87mg, 0.16mmol, 42%) を油状物質として得た。
1H NMR (CDCl3) δ(ppm): 0.90 (3H, t, J = 7.3 Hz), 1.30-1.38 (2H, m), 1.56-1.63 (2H, m), 3.13 (1H, dd, J = 11.7, 9.8 Hz), 3.40-3.47 (2H, m), 3.57-3.68 (4H, m), 3.58 (2H, s), 3.86-3.91 (1H, m), 4.04 (1H, dd, J = 9.8, 4.9 Hz), 4.09 (2H, t, J = 6.6 Hz).7.04 (1H, d, J= 8.3 Hz), 7.08-7.14 (3H, m), 7.42-7.48 (2H, m), 7.60 (1H, dd, J = 7.6, 1.7 Hz), 7.77 (1H, d, J = 5.4 Hz), 8.76 (1H, t, J = 8.8 Hz). Step 16 (b): n-butyl [4-({7- [2- (1,4-dioxan-2-ylmethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) -3 -Fluorophenyl] carboxylate In the same manner as in production step 4 (b), the compound obtained in step 16 (a) (135 mg, 0.37 mmol), n-butanol (15 mL), butyl (4-amino-3 Using -fluorophenyl) acetate (110 mg, 0.48 mmol) and trifluoroacetic acid (0.085 mL, 1.1 mmol), the title compound (87 mg, 0.16 mmol, 42%) was obtained as an oily substance.
1 H NMR (CDCl 3 ) δ (ppm): 0.90 (3H, t, J = 7.3 Hz), 1.30-1.38 (2H, m), 1.56-1.63 (2H, m), 3.13 (1H, dd, J = 11.7, 9.8 Hz), 3.40-3.47 (2H, m), 3.57-3.68 (4H, m), 3.58 (2H, s), 3.86-3.91 (1H, m), 4.04 (1H, dd, J = 9.8, 4.9 Hz), 4.09 (2H, t, J = 6.6 Hz) .7.04 (1H, d, J = 8.3 Hz), 7.08-7.14 (3H, m), 7.42-7.48 (2H, m), 7.60 (1H, dd, J = 7.6, 1.7 Hz), 7.77 (1H, d, J = 5.4 Hz), 8.76 (1H, t, J = 8.8 Hz).
工程16(c)：2-[4-({7-[2-(1,4-ジオキサン-2-イルメトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)-3-フルオロフェニル]アセタミドの製造
工程3(c)と同様にして、工程16(b)で得られた化合物(87mg, 0.16mmol)、1規定 水酸化ナトリウム水溶液(1.0mL)、メタノール(5mL)、2規定アンモニア・イソプロパノール溶液(0.16mL, 0.32mmol)、O-(7-アザ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ホスフェート(130mg, 0.32mmol)、N,N-ジイソプロピルエチルアミン(0.060mL, 0.032mmol)、N,N-ジメチルホルムアミド(10mL)を用いて、標記化合物(50mg, 0.10mmol, 63%)を固体として得た。
LCMS (ES): m/z 495 [M+H]+.
1H NMR (DMSO-D6) δ(ppm): 3.01 (1H, t, J = 11.5 Hz), 3.22-3.45 (5H, m), 3.50 (1H, d, J= 11.7 Hz), 3.56-3.61 (2H, m), 3.93 (1H, dd, J = 10.5, 5.1 Hz), 4.02 (1H, dd, J = 10.3, 5.4 Hz), 6.92 (1H, s), 7.07-7.11 (2H, m), 7.18 (1H, dd, J = 11.7, 2.0 Hz), 7.21 (1H, d, J = 8.3 Hz), 7.40 (1H, dd, J = 7.3, 2.0 Hz), 7.44-7.51 (2H, m), 7.62 (1H, t, J = 8.3 Hz), 7.95 (1H, d, J = 5.4 Hz), 8.14 (1H, d, J = 5.4 Hz), 9.03 (1H, s). Step 16 (c): 2- [4-({7- [2- (1,4-dioxan-2-ylmethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) -3- Fluorophenyl] acetamide In the same manner as in production step 3 (c), the compound obtained in step 16 (b) (87 mg, 0.16 mmol), 1N aqueous sodium hydroxide solution (1.0 mL), methanol (5 mL), 2 Normal ammonia / isopropanol solution (0.16mL, 0.32mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (130mg, 0.32mmol) , N, N-diisopropylethylamine (0.060 mL, 0.032 mmol) and N, N-dimethylformamide (10 mL) were used to obtain the title compound (50 mg, 0.10 mmol, 63%) as a solid.
LCMS (ES): m / z 495 [M + H] + .
1 H NMR (DMSO-D 6 ) δ (ppm): 3.01 (1H, t, J = 11.5 Hz), 3.22-3.45 (5H, m), 3.50 (1H, d, J = 11.7 Hz), 3.56-3.61 (2H, m), 3.93 (1H, dd, J = 10.5, 5.1 Hz), 4.02 (1H, dd, J = 10.3, 5.4 Hz), 6.92 (1H, s), 7.07-7.11 (2H, m), 7.18 (1H, dd, J = 11.7, 2.0 Hz), 7.21 (1H, d, J = 8.3 Hz), 7.40 (1H, dd, J = 7.3, 2.0 Hz), 7.44-7.51 (2H, m), 7.62 (1H, t, J = 8.3 Hz), 7.95 (1H, d, J = 5.4 Hz), 8.14 (1H, d, J = 5.4 Hz), 9.03 (1H, s).
（実施例１７）
2-[3-フルオロ-4-({7-[2-(1,3-チアゾール-2-イルメトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)フェニル]アセタミド (Example 17)
2- [3-Fluoro-4-({7- [2- (1,3-thiazol-2-ylmethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) phenyl] acetamide
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
工程17(a)：4-クロロ-7-[2-(1,3-チアゾール-2-イルメトキシ)フェニル]チエノ[2,3-d]ピリダジンの製造
参考例R3の化合物(100mg, 0.38mmol)をアセトン(3mL)に溶解させ、2-(ブロモメチル)-1,3-チアゾール (参考文献：Inorganic Chemistry, 2016 , vol. 55, 619 - 632；88mg, 0.49mmol) と、炭酸カリウム(100mg, 0.76mmol)を加え、室温で12時間攪拌した。反応液に飽和塩化アンモニウム水溶液(10mL)を加え、酢酸エチルを加えて抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝90/10-50/50(v/v)］にて精製し、標記化合物(98 mg, 0.27 mmol, 72%)を固体として得た。
LCMS (ES): m/z 360 [M+H]+.
1H NMR (CDCl3) δ(ppm): 5.38 (2H, s), 7.16 (1H, d, J = 8.3 Hz), 7.18-7.21 (2H, m), 7.50-7.54 (1H, m), 7.62 (1H, d, J = 5.4 Hz), 7.63 (1H, dd, J = 7.8, 1.5 Hz), 7.68 (1H, d, J = 3.4 Hz), 7.85 (1H, d, J = 5.4 Hz). Step 17 (a): Preparation of 4-chloro-7- [2- (1,3-thiazol-2-ylmethoxy) phenyl] thieno [2,3-d] pyridazine Compound of Reference Example R3 (100 mg, 0.38 mmol) Is dissolved in acetone (3 mL), 2- (bromomethyl) -1,3-thiazole (reference: Inorganic Chemistry, 2016, vol. 55, 619-632; 88 mg, 0.49 mmol) and potassium carbonate (100 mg, 0.76 mmol) was added and stirred at room temperature for 12 hours. Saturated aqueous ammonium chloride solution (10 mL) was added to the reaction mixture, ethyl acetate was added for extraction, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-50 / 50 (v / v)] to give the title compound (98 mg , 0.27 mmol, 72%) was obtained as a solid.
LCMS (ES): m / z 360 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 5.38 (2H, s), 7.16 (1H, d, J = 8.3 Hz), 7.18-7.21 (2H, m), 7.50-7.54 (1H, m), 7.62 (1H, d, J = 5.4 Hz), 7.63 (1H, dd, J = 7.8, 1.5 Hz), 7.68 (1H, d, J = 3.4 Hz), 7.85 (1H, d, J = 5.4 Hz).
工程17(b)：エチル　[3-フルオロ-4-({7-[2-(1,3-チアゾール-2-イルメトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)フェニル]アセテートの製造
工程4(b)と同様にして、工程17(a)で得られた化合物(98mg, 0.27mmol) と、エチル　(4-アミノ-3-フルオロフェニル)アセテート・臭化水素塩(75mg, 0.27mmol)、トリフルオロ酢酸(0.1mL)とn-ブタノール(3mL)を用いて、標記化合物(96mg, 0.18mmol, 68%)を固体として得た。
LCMS (ES): m/z 549 [M+H]+. Step 17 (b): ethyl [3-fluoro-4-({7- [2- (1,3-thiazol-2-ylmethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) In the same manner as in production step 4 (b) of phenyl] acetate, the compound (98 mg, 0.27 mmol) obtained in step 17 (a) and ethyl (4-amino-3-fluorophenyl) acetate / hydrobromide (75 mg, 0.27 mmol), trifluoroacetic acid (0.1 mL) and n-butanol (3 mL) were used to obtain the title compound (96 mg, 0.18 mmol, 68%) as a solid.
LCMS (ES): m / z 549 [M + H] + .
工程17(c)：2-[3-フルオロ-4-({7-[2-(1,3-チアゾール-2-イルメトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)フェニル]アセタミドの製造
工程3(c)と同様にして、工程17(b)で得られた化合物(95mg, 0.18mmol) と、1規定水酸化ナトリウム水溶液(0.42mL)、テトラヒドロフラン(0.5mL)、メタノール(0.5mL)、2規定アンモニア・イソプロパノール溶液(0.15mL, 0.30mmol)、O-(7-アザ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ホスフェート(48mg, 0.13mmol)、N,N-ジメチルホルムアミド(1mL)を用いて、標記化合物(21mg, 0.043 mmol, 24%)を固体として得た。
LCMS (ES): m/z 492 [M+H]+.
1H NMR (DMSO-D6) δ(ppm): 3.42 (2H, s), 5.47 (2H, s), 6.95 (1H, s), 7.11-7.26 (3H, m), 7.39 (1H, d, J = 8.3 Hz), 7.49-7.65 (6H, m), 7.73 (1H, d, J = 2.9 Hz), 8.06 (1H, s), 8.30 (1H, s). Step 17 (c): 2- [3-Fluoro-4-({7- [2- (1,3-thiazol-2-ylmethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino ) Phenyl] acetamide in the same manner as in production step 3 (c), the compound obtained in step 17 (b) (95 mg, 0.18 mmol), 1N aqueous sodium hydroxide solution (0.42 mL), tetrahydrofuran (0.5 mL) , Methanol (0.5 mL), 2 N ammonia / isopropanol solution (0.15 mL, 0.30 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexa Fluorophosphate (48 mg, 0.13 mmol) and N, N-dimethylformamide (1 mL) were used to give the title compound (21 mg, 0.043 mmol, 24%) as a solid.
LCMS (ES): m / z 492 [M + H] + .
1 H NMR (DMSO-D 6 ) δ (ppm): 3.42 (2H, s), 5.47 (2H, s), 6.95 (1H, s), 7.11-7.26 (3H, m), 7.39 (1H, d, J = 8.3 Hz), 7.49-7.65 (6H, m), 7.73 (1H, d, J = 2.9 Hz), 8.06 (1H, s), 8.30 (1H, s).
（実施例１８）
エチル　2-{[2-]4-{[4-(2-アミノ-2-オキソエチル)-2-フルオロフェニル]アミノ}チエノ[2,3-d]ピリダジン-7-イル}フェノキシ]メチル}アセテート (Example 18)
Ethyl 2-{[2-] 4-{[4- (2-amino-2-oxoethyl) -2-fluorophenyl] amino} thieno [2,3-d] pyridazin-7-yl} phenoxy] methyl} acetate
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
工程18(a)：メチル　2-{[2-(4-クロロチエノ[2,3-d]ピリダジン-7-イル)フェノキシ]メチル}ベンゾエートの製造
工程3(a)と同様にして、参考例R3の化合物(300mg, 1.14mmol)、メチル2-(ブロモメチル)フェニルアセテート(314mg, 1.4mmol)、水素化ナトリウム(70mg, 1.7mmol）、N,N-ジメチルホルムアミド(10mL)を用いて、標記化合物(200mg, 0.49mmol, 43%) を固体として得た。
LCMS (ES): m/z 411 [M+H]+.
1H NMR (CDCl3) δ(ppm) : 3.86 (3H, s), 5.57 (2H, s), 7.08 (1H, t, J= 5.4 Hz), 7.15 (2H, tt, J = 8.3, 3.7 Hz), 7.23-7.28 (1H, m), 7.29-7.32 (1H, m), 7.44-7.48 (1H, m), 7.55-7.64 (2H, m), 7.82 (1H, dd, J= 5.4, 2.4 Hz), 7.94 (1H, dd, J= 7.6, 1.2 Hz). Step 18 (a): Preparation of methyl 2-{[2- (4-chlorothieno [2,3-d] pyridazin-7-yl) phenoxy] methyl} benzoate In the same manner as in Step 3 (a), Reference Example R3 Of the title compound (300 mg, 1.14 mmol), methyl 2- (bromomethyl) phenyl acetate (314 mg, 1.4 mmol), sodium hydride (70 mg, 1.7 mmol), N, N-dimethylformamide (10 mL). 200 mg, 0.49 mmol, 43%) was obtained as a solid.
LCMS (ES): m / z 411 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 3.86 (3H, s), 5.57 (2H, s), 7.08 (1H, t, J = 5.4 Hz), 7.15 (2H, tt, J = 8.3, 3.7 Hz ), 7.23-7.28 (1H, m), 7.29-7.32 (1H, m), 7.44-7.48 (1H, m), 7.55-7.64 (2H, m), 7.82 (1H, dd, J = 5.4, 2.4 Hz ), 7.94 (1H, dd, J = 7.6, 1.2 Hz).
工程18(b)：メチル　2-{[2-]4-{[4-(2-アミノ-2-オキソエチル)-2-フルオロフェニル]アミノ}チエノ[2,3-d]ピリダジン-7-イル}フェノキシ]メチル}ベンゾエートの製造
工程18(a)で化合物(200mg, 0.49mmol)をエタノール(15mL)に溶解し、2-(4-アミノ-3-フルオロフェニル)アセタミド(220mg, 1.3mmol)を加え、100℃にて2時間攪拌した。反応液を減圧下濃縮した後、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/メタノール＝100/0-80/20(v/v)］にて精製し、標記化合物(50mg, 0.092mmol, 19%) を固体として得た。
LCMS (ES): m/z 543 [M+H]+.
1H NMR (CD3OD) δ(ppm) : 3.52 (2H, s), 3.78 (3H, s), 5.48 (2H, s), 7.13 (2H, t, J = 7.6 Hz), 7.18 (3H, d, J= 8.8 Hz), 7.24-7.33 (2H, m), 7.49 (2H, t, J = 6.8 Hz), 7.80-7.87 (3H, m), 7.95 (1H, d, J = 5.4 Hz). Step 18 (b): methyl 2-{[2-] 4-{[4- (2-amino-2-oxoethyl) -2-fluorophenyl] amino} thieno [2,3-d] pyridazin-7-yl } Phenoxy] methyl} benzoate In step 18 (a), compound (200 mg, 0.49 mmol) was dissolved in ethanol (15 mL), and 2- (4-amino-3-fluorophenyl) acetamide (220 mg, 1.3 mmol) was dissolved. In addition, the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: ethyl acetate / methanol = 100 / 0-80 / 20 (v / v)] to give the title compound (50 mg, 0.092 mmol, 19%) was obtained as a solid.
LCMS (ES): m / z 543 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 3.52 (2H, s), 3.78 (3H, s), 5.48 (2H, s), 7.13 (2H, t, J = 7.6 Hz), 7.18 (3H, d, J = 8.8 Hz), 7.24-7.33 (2H, m), 7.49 (2H, t, J = 6.8 Hz), 7.80-7.87 (3H, m), 7.95 (1H, d, J = 5.4 Hz).
工程18(c)：2-{[2-(4-{[4-(2-アミノ-2-オキソエチル)-2-フルオロフェニル]アミノ｝チエノ[2,3-d]ピリダジン-7-イル}フェノキシ]メチル}ベンゾイックアシッドの製造
工程18(b)で得られた化合物(50mg, 0.092mmol)をテトラヒドロフラン(3mL)とメタノール(3mL)に溶解し、1規定水酸化ナトリウム水溶液(1mL)を加え、45℃で1時間攪拌した。反応液を室温まで冷却し、1規定塩酸(1mL)を加えて中和した後、減圧下濃縮した。析出した固体を水を用いてろ取し、得られた固体を減圧下、50℃で1時間乾燥し、標記化合物(14mg, 0.026mmol, 29%)を固体として得た。
LCMS (ES): m/z 529 [M+H]+.
1H NMR (DMSO-D6) δ(ppm): 3.41 (2H, s), 5.50 (2H, s), 6.93 (1H, s), 7.11-7.24 (6H, m), 7.30-7.39 (2H, m), 7.48-7.53 (4H, m), 7.60 (1H, t, J= 8.8 Hz), 7.87 (1H, d, J = 7.8 Hz), 8.01 (1H, s). Step 18 (c): 2-{[2- (4-{[4- (2-amino-2-oxoethyl) -2-fluorophenyl] amino} thieno [2,3-d] pyridazin-7-yl} Phenoxy] methyl} benzoic acid Compound (50 mg, 0.092 mmol) obtained in Step 18 (b) was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL), and 1N aqueous sodium hydroxide solution (1 mL) was added. The mixture was stirred for 1 hour at 45 ° C. The reaction mixture was cooled to room temperature, neutralized with 1N hydrochloric acid (1 mL), and concentrated under reduced pressure, and the resulting solid was collected by filtration with water. The solid was dried under reduced pressure at 50 ° C. for 1 hour to obtain the title compound (14 mg, 0.026 mmol, 29%) as a solid.
LCMS (ES): m / z 529 [M + H] + .
1 H NMR (DMSO-D 6 ) δ (ppm): 3.41 (2H, s), 5.50 (2H, s), 6.93 (1H, s), 7.11-7.24 (6H, m), 7.30-7.39 (2H, m), 7.48-7.53 (4H, m), 7.60 (1H, t, J = 8.8 Hz), 7.87 (1H, d, J = 7.8 Hz), 8.01 (1H, s).
（実施例１９）
tert-ブチル　(2-{2-[2-(4-{[4-(2-アミノ-2-オキソエチル)-2-フルオロフェニル]アミノ}チエノ[2,3-d]ピリダジン-7-イル)フェノキシ]エトキシ}エチル)カルバメート (Example 19)
tert-butyl (2- {2- [2- (4-{[4- (2-amino-2-oxoethyl) -2-fluorophenyl] amino} thieno [2,3-d] pyridazin-7-yl) Phenoxy] ethoxy} ethyl) carbamate
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
工程19(a)：tert-ブチル{2-[2-(2-ヨードフェノキシ)エトキシ]エチル}カルバメートの製造
工程13(a)と同様にして、2-ヨードフェノール(1.5g, 6.8mmol)、テトラヒドロフラン(20mL)、tert-ブチル[2-(2-ヒドロキシエトキシ)エチル]カルバメート(参考文献：Journal of Medicinal Chemistry, 2000,  vol. 43, p. 475 - 487；1.5g, 7.3mmol)と（トリブチルホスホラニリデン）アセトニトリル(2.7mL, 10mmol)を用いて、標記化合物(1.4g, 3.4mmol, 49%) を油状物質として得た。
LCMS (ES): m/z 308 [M+H-BOC]+.
1H NMR (CDCl3) δ(ppm): 1.41 (9H, s), 3.33 (2H, q, J = 5.0 Hz), 3.65 (2H, t, J = 5.1 Hz), 3.84-3.86 (2H, m), 4.13 (2H, t, J= 4.6 Hz), 5.02 (1H, s), 6.70 (1H, td, J= 7.6, 1.5 Hz), 6.80 (1H, dd, J= 8.3, 1.5 Hz), 7.25-7.28 (1H, m), 7.75 (1H, dd, J = 7.8, 2.0 Hz). Step 19 (a): Preparation of tert-butyl {2- [2- (2-iodophenoxy) ethoxy] ethyl} carbamate In the same manner as in Step 13 (a), 2-iodophenol (1.5 g, 6.8 mmol), Tetrahydrofuran (20 mL), tert-butyl [2- (2-hydroxyethoxy) ethyl] carbamate (reference: Journal of Medicinal Chemistry, 2000, vol. 43, p. 475-487; 1.5 g, 7.3 mmol) and (tributyl The title compound (1.4 g, 3.4 mmol, 49%) was obtained as an oily substance using phosphoranilidene) acetonitrile (2.7 mL, 10 mmol).
LCMS (ES): m / z 308 [M + H-BOC] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.41 (9H, s), 3.33 (2H, q, J = 5.0 Hz), 3.65 (2H, t, J = 5.1 Hz), 3.84-3.86 (2H, m ), 4.13 (2H, t, J = 4.6 Hz), 5.02 (1H, s), 6.70 (1H, td, J = 7.6, 1.5 Hz), 6.80 (1H, dd, J = 8.3, 1.5 Hz), 7.25 -7.28 (1H, m), 7.75 (1H, dd, J = 7.8, 2.0 Hz).
工程19(b)：tert-ブチル　(2-{2-[2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル）フェノキシ]エトキシ}エチル)カルバメートの製造
工程19(a)で得られた化合物(1.4g, 3.4mmol)をトルエン(25mL)に溶解し、反応液に4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン(1.3g, 10mmol)、テトラキス(トリフェニルホスフィン)パラジウム(200mg, 0.17mmol)、トリエチルアミン(1.9mL, 13mmol)を加え、120℃で3時間攪拌した。反応液を室温まで冷却し、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝90/10-50/50(v/v)］にて精製し、標記化合物 (1.2g, 2.9mmol, 88%) を油状物質として得た。
1H NMR (CDCl3) δ(ppm): 1.31 (12H, s), 1.38 (9H, s), 3.27-3.33 (2H, m), 3.67 (2H, t, J = 5.1 Hz), 3.83 (2H, t, J = 4.6 Hz), 4.07-4.11 (2H, m), 6.82 (1H, d, J = 8.3 Hz), 6.93 (1H, td, J = 7.3, 1.0 Hz), 7.35 (1H, dt, J = 10.9, 4.1 Hz), 7.64 (1H, dd, J = 7.3, 1.5 Hz). Step 19 (b): of tert-butyl (2- {2- [2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] ethoxy} ethyl) carbamate The compound (1.4 g, 3.4 mmol) obtained in production step 19 (a) was dissolved in toluene (25 mL), and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 g, 10 mmol), tetrakis (triphenylphosphine) palladium (200 mg, 0.17 mmol), and triethylamine (1.9 mL, 13 mmol) were added, and the mixture was stirred at 120 ° C. for 3 hours. The reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution was added, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-50 / 50 (v / v)] to give the title compound (1.2 g , 2.9 mmol, 88%) was obtained as an oily substance.
1 H NMR (CDCl 3 ) δ (ppm): 1.31 (12H, s), 1.38 (9H, s), 3.27-3.33 (2H, m), 3.67 (2H, t, J = 5.1 Hz), 3.83 (2H , t, J = 4.6 Hz), 4.07-4.11 (2H, m), 6.82 (1H, d, J = 8.3 Hz), 6.93 (1H, td, J = 7.3, 1.0 Hz), 7.35 (1H, dt, J = 10.9, 4.1 Hz), 7.64 (1H, dd, J = 7.3, 1.5 Hz).
工程19(c)：n-ブチル　[4-({7-[2-(2-{2-[(tert-ブトキシカルボニル)アミノ]エトキシ}エトキシ）フェニル］チエノ[2,3-d]ピリダジン-4-イル}アミノ)-3-フルオロフェニル］アセテートの製造
工程4(b)と同様にして、工程19(b)で得られた化合物(143mg, 0.36mmol)、tert-ブチル(2-{2-[2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノキシ]エトキシ}エチル)カルバメート(300mg, 0.72mmol)、[1,1’-ビス（ジフェニルホスフィノ）フェロセン]ジクロロパラジウム(II)・ジクロロメタン錯体 (40mg, 0.050mmol)、リン酸カリウム・n-水和物(400mg, 1.5 mmol)、1,2-ジメトキシエタン(20ml)、水(0.5mL)を用いて、標記化合物(164mg, 0.26mmol, 72%)を油状物質として得た。
LCMS (ES): m/z 639 [M+H]+.
1H NMR (CDCl3) δ(ppm): 0.90 (3H, t, J = 7.6 Hz), 1.31-1.37 (2H, m), 1.39 (9H, s), 1.55-1.63 (2H, m), 3.08-3.14 (2H, m), 3.27 (2H, t, J = 5.4 Hz), 3.57 (2H, t, J = 4.9 Hz), 3.58 (2H, s), 4.09 (2H, t, J = 7.6 Hz), 4.12 (2H, t, J = 4.9 Hz), 7.04-7.14 (4H, m), 7.43-7.47 (2H, m), 7.61 (1H, dd, J= 7.3, 2.0 Hz), 7.78 (1H, d, J= 5.4 Hz), 8.76 (1H, t, J = 8.8 Hz). Step 19 (c): n-butyl [4-({7- [2- (2- {2-[(tert-butoxycarbonyl) amino] ethoxy} ethoxy) phenyl] thieno [2,3-d] pyridazine- 4-yl} amino) -3-fluorophenyl] acetate In the same manner as in Step 4 (b), the compound obtained in Step 19 (b) (143 mg, 0.36 mmol), tert-butyl (2- {2 -[2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] ethoxy} ethyl) carbamate (300 mg, 0.72 mmol), [1,1′-bis ( Diphenylphosphino) ferrocene] dichloropalladium (II) / dichloromethane complex (40 mg, 0.050 mmol), potassium phosphate / n-hydrate (400 mg, 1.5 mmol), 1,2-dimethoxyethane (20 ml), water (0.5 to give the title compound (164 mg, 0.26 mmol, 72%) as an oil.
LCMS (ES): m / z 639 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 0.90 (3H, t, J = 7.6 Hz), 1.31-1.37 (2H, m), 1.39 (9H, s), 1.55-1.63 (2H, m), 3.08 -3.14 (2H, m), 3.27 (2H, t, J = 5.4 Hz), 3.57 (2H, t, J = 4.9 Hz), 3.58 (2H, s), 4.09 (2H, t, J = 7.6 Hz) , 4.12 (2H, t, J = 4.9 Hz), 7.04-7.14 (4H, m), 7.43-7.47 (2H, m), 7.61 (1H, dd, J = 7.3, 2.0 Hz), 7.78 (1H, d , J = 5.4 Hz), 8.76 (1H, t, J = 8.8 Hz).
工程19(d)：tert-ブチル　(2-{2-[2-(4-{[4-(2-アミノ-2-オキソエチル)-2-フルオロフェニル]アミノ}チエノ[2,3-d]ピリダジン-7-イル)フェノキシ]エトキシ}エチル)カルバメートの製造
工程3(c)と同様にして、工程19(c)で得られた化合物(164mg, 0.26mmol)、1規定 水酸化ナトリウム水溶液(2.0mL)、メタノール(10mL)、2規定アンモニア・イソプロパノール溶液(0.26mL, 0.52mmol)、O-(7-アザ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ホスフェート(200mg, 0.52mmol)、N,N-ジイソプロピルエチルアミン(0.088mL, 0.52mmol)、N,N-ジメチルホルムアミド(10mL)を用いて、標記化合物(120mg, 0.21mmol, 79%)を固体として得た。
LCMS (ES): m/z 582 [M+H]+.
1H NMR (CD3OD) δ(ppm): 1.37 (9H, s), 3.20 (2H, t, J = 5.6 Hz), 3.23-3.31 (2H, m), 3.52 (2H, s), 3.57 (2H, t, J = 4.6 Hz), 4.13 (2H, t, J= 4.6 Hz), 7.09-7.19 (4H, m), 7.43-7.51 (2H, m), 7.83-7.87 (2H, m), 8.02 (1H, d, J = 5.4 Hz). Step 19 (d): tert-butyl (2- {2- [2- (4-{[4- (2-amino-2-oxoethyl) -2-fluorophenyl] amino} thieno [2,3-d] Pyridazine-7-yl) phenoxy] ethoxy} ethyl) carbamate In the same manner as in Step 3 (c), the compound obtained in Step 19 (c) (164 mg, 0.26 mmol), 1N aqueous sodium hydroxide solution (2.0 mL), methanol (10 mL), 2N ammonia / isopropanol solution (0.26 mL, 0.52 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium Hexafluorophosphate (200 mg, 0.52 mmol), N, N-diisopropylethylamine (0.088 mL, 0.52 mmol), N, N-dimethylformamide (10 mL) were used to solidify the title compound (120 mg, 0.21 mmol, 79%) Got as.
LCMS (ES): m / z 582 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 1.37 (9H, s), 3.20 (2H, t, J = 5.6 Hz), 3.23-3.31 (2H, m), 3.52 (2H, s), 3.57 ( 2H, t, J = 4.6 Hz), 4.13 (2H, t, J = 4.6 Hz), 7.09-7.19 (4H, m), 7.43-7.51 (2H, m), 7.83-7.87 (2H, m), 8.02 (1H, d, J = 5.4 Hz).
（実施例２０）
tert-ブチル　{4-[2-(4-{[4-(2-アミノ-2-オキソエチル)-2-フルオロフェニル]アミノ}チエノ[2,3-d]ピリダジン-7-イル)フェノキシ]ブチル}カルバメート (Example 20)
tert-butyl {4- [2- (4-{[4- (2-amino-2-oxoethyl) -2-fluorophenyl] amino} thieno [2,3-d] pyridazin-7-yl) phenoxy] butyl } Carbamate
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
工程20(a)：tert-ブチル　[4-(2-ヨードフェノキシ)ブチル]カルバメートの製造
工程19(a)と同様にして、2-ヨードフェノール(1.5g, 6.8mmol)、テトラヒドロフラン(20mL)、tert-ブチル[2-(2-ヒドロキシエトキシ)エチル]カルバメート(参考文献：Bioorganic and Medicinal Chemistry, 2009, vol. 17, p. 2536-2543；1.9 g, 10 mmol)と(トリブチルホスホラニリデン)アセトニトリル(2.7mL, 10mmol)を用いて、標記化合物(3.1g, 8.0mmol, 100%) を油状物質として得た。
1H NMR (CDCl3) δ(ppm): 1.45 (9H, d, J = 9.8 Hz), 1.72-1.77 (2H, m), 1.84-1.91 (2H, m), 3.18-3.27 (2H, m), 4.03 (2H, t, J = 6.1 Hz), 4.64 (1H, s), 6.70 (1H, td, J = 7.6, 1.5 Hz), 6.80 (1H, dd, J = 8.1, 1.2 Hz), 7.28-7.30 (1H, m), 7.76 (1H, dd, J = 7.8, 2.0 Hz). Step 20 (a): Production of tert-butyl [4- (2-iodophenoxy) butyl] carbamate In the same manner as in Step 19 (a), 2-iodophenol (1.5 g, 6.8 mmol), tetrahydrofuran (20 mL), tert-butyl [2- (2-hydroxyethoxy) ethyl] carbamate (reference: Bioorganic and Medicinal Chemistry, 2009, vol. 17, p. 2536-2543; 1.9 g, 10 mmol) and (tributylphosphoranylidene) acetonitrile (2.7 mL, 10 mmol) was used to give the title compound (3.1 g, 8.0 mmol, 100%) as an oil.
1 H NMR (CDCl 3 ) δ (ppm): 1.45 (9H, d, J = 9.8 Hz), 1.72-1.77 (2H, m), 1.84-1.91 (2H, m), 3.18-3.27 (2H, m) , 4.03 (2H, t, J = 6.1 Hz), 4.64 (1H, s), 6.70 (1H, td, J = 7.6, 1.5 Hz), 6.80 (1H, dd, J = 8.1, 1.2 Hz), 7.28- 7.30 (1H, m), 7.76 (1H, dd, J = 7.8, 2.0 Hz).
工程20(b)：tert-ブチル　{4-[2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェノキシ]エトキシ}エチル)カルバメートの製造
工程19(b)と同様にして、工程20(a)で得られた化合物(3.1g, 8.0mmol)、トルエン(30mL)、4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン(1.8g, 14mmol)、テトラキス(トリフェニルホスフィン)パラジウム(470mg, 0.40mmol)、トリエチルアミン(4.5mL, 32mmol)を用いて、標記化合物(1.0g, 2.5mmol, 31%) を油状物質として得た。
1H NMR (CDCl3) δ(ppm): 1.32 (12H, s), 1.39 (9H, s), 1.71-1.89 (4H, m), 6.81 (1H, d, J = 8.3 Hz), 6.89-6.93 (1H, m), 7.32-7.38 (1H, m), 7.65 (1H, dd, J = 7.3, 2.0 Hz). Step 20 (b): Production step 19 of tert-butyl {4- [2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenoxy] ethoxy} ethyl) carbamate In the same manner as in (b), the compound obtained in Step 20 (a) (3.1 g, 8.0 mmol), toluene (30 mL), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane ( The title compound (1.0 g, 2.5 mmol, 31%) was obtained as an oily substance using 1.8 g, 14 mmol), tetrakis (triphenylphosphine) palladium (470 mg, 0.40 mmol), and triethylamine (4.5 mL, 32 mmol).
1 H NMR (CDCl 3 ) δ (ppm): 1.32 (12H, s), 1.39 (9H, s), 1.71-1.89 (4H, m), 6.81 (1H, d, J = 8.3 Hz), 6.89-6.93 (1H, m), 7.32-7.38 (1H, m), 7.65 (1H, dd, J = 7.3, 2.0 Hz).
工程20(c)：エチル　(4-{[7-(2-{4-[(tert-ブトキシカルボニル)アミノ]ブトキシ}フェニル)チエノ[2,3-d]ピリダジン-4-イル]アミノ}-3-フルオロフェニル)アセテートの製造
工程5(b)と同様にして、工程10(a)で得られた化合物(350mg, 0.96mmol)、実施例20(b)で得られた化合物(1.0g, 2.5mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)・ジクロロメタン錯体(250mg, 0.31mmol)、リン酸カリウム・n-水和物(2.5g, 3.0mmol)、1,2-ジメトキシエタン(30ml)、水(0.5mL)を用いて、標記化合物(330mg, 0.55mmol, 57%)を油状物質として得た。
LCMS (ES): m/z 595 [M+H]+.
1H NMR (CDCl3) δ(ppm): 1.24 (3H, t, J = 7.0 Hz), 1.30-1.37 (2H, m), 1.37 (9H, s), 1.50-1.61 (2H, m), 2.90-2.97 (2H, m), 3.58 (2H, s), 3.99 (2H, t, J = 6.3 Hz), 4.15 (2H, q, J = 7.0 Hz), 7.01-7.11 (4H, m), 7.41-7.46 (2H, m), 7.59 (1H, dd, J = 7.6, 1.7 Hz), 7.77 (1H, d, J = 5.4 Hz), 8.77 (1H, t, J = 8.8 Hz). Step 20 (c): Ethyl (4-{[7- (2- {4-[(tert-butoxycarbonyl) amino] butoxy} phenyl) thieno [2,3-d] pyridazin-4-yl] amino}- 3-Fluorophenyl) acetate In the same manner as in Step 5 (b), the compound obtained in Step 10 (a) (350 mg, 0.96 mmol), the compound obtained in Example 20 (b) (1.0 g, 2.5 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) · dichloromethane complex (250 mg, 0.31 mmol), potassium phosphate · n-hydrate (2.5 g, 3.0 mmol), The title compound (330 mg, 0.55 mmol, 57%) was obtained as an oily substance using 1,2-dimethoxyethane (30 ml) and water (0.5 mL).
LCMS (ES): m / z 595 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.24 (3H, t, J = 7.0 Hz), 1.30-1.37 (2H, m), 1.37 (9H, s), 1.50-1.61 (2H, m), 2.90 -2.97 (2H, m), 3.58 (2H, s), 3.99 (2H, t, J = 6.3 Hz), 4.15 (2H, q, J = 7.0 Hz), 7.01-7.11 (4H, m), 7.41- 7.46 (2H, m), 7.59 (1H, dd, J = 7.6, 1.7 Hz), 7.77 (1H, d, J = 5.4 Hz), 8.77 (1H, t, J = 8.8 Hz).
工程20(d)：tert-ブチル　{4-[2-(4-{[4-(2-アミノ-2-オキソエチル）-2-フルオロフェニル]アミノ}チエノ[2,3-d]ピリダジン-7-イル)フェノキシ]ブチル}カルバメートの製造
工程3(c)と同様にして、工程20(c)で得られた化合物(100mg, 0.17mmol)、1規定 水酸化ナトリウム水溶液(1.0mL)、メタノール(5mL)、2規定アンモニア・イソプロパノール溶液(0.20mL, 0.40mmol)、O-(7-アザ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ホスフェート(150mg, 0.39mmol)、N,N-ジイソプロピルエチルアミン(0.070mL, 0.39mmol)、N,N-ジメチルホルムアミド(5mL)を用いて、標記化合物(120mg, 0.21mmol, 79%)を固体として得た。
LCMS (ES): m/z 566 [M+H]+.
1H NMR (CD3OD) δ(ppm):1.26-1.33 (2H, m), 1.36 (9H, s), 1.52-1.59 (2H, m), 2.84 (2H, t, J = 6.6 Hz), 3.52 (2H, s), 4.01 (2H, t, J = 6.3 Hz), 7.07 (1H, t, J = 7.1 Hz), 7.11-7.20 (3H, m), 7.42 (1H, dd, J = 7.6, 1.7 Hz), 7.45-7.49 (1H, m), 7.82-7.86 (2H, m), 8.00 (1H, d, J = 5.4 Hz). Step 20 (d): tert-butyl {4- [2- (4-{[4- (2-amino-2-oxoethyl) -2-fluorophenyl] amino} thieno [2,3-d] pyridazine-7 -Yl) phenoxy] butyl} carbamate In the same manner as in Step 3 (c), the compound obtained in Step 20 (c) (100 mg, 0.17 mmol), 1N aqueous sodium hydroxide solution (1.0 mL), methanol ( 5 mL), 2 N ammonia / isopropanol solution (0.20 mL, 0.40 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (150 mg , 0.39 mmol), N, N-diisopropylethylamine (0.070 mL, 0.39 mmol) and N, N-dimethylformamide (5 mL) were used to obtain the title compound (120 mg, 0.21 mmol, 79%) as a solid.
LCMS (ES): m / z 566 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 1.26-1.33 (2H, m), 1.36 (9H, s), 1.52-1.59 (2H, m), 2.84 (2H, t, J = 6.6 Hz), 3.52 (2H, s), 4.01 (2H, t, J = 6.3 Hz), 7.07 (1H, t, J = 7.1 Hz), 7.11-7.20 (3H, m), 7.42 (1H, dd, J = 7.6, 1.7 Hz), 7.45-7.49 (1H, m), 7.82-7.86 (2H, m), 8.00 (1H, d, J = 5.4 Hz).
（実施例２１）
2-[3-({7-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)アゼチジン-1-イル]-2-オキソアセタミド (Example 21)
2- [3-({7- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) azetidin-1-yl] -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
工程21(a)：4-クロロ-7-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジンの製造
工程3(a)と同様にして、参考例3の化合物(11.6g, 44.2mmol) 、1-ブロモ-2-メトキシエタン(9.22g, 66.4mmol)、水素化ナトリウム(1.95g, 48.7mmol）、N,N-ジメチルホルムアミド(140mL)を用いて、標記化合物(9.24g, 28.8mmol, 65%) を固体として得た。
LCMS (ES): m/z 321 [M+H]+.
1H NMR (CDCl3) δ(ppm): 3.17 (3H, s), 3.53 (2H, t, J = 4.9 Hz), 4.17 (2H, t, J = 4.9 Hz), 7.11 (1H, d, J = 7.8 Hz), 7.16 (1H, td, J = 7.5, 0.9 Hz), 7.26 (2H, s), 7.49-7.54 (1H, m), 7.60-7.63 (2H, m), 7.90 (1H, d, J = 5.5 Hz). Step 21 (a): Production of 4-chloro-7- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazine In the same manner as in Step 3 (a), the compound of Reference Example 3 ( 11.6 g, 44.2 mmol), 1-bromo-2-methoxyethane (9.22 g, 66.4 mmol), sodium hydride (1.95 g, 48.7 mmol), N, N-dimethylformamide (140 mL), and the title compound ( 9.24 g, 28.8 mmol, 65%) was obtained as a solid.
LCMS (ES): m / z 321 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 3.17 (3H, s), 3.53 (2H, t, J = 4.9 Hz), 4.17 (2H, t, J = 4.9 Hz), 7.11 (1H, d, J = 7.8 Hz), 7.16 (1H, td, J = 7.5, 0.9 Hz), 7.26 (2H, s), 7.49-7.54 (1H, m), 7.60-7.63 (2H, m), 7.90 (1H, d, J = 5.5 Hz).
工程21(b)：tert-ブチル　3-({7-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)アゼチジン-1-カルボキシレートの製造
工程21(a)で得られた化合物(0.30g, 0.94mmol)およびtert-ブチル　3-アミノアゼチジン-1-カルボキシレート(0.32g, 1.9mmol)の混合物を120℃で2時間攪拌した。得られた混合物をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝50/50-0/100(v/v)］にて精製し、標記化合物(0.35g, 0.76mmol, 49%) を固体として得た。
LCMS (ES): m/z 457 [M+H]+.
1H NMR (CDCl3) δ: 1.46 (9H, s), 3.17 (3H, s), 3.53 (2H, t, J = 2.0 Hz), 3.92 (2H, dd, J = 9.4, 4.7 Hz), 4.14 (2H, t, J = 5.5 Hz), 4.48 (2H, dd, J = 9.4, 7.2 Hz), 5.00-5.09 (1H, m), 5.16 (1H, d, J = 5.9 Hz), 7.07 (1H, dd, J = 8.2, 0.8 Hz), 7.09-7.14 (1H, m), 7.36 (1H, d, J = 5.5 Hz), 7.43-7.48 (1H, m), 7.60 (1H, dd, J = 7.8, 1.8 Hz), 7.73 (1H, d, J = 5.5 Hz). Step 21 (b): Preparation of tert-butyl 3-({7- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) azetidine-1-carboxylate A mixture of the compound obtained in Step 21 (a) (0.30 g, 0.94 mmol) and tert-butyl 3-aminoazetidine-1-carboxylate (0.32 g, 1.9 mmol) was stirred at 120 ° C. for 2 hours. The resulting mixture was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100 (v / v)] to give the title compound (0.35 g, 0.76 mmol, 49%) as a solid Got as.
LCMS (ES): m / z 457 [M + H] + .
1H NMR (CDCl 3 ) δ: 1.46 (9H, s), 3.17 (3H, s), 3.53 (2H, t, J = 2.0 Hz), 3.92 (2H, dd, J = 9.4, 4.7 Hz), 4.14 ( 2H, t, J = 5.5 Hz), 4.48 (2H, dd, J = 9.4, 7.2 Hz), 5.00-5.09 (1H, m), 5.16 (1H, d, J = 5.9 Hz), 7.07 (1H, dd , J = 8.2, 0.8 Hz), 7.09-7.14 (1H, m), 7.36 (1H, d, J = 5.5 Hz), 7.43-7.48 (1H, m), 7.60 (1H, dd, J = 7.8, 1.8 Hz), 7.73 (1H, d, J = 5.5 Hz).
工程21(c)：2-[3-({7-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)アゼチジン-1-イル]-2-オキソアセタミドの製造
工程5(c)と同様にして、工程21(b)で得られた化合物(0.050g, 0.11mmol)、4規定塩酸-1,4-ジオキサン溶液(0.5mL)、オキサミン酸(0.0098g, 0.11mmol)、O-(7-アザ-1H-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　ヘキサフルオロホスフェート(0.046g, 0.12mmol) およびトリエチルアミン(0.046mL, 0.33mmol) を用いて、標記化合物(0.007g, 0.016mmol, 15%) を固体として得た。
LCMS (ES): m/z 428 [M+H]+.
1H NMR (DMSO-D6) δ: 3.04 (3H, s), 3.44-3.48 (2H, m), 4.01 (1H, dd, J = 10.6, 4.7 Hz), 4.11-4.17 (2H, m), 4.39-4.46 (1H, m), 4.50 (1H, dd, J = 10.6, 4.7 Hz), 4.83-5.00 (2H, m), 7.10 (1H, t, J = 7.4 Hz), 7.22 (1H, d, J = 8.2 Hz), 7.42 (1H, dd, J = 7.8, 1.8 Hz), 7.45-7.51 (1H, m), 7.71 (1H, br s), 7.81 (1H, d, J = 5.1 Hz), 7.88 (1H, d, J = 5.9 Hz), 8.02 (1H, s), 8.10 (1H, d, J = 5.1 Hz). Step 21 (c): 2- [3-({7- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) azetidin-1-yl] -2 -Oxoacetamide production In the same manner as in Step 5 (c), the compound obtained in Step 21 (b) (0.050 g, 0.11 mmol), 4N hydrochloric acid-1,4-dioxane solution (0.5 mL), oxamic acid ( 0.0098g, 0.11mmol), O- (7-aza-1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (0.046g, 0.12mmol) and triethylamine (0.046 mL, 0.33 mmol) was used to obtain the title compound (0.007 g, 0.016 mmol, 15%) as a solid.
LCMS (ES): m / z 428 [M + H] + .
1H NMR (DMSO-D6) δ: 3.04 (3H, s), 3.44-3.48 (2H, m), 4.01 (1H, dd, J = 10.6, 4.7 Hz), 4.11-4.17 (2H, m), 4.39- 4.46 (1H, m), 4.50 (1H, dd, J = 10.6, 4.7 Hz), 4.83-5.00 (2H, m), 7.10 (1H, t, J = 7.4 Hz), 7.22 (1H, d, J = 8.2 Hz), 7.42 (1H, dd, J = 7.8, 1.8 Hz), 7.45-7.51 (1H, m), 7.71 (1H, br s), 7.81 (1H, d, J = 5.1 Hz), 7.88 (1H , d, J = 5.9 Hz), 8.02 (1H, s), 8.10 (1H, d, J = 5.1 Hz).
（実施例２２）
2-{3-フルオロ-4-[(7-{2-[(2-メトキシエチル)アミノ]フェニル}チエノ[2,3-d]ピリダジン-4-イル)アミノ]フェニル}アセタミド (Example 22)
2- {3-Fluoro-4-[(7- {2-[(2-methoxyethyl) amino] phenyl} thieno [2,3-d] pyridazin-4-yl) amino] phenyl} acetamide
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
工程22(a)：n-ブチル　{3-フルオロ-4-[(7-{2-[(2-メトキシエチル)アミノ]フェニル}チエノ[2,3-d]ピリダジン-4-イル)アミノ]フェニル}アセテートの製造
工程5(b)と同様にして、工程19(b)で得られた化合物(200mg, 0.50mmol)、参考例2の化合物(280mg, 1.0mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)・ジクロロメタン錯体 (40mg, 0.050mmol)、リン酸カリウム・n-水和物(400mg, 1.5mmol)、1,2-ジメトキシエタン(20ml)、水(0.5mL)を用いて、標記化合物(120mg, 0.24mmol, 47%)を固体として得た。
LCMS (ES): m/z 509 [M+H]+.
1H NMR (CDCl3) δ(ppm): 0.90 (3H, t, J = 7.8 Hz), 1.31-1.38 (2H, m), 1.57-1.63 (2H, m), 3.33 (3H, s), 3.55-3.60 (4H, m), 4.09 (2H, t, J = 7.3 Hz), 6.80 (1H, t, J = 7.8 Hz), 6.84 (1H, d, J = 7.8 Hz), 6.94-6.96 (1H, m), 7.08-7.14 (1H, m), 7.30-7.34 (1H, m), 7.45 (1H, d, J = 5.4 Hz), 7.69 (1H, dd, J = 7.8, 1.5 Hz), 7.81 (1H, d, J = 5.4 Hz), 8.60 (1H, t, J= 8.5 Hz). Step 22 (a): n-butyl {3-fluoro-4-[(7- {2-[(2-methoxyethyl) amino] phenyl} thieno [2,3-d] pyridazin-4-yl) amino] In the same manner as in production step 5 (b) of phenyl} acetate, the compound (200 mg, 0.50 mmol) obtained in step 19 (b), the compound of Reference Example 2 (280 mg, 1.0 mmol), [1,1′- Bis (diphenylphosphino) ferrocene] dichloropalladium (II) / dichloromethane complex (40 mg, 0.050 mmol), potassium phosphate / n-hydrate (400 mg, 1.5 mmol), 1,2-dimethoxyethane (20 ml), water (0.5 mL) was used to give the title compound (120 mg, 0.24 mmol, 47%) as a solid.
LCMS (ES): m / z 509 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 0.90 (3H, t, J = 7.8 Hz), 1.31-1.38 (2H, m), 1.57-1.63 (2H, m), 3.33 (3H, s), 3.55 -3.60 (4H, m), 4.09 (2H, t, J = 7.3 Hz), 6.80 (1H, t, J = 7.8 Hz), 6.84 (1H, d, J = 7.8 Hz), 6.94-6.96 (1H, m), 7.08-7.14 (1H, m), 7.30-7.34 (1H, m), 7.45 (1H, d, J = 5.4 Hz), 7.69 (1H, dd, J = 7.8, 1.5 Hz), 7.81 (1H , d, J = 5.4 Hz), 8.60 (1H, t, J = 8.5 Hz).
工程22(b)：2-{3-フルオロ-4-[(7-{2-[(2-メトキシエチル)アミノ]フェニル}チエノ[2,3-d]ピリダジン-4-イル)アミノ]フェニル}アセタミドの製造
工程3(c)と同様にして、工程22(a)で得られた化合物(164mg, 0.26mmol)、1規定 水酸化ナトリウム水溶液(2.0mL)、メタノール(10mL)、2規定アンモニア・イソプロパノール溶液(0.26mL, 0.52mmol)、O-(7-アザ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ホスフェート(200mg, 0.52mmol)、N,N-ジイソプロピルエチルアミン(0.088mL, 0.52mmol)、N,N-ジメチルホルムアミド(10mL)を用いて、標記化合物(120mg, 0.21mmol, 79%)を固体として得た。
LCMS (ES): m/z 452 [M+H]+.
1H NMR (CD3OD) δ(ppm): 3.23-3.29 (2H, m), 3.23 (3H, s), 3.49 (2H, t, J = 5.4 Hz), 3.53 (2H, s), 6.79 (1H, t, J=7.8 Hz), 6.86 (1H, d, J=8.3 Hz), 7.14 (1H, d, J=8.3 Hz), 7.18 (1H, d, J=11.2 Hz), 7.29-7.32 (1H, m), 7.53 (1H, dd, J=7.8, 1.5 Hz), 7.74 (1H, t, J=8.3 Hz), 7.87 (1H, q, J=2.9 Hz), 8.05 (1H, t, J=4.9 Hz). Step 22 (b): 2- {3-Fluoro-4-[(7- {2-[(2-methoxyethyl) amino] phenyl} thieno [2,3-d] pyridazin-4-yl) amino] phenyl } In the same manner as in production step 3 (c) of acetamide, the compound obtained in step 22 (a) (164 mg, 0.26 mmol), 1 N aqueous sodium hydroxide (2.0 mL), methanol (10 mL), 2 N ammonia Isopropanol solution (0.26 mL, 0.52 mmol), O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (200 mg, 0.52 mmol), N , N-diisopropylethylamine (0.088 mL, 0.52 mmol) and N, N-dimethylformamide (10 mL) were used to obtain the title compound (120 mg, 0.21 mmol, 79%) as a solid.
LCMS (ES): m / z 452 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 3.23-3.29 (2H, m), 3.23 (3H, s), 3.49 (2H, t, J = 5.4 Hz), 3.53 (2H, s), 6.79 ( 1H, t, J = 7.8 Hz), 6.86 (1H, d, J = 8.3 Hz), 7.14 (1H, d, J = 8.3 Hz), 7.18 (1H, d, J = 11.2 Hz), 7.29-7.32 ( 1H, m), 7.53 (1H, dd, J = 7.8, 1.5 Hz), 7.74 (1H, t, J = 8.3 Hz), 7.87 (1H, q, J = 2.9 Hz), 8.05 (1H, t, J = 4.9 Hz).
（実施例２３）
2-[3-フルオロ-4-({7-[2-(3-メトキシプロピル)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)フェニル]アセタミド (Example 23)
2- [3-Fluoro-4-({7- [2- (3-methoxypropyl) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) phenyl] acetamide
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
工程23(a)：2-[2-(3-メトキシプロピル)フェニル]-4,4,5,5-テトラメチル-1,3,2-ジオキサボロランの製造
1-ブロモ-2-(3-メトキシプロピル)ベンゼン(参考文献：ACS Medicinal Chemistry Letters，2016, vol. 7，p. 1097-1101，590mg, 2.6mmol)をジメチルスルホキシド(20mL)に溶解し、ビス（ピナコラト）ジボラン(840mg, 3.3mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)・ジクロロメタン錯体(250mg, 0.26mmol)、酢酸カリウム(880mg, 9.0mmol)を加え、90℃で5時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。減圧下溶媒を留去し、粗製の標記化合物(720mg)を油状物質として得た。得られた化合物は精製することなく、次の反応に使用した。 Step 23 (a): Preparation of 2- [2- (3-methoxypropyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane
1-Bromo-2- (3-methoxypropyl) benzene (Reference: ACS Medicinal Chemistry Letters, 2016, vol. 7, p. 1097-1101, 590 mg, 2.6 mmol) is dissolved in dimethyl sulfoxide (20 mL) Add (pinacolato) diborane (840mg, 3.3mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane complex (250mg, 0.26mmol), potassium acetate (880mg, 9.0mmol) And stirred at 90 ° C. for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. The solvent was distilled off under reduced pressure to obtain the crude title compound (720 mg) as an oily substance. The obtained compound was used for the next reaction without purification.
工程23(b)：エチル　[3-フルオロ-4-({7-[2-(3-メトキシプロピル)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)フェニル]アセテートの製造
工程5(b)と同様にして、工程10(a)で得られた化合物(500mg, 1.37mmol)、工程23(a)で得られた化合物(707mg, 2.56mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)・ジクロロメタン錯体(110mg, 0.137mmol)、リン酸カリウム・n-水和物(1.1g, 1.37mmol)、1,2-ジメトキシエタン(20mL)、水(1mL)を用いて、標記化合物(100mg, 0.209mmol, 15%)を油状物質として得た。
LCMS (ES): m/z 480 [M+H]+. Step 23 (b): Preparation of ethyl [3-fluoro-4-({7- [2- (3-methoxypropyl) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) phenyl] acetate In the same manner as in Step 5 (b), the compound obtained in Step 10 (a) (500 mg, 1.37 mmol), the compound obtained in Step 23 (a) (707 mg, 2.56 mmol), [1,1′- Bis (diphenylphosphino) ferrocene] dichloropalladium (II) dichloromethane complex (110 mg, 0.137 mmol), potassium phosphate n-hydrate (1.1 g, 1.37 mmol), 1,2-dimethoxyethane (20 mL), Water (1 mL) was used to give the title compound (100 mg, 0.209 mmol, 15%) as an oil.
LCMS (ES): m / z 480 [M + H] + .
工程23(c)：2-[3-フルオロ-4-({7-[2-(3-メトキシプロピル)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)フェニル]アセタミドの製造
工程3(c)と同様にして、工程23(b)で得られた化合物(100mg, 0.21mmol)、1規定水酸化ナトリウム水溶液 (1.0mL)、メタノール(10mL)、2規定アンモニア・イソプロパノール溶液(0.420mL, 0.84mmol)、(ジメチルアミノ)-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ）メタンイミニウム　ヘキサフルオロホスフェート(160mg, 0.42mmol)、N,N-ジメチルホルムアミド(10mL)を用いて、標記化合物(30mg, 0.067mmol, 32%)を固体として得た。
LCMS (ES): m/z 451 [M+H]+.
1H NMR (CD3OD) δ(ppm): 1.56-1.63 (2H, m), 2.61 (2H, t, J= 7.8 Hz), 3.07 (3H, s), 3.12 (2H, q, J= 6.3 Hz), 3.52 (2H, s), 7.13-7.19 (2H, m), 7.32-7.36 (1H, m), 7.38-7.48 (3H, m), 7.80 (1H, t, J = 8.2 Hz), 7.88 (1H, d, J = 5.5 Hz), 8.04 (1H, d, J = 5.5 Hz). Step 23 (c): 2- [3-Fluoro-4-({7- [2- (3-methoxypropyl) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) phenyl] acetamide In the same manner as in production step 3 (c), the compound obtained in step 23 (b) (100 mg, 0.21 mmol), 1N aqueous sodium hydroxide solution (1.0 mL), methanol (10 mL), 2N ammonia / isopropanol solution (0.420 mL, 0.84 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methaninium hexafluorophosphate (160 mg , 0.42 mmol) and N, N-dimethylformamide (10 mL) to give the title compound (30 mg, 0.067 mmol, 32%) as a solid.
LCMS (ES): m / z 451 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 1.56-1.63 (2H, m), 2.61 (2H, t, J = 7.8 Hz), 3.07 (3H, s), 3.12 (2H, q, J = 6.3 Hz), 3.52 (2H, s), 7.13-7.19 (2H, m), 7.32-7.36 (1H, m), 7.38-7.48 (3H, m), 7.80 (1H, t, J = 8.2 Hz), 7.88 (1H, d, J = 5.5 Hz), 8.04 (1H, d, J = 5.5 Hz).
（実施例２４）
2-[(3aRS,6aRS)-1-{7-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル｝ヘキサヒドロピロロ[3,4-b]ピロロ-5(1H)-イル]-2-オキソアセタミド　塩酸塩 (Example 24)
2-[(3aRS, 6aRS) -1- {7- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} hexahydropyrrolo [3,4-b] pyrrolo -5 (1H) -yl] -2-oxoacetamide hydrochloride
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
工程24(a)：tert-ブチル　(3aRS,6aRS)-5-[アミノ(オキソ)アセチル]ヘキサヒドロピロロ[3,4-b]ピロール-1(2H)-カルボキシレートの製造
工程5(c)と同様にして、tert-ブチル　(3aRS,6aRS)-ヘキサヒドロピロロ[3,4-b]ピロール-1(2H)-カルボキシレート　塩酸塩(0.302g, 1.21mmol)、オキサミン酸(0.119g, 1.34mol)、(ジメチルアミノ)-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ)メタンイミニウム　ヘキサフルオロホスフェート (0.508g, 1.34mmol)およびトリエチルアミン(0.508mL, 3.64mmol)を用いて、標記化合物(0.145g, 0.512mmol, 42%)を油状物質として得た。
1H NMR (CDCl3) δ (ppm) : 1.47 (9H, s), 1.73-1.81 (1H, m), 1.98-2.07 (1H, m), 2.85-3.05 (1H, m), 3.39-3.64 (2H, m), 3.73-3.94 (2H, m), 4.07-4.40 (2H, m), 5.44 (1H, br s). Step 24 (a): Production of tert-butyl (3aRS, 6aRS) -5- [amino (oxo) acetyl] hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -carboxylate 5 (c) Tert-butyl (3aRS, 6aRS) -hexahydropyrrolo [3,4-b] pyrrole-1 (2H) -carboxylate hydrochloride (0.302 g, 1.21 mmol), oxamic acid (0.119 g, 1.34) mol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methaniminium hexafluorophosphate (0.508 g, 1.34 mmol) And triethylamine (0.508 mL, 3.64 mmol) was used to give the title compound (0.145 g, 0.512 mmol, 42%) as an oil.
1 H NMR (CDCl 3 ) δ (ppm): 1.47 (9H, s), 1.73-1.81 (1H, m), 1.98-2.07 (1H, m), 2.85-3.05 (1H, m), 3.39-3.64 ( 2H, m), 3.73-3.94 (2H, m), 4.07-4.40 (2H, m), 5.44 (1H, br s).
工程24(b)：2-[(3aRS,6aRS)-1-{7-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}ヘキサヒドロピロロ[3,4-b]ピロロ-5(1H)-イル]-2-オキソアセタミドの製造
工程24(a)で得られた化合物(0.144g, 0.508mmol)の1,4-ジオキサン(1mL)溶液に、室温にて4規定塩酸-1,4-ジオキサン溶液(2mL)を加え、室温で1時間攪拌した。反応液を減圧濃縮して得られた残渣を、4-クロロ-7-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン(0.163g, 0.508mmol)およびジイソプロピルエチルアミン(0.259mL, 1.52mmol)と混合し、140℃で2時間攪拌した。得られた混合物をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/メタノール＝10/1(V/V)］にて精製し、標記化合物(0.110g, 0.235mmol, 46%)を固体として得た。
1H NMR (CDCl3) δ (ppm) : 2.05-2.15 (1H, m), 2.21-2.31 (1H, m), 3.19 (3H, s), 3.51-4.45 (10H, m), 5.06-5.23 (1H, m), 5.55 (1H, br s), 7.04-7.18 (3H, m), 7.36 (1H, br s), 7.41-7.47 (1H, m), 7.57-7.67 (3H, m). Step 24 (b): 2-[(3aRS, 6aRS) -1- {7- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} hexahydropyrrolo [3 , 4-b] pyrrolo-5 (1H) -yl] -2-oxoacetamide in a solution of compound (0.144 g, 0.508 mmol) obtained in Step 24 (a) in 1,4-dioxane (1 mL) at room temperature 4N hydrochloric acid-1,4-dioxane solution (2 mL) was added and stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction solution under reduced pressure was subjected to 4-chloro-7- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazine (0.163 g, 0.508 mmol) and diisopropylethylamine ( 0.259 mL, 1.52 mmol) and stirred at 140 ° C. for 2 hours. The resulting mixture was purified by silica gel column chromatography [elution solvent: ethyl acetate / methanol = 10/1 (V / V)] to obtain the title compound (0.110 g, 0.235 mmol, 46%) as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 2.05-2.15 (1H, m), 2.21-2.31 (1H, m), 3.19 (3H, s), 3.51-4.45 (10H, m), 5.06-5.23 ( 1H, m), 5.55 (1H, br s), 7.04-7.18 (3H, m), 7.36 (1H, br s), 7.41-7.47 (1H, m), 7.57-7.67 (3H, m).
工程24(c)：2-[(3aRS,6aRS)-1-{7-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}ヘキサヒドロピロロ[3,4-b]ピロロ-5(1H)-イル]-2-オキソアセタミド　塩酸塩の製造
工程24(b)で得られた化合物(0.083g, 0.178mmol)のエタノール(1mL)溶液に、室温にて1規定塩酸水溶液(0.355mL)を加え、室温で1時間攪拌した。反応液を減圧濃縮して得られた残渣にジエチルエーテルを加え、析出物をろ取して標記化合物(0.081g)を固体として得た。
1H NMR (CD3OD) δ (ppm) : 2.11-2.24 (1H, m), 2.31-2.43 (1H, m), 3.17 (3H, s), 4.95-4.95 (11H, m), 4.93-5.09 (1H, m), 7.16-7.33 (2H, m), 7.55-7.67 (2H, m), 8.05-8.15 (1H, m), 8.28-8.42 (1H, m). Step 24 (c): 2-[(3aRS, 6aRS) -1- {7- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} hexahydropyrrolo [3 , 4-b] pyrrolo-5 (1H) -yl] -2-oxoacetamide hydrochloride Preparation of the compound (0.083 g, 0.178 mmol) obtained in step 24 (b) in ethanol (1 mL) at room temperature 1N Aqueous hydrochloric acid solution (0.355 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the resulting residue, and the precipitate was collected by filtration to give the title compound (0.081 g) as a solid.
1 H NMR (CD 3 OD) δ (ppm): 2.11-2.24 (1H, m), 2.31-2.43 (1H, m), 3.17 (3H, s), 4.95-4.95 (11H, m), 4.93-5.09 (1H, m), 7.16-7.33 (2H, m), 7.55-7.67 (2H, m), 8.05-8.15 (1H, m), 8.28-8.42 (1H, m).
（実施例２５）
2-{3-フルオロ-4-[(4-{2-[(2-メトキシエチル)アミノ]フェニル}フロ[2,3-d]ピリダジン-7-イル)アミノ]フェニル}アセタミド (Example 25)
2- {3-Fluoro-4-[(4- {2-[(2-methoxyethyl) amino] phenyl} furo [2,3-d] pyridazin-7-yl) amino] phenyl} acetamide
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
工程25(a)：2-(7-クロロフロ[2,3-d]ピリダジン-4-イル)-N-(2-メトキシエチル)アニリンの製造
4,7-ジクロロフロ[2,3-d]ピリダジン(312mg, 1.65mmol)を1,4-ジオキサン(10mL)に溶解し、反応液に水(5ml)、N-(2-メトキシエチル)-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン(550mg, 2.0mmol)、テトラキス(トリフェニルホスフィン)パラジウム(200mg, 0.168mmol)、炭酸セシウム(1.6g, 4.95mmol)を加え、90℃で5時間攪拌した。反応液を室温まで冷却した後、水を加え、酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝100/0-70/30(V/V)］にて精製し、標記化合物 (460mg, 1.51mmol, 76%) を油状物質として得た。
LCMS (ES): m/z 304 [M+H]+.　 Step 25 (a): Preparation of 2- (7-chlorofuro [2,3-d] pyridazin-4-yl) -N- (2-methoxyethyl) aniline
4,7-dichlorofuro [2,3-d] pyridazine (312 mg, 1.65 mmol) was dissolved in 1,4-dioxane (10 mL), and water (5 ml), N- (2-methoxyethyl) -2 was added to the reaction solution. -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (550 mg, 2.0 mmol), tetrakis (triphenylphosphine) palladium (200 mg, 0.168 mmol), cesium carbonate ( 1.6 g, 4.95 mmol) was added, and the mixture was stirred at 90 ° C. for 5 hours. The reaction solution was cooled to room temperature, water was added, the mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-70 / 30 (V / V)] to give the title compound (460 mg, 1.51 mmol, 76%) was obtained as an oil.
LCMS (ES): m / z 304 [M + H] + .
工程25(b)：エチル　{3-フルオロ-4-[(4-{2-[(2-メトキシエチル）アミノ]フェニル}フロ[2,3-d]ピリダジン-7-イル)アミノ]フェニル}アセテートの製造
工程25(a)で得られた化合物(460mg, 1.51mmol) をエタノール(20mL)に溶解し、エチル(4-アミノ-3-フルオロフェニル)アセテート(450mg, 2.3mmol)、トリフルオロ酢酸(0.12mL, 1.51mmol)を加え、100℃で5時間攪拌した。反応液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝100/0-50/50(V/V)］にて精製し、標記化合物(440mg, 0.947mmol, 63%)を油状物質として得た。
LCMS (ES): m/z 465 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 1.24 (3H, q, J = 7.3 Hz), 3.38 (3H, s), 3.46 (2H, t, J = 6.1 Hz), 3.59 (2H, s), 3.64 (2H, t, J = 6.1 Hz), 4.09 (2H, t, J = 7.3 Hz), 6.71 (1H, d, J = 2.0 Hz), 6.78 (1H, td, J = 7.6, 1.5 Hz), 6.85 (1H, d, J = 8.8 Hz), 7.08-7.14 (2H, m), 7.28-7.32 (1H, m), 7.81 (1H, d, J= 2.4 Hz), 8.04 (1H, dd, J = 7.8, 1.5 Hz), 8.30 (1H, t, J = 8.5 Hz), 8.35 (1H, s). Step 25 (b): ethyl {3-fluoro-4-[(4- {2-[(2-methoxyethyl) amino] phenyl} furo [2,3-d] pyridazin-7-yl) amino] phenyl} Acetate production step 25 (a) compound (460 mg, 1.51 mmol) was dissolved in ethanol (20 mL), ethyl (4-amino-3-fluorophenyl) acetate (450 mg, 2.3 mmol), trifluoroacetic acid (0.12 mL, 1.51 mmol) was added, and the mixture was stirred at 100 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-50 / 50 (V / V)] to give the title compound (440 mg, 0.947 mmol, 63%) as an oil.
LCMS (ES): m / z 465 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.24 (3H, q, J = 7.3 Hz), 3.38 (3H, s), 3.46 (2H, t, J = 6.1 Hz), 3.59 (2H, s), 3.64 (2H, t, J = 6.1 Hz), 4.09 (2H, t, J = 7.3 Hz), 6.71 (1H, d, J = 2.0 Hz), 6.78 (1H, td, J = 7.6, 1.5 Hz), 6.85 (1H, d, J = 8.8 Hz), 7.08-7.14 (2H, m), 7.28-7.32 (1H, m), 7.81 (1H, d, J = 2.4 Hz), 8.04 (1H, dd, J = 7.8, 1.5 Hz), 8.30 (1H, t, J = 8.5 Hz), 8.35 (1H, s).
工程25(c)：2-{3-フルオロ-4-[(4-{2-[(2-メトキシエチル)アミノ]フェニル｝フロ[2,3-d]ピリダジン-7-イル)アミノ]フェニル}アセタミドの製造
工程2(b)と同様にして、工程25(b)で得られた化合物(170 mg, 0.37 mmol)、1規定水酸化ナトリウム水溶液(2.0mL)、メタノール(10mL)、2規定アンモニア・イソプロパノール溶液(0.73mL, 1.46mmol)、(ジメチルアミノ)-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ）メタンイミニウム　ヘキサフルオロホスフェート(280mg, 0.73mmol)、N,N-ジメチルホルムアミド(10mL)を用いて、標記化合物(50mg, 0.115mmol, 31%)を固体として得た。
LCMS (ES): m/z 436 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 3.30 (3H, s), 3.35 (2H, t, J = 5.6 Hz), 3.53 (2H, s), 3.57 (2H, t, J= 5.9 Hz), 6.76 (1H, t, J = 7.6 Hz), 6.85 (1H, d, J = 8.3 Hz), 7.11-7.20 (3H, m), 7.25-7.28 (1H, m), 7.74 (1H, t, J = 8.1 Hz), 7.90 (1H, dd, J = 7.8, 1.5 Hz), 8.06 (1H, d, J = 2.0 Hz). Step 25 (c): 2- {3-Fluoro-4-[(4- {2-[(2-methoxyethyl) amino] phenyl} furo [2,3-d] pyridazin-7-yl) amino] phenyl } In the same manner as in production step 2 (b) of acetamide, the compound obtained in step 25 (b) (170 mg, 0.37 mmol), 1N aqueous sodium hydroxide solution (2.0 mL), methanol (10 mL), 2N Ammonia / isopropanol solution (0.73 mL, 1.46 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methaniminium hexa The title compound (50 mg, 0.115 mmol, 31%) was obtained as a solid using fluorophosphate (280 mg, 0.73 mmol) and N, N-dimethylformamide (10 mL).
LCMS (ES): m / z 436 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 3.30 (3H, s), 3.35 (2H, t, J = 5.6 Hz), 3.53 (2H, s), 3.57 (2H, t, J = 5.9 Hz) , 6.76 (1H, t, J = 7.6 Hz), 6.85 (1H, d, J = 8.3 Hz), 7.11-7.20 (3H, m), 7.25-7.28 (1H, m), 7.74 (1H, t, J = 8.1 Hz), 7.90 (1H, dd, J = 7.8, 1.5 Hz), 8.06 (1H, d, J = 2.0 Hz).
（実施例２６）
2-{3-フルオロ-4-[(7-{4-フルオロ-2-[2-(プロパン-2-イルオキシ)エトキシ]フェニル}-2,3-ジヒドロフロ[2,3-d]ピリダジン-4-イル)アミノ]フェニル}アセタミド (Example 26)
2- {3-Fluoro-4-[(7- {4-fluoro-2- [2- (propan-2-yloxy) ethoxy] phenyl} -2,3-dihydrofuro [2,3-d] pyridazine-4 -Yl) amino] phenyl} acetamide
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
工程26(a)：4-フルオロ-N,2-ジメトキシ-N-メチルベンズアミドの製造
4－フルオロ－2－ヒドロキシ安息香酸(58.9g)をアセトン(500mL)に溶解し、ジメチル硫酸(63.8mL)、炭酸カリウム(93.0g)を加え、70℃で3時間撹拌した。反応液を冷却後、不溶物をろ別し、ろ液を減圧下濃縮した。残渣をメタノール(300mL)、テトラヒドロフラン(200mL) に溶解し、5規定水酸化ナトリウム(96mL)を加え、室温で16時間撹拌した。反応液を減圧下濃縮し、残渣に5規定塩酸(96mL)を加えて中和し、ジクロロメタンで3回抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をジクロロメタン(500mL)に溶解し、室温で撹拌中、オキサリルクロリド(32.5mL)を滴下した。さらにN,N-ジメチルホルムアミド(0.5mL)を加えた。室温で3時間撹拌後、反応液を減圧下濃縮し、さらにトルエンで一度共沸した。N,O-ジメチルヒドロキシルアミン塩酸塩(31.2g)のジクロロメタン(400mL)懸濁液にN,N-ジイソプロピルエチルアミン(121mL)を加えて溶液化し、氷浴下撹拌中、調整した酸クロリドのジクロロメタン(100 mL)溶液を滴下した。滴下終了後、室温で1時間撹拌した。反応液を水に注ぎ、分液した。水層はジクロロメタンでさらに2回抽出し、有機層を無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー [溶出溶媒：ヘキサン/酢酸エチル=90/10-70/30 (v/v)] で精製し、標記化合物(54.7g)を固体として得た。
1H NMR (CDCl3): 3.31 (3H, br s), 3.53 (3H, br s), 3.83 (3H, s), 6.65 (1H, dd, J=2.3, 9.6 Hz), 6.70 (1H, dd, J=2.3, 9.6 Hz), 7.24-7.27 (1H, m). Step 26 (a): Preparation of 4-fluoro-N, 2-dimethoxy-N-methylbenzamide
4-Fluoro-2-hydroxybenzoic acid (58.9 g) was dissolved in acetone (500 mL), dimethyl sulfate (63.8 mL) and potassium carbonate (93.0 g) were added, and the mixture was stirred at 70 ° C. for 3 hours. After cooling the reaction solution, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (300 mL) and tetrahydrofuran (200 mL), 5N sodium hydroxide (96 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, the residue was neutralized with 5N hydrochloric acid (96 mL), and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in dichloromethane (500 mL), and oxalyl chloride (32.5 mL) was added dropwise while stirring at room temperature. Further N, N-dimethylformamide (0.5 mL) was added. After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure and further azeotroped once with toluene. To a suspension of N, O-dimethylhydroxylamine hydrochloride (31.2 g) in dichloromethane (400 mL) was added N, N-diisopropylethylamine (121 mL) to form a solution. While stirring in an ice bath, the adjusted acid chloride in dichloromethane ( 100 mL) solution was added dropwise. After completion of dropping, the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and separated. The aqueous layer was further extracted twice with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-70 / 30 (v / v)] to obtain the title compound (54.7 g) as a solid.
1 H NMR (CDCl 3 ): 3.31 (3H, br s), 3.53 (3H, br s), 3.83 (3H, s), 6.65 (1H, dd, J = 2.3, 9.6 Hz), 6.70 (1H, dd , J = 2.3, 9.6 Hz), 7.24-7.27 (1H, m).
工程26(b)：2-(4-フルオロ-2-メトキシベンゾイル)フラン-3-カルボン酸の製造
フラン-3-カルボン酸(14.5 g)をテトラヒドロフラン(300 mL)に溶解し、ドライアイス－アセトン浴にて冷却中、n-ブチルリチウム(2.6M, 97.6mL)を滴下した。10分間撹拌後、氷浴下30分間撹拌した。反応液を再びドライアイス－アセトン浴で冷却し、実施例26(a)で得られた化合物(22.1g)のテトラヒドロフラン(80mL)溶液を滴下した。10分間撹拌後、氷浴下2時間撹拌した。反応液を水に注ぎ、5規定塩酸を加えて酸性にした後、分液した。水層は酢酸エチルでさらに2回抽出し、有機層を合わせて飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥後、減圧下濃縮し、標記化合物の粗生成物 (34.1g)を得た。
LCMS (ES): m/z 263 [M-H]-. Step 26 (b): Preparation of 2- (4-fluoro-2-methoxybenzoyl) furan-3-carboxylic acid Furan-3-carboxylic acid (14.5 g) was dissolved in tetrahydrofuran (300 mL) and dried ice-acetone While cooling in a bath, n-butyllithium (2.6M, 97.6 mL) was added dropwise. After stirring for 10 minutes, the mixture was stirred for 30 minutes in an ice bath. The reaction solution was cooled again in a dry ice-acetone bath, and a solution of the compound (22.1 g) obtained in Example 26 (a) in tetrahydrofuran (80 mL) was added dropwise. After stirring for 10 minutes, the mixture was stirred for 2 hours in an ice bath. The reaction mixture was poured into water, acidified with 5N hydrochloric acid, and separated. The aqueous layer was further extracted twice with ethyl acetate, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a crude product (34.1 g).
LCMS (ES): m / z 263 [MH] - .
工程26(c)：7-(4-フルオロ-2-メトキシフェニル)フロ[2,3-d]ピリダジン-4(5H)-オンの製造
工程26(b)で得られた化合物(34.1g)をブタノール(400mL)に懸濁し、ヒドラジン一水和物(12.5mL)を加え、140℃で6.5時間撹拌した。反応液を冷却後、減圧下濃縮した。残渣にジエチルエーテルを加えて析出物をろ取し、標記化合物(24.7g)を固体として得た。
1H NMR (DMSO-d6): 3.78 (3H, s), 6.94 (1H, td, J=2.5, 8.5 Hz), 7.14 (1H, dd, J=2.5, 8.5 Hz), 7.16 (1H, d, J=2.0 Hz), 7.46 (1H, dd, J=6.8, 8.5 Hz), 8.17 (1H, d, J=2.0 Hz). Step 26 (c): Preparation of 7- (4-fluoro-2-methoxyphenyl) furo [2,3-d] pyridazin-4 (5H) -one Compound obtained in Step 26 (b) (34.1 g) Was suspended in butanol (400 mL), hydrazine monohydrate (12.5 mL) was added, and the mixture was stirred at 140 ° C. for 6.5 hours. The reaction mixture was cooled and concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitate was collected by filtration to give the title compound (24.7 g) as a solid.
1 H NMR (DMSO-d 6 ): 3.78 (3H, s), 6.94 (1H, td, J = 2.5, 8.5 Hz), 7.14 (1H, dd, J = 2.5, 8.5 Hz), 7.16 (1H, d , J = 2.0 Hz), 7.46 (1H, dd, J = 6.8, 8.5 Hz), 8.17 (1H, d, J = 2.0 Hz).
工程26(d)：4-クロロ-7-(4-フルオロ-2-メトキシフェニル)フロ[2,3-d]ピリダジンの製造
工程26(c)で得られた化合物(24.7g)を1,2-ジクロロエタン(30mL)に懸濁し、オキシ塩化リン(21.7mL)を加え、90℃で4時間撹拌した。反応液を冷却し、氷に注いだ。ここに5規定水酸化ナトリウム水溶液を加えて中和し、ジクロロメタンで3回抽出した。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後、減圧下濃縮した。残渣にジエチルエーテル－ヘキサンを加えて不溶物をろ取し、標記化合物(23.2g)を固体として得た。
LCMS (ES): m/z 279 [M+H]+.
1H NMR (CDCl3): 3.81 (3H, br s), 6.81 (1H, dd, J=2.4, 9.5 Hz), 6.86 (1H, td, J=2.4, 9.5 Hz), 7.00 (1H, d, J=2.4 Hz), 7.64 (1H, dd, J=6.8, 9.5 Hz), 7.87 (1H, d, J=2.4 Hz). Step 26 (d): Production of 4-chloro-7- (4-fluoro-2-methoxyphenyl) furo [2,3-d] pyridazine The compound (24.7 g) obtained in Step 26 (c) was converted to 1, The mixture was suspended in 2-dichloroethane (30 mL), phosphorus oxychloride (21.7 mL) was added, and the mixture was stirred at 90 ° C. for 4 hours. The reaction was cooled and poured onto ice. The mixture was neutralized with 5N aqueous sodium hydroxide solution, and extracted three times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diethyl ether-hexane was added to the residue and the insoluble material was collected by filtration to give the title compound (23.2 g) as a solid.
LCMS (ES): m / z 279 [M + H] + .
1 H NMR (CDCl 3 ): 3.81 (3H, br s), 6.81 (1H, dd, J = 2.4, 9.5 Hz), 6.86 (1H, td, J = 2.4, 9.5 Hz), 7.00 (1H, d, J = 2.4 Hz), 7.64 (1H, dd, J = 6.8, 9.5 Hz), 7.87 (1H, d, J = 2.4 Hz).
工程26(e)：2-(4-クロロフロ[2,3-d]ピリダジン-7-イル)-5-フルオロフェノールの製造
工程26(d)で得られた化合物(23.2g)をジクロロメタン(200mL)に懸濁し、氷浴下撹拌中、三臭化ホウ素(25g)のジクロロメタン(50mL)溶液を滴下した。滴下終了後、室温で4時間撹拌後、反応液に飽和炭酸水素ナトリウム水溶液を加え、室温で3時間撹拌後、一晩静置した。反応液を分液ロートに移し、5規定水酸化ナトリウムを徐々に加えて中和し、ジクロロメタン－メタノールで4回抽出した。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後、減圧下濃縮した。標記化合物の粗生成物 (22.8g)を固体として得た。
LCMS (ES): m/z 265 [M+H]+.
1H NMR (DMSO-d6): 6.72-6.81 (1H, m), 6.84 (1H, dd, J=2.5, 9.0 Hz), 7.10 (1H, d, J=2.0 Hz), 8.10 (1H, d, J=2.0 Hz), 8.54(1H, dd, J=6.3, 9.0 Hz), 13.9 (1H, s). Step 26 (e): Preparation of 2- (4-chlorofuro [2,3-d] pyridazin-7-yl) -5-fluorophenol The compound (23.2 g) obtained in Step 26 (d) was dissolved in dichloromethane (200 mL). And a solution of boron tribromide (25 g) in dichloromethane (50 mL) was added dropwise while stirring in an ice bath. After completion of the dropwise addition, the mixture was stirred at room temperature for 4 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours and allowed to stand overnight. The reaction mixture was transferred to a separatory funnel, neutralized by gradually adding 5N sodium hydroxide, and extracted four times with dichloromethane-methanol. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product of the title compound (22.8 g) was obtained as a solid.
LCMS (ES): m / z 265 [M + H] + .
1 H NMR (DMSO-d 6 ): 6.72-6.81 (1H, m), 6.84 (1H, dd, J = 2.5, 9.0 Hz), 7.10 (1H, d, J = 2.0 Hz), 8.10 (1H, d , J = 2.0 Hz), 8.54 (1H, dd, J = 6.3, 9.0 Hz), 13.9 (1H, s).
工程26(f)：4-クロロ-7-{4-フルオロ-2-[2-(プロパン-2-イルオキシ)エトキシ]フェニル}フロ[2,3-d]ピリダジンの製造
工程26(e)で得られた化合物(22.0g)をジクロロメタン(200mL)－トルエン(200mL)に懸濁し、エチレングリコールモノイソプロピルエーテル(13.0g)、トリフェニルホスフィン(24.0g)を加えて氷浴下撹拌中、ジtert-ブチルアゾジカルボキシレート(21.1g)を徐々に加えた。添加終了後、室温で15時間撹拌した。反応液を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー [溶出溶媒：ヘキサン/酢酸エチル=90/10-65/35(V/V)] で精製し、標記化合物(12.9g)を固体として得た。
LCMS (ES): m/z 351 [M+H]+.
1H NMR (CDCl3): 0.99 (6H, d, J=5.9 Hz), 3.39 (1H, sept, J=5.9 Hz), 3.54 (2H, t, J=4.9 Hz), 4.13 (2H, t, J=4.9 Hz), 6.82-6.88 (2H, m), 6.99 (1H, d, J=2.0 Hz), 7.66 (1H, dd, J=6.6, 8.5 Hz), 7.87 (1H, d, J=2.0 Hz). Step 26 (f): 4-Chloro-7- {4-fluoro-2- [2- (propan-2-yloxy) ethoxy] phenyl} furo [2,3-d] pyridazine in Step 26 (e) The obtained compound (22.0 g) was suspended in dichloromethane (200 mL) -toluene (200 mL), and ethylene glycol monoisopropyl ether (13.0 g) and triphenylphosphine (24.0 g) were added. -Butyl azodicarboxylate (21.1 g) was added slowly. After completion of the addition, the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-65 / 35 (V / V)] to give the title compound (12.9 g) as a solid. It was.
LCMS (ES): m / z 351 [M + H] + .
1 H NMR (CDCl 3 ): 0.99 (6H, d, J = 5.9 Hz), 3.39 (1H, sept, J = 5.9 Hz), 3.54 (2H, t, J = 4.9 Hz), 4.13 (2H, t, J = 4.9 Hz), 6.82-6.88 (2H, m), 6.99 (1H, d, J = 2.0 Hz), 7.66 (1H, dd, J = 6.6, 8.5 Hz), 7.87 (1H, d, J = 2.0 Hz).
工程26(g)：エチル　{3-フルオロ-4-[(7-{4-フルオロ-2-[2-(プロパン-2-イルオキシ)エトキシ］フェニル}フロ[2,3-d]ピリダジン-4-イル)アミノ]フェニル}アセテートの製造
工程26(f)で得られた化合物(12.0g)、エチル　2-(4-アミノ-3-フルオロフェニル)アセテート(7.08g) をエタノール(100mL)に溶解し、トリフルオロ酢酸(0.5mL)を加え、120℃で8時間撹拌した。反応液を冷却し、減圧下濃縮した。残渣にジクロロメタンを加え、炭酸水素ナトリウム水溶液に注ぎ、分液した。水層はジクロロメタンでさらに2回抽出し、有機層を無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー [溶出溶媒：ヘキサン/酢酸エチル=80/20-20/80(V/V)] で精製し、標記化合物(8.94g)を油状物質として得た。
LCMS (ES): m/z 512 [M+H]+.
1H NMR (CDCl3): 1.00 (6H, d, J=5.9 Hz), 1.27 (3H, t, J=6.9 Hz), 3.40 (1H, sept, J=5.9 Hz), 3.56 (2H, t, J=4.9 Hz), 3.61 (2H, s), 4.10-4.15 (2H, m), 4.18 (2H, q, J=6.9 Hz), 6.74 (1H, d, J=2.0 Hz), 6.80-6.92 (2H, m), 7.10 (1H, d, J=7.0 Hz), 7.15 (1H, dd, J=1.2, 8.2 Hz), 7.66 (1H, dd, J=7.0, 8.2 Hz), 7.75 (1H, d, J=2.0 Hz), 8.49 (1H, t, J=8.6 Hz). Step 26 (g): ethyl {3-fluoro-4-[(7- {4-fluoro-2- [2- (propan-2-yloxy) ethoxy] phenyl} furo [2,3-d] pyridazine-4 -Il) amino] phenyl} acetate Compound (12.0 g) obtained in Step 26 (f), ethyl 2- (4-amino-3-fluorophenyl) acetate (7.08 g) dissolved in ethanol (100 mL) Trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at 120 ° C. for 8 hours. The reaction mixture was cooled and concentrated under reduced pressure. Dichloromethane was added to the residue, and the mixture was poured into an aqueous sodium hydrogen carbonate solution and separated. The aqueous layer was further extracted twice with dichloromethane, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 80 / 20-20 / 80 (V / V)] to give the title compound (8.94 g) as an oil.
LCMS (ES): m / z 512 [M + H] + .
1 H NMR (CDCl 3 ): 1.00 (6H, d, J = 5.9 Hz), 1.27 (3H, t, J = 6.9 Hz), 3.40 (1H, sept, J = 5.9 Hz), 3.56 (2H, t, J = 4.9 Hz), 3.61 (2H, s), 4.10-4.15 (2H, m), 4.18 (2H, q, J = 6.9 Hz), 6.74 (1H, d, J = 2.0 Hz), 6.80-6.92 ( 2H, m), 7.10 (1H, d, J = 7.0 Hz), 7.15 (1H, dd, J = 1.2, 8.2 Hz), 7.66 (1H, dd, J = 7.0, 8.2 Hz), 7.75 (1H, d , J = 2.0 Hz), 8.49 (1H, t, J = 8.6 Hz).
工程26(h)：エチル　{3-フルオロ-4-[(7-{4-フルオロ-2-[2-(プロパン-2-イルオキシ)エトキシ］フェニル}-2,3-ジヒドロフロ[2,3-d]ピリダジン-4-イル)アミノ]フェニル}アセテートの製造
工程26(g)で得られた化合物(5.46g) をエタノール(100mL)、酢酸(50mL)に溶解し、10% パラジウム－炭素(4.98g)を加え、水素雰囲気下50℃で6時間撹拌した。触媒をろ別し、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー[溶出溶媒：ヘキサン/酢酸エチル=70/30-30/70 (V/V)]で精製し、標記化合物(4.01g)を油状物質として得た。
LCMS (ES): m/z 514 [M+H]+.
1H NMR (CDCl3): 1.10 (6H, d, J=6.4 Hz), 1.26 (3H, t, J=7.2 Hz), 3.12 (2H, t, J=9.0 Hz), 3.56 (1H, sept, J=6.4 Hz), 3.59 (2H, s), 3.67 (2H, t, J=5.4 Hz), 4.11 (2H, t, J=5.4 Hz), 4.18 (2H, q, J=7.2 Hz), 4.73 (2H, t, J=9.0 Hz), 6.74-6.80 (2H, m), 7.05-7.12 (2H, m), 7.50 (1H, dd, J=6.8, 8.3 Hz)8.38 (1H, t, J=8.3 Hz). Step 26 (h): ethyl {3-fluoro-4-[(7- {4-fluoro-2- [2- (propan-2-yloxy) ethoxy] phenyl} -2,3-dihydrofuro [2,3- d] pyridazin-4-yl) amino] phenyl} acetate Compound (5.46 g) obtained in Step 26 (g) was dissolved in ethanol (100 mL) and acetic acid (50 mL), and 10% palladium-carbon (4.98 g) was added, and the mixture was stirred at 50 ° C. for 6 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 70 / 30-30 / 70 (V / V)] to give the title compound (4.01 g) as an oil.
LCMS (ES): m / z 514 [M + H] + .
1 H NMR (CDCl 3 ): 1.10 (6H, d, J = 6.4 Hz), 1.26 (3H, t, J = 7.2 Hz), 3.12 (2H, t, J = 9.0 Hz), 3.56 (1H, sept, J = 6.4 Hz), 3.59 (2H, s), 3.67 (2H, t, J = 5.4 Hz), 4.11 (2H, t, J = 5.4 Hz), 4.18 (2H, q, J = 7.2 Hz), 4.73 (2H, t, J = 9.0 Hz), 6.74-6.80 (2H, m), 7.05-7.12 (2H, m), 7.50 (1H, dd, J = 6.8, 8.3 Hz) 8.38 (1H, t, J = (8.3 Hz).
工程26(i)：2-{3-フルオロ-4-[(7-{4-フルオロ-2-[2-(プロパン-2-イルオキシ)エトキシ]フェニル}-2,3-ジヒドロフロ[2,3-d]ピリダジン-4-イル)アミノ]フェニル}アセタミドの製造
工程26(h)で得られた化合物(9.0g)をエタノール(50mL)、テトラヒドロフラン(50mL)に溶解し、5規定水酸化ナトリウム(5.3mL)を加えて室温で3日間撹拌した。反応液に5規定塩酸(5.3mL)を加え、減圧下濃縮した。残渣に水を加え、酢酸エチル、テトラヒドロフランで3回抽出した。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後、減圧下濃縮した。残渣をN,N－ジメチルホルムアミド(120mL)に溶解し、O-(7-アザ-1H-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　ヘキサフルオロホスフェート(6.7g)、2規定アンモニア－イソプロパノール溶液(22mL)を加え、室温で2日間撹拌した。反応液を減圧下濃縮し、残渣を水に注ぎ、酢酸エチルで3回抽出した。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後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー[溶出溶媒：酢酸エチル/メタノール=98/2-82/18 (V/V)]で精製後、水、酢酸エチルを加えて析出物をろ取し、標記化合物(6.4g)を固体として得た。
LCMS (ES): m/z 485 [M+H]+.
1H NMR (DMSO-d6): 1.01 (6H, d, J=3.4 Hz), 3.16 (2H, t, J=9.0 Hz), 3.32 (2H, s), 3.51 (1H, sept, J=9.0 Hz), 3.59 (2H, t, J=4.9 Hz), 4.08 (2H, t, J=4.9 Hz), 4.64 (2H, t, J=9.0 Hz), 6.86 (1H, td, J=2.4, 8.5 Hz), 6.92 (1H, s), 7.03-7.06 (2H, m), 7.15 (1H, dd, J=1.7, 12.0 Hz), 7.34 (1H, dd, J=7.3, 8.3 Hz), 7.49 (1H, s), 7.55 (1H, t, J=8.3 Hz), 8.40 (2H, s). Step 26 (i): 2- {3-fluoro-4-[(7- {4-fluoro-2- [2- (propan-2-yloxy) ethoxy] phenyl} -2,3-dihydrofuro [2,3 -d] pyridazin-4-yl) amino] phenyl} acetamide The compound (9.0 g) obtained in Step 26 (h) was dissolved in ethanol (50 mL) and tetrahydrofuran (50 mL), and 5N sodium hydroxide ( 5.3 mL) was added and stirred at room temperature for 3 days. 5N Hydrochloric acid (5.3 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted 3 times with ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in N, N-dimethylformamide (120 mL) and O- (7-aza-1H-benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate ( 6.7 g) and 2N ammonia-isopropanol solution (22 mL) were added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and the residue was poured into water and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: ethyl acetate / methanol = 98 / 2-82 / 18 (V / V)], water and ethyl acetate were added, and the precipitate was collected by filtration to give the title compound (6.4 g) was obtained as a solid.
LCMS (ES): m / z 485 [M + H] + .
1 H NMR (DMSO-d 6 ): 1.01 (6H, d, J = 3.4 Hz), 3.16 (2H, t, J = 9.0 Hz), 3.32 (2H, s), 3.51 (1H, sept, J = 9.0 Hz), 3.59 (2H, t, J = 4.9 Hz), 4.08 (2H, t, J = 4.9 Hz), 4.64 (2H, t, J = 9.0 Hz), 6.86 (1H, td, J = 2.4, 8.5 Hz), 6.92 (1H, s), 7.03-7.06 (2H, m), 7.15 (1H, dd, J = 1.7, 12.0 Hz), 7.34 (1H, dd, J = 7.3, 8.3 Hz), 7.49 (1H , s), 7.55 (1H, t, J = 8.3 Hz), 8.40 (2H, s).
（実施例２７）
2-[3-フルオロ-4-({4-[2-(2-メトキシエトキシ)フェニル]チエノ[3,4-d]ピリダジン-1-イル}アミノ)フェニル]アセタミド (Example 27)
2- [3-Fluoro-4-({4- [2- (2-methoxyethoxy) phenyl] thieno [3,4-d] pyridazin-1-yl} amino) phenyl] acetamide
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
工程27(a)：1H,3H-チエノ[3,4-c]フラン-1,3-ジオンの製造
チオフェン-3,4-ジカルボキシリックアシッド(5.0g, 29mmol)を無水酢酸(30mL)に溶解し、120℃で6時間攪拌した。反応液を減圧下濃縮し、得られた残渣にヘキサン、酢酸エチルを適量加え、析出した固体をろ取した。得られた固体は精製することなく、次の反応に使用した。 Step 27 (a): Preparation of 1H, 3H-thieno [3,4-c] furan-1,3-dione Thiophene-3,4-dicarboxylic acid (5.0 g, 29 mmol) was added to acetic anhydride (30 mL). Dissolved and stirred at 120 ° C. for 6 hours. The reaction solution was concentrated under reduced pressure, hexane and ethyl acetate were added to the resulting residue, and the precipitated solid was collected by filtration. The obtained solid was used for the next reaction without purification.
工程27(b)：4-(2-メトキシベンゾイル)チオフェン-3-カルボキシリックアシッドの製造
工程27(a)で得られた化合物(300mg, 1.95mmol)をテトラヒドロフラン(10mL)に溶解し、-78℃に冷却した後、2-メトキシフェニルマグネシウムブロミド・テトラヒドロフラン溶液(1.0M, 2.33mL, 2.33mmol)を滴下し、1時間攪拌した。反応液に1規定塩酸を加え、酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣は精製することなく次の反応に使用した。
LCMS (ES): m/z 263 [M+H]+. Step 27 (b): Preparation of 4- (2-methoxybenzoyl) thiophene-3-carboxylic acid The compound obtained in Step 27 (a) (300 mg, 1.95 mmol) was dissolved in tetrahydrofuran (10 mL), and -78 After cooling to 0 ° C., 2-methoxyphenylmagnesium bromide / tetrahydrofuran solution (1.0 M, 2.33 mL, 2.33 mmol) was added dropwise and stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was used for the next reaction without purification.
LCMS (ES): m / z 263 [M + H] + .
工程27(c)：4-(2-メトキシフェニル)チエノ[3,4-d]ピリダジン-1(2H)-オンの製造
工程27(b)で得られた化合物(610mg, 2.33mmol)をエタノール(5mL)に溶解し、ヒドラジン1水和物(150mg, 3.0mmol)を加え、100℃で5時間攪拌した。反応液を室温まで冷却した後、水を加え、ジクロロメタン/メタノール(10/1)の混合溶媒で抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣は精製することなく次の反応に使用した。
LCMS (ES): m/z 259 [M+H]+.　 Step 27 (c): Preparation of 4- (2-methoxyphenyl) thieno [3,4-d] pyridazin-1 (2H) -one The compound (610 mg, 2.33 mmol) obtained in Step 27 (b) was treated with ethanol. (5 mL), hydrazine monohydrate (150 mg, 3.0 mmol) was added, and the mixture was stirred at 100 ° C. for 5 hr. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with a mixed solvent of dichloromethane / methanol (10/1), and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was used for the next reaction without purification.
LCMS (ES): m / z 259 [M + H] + .
工程27(d)：1-クロロ-4-(2-メトキシフェニル)チエノ[3,4-d]ピリダジンの製造
工程R1(d)と同様にして、工程27(c)で得られた化合物(510mg, 2.0mmol)、ホスホリックトリクロリド(2.0mL)を用いて、標記化合物(510mg, 1.85mmol, 93%)を油状物質として得た。
LCMS (ES): m/z 277 [M+H]+.  Step 27 (d): Production of 1-chloro-4- (2-methoxyphenyl) thieno [3,4-d] pyridazine In the same manner as in Step R1 (d), the compound obtained in Step 27 (c) ( The title compound (510 mg, 1.85 mmol, 93%) was obtained as an oily substance using 510 mg, 2.0 mmol) and phosphoric trichloride (2.0 mL).
LCMS (ES): m / z 277 [M + H] + .
工程27(e)：2-(4-ブロモチエノ[3,4-d]ピリダジン-1-イル)フェノールの製造
工程27(d)で得られた化合物(510mg, 1.85mmol)をジクロロメタン(6mL)に溶解し、室温でトリブロモボラン・ジクロロメタン溶液(1.0M, 3.0mL, 3.0mmol)を加え、3時間攪拌した。反応液を0℃に冷却後、飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣は精製することなく次の反応に使用した。
LCMS (ES): m/z 307 [M+H]+.　 Step 27 (e): Preparation of 2- (4-bromothieno [3,4-d] pyridazin-1-yl) phenol The compound obtained in Step 27 (d) (510 mg, 1.85 mmol) was added to dichloromethane (6 mL). After dissolution, tribromoborane / dichloromethane solution (1.0 M, 3.0 mL, 3.0 mmol) was added at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was cooled to 0 ° C., saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was used for the next reaction without purification.
LCMS (ES): m / z 307 [M + H] + .
工程27(f)：1-ブロモ-4-[2-(2-メトキシエトキシ)フェニル]チエノ[3,4-d]ピリダジンの製造
工程3(a)と同様にして、工程27(e)で得られた化合物(227mg, 0.74mmol)、水素化ナトリウム(40mg, 2.8mmol)、1-ブロモ-2-メトキシエタン(0.20mL, 2.2mmol)、N,N-ジメチルホルムアミド(10mL)を用いて、標記化合物(29mg, 0.0794mmol, 11%)を油状物質として得た。
LCMS (ES): m/z 365 [M+H]+.　
1H NMR (CDCl3) δ (ppm) : 3.12 (3H, s), 3.44 (2H, t, J = 4.9 Hz), 4.09 (2H, t, J = 4.9 Hz), 7.04-7.07 (1H, m), 7.09-7.14 (1H, m), 7.44-7.51 (1H, m), 7.55-7.59 (1H, m), 8.06 (1H, d, J = 3.4 Hz), 8.12 (1H, d, J = 3.4 Hz). Step 27 (f): Preparation of 1-bromo-4- [2- (2-methoxyethoxy) phenyl] thieno [3,4-d] pyridazine In the same manner as in Step 3 (a), in Step 27 (e) Using the obtained compound (227 mg, 0.74 mmol), sodium hydride (40 mg, 2.8 mmol), 1-bromo-2-methoxyethane (0.20 mL, 2.2 mmol), N, N-dimethylformamide (10 mL), The title compound (29 mg, 0.0794 mmol, 11%) was obtained as an oily substance.
LCMS (ES): m / z 365 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 3.12 (3H, s), 3.44 (2H, t, J = 4.9 Hz), 4.09 (2H, t, J = 4.9 Hz), 7.04-7.07 (1H, m ), 7.09-7.14 (1H, m), 7.44-7.51 (1H, m), 7.55-7.59 (1H, m), 8.06 (1H, d, J = 3.4 Hz), 8.12 (1H, d, J = 3.4 Hz).
工程27(g)：エチル　[3-フルオロ-4-({4-[2-(2-メトキシエトキシ)フェニル]チエノ[3,4-d]ピリダジン-1-イル}アミノ)フェニル]アセテートの製造
工程10(a)と同様にして、工程27(f)で得られた化合物(29mg, 0.0794mmol)、(4-アミノ-3-フルオロフェニル)酢酸エチル(0.140g, 0.71mmol)、エタノール(8mL)を用いて、標記化合物(20mg, 0.0415mmol, 52%)を固体として得た。
LCMS (ES): m/z 482 [M+H]+.　 Step 27 (g): Preparation of ethyl [3-fluoro-4-({4- [2- (2-methoxyethoxy) phenyl] thieno [3,4-d] pyridazin-1-yl} amino) phenyl] acetate In the same manner as in Step 10 (a), the compound obtained in Step 27 (f) (29 mg, 0.0794 mmol), ethyl (4-amino-3-fluorophenyl) acetate (0.140 g, 0.71 mmol), ethanol (8 mL ) To give the title compound (20 mg, 0.0415 mmol, 52%) as a solid.
LCMS (ES): m / z 482 [M + H] + .
工程27(h)：2-[3-フルオロ-4-({4-[2-(2-メトキシエトキシ)フェニル]チエノ[3,4-d]ピリダジン-1-イル}アミノ)フェニル]アセタミドの製造
工程1(b)と同様にして、工程27(g)で得られた化合物(20mg, 0.0415mmol)、1規定水酸化ナトリウム水溶液(2mL)、メタノール(5mL)、2規定アンモニア・イソプロパノール溶液(0.073mL, 0.146mmol)、(ジメチルアミノ)-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ）メタンイミニウム　ヘキサフルオロホスフェート(28mg, 0.073mmol)、N,N-ジメチルホルムアミド(4mL)を用いて、標記化合物(15mg, 0.033mmol, 80%)を固体として得た。
LCMS (ES): m/z 453 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 3.11 (3H, s), 3.48 (2H, t, J = 4.6 Hz), 3.53 (2H, s), 4.11 (2H, t, J= 5.1 Hz), 7.06 (1H, t, J = 7.3 Hz), 7.10-7.15 (4H, m), 7.38 (1H, d, J= 7.8 Hz), 7.43-7.46 (1H, m), 7.76 (1H, s), 8.46 (1H, s). Step 27 (h): of 2- [3-Fluoro-4-({4- [2- (2-methoxyethoxy) phenyl] thieno [3,4-d] pyridazin-1-yl} amino) phenyl] acetamide In the same manner as in production step 1 (b), the compound obtained in step 27 (g) (20 mg, 0.0415 mmol), 1N aqueous sodium hydroxide solution (2 mL), methanol (5 mL), 2N ammonia / isopropanol solution ( 0.073 mL, 0.146 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methaninium hexafluorophosphate (28 mg, 0.073 mmol) and N, N-dimethylformamide (4 mL) were used to obtain the title compound (15 mg, 0.033 mmol, 80%) as a solid.
LCMS (ES): m / z 453 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 3.11 (3H, s), 3.48 (2H, t, J = 4.6 Hz), 3.53 (2H, s), 4.11 (2H, t, J = 5.1 Hz) , 7.06 (1H, t, J = 7.3 Hz), 7.10-7.15 (4H, m), 7.38 (1H, d, J = 7.8 Hz), 7.43-7.46 (1H, m), 7.76 (1H, s), 8.46 (1H, s).
（実施例２８）
2-{4-[(4-{2-[(3-クロロピリジン-2-イル)メトキシ]フェニル}-6-フルオロフタラジン-1-イル)アミノ]-3-フルオロフェニル}アセタミド (Example 28)
2- {4-[(4- {2-[(3-chloropyridin-2-yl) methoxy] phenyl} -6-fluorophthalazin-1-yl) amino] -3-fluorophenyl} acetamide
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
工程28(a)：4-フルオロ-2-(2-メトキシベンゾイル)安息香酸の製造
2-ブロモ-4-フルオロ安息香酸(4.24g, 19.4mmol)をテトラヒドロフラン(50mL)に溶解し、-78℃に冷却した後、n-ブチルリチルム－ヘキサン溶液(f=2.69, 15mL, 40.7mmol)を滴下し、1時間攪拌した。反応液にN,2-ジメトキシ-N-メチルベンズアミド(4.54g, 23.2mmol)のテトラヒドロフラン溶液(20mL)を加えた後、室温まで昇温し、1時間攪拌した。反応液に１規定塩酸を加え、酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣は精製することなく次の反応に使用した。
LCMS (ES): m/z 275 [M+H]+. Step 28 (a): Production of 4-fluoro-2- (2-methoxybenzoyl) benzoic acid
2-Bromo-4-fluorobenzoic acid (4.24 g, 19.4 mmol) is dissolved in tetrahydrofuran (50 mL), cooled to −78 ° C., and then n-butyllithyl-hexane solution (f = 2.69, 15 mL, 40.7 mmol) is added. The solution was added dropwise and stirred for 1 hour. A tetrahydrofuran solution (20 mL) of N, 2-dimethoxy-N-methylbenzamide (4.54 g, 23.2 mmol) was added to the reaction solution, and then the mixture was warmed to room temperature and stirred for 1 hour. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was used for the next reaction without purification.
LCMS (ES): m / z 275 [M + H] + .
工程28(b)：6-フルオロ-4-(2-メトキシフェニル)フタラジン-1(2H)-オンの製造
工程27(c)と同様にして、工程28(a)で得られた化合物(2.75g, 10mmol)、n-ブタノール(20mL)、ヒドラジン1水和物(1.45mL, 30mmol)を用いて標記化合物(1.8g, 6.7mmol, 67%)を固体として得た。
LCMS (ES): m/z 271 [M+H]+.
1H NMR (CD3OD) δ(ppm): 3.72 (3H, s), 6.94 (1H, dd, J = 9.3, 2.4 Hz), 7.11 (1H, d, J = 8.3 Hz), 7.16 (1H, d, J = 8.3 Hz), 7.32 (1H, dd, J = 7.6, 1.7 Hz), 7.51-7.54 (1H, m), 7.58 (1H, td, J= 8.8, 2.4 Hz), 8.42 (1H, dd, J= 8.8, 5.4 Hz). Step 28 (b): Preparation of 6-fluoro-4- (2-methoxyphenyl) phthalazin-1 (2H) -one In the same manner as in Step 27 (c), the compound (2.75 g, 10 mmol), n-butanol (20 mL), and hydrazine monohydrate (1.45 mL, 30 mmol) were used to obtain the title compound (1.8 g, 6.7 mmol, 67%) as a solid.
LCMS (ES): m / z 271 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 3.72 (3H, s), 6.94 (1H, dd, J = 9.3, 2.4 Hz), 7.11 (1H, d, J = 8.3 Hz), 7.16 (1H, d, J = 8.3 Hz), 7.32 (1H, dd, J = 7.6, 1.7 Hz), 7.51-7.54 (1H, m), 7.58 (1H, td, J = 8.8, 2.4 Hz), 8.42 (1H, dd , J = 8.8, 5.4 Hz).
工程28(c)：1-クロロ-6-フルオロ-4-(2-メトキシフェニル)フタラジンの製造
工程1(d)と同様にして、工程28(b)で得られた化合物(1.8g, 6.66mmol)と、ホスホリックトリクロリド(2.5mL)を用いて、標記化合物(820mg, 2.84mmol, 43%)を固体として得た。
LCMS (ES): m/z 289 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 3.69 (3H, s), 7.06 (1H, d, J = 8.3 Hz), 7.14 (1H, td, J = 7.6, 1.0 Hz), 7.27 (1H, dd, J = 8.8, 2.4 Hz), 7.43 (1H, dd, J = 7.3, 1.5 Hz), 7.53 (1H, dt, J = 10.9, 4.1 Hz), 7.66 (1H, td, J= 8.5, 2.6 Hz), 8.37 (1H, dd, J= 9.0, 5.1 Hz). Step 28 (c): Production of 1-chloro-6-fluoro-4- (2-methoxyphenyl) phthalazine In the same manner as in Step 1 (d), the compound (1.8 g, 6.66) obtained in Step 28 (b) was used. mmol) and phosphoric trichloride (2.5 mL) to give the title compound (820 mg, 2.84 mmol, 43%) as a solid.
LCMS (ES): m / z 289 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 3.69 (3H, s), 7.06 (1H, d, J = 8.3 Hz), 7.14 (1H, td, J = 7.6, 1.0 Hz), 7.27 (1H, dd , J = 8.8, 2.4 Hz), 7.43 (1H, dd, J = 7.3, 1.5 Hz), 7.53 (1H, dt, J = 10.9, 4.1 Hz), 7.66 (1H, td, J = 8.5, 2.6 Hz) , 8.37 (1H, dd, J = 9.0, 5.1 Hz).
工程28(d)：2-(4-クロロ-7-フルオロフタラジン-1-イル)フェノールの製造
工程28(c)で得られた化合物(320mg, 1.10mmol)をジクロロメタン(4mL)に溶解し、室温でトリブロモボラン・ジクロロメタン溶液(1.0M, 2.0mL, 2.0mmol)を加え、3時間攪拌した。反応液を0℃に冷却後、飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣は精製することなく次の反応に使用した。
LCMS (ES): m/z 275 [M+H]+. Step 28 (d): Preparation of 2- (4-chloro-7-fluorophthalazin-1-yl) phenol The compound obtained in Step 28 (c) (320 mg, 1.10 mmol) was dissolved in dichloromethane (4 mL). Then, a tribromoborane / dichloromethane solution (1.0 M, 2.0 mL, 2.0 mmol) was added at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was cooled to 0 ° C., saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was used for the next reaction without purification.
LCMS (ES): m / z 275 [M + H] + .
工程28(e)：1-クロロ-4-{2-[(3-クロロピリジン-2-イル)メトキシ]フェニル}-6-フルオロフタラジンの製造
工程16(a)と同様にして、工程28(d)で得られた化合物(c.a. 1.1mmol)、(3-クロロピリジン-2-イル)メチル　メタンスルホネート(366mg, 1.65mmol)、炭酸セシウム(780mg, 2.4mmol)、N,N-ジメチルホルムアミド(15mL)を用いて、標記化合物(280mg, 0.700mmol, 64%)を固体として得た。
LCMS (ES): m/z 400 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 5.15 (1H, d, J = 12.7 Hz), 5.29 (1H, d, J = 12.7 Hz), 7.14 (3H, dd, J = 9.3, 4.4 Hz), 7.47 (2H, td, J = 7.0, 1.6 Hz), 7.56-7.64 (3H, m), 8.27-8.36 (1H, m), 8.39 (1H, t, J= 2.2 Hz). Step 28 (e): Production of 1-chloro-4- {2-[(3-chloropyridin-2-yl) methoxy] phenyl} -6-fluorophthalazine in the same manner as in Step 16 (a), Step 28 The compound (ca 1.1 mmol) obtained in (d), (3-chloropyridin-2-yl) methyl methanesulfonate (366 mg, 1.65 mmol), cesium carbonate (780 mg, 2.4 mmol), N, N-dimethylformamide ( 15 mL) was used to give the title compound (280 mg, 0.700 mmol, 64%) as a solid.
LCMS (ES): m / z 400 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 5.15 (1H, d, J = 12.7 Hz), 5.29 (1H, d, J = 12.7 Hz), 7.14 (3H, dd, J = 9.3, 4.4 Hz), 7.47 (2H, td, J = 7.0, 1.6 Hz), 7.56-7.64 (3H, m), 8.27-8.36 (1H, m), 8.39 (1H, t, J = 2.2 Hz).
工程28(f)：エチル　{4-[(4-{2-[(3-クロロピリジン-2-イル)メトキシ]フェニル}-6-フルオロフタラジン-1-イル)アミノ]-3-フルオロフェニル}アセテートの製造
工程25(b)と同様にして、工程28(e)で得られた化合物(100mg, 0.25mmol)、(4-アミノ-3-フルオロフェニル）酢酸エチル(0.140g, 0.71mmol)、トリフルオロ酢酸(0.020mL)、エタノール(5mL)を用いて、標記化合物(127mg, 0.226mmol, 90%)を固体として得た。
LCMS (ES): m/z 561 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 1.24 (3H, t, J = 7.2 Hz), 4.15 (2H, q, J = 7.2 Hz), 5.25 (2H, s), 7.09-7.16 (6H, m), 7.42-7.46 (5H, m), 7.58 (1H, dd, J = 8.3, 1.5 Hz), 8.18-8.25 (1H, m), 8.39 (1H, dd, J = 4.4, 1.5 Hz). Step 28 (f): ethyl {4-[(4- {2-[(3-chloropyridin-2-yl) methoxy] phenyl} -6-fluorophthalazin-1-yl) amino] -3-fluorophenyl } In the same manner as in acetate production step 25 (b), the compound obtained in step 28 (e) (100 mg, 0.25 mmol), ethyl (4-amino-3-fluorophenyl) acetate (0.140 g, 0.71 mmol) , Trifluoroacetic acid (0.020 mL) and ethanol (5 mL) were used to obtain the title compound (127 mg, 0.226 mmol, 90%) as a solid.
LCMS (ES): m / z 561 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.24 (3H, t, J = 7.2 Hz), 4.15 (2H, q, J = 7.2 Hz), 5.25 (2H, s), 7.09-7.16 (6H, m ), 7.42-7.46 (5H, m), 7.58 (1H, dd, J = 8.3, 1.5 Hz), 8.18-8.25 (1H, m), 8.39 (1H, dd, J = 4.4, 1.5 Hz).
工程28(g)：2-{4-[(4-{2-[(3-クロロピリジン-2-イル)メトキシ]フェニル}-6-フルオロフタラジン-1-イル)アミノ]-3-フルオロフェニル}アセタミドの製造
工程1(b)と同様にして、工程28(f)で得られた化合物(127mmol, 0.226mmol)、1規定水酸化ナトリウム水溶液(2mL)、メタノール(5mL)、2規定アンモニア・イソプロパノール溶液(0.500mL, 1.00mmol)、(ジメチルアミノ)-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ)メタンイミニウム　ヘキサフルオロホスフェート(180 mg, 0.500 mmol)、N,N-ジメチルホルムアミド(4 mL)を用いて、標記化合物(85 mg, 0.160 mmol, 71%)を固体として得た。
LCMS (ES): m/z 532 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 3.52 (2H, s), 5.16 (1H, d, J = 12.7 Hz), 5.31 (1H, d, J = 12.7 Hz), 7.15 (3H, t, J = 9.0 Hz), 7.24 (2H, d, J = 7.8 Hz), 7.30 (1H, d, J = 8.3 Hz), 7.38 (1H, d, J = 7.3 Hz), 7.47-7.53 (1H, m), 7.62-7.76 (3H, m), 8.32 (1H, s), 8.39-8.45 (1H, m).　 Step 28 (g): 2- {4-[(4- {2-[(3-chloropyridin-2-yl) methoxy] phenyl} -6-fluorophthalazin-1-yl) amino] -3-fluoro In the same manner as in Step 1 (b) for the production of phenyl} acetamide, the compound obtained in Step 28 (f) (127 mmol, 0.226 mmol), 1N aqueous sodium hydroxide solution (2 mL), methanol (5 mL), 2N ammonia・ Isopropanol solution (0.500 mL, 1.00 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methaninium hexafluoro The title compound (85 mg, 0.160 mmol, 71%) was obtained as a solid using phosphate (180 mg, 0.500 mmol) and N, N-dimethylformamide (4 mL).
LCMS (ES): m / z 532 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 3.52 (2H, s), 5.16 (1H, d, J = 12.7 Hz), 5.31 (1H, d, J = 12.7 Hz), 7.15 (3H, t, J = 9.0 Hz), 7.24 (2H, d, J = 7.8 Hz), 7.30 (1H, d, J = 8.3 Hz), 7.38 (1H, d, J = 7.3 Hz), 7.47-7.53 (1H, m) , 7.62-7.76 (3H, m), 8.32 (1H, s), 8.39-8.45 (1H, m).
（実施例２９） 
2-(3-フルオロ-4-{[1-(2-メトキシフェニル)ピロロ[1,2-d][1,2,4]トリアジン-4-イル]アミノ}フェニル)アセタミド (Example 29)
2- (3-Fluoro-4-{[1- (2-methoxyphenyl) pyrrolo [1,2-d] [1,2,4] triazin-4-yl] amino} phenyl) acetamide
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
工程29(a)：エチル　(2E)-2-[(2-メトキシフェニル)(1H-ピロール-2-イル)メチリデン]ヒドラジンカルボキシレートの製造
(2-メトキシフェニル)(1H-ピロール-2-イル）メタノン(参考文献；Organic Letters, 2010, vol.12, 4872-4875, 2.0g, 10mmol)と、エチル　ヒドラジンカルボキシレート(5.2g, 50mmol)をエタノール(20mL)に溶解し、酢酸(10mL)を加え、100℃で6時間攪拌した。反応液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝90/10-50/50(V/V)］にて精製し、標記化合物 (2.0 g, 6.96 mmol, 70%) を油状物質として得た。
LCMS (ES): m/z 288 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 1.24 (3H, t, J = 7.3 Hz), 3.77 (3H, s), 4.18 (2H, q, J = 7.3 Hz), 5.84-5.86 (1H, m), 6.07-6.12 (1H, m), 6.87-6.88 (1H, m), 7.01-7.07 (2H, m), 7.20 (1H, d, J = 7.3 Hz), 7.44-7.47 (1H, m), 7.59 (1H, s). Step 29 (a): Preparation of ethyl (2E) -2-[(2-methoxyphenyl) (1H-pyrrol-2-yl) methylidene] hydrazine carboxylate
(2-Methoxyphenyl) (1H-pyrrol-2-yl) methanone (reference: Organic Letters, 2010, vol. 12, 4872-4875, 2.0 g, 10 mmol) and ethyl hydrazine carboxylate (5.2 g, 50 mmol) Was dissolved in ethanol (20 mL), acetic acid (10 mL) was added, and the mixture was stirred at 100 ° C. for 6 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-50 / 50 (V / V)] to give the title compound (2.0 g, 6.96 mmol, 70%) was obtained as an oil.
LCMS (ES): m / z 288 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.24 (3H, t, J = 7.3 Hz), 3.77 (3H, s), 4.18 (2H, q, J = 7.3 Hz), 5.84-5.86 (1H, m ), 6.07-6.12 (1H, m), 6.87-6.88 (1H, m), 7.01-7.07 (2H, m), 7.20 (1H, d, J = 7.3 Hz), 7.44-7.47 (1H, m), 7.59 (1H, s).
工程29(b)：1-(2-メトキシフェニル)ピロロ[1,2-d][1,2,4]トリアジン-4(3H)-オンの製造
工程29(a)で得られた化合物(620mg, 2.16mmol)をN,N-ジメチルホルムアミド(10mL)に溶解し、水素化ナトリウム(100mg, 2.6mmol)を加え、100℃で5時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、ジクロロメタン、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝90/10-0/100(V/V)］にて精製し、標記化合物 (280mg, 3.18mmol, 54%)を固体として得た。
LCMS (ES): m/z 242 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 3.78 (3H, s), 6.44 (1H, dd, J = 3.7, 1.2 Hz), 6.70 (1H, t, J = 3.2 Hz), 7.00-7.07 (2H, m), 7.39 (1H, dd, J = 7.6, 1.7 Hz), 7.43-7.47 (1H, m), 7.77 (1H, dd, J= 2.9, 1.5 Hz), 9.12 (1H, s). Step 29 (b): Preparation of 1- (2-methoxyphenyl) pyrrolo [1,2-d] [1,2,4] triazin-4 (3H) -one The compound obtained in Step 29 (a) ( 620 mg, 2.16 mmol) was dissolved in N, N-dimethylformamide (10 mL), sodium hydride (100 mg, 2.6 mmol) was added, and the mixture was stirred at 100 ° C. for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with dichloromethane and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-0 / 100 (V / V)] to give the title compound (280 mg, 3.18 mmol, 54%) was obtained as a solid.
LCMS (ES): m / z 242 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 3.78 (3H, s), 6.44 (1H, dd, J = 3.7, 1.2 Hz), 6.70 (1H, t, J = 3.2 Hz), 7.00-7.07 (2H , m), 7.39 (1H, dd, J = 7.6, 1.7 Hz), 7.43-7.47 (1H, m), 7.77 (1H, dd, J = 2.9, 1.5 Hz), 9.12 (1H, s).
工程29(c)：1-(2-メトキシフェニル)ピロロ[1,2-d][1,2,4]トリアジン-4(3H)-チオンの製造
工程29(b)で得られた化合物(230mg, 0.953mmol)をピリジン(5mL)に溶解し、五硫化二リン(233mg, 1.05mmol)を加え、110℃で5時間攪拌した。その後、反応液に五硫化二リン(270mg, 1.21mmol)を加え、150℃で5時間攪拌した。反応液に水を加え、ジクロロメタン、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣は精製することなく、次の反応に使用した。
LCMS (ES): m/z 242 [M+H]+. Step 29 (c): Preparation of 1- (2-methoxyphenyl) pyrrolo [1,2-d] [1,2,4] triazine-4 (3H) -thione The compound obtained in Step 29 (b) ( 230 mg, 0.953 mmol) was dissolved in pyridine (5 mL), diphosphorus pentasulfide (233 mg, 1.05 mmol) was added, and the mixture was stirred at 110 ° C. for 5 hours. Thereafter, diphosphorus pentasulfide (270 mg, 1.21 mmol) was added to the reaction solution, and the mixture was stirred at 150 ° C. for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was used for the next reaction without purification.
LCMS (ES): m / z 242 [M + H] + .
工程29(d)：エチル　{[1-(2-メトキシフェニル）ピロロ[1,2-d][1,2,4]トリアジン-4-イル]スルファニル}アセテートの製造
工程29(c)で得られた化合物(c.a. 1.0mmol)に炭酸カリウム(690mg, 5.0mmol)、テトラヒドロフラン(10mL)、水(5mL)を加えた。反応液に、エチル　ブロモアセテート(0.42mL, 2.0mmol)を加え、室温で5時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝70/30-0/100(V/V)］にて精製し、標記化合物 (170mg, 0.50mmol, 50%) を油状物質として得た。
LCMS (ES): m/z 344 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 1.29 (3H, t, J = 7.2 Hz), 3.75 (3H, s), 4.24 (2H, q, J = 7.2 Hz), 4.33 (2H, s), 6.59 (1H, dd, J= 3.9, 1.0 Hz), 6.91 (1H, dd, J= 4.1, 2.7 Hz), 7.02 (1H, d, J= 8.3 Hz), 7.06 (1H, dd, J = 10.7, 4.4 Hz), 7.41 (1H, dd, J= 2.7, 1.2 Hz), 7.43-7.47 (1H, m), 7.49 (1H, dd, J = 7.3, 2.0 Hz). Step 29 (d): Preparation of ethyl {[1- (2-methoxyphenyl) pyrrolo [1,2-d] [1,2,4] triazin-4-yl] sulfanyl} acetate obtained in Step 29 (c) To the obtained compound (ca 1.0 mmol), potassium carbonate (690 mg, 5.0 mmol), tetrahydrofuran (10 mL) and water (5 mL) were added. Ethyl bromoacetate (0.42 mL, 2.0 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 70 / 30-0 / 100 (V / V)] to give the title compound (170 mg, 0.50 mmol, 50%) was obtained as an oil.
LCMS (ES): m / z 344 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.29 (3H, t, J = 7.2 Hz), 3.75 (3H, s), 4.24 (2H, q, J = 7.2 Hz), 4.33 (2H, s), 6.59 (1H, dd, J = 3.9, 1.0 Hz), 6.91 (1H, dd, J = 4.1, 2.7 Hz), 7.02 (1H, d, J = 8.3 Hz), 7.06 (1H, dd, J = 10.7, 4.4 Hz), 7.41 (1H, dd, J = 2.7, 1.2 Hz), 7.43-7.47 (1H, m), 7.49 (1H, dd, J = 7.3, 2.0 Hz).
工程29(e)：2-(3-フルオロ-4-{[1-(2-メトキシフェニル)ピロロ[1,2-d][1,2,4]トリアジン-4-イル]アミノ}フェニル)アセタミドの製造
工程29(d)で得られた化合物(90mg, 0.26mmol)を酢酸(5mL)に溶解し、2-(4-アミノ-3-フルオロフェニル)アセタミド(100mg, 0.595mmol)を加え、130℃で5時間攪拌した。反応液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー[溶出溶媒：酢酸エチル/メタノール＝100/0-80/20(V/V)]にて精製し、標記化合物(50mg, 0.127mmol, 49%)を油状物質として得た。
LCMS (ES): m/z 392 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 3.53 (2H, s), 3.75 (3H, s), 6.36 (1H, s), 6.70-6.77 (1H, m), 7.02 (1H, t, J = 7.3 Hz), 7.10 (4H, t, J = 9.8 Hz), 7.33 (1H, d, J = 6.8 Hz), 7.45 (1H, t, J = 7.8 Hz), 7.88 (1H, dd, J = 2.9, 1.5 Hz). Step 29 (e): 2- (3-Fluoro-4-{[1- (2-methoxyphenyl) pyrrolo [1,2-d] [1,2,4] triazin-4-yl] amino} phenyl) Acetamide production step 29 (d) compound (90 mg, 0.26 mmol) was dissolved in acetic acid (5 mL), 2- (4-amino-3-fluorophenyl) acetamide (100 mg, 0.595 mmol) was added, Stir at 130 ° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: ethyl acetate / methanol = 100 / 0-80 / 20 (V / V)] to give the title compound (50 mg, 0.127 mmol, 49%) as an oil.
LCMS (ES): m / z 392 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 3.53 (2H, s), 3.75 (3H, s), 6.36 (1H, s), 6.70-6.77 (1H, m), 7.02 (1H, t, J = 7.3 Hz), 7.10 (4H, t, J = 9.8 Hz), 7.33 (1H, d, J = 6.8 Hz), 7.45 (1H, t, J = 7.8 Hz), 7.88 (1H, dd, J = 2.9 , 1.5 Hz).
（実施例３０）
2-[4-({1-[2-(1,4-ジオキサン-2-イルメトキシ)フェニル]ピロロ[1,2-d][1,2,4]トリアジン-4-イル}アミノ)-3-フルオロフェニル]アセタミド (Example 30)
2- [4-({1- [2- (1,4-Dioxane-2-ylmethoxy) phenyl] pyrrolo [1,2-d] [1,2,4] triazin-4-yl} amino) -3 -Fluorophenyl] acetamide
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
工程30(a)：4-(エチルスルファニル)-1-(2-メトキシフェニル)ピロロ[1,2-d][1,2,4]トリアジンの製造
工程29(c)で得られた化合物(8.3mmol)に炭酸カリウム(5.7g, 42mmol)、テトラヒドロフラン(10mL)、水(5mL)を加えた。その後、反応液に、ヨードエタン(1.94g, 12.4mmol)を加え、室温で5時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝70/30-40/60(V/V)］にて精製し、標記化合物(1.2g, 4.2mmol, 51%)を油状物質として得た。
LCMS (ES): m/z 286 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 1.53 (3H, t, J = 7.6 Hz), 3.52 (2H, q, J = 7.6 Hz), 3.76 (3H, s), 6.58 (1H, dd, J = 3.9, 1.5 Hz), 6.88 (1H, dd, J = 3.9, 2.9 Hz), 7.03 (1H, d, J = 8.3 Hz), 7.06 (1H, td, J = 7.6, 1.0 Hz), 7.37 (1H, dd, J = 2.9, 1.5 Hz), 7.45 (1H, td, J = 7.9, 2.0 Hz), 7.52 (1H, dd, J = 7.3, 2.0 Hz). Step 30 (a): Preparation of 4- (ethylsulfanyl) -1- (2-methoxyphenyl) pyrrolo [1,2-d] [1,2,4] triazine The compound obtained in Step 29 (c) ( To 8.3 mmol), potassium carbonate (5.7 g, 42 mmol), tetrahydrofuran (10 mL) and water (5 mL) were added. Thereafter, iodoethane (1.94 g, 12.4 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 70 / 30-40 / 60 (V / V)] to give the title compound (1.2 g , 4.2 mmol, 51%) was obtained as an oily substance.
LCMS (ES): m / z 286 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.53 (3H, t, J = 7.6 Hz), 3.52 (2H, q, J = 7.6 Hz), 3.76 (3H, s), 6.58 (1H, dd, J = 3.9, 1.5 Hz), 6.88 (1H, dd, J = 3.9, 2.9 Hz), 7.03 (1H, d, J = 8.3 Hz), 7.06 (1H, td, J = 7.6, 1.0 Hz), 7.37 (1H , dd, J = 2.9, 1.5 Hz), 7.45 (1H, td, J = 7.9, 2.0 Hz), 7.52 (1H, dd, J = 7.3, 2.0 Hz).
工程30(b)：2-[4-(エチルスルファニル)ピロロ[1,2-d][1,2,4]トリアジン-1-イル]フェノールの製造
工程30(a)で得られた化合物(600mg, 2.1mmol)をジクロロメタン(4mL)に溶解した。反応液を0℃に冷却し、ボロントリブロミド(17%ジクロロメタン溶液、3.2mL, 3.2mmol)を加え、2時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタン、酢酸エチルで抽出した。有機層を水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣は精製することなく、次の反応に使用した。
LCMS (ES): m/z 272 [M+H]+. Step 30 (b): Preparation of 2- [4- (ethylsulfanyl) pyrrolo [1,2-d] [1,2,4] triazin-1-yl] phenol The compound obtained in Step 30 (a) ( 600 mg, 2.1 mmol) was dissolved in dichloromethane (4 mL). The reaction solution was cooled to 0 ° C., boron tribromide (17% dichloromethane solution, 3.2 mL, 3.2 mmol) was added, and the mixture was stirred for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane and ethyl acetate. The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was used for the next reaction without purification.
LCMS (ES): m / z 272 [M + H] + .
工程30(c)：1-[2-(1,4-ジオキサン-2-イルメトキシ)フェニル]-4-(エチルスルファニル)ピロロ[1,2-d][1,2,4]トリアジンの製造
工程15(a)と同様にして、工程30(b)で得られた化合物(1.0mmol)と、2-(ブロモメチル)-1,4-ジオキサン(0.26mL, 2.0mmol)、炭酸セシウム(1.0g, 3.0mmol)、N,N-ジメチルホルムアミド(10mL)を用いて、標記化合物(160 mg, 0.43 mmol, 43%)を油状物質として得た。
LCMS (ES): m/z 372 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 1.53 (3H, q, J = 7.5 Hz), 3.16 (1H, dd, J = 11.5, 10.0 Hz), 3.42-3.73 (8H, m), 3.87 (1H, dd, J = 9.8, 6.3 Hz), 4.01 (1H, dd, J = 9.5, 4.6 Hz), 6.60 (1H, dd, J = 3.9, 1.0 Hz), 6.89 (1H, dd, J = 3.9, 2.4 Hz), 7.02 (1H, d, J = 8.3 Hz), 7.10 (1H, t, J = 7.6 Hz), 7.38 (1H, dd, J = 2.7, 1.2 Hz), 7.42-7.45 (1H, m), 7.54 (1H, dd, J= 7.6, 1.7 Hz). Step 30 (c): Step of producing 1- [2- (1,4-dioxan-2-ylmethoxy) phenyl] -4- (ethylsulfanyl) pyrrolo [1,2-d] [1,2,4] triazine In the same manner as in 15 (a), the compound (1.0 mmol) obtained in Step 30 (b), 2- (bromomethyl) -1,4-dioxane (0.26 mL, 2.0 mmol), cesium carbonate (1.0 g, 3.0 mmol) and N, N-dimethylformamide (10 mL) were used to give the title compound (160 mg, 0.43 mmol, 43%) as an oil.
LCMS (ES): m / z 372 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.53 (3H, q, J = 7.5 Hz), 3.16 (1H, dd, J = 11.5, 10.0 Hz), 3.42-3.73 (8H, m), 3.87 (1H , dd, J = 9.8, 6.3 Hz), 4.01 (1H, dd, J = 9.5, 4.6 Hz), 6.60 (1H, dd, J = 3.9, 1.0 Hz), 6.89 (1H, dd, J = 3.9, 2.4 Hz), 7.02 (1H, d, J = 8.3 Hz), 7.10 (1H, t, J = 7.6 Hz), 7.38 (1H, dd, J = 2.7, 1.2 Hz), 7.42-7.45 (1H, m), 7.54 (1H, dd, J = 7.6, 1.7 Hz).
工程30(d)：エチル [4-({1-[2-(1,4-ジオキサン-2-イルメトキシ)フェニル]ピロロ[1,2-d][1,2,4]トリアジン-4-イル}アミノ)-3-フルオロフェニル]アセテートの製造
工程30(c)で得られた化合物(95mg, 0.256mmol)、エチル (4-アミノ- 3-フルオロフェニル)アセテート(95mg, 0.482mmol)を酢酸(5mL)に溶解し、130℃で12時間攪拌した。反応液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝70/30-40/60(V/V)］にて精製し、標記化合物 (75mg, 0.15mmol, 59%)を油状物質として得た。
LCMS (ES): m/z 507 [M+H]+. Step 30 (d): ethyl [4-({1- [2- (1,4-dioxan-2-ylmethoxy) phenyl] pyrrolo [1,2-d] [1,2,4] triazin-4-yl } Preparation of amino) -3-fluorophenyl] acetate 30 (c) (95 mg, 0.256 mmol), ethyl (4-amino-3-fluorophenyl) acetate (95 mg, 0.482 mmol) with acetic acid ( 5 mL) and stirred at 130 ° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 70 / 30-40 / 60 (V / V)] to give the title compound (75 mg, 0.15 mmol, 59%) as an oil.
LCMS (ES): m / z 507 [M + H] + .
工程30(e)：2-[4-({1-[2-(1,4-ジオキサン-2-イルメトキシ)フェニル]ピロロ[1,2-d][1,2,4]トリアジン-4-イル}アミノ)-3-フルオロフェニル]アセタミドの製造
工程1(b)と同様にして、工程30(d)で得られた化合物(75mg, 0.15mmol)、1規定水酸化ナトリウム水溶液(1.0mL)、メタノール(5mL)、2規定アンモニア、イソプロパノール溶液(0.300mL, 0.60mmol)、(ジメチルアミノ)-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ）メタンイミニウム　ヘキサフルオロホスフェート(100mg, 0.30mmol)、N,N-ジメチルホルムアミド(5mL)を用いて、標記化合物(56mg, 0.12mmol, 81%)を固体として得た。
LCMS (ES): m/z 478 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 3.23 (1H, t, J = 10.7 Hz), 3.41 (1H, t, J = 10.7 Hz), 3.46-3.68 (5H, m), 3.54 (2H, s), 3.93 (1H, dd, J= 10.3, 5.4 Hz), 4.01 (1H, dd, J= 10.3, 4.9 Hz), 6.42 (1H, s), 6.76 (1H, s), 7.04-7.13 (4H, m), 7.37 (1H, d, J = 7.3 Hz), 7.43 (1H, t, J = 7.8 Hz), 7.90 (1H, dd, J = 3.9, 2.4 Hz), 7.95 (1H, s). Step 30 (e): 2- [4-({1- [2- (1,4-dioxan-2-ylmethoxy) phenyl] pyrrolo [1,2-d] [1,2,4] triazine-4- Yl} amino) -3-fluorophenyl] acetamide In the same manner as in Step 1 (b), the compound obtained in Step 30 (d) (75 mg, 0.15 mmol), 1N aqueous sodium hydroxide solution (1.0 mL) , Methanol (5 mL), 2N ammonia, isopropanol solution (0.300 mL, 0.60 mmol), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridine- The title compound (56 mg, 0.12 mmol, 81%) was obtained as a solid using 3-yloxy) methaniminium hexafluorophosphate (100 mg, 0.30 mmol) and N, N-dimethylformamide (5 mL).
LCMS (ES): m / z 478 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 3.23 (1H, t, J = 10.7 Hz), 3.41 (1H, t, J = 10.7 Hz), 3.46-3.68 (5H, m), 3.54 (2H, s), 3.93 (1H, dd, J = 10.3, 5.4 Hz), 4.01 (1H, dd, J = 10.3, 4.9 Hz), 6.42 (1H, s), 6.76 (1H, s), 7.04-7.13 (4H , m), 7.37 (1H, d, J = 7.3 Hz), 7.43 (1H, t, J = 7.8 Hz), 7.90 (1H, dd, J = 3.9, 2.4 Hz), 7.95 (1H, s).
（実施例３１）
2-[3-({4-[4-クロロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-7-イル}アミノ）アゼチジン-1-イル]-2-オキソアセタミド　塩酸塩 (Example 31)
2- [3-({4- [4-Chloro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-7-yl} amino) azetidin-1-yl] -2-oxoacetamide Hydrochloride
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
工程31(a)：tert-ブチル 3-[(7-クロロチエノ[2,3-d]ピリダジン-4-イル)アミノ]アゼチジン-1-カルボキシレートおよびtert-ブチル3-[(4-クロロチエノ[2,3-d]ピリダジン-7-イル)アミノ]アゼチジン-1-カルボキシレートの製造
4,7-ジクロロチエノ[2,3-d]ピリダジン(1.00g, 4.88mmol)およびtert-ブチル 3-アミノアゼチジン-1-カルボキシレート(1.26g, 7.31mmol)の混合物を100℃で4時間攪拌した。得られた混合物を酢酸エチルに溶解し、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄した。有機層を減圧濃縮して得られた固体にヘキサン/酢酸エチル＝33/67(V/V)を40mL加えて、加熱還流した。得られた混合物を冷却し、析出物をろ取して、標記化合物の混合物(0.920g, 2.70mmol, 55%)を固体として得た。
1H NMR (CDCl3) δ: 1.41-1.54 (9H, m), 3.85-3.90 (2H, m), 4.41-4.47 (2H, m), 4.80-5.13 (2H, m), 7.37-7.56 (1H, m), 8.20-8.20 (1H, m). Step 31 (a): tert-butyl 3-[(7-chlorothieno [2,3-d] pyridazin-4-yl) amino] azetidine-1-carboxylate and tert-butyl 3-[(4-chlorothieno [2 , 3-d] pyridazin-7-yl) amino] azetidine-1-carboxylate
Mixture of 4,7-dichlorothieno [2,3-d] pyridazine (1.00 g, 4.88 mmol) and tert-butyl 3-aminoazetidine-1-carboxylate (1.26 g, 7.31 mmol) at 100 ° C. for 4 hours Stir. The obtained mixture was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. 40 mL of hexane / ethyl acetate = 33/67 (V / V) was added to the solid obtained by concentrating the organic layer under reduced pressure, and the mixture was heated to reflux. The resulting mixture was cooled and the precipitate was collected by filtration to give the title compound mixture (0.920 g, 2.70 mmol, 55%) as a solid.
1 H NMR (CDCl 3 ) δ: 1.41-1.54 (9H, m), 3.85-3.90 (2H, m), 4.41-4.47 (2H, m), 4.80-5.13 (2H, m), 7.37-7.56 (1H , m), 8.20-8.20 (1H, m).
工程31(b)：tert-ブチル 3-({7-[4-クロロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)アゼチジン-1-カルボキシレートおよびtert-ブチル3-({4-[4-クロロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-7-イル}アミノ)アゼチジン-1-カルボキシレートの製造
工程31(a)で得られた混合物(0.300g, 0.880mmol)を1,2-ジメトキシエタン(10mL)および水(1mL)に溶解し、室温にて4-クロロ-2-(2-メトキシエトキシ)フェニルボロン酸(0.304 g, 1.32mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)・ジクロロメタン錯体(0.144g, 0.176mmol)およびリン酸三カリウム(0.374g, 1.76mmol)を加えた後、100℃で3時間攪拌した。反応液に酢酸エチルを加え、無水硫酸ナトリウムで乾燥した。不溶物をろ別して得られたろ液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝50/50-0/100(V/V)］にて精製し、tert-ブチル3-({7-[4-クロロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル｝アミノ)アゼチジン-1-カルボキシレート(0.215g, 0.438mmol, 50%) およびtert-ブチル 3-({4-[4-クロロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-7-イル}アミノ)アゼチジン-1-カルボキシレート(0.090g, 0.183mmol, 21%) をそれぞれ固体として得た。
tert-ブチル3-({7-[4-クロロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル｝アミノ)アゼチジン-1-カルボキシレート
1H NMR (CDCl3) δ: 1.46 (9H, s), 3.16 (3H, s), 3.54 (2H, t, J = 5.1 Hz), 3.91 (2H, dd, J = 9.3, 4.9 Hz), 4.13 (2H, t, J = 5.1 Hz), 4.48 (2H, dd, J = 9.3, 7.6 Hz), 5.00-5.07 (1H, m), 5.13 (1H, d, J = 5.9 Hz), 7.07 (1H, d, J = 2.0 Hz), 7.11 (1H, dd, J = 8.3, 2.0 Hz), 7.36 (1H, d, J = 5.4 Hz), 7.54 (1H, d, J = 40.5 Hz), 7.73 (1H, d, J = 5.4 Hz). Step 31 (b): tert-butyl 3-({7- [4-chloro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) azetidine-1- Of carboxylate and tert-butyl 3-({4- [4-chloro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-7-yl} amino) azetidine-1-carboxylate The mixture (0.300 g, 0.880 mmol) obtained in production step 31 (a) was dissolved in 1,2-dimethoxyethane (10 mL) and water (1 mL), and 4-chloro-2- (2-methoxy) was obtained at room temperature. Ethoxy) phenylboronic acid (0.304 g, 1.32 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane complex (0.144 g, 0.176 mmol) and tripotassium phosphate (0.374 g , 1.76 mmol), and the mixture was stirred at 100 ° C. for 3 hours. Ethyl acetate was added to the reaction solution and dried over anhydrous sodium sulfate. The filtrate obtained by filtering insolubles was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100 (V / V)], tert-butyl 3-({7- [4-chloro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) azetidine-1-carboxylate (0.215 g, 0.438mmol, 50%) and tert-butyl 3-({4- [4-chloro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-7-yl} amino) azetidine-1 -Carboxylate (0.090 g, 0.183 mmol, 21%) was obtained as a solid respectively.
tert-butyl 3-({7- [4-chloro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) azetidine-1-carboxylate
1 H NMR (CDCl 3 ) δ: 1.46 (9H, s), 3.16 (3H, s), 3.54 (2H, t, J = 5.1 Hz), 3.91 (2H, dd, J = 9.3, 4.9 Hz), 4.13 (2H, t, J = 5.1 Hz), 4.48 (2H, dd, J = 9.3, 7.6 Hz), 5.00-5.07 (1H, m), 5.13 (1H, d, J = 5.9 Hz), 7.07 (1H, d, J = 2.0 Hz), 7.11 (1H, dd, J = 8.3, 2.0 Hz), 7.36 (1H, d, J = 5.4 Hz), 7.54 (1H, d, J = 40.5 Hz), 7.73 (1H, d, J = 5.4 Hz).
tert-ブチル3-({4-[4-クロロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-7-イル}アミノ)アゼチジン-1-カルボキシレート
1H NMR (CDCl3) δ: 1.46 (9H, s), 3.14 (3H, s), 3.46 (2H, t, J = 4.9 Hz), 3.93 (2H, dd, J = 9.3, 4.9 Hz), 4.07 (2H, t, J = 4.9 Hz), 4.48 (2H, dd, J = 9.3, 7.8 Hz), 4.83 (1H, d, J = 6.3 Hz), 5.02-5.09 (1H, m), 7.04 (1H, d, J = 2.0 Hz), 7.12 (1H, dd, J = 7.8, 2.0 Hz), 7.28 (1H, d, J = 5.4 Hz), 7.54 (1H, d, J = 7.8 Hz), 7.61 (1H, d, J = 5.4 Hz). tert-butyl 3-({4- [4-chloro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-7-yl} amino) azetidine-1-carboxylate
1 H NMR (CDCl 3 ) δ: 1.46 (9H, s), 3.14 (3H, s), 3.46 (2H, t, J = 4.9 Hz), 3.93 (2H, dd, J = 9.3, 4.9 Hz), 4.07 (2H, t, J = 4.9 Hz), 4.48 (2H, dd, J = 9.3, 7.8 Hz), 4.83 (1H, d, J = 6.3 Hz), 5.02-5.09 (1H, m), 7.04 (1H, d, J = 2.0 Hz), 7.12 (1H, dd, J = 7.8, 2.0 Hz), 7.28 (1H, d, J = 5.4 Hz), 7.54 (1H, d, J = 7.8 Hz), 7.61 (1H, d, J = 5.4 Hz).
工程31(c)：2-[3-({4-[4-クロロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-7-イル}アミノ)アゼチジン-1-イル]-2-オキソアセタミドの製造
工程5(c)と同様にして、工程31(b)で得られたtert-ブチル3-({4-[4-クロロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-7-イル}アミノ)アゼチジン-1-カルボキシレート (0.119 g, 0.242 mmol)、トリフルオロ酢酸(1mL)、オキサミン酸(0.024g, 0.267mmol)、O-(7-アザ-1H-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　ヘキサフルオロホスフェート(0.101g, 0.267mmol) およびトリエチルアミン(0.169 mL, 1.21 mmol)を用いて、標記化合物(0.087g, 0.188mmol, 78%)を固体として得た。
LCMS (ES): m/z 462 [M+H]+.
1H NMR [CDCl3/CD3OD=10/1(v/v)] δ: 3.12-3.15 (3H, m), 3.23-3.25 (2H, m), 4.05-4.18 (3H, m), 4.57-4.69 (2H, m), 5.05-5.16 (2H, m), 7.06 (1H, s), 7.10-7.14 (1H, m), 7.22-7.25 (1H, m), 7.46-7.50 (1H, m), 7.64-7.68 (1H, m). Step 31 (c): 2- [3-({4- [4-Chloro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-7-yl} amino) azetidine-1- Tert-butyl 3-({4- [4-chloro-2- (2-methoxyethoxy) phenyl] obtained in step 31 (b) in the same manner as in production step 5 (c) of yl] -2-oxoacetamide ] Thieno [2,3-d] pyridazin-7-yl} amino) azetidine-1-carboxylate (0.119 g, 0.242 mmol), trifluoroacetic acid (1 mL), oxamic acid (0.024 g, 0.267 mmol), O- Using (7-aza-1H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (0.101 g, 0.267 mmol) and triethylamine (0.169 mL, 1.21 mmol) The title compound (0.087 g, 0.188 mmol, 78%) was obtained as a solid.
LCMS (ES): m / z 462 [M + H] + .
1 H NMR [CDCl 3 / CD 3 OD = 10/1 (v / v)] δ: 3.12-3.15 (3H, m), 3.23-3.25 (2H, m), 4.05-4.18 (3H, m), 4.57 -4.69 (2H, m), 5.05-5.16 (2H, m), 7.06 (1H, s), 7.10-7.14 (1H, m), 7.22-7.25 (1H, m), 7.46-7.50 (1H, m) , 7.64-7.68 (1H, m).
工程31(d)：2-[3-({4-[4-クロロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-7-イル}アミノ)アゼチジン-1-イル]-2-オキソアセタミド　塩酸塩の製造
工程31(c)で得られた化合物(0.065g, 0.141mmol)のエタノール(1.5mL)溶液に、室温にて1規定塩酸水溶液(0.28mL) を加え、室温で1時間攪拌した。反応液を減圧濃縮して得られた残渣にジエチルエーテルを加え、析出物をろ取して標記化合物(0.058g, 0.116mmol, 49%)を固体として得た。
1H NMR (CD3OD) δ (ppm) : 3.19 (3H, s), 3.53-3.57 (2H, m), 4.21-4.26 (3H, m), 4.57 (1H, ddd, J = 11.3, 7.4, 1.6 Hz), 4.72 (1H, ddd, J = 11.3, 5.1, 1.6 Hz), 4.89-4.96 (1H, m), 5.06 (1H, ddd, J = 11.3, 7.4, 1.6 Hz), 7.29 (1H, dd, J = 8.2, 2.0 Hz), 7.43 (1H, d, J = 2.0 Hz), 7.60 (1H, d, J = 8.2 Hz), 7.65 (1H, d, J = 5.5 Hz), 8.39 (1H, d, J = 5.5 Hz). Step 31 (d): 2- [3-({4- [4-Chloro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-7-yl} amino) azetidine-1- Yl] -2-oxoacetamide hydrochloride 1% aqueous hydrochloric acid (0.28 mL) was added to a solution of the compound (0.065 g, 0.141 mmol) obtained in Step 31 (c) in ethanol (1.5 mL) at room temperature, Stir at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the resulting residue, and the precipitate was collected by filtration to give the title compound (0.058 g, 0.116 mmol, 49%) as a solid.
1 H NMR (CD 3 OD) δ (ppm): 3.19 (3H, s), 3.53-3.57 (2H, m), 4.21-4.26 (3H, m), 4.57 (1H, ddd, J = 11.3, 7.4, 1.6 Hz), 4.72 (1H, ddd, J = 11.3, 5.1, 1.6 Hz), 4.89-4.96 (1H, m), 5.06 (1H, ddd, J = 11.3, 7.4, 1.6 Hz), 7.29 (1H, dd , J = 8.2, 2.0 Hz), 7.43 (1H, d, J = 2.0 Hz), 7.60 (1H, d, J = 8.2 Hz), 7.65 (1H, d, J = 5.5 Hz), 8.39 (1H, d , J = 5.5 Hz).
（実施例３２）
2-オキソ-2-{3-[(4-{2-[(テトラヒドロ-2H-ピラン-4-イルメチル)アミノ]フェニル}チエノ[2,3-d]ピリダジン-7-イル)アミノ]アゼチジン-1-イル}アセタミド (Example 32)
2-oxo-2- {3-[(4- {2-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} thieno [2,3-d] pyridazin-7-yl) amino] azetidine- 1-yl} acetamide
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075
工程32(a)：N-[2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]テトラヒドロ-2H-ピラン-4-カルボキサミドの製造
工程R2(a)と同様にして、2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン(2.0g, 9.0mmol)、アセトニトリル(20mL)、炭酸カリウム(1.45g, 10.5mmol)、テトラヒドロ-2H-ピラン-4-カルボニルクロリド(参考文献：WO2008/71948, 10 mmol)を用いて、粗製の標記化合物(9.0mmol)を得た。得られた化合物は精製することなく、次の反応に使用した。 Step 32 (a): Production step R2 of N- [2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] tetrahydro-2H-pyran-4-carboxamide In the same manner as (a), 2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (2.0 g, 9.0 mmol), acetonitrile (20 mL), potassium carbonate (1.45 g, 10.5 mmol), tetrahydro-2H-pyran-4-carbonyl chloride (reference: WO2008 / 71948, 10 mmol) was used to obtain the crude title compound (9.0 mmol). The obtained compound was used for the next reaction without purification.
工程32(b)：N-(テトラヒドロ-2H-ピラン-4-イルメチル)-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリンの製造
工程R2(b)と同様にして、工程32(a)で得られた化合物(9.0mmol)と、1規定ボラン・テトラヒドロフラン溶液(63mL, 63mmol)を用いて、標記化合物(1.4g, 4.5mmol, 50%)を油状物質として得た。
LCMS (ES): m/z 318 [M+H]+.　 Step 32 (b): Step of producing N- (tetrahydro-2H-pyran-4-ylmethyl) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline In the same manner as in R2 (b), using the compound obtained in Step 32 (a) (9.0 mmol) and 1N borane-tetrahydrofuran solution (63 mL, 63 mmol), the title compound (1.4 g, 4.5 mmol, 50 %) Was obtained as an oil.
LCMS (ES): m / z 318 [M + H] + .
工程32(c)：tert-ブチル 3-[(4-{2-[(テトラヒドロ-2H-ピラン-4-イルメチル)アミノ]フェニル}チエノ[2,3-d]ピリダジン-7-イル)アミノ]アゼチジン-1-カルボキシレートの製造
工程5(b)と同様にして、工程31(a)で得られた化合物（100 mg, 0.293 mmol）、工程32(b)で得られた化合物(280mg, 0.88mmol) 、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)・ジクロロメタン錯体(47mg, 0.059mmol)、リン酸カリウムn-水和物(405mg, 1.76mmol)、1,2-ジメトキシエタン(15ml)を用いて、標記化合物(100mg, 0.202mmol, 69%)を油状物質として得た。　 Step 32 (c): tert-butyl 3-[(4- {2-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} thieno [2,3-d] pyridazin-7-yl) amino] In the same manner as in production step 5 (b) of azetidine-1-carboxylate, the compound obtained in step 31 (a) (100 mg, 0.293 mmol) and the compound obtained in step 32 (b) (280 mg, 0.88 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) -dichloromethane complex (47 mg, 0.059 mmol), potassium phosphate n-hydrate (405 mg, 1.76 mmol), 1,2 -Dimethoxyethane (15 ml) was used to give the title compound (100 mg, 0.202 mmol, 69%) as an oil.
工程32(d)：2-オキソ-2-{3-[(4-{2-[(テトラヒドロ-2H-ピラン-4-イルメチル)アミノ]フェニル}チエノ[2,3-d]ピリダジン-7-イル)アミノ]アゼチジン-1-イル}アセタミドの製造
工程5(c)と同様にして、工程32(c)で得られた化合物(260mg, 0.525mmol)、ジクロロメタン(6ml)、トリフルオロ酢酸(1.5mL)、 オキサミン酸(186mg, 0.186mmol)、N,N-ジメチルホルムアミド(5mL)、（ジメチルアミノ）-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ）メタンイミニウム　ヘキサフルオロホスフェート(780mg, 2.10mmol)、N,N-ジイソプロピルアミン(0.36mL, 2.10mmol)を用いて、標記化合物(10mg, 0.021mmol, 4%)を固体として得た。
LCMS (ES): m/z 467 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 1.20-1.28 (2H, m), 1.59-1.66 (2H, m), 1.77-1.87 (1H, m), 3.02 (2H, d, J = 6.8 Hz), 3.33 (2H, t, J = 16.8 Hz), 3.87 (2H, dd, J = 11.5, 3.7 Hz), 4.09-4.14 (1H, m), 4.54-4.62 (2H, m), 4.95-5.06 (2H, m), 6.74 (1H, td, J = 7.4, 1.1 Hz), 6.83 (1H, d, J = 8.3 Hz), 7.28 (1H, td, J = 7.8, 1.5 Hz), 7.48 (1H, dd, J = 7.6, 1.2 Hz), 7.78 (1H, d, J = 5.4 Hz), 7.99 (1H, dd, J = 5.4, 1.5 Hz). Step 32 (d): 2-oxo-2- {3-[(4- {2-[(tetrahydro-2H-pyran-4-ylmethyl) amino] phenyl} thieno [2,3-d] pyridazine-7- Yl) amino] azetidin-1-yl} acetamide In the same manner as in Step 5 (c), the compound obtained in Step 32 (c) (260 mg, 0.525 mmol), dichloromethane (6 ml), trifluoroacetic acid (1.5 mL), oxamic acid (186 mg, 0.186 mmol), N, N-dimethylformamide (5 mL), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] Pyridin-3-yloxy) methaniminium hexafluorophosphate (780 mg, 2.10 mmol), N, N-diisopropylamine (0.36 mL, 2.10 mmol) and the title compound (10 mg, 0.021 mmol, 4%) as a solid Obtained.
LCMS (ES): m / z 467 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 1.20-1.28 (2H, m), 1.59-1.66 (2H, m), 1.77-1.87 (1H, m), 3.02 (2H, d, J = 6.8 Hz ), 3.33 (2H, t, J = 16.8 Hz), 3.87 (2H, dd, J = 11.5, 3.7 Hz), 4.09-4.14 (1H, m), 4.54-4.62 (2H, m), 4.95-5.06 ( 2H, m), 6.74 (1H, td, J = 7.4, 1.1 Hz), 6.83 (1H, d, J = 8.3 Hz), 7.28 (1H, td, J = 7.8, 1.5 Hz), 7.48 (1H, dd , J = 7.6, 1.2 Hz), 7.78 (1H, d, J = 5.4 Hz), 7.99 (1H, dd, J = 5.4, 1.5 Hz).
（実施例３３）
2-[3-フルオロ-4-({4-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-7-イル}アミノ)フェニル]アセタミド (Example 33)
2- [3-Fluoro-4-({4- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-7-yl} amino) phenyl] acetamide
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
工程33(a):エチル {4-[(4-クロロチエノ[2,3-d]ピリダジン-7-イル)アミノ]-3-フルオロフェニル}アセテートの製造
工程10(a)と同様にして、4,7-ジクロロチエノ[2,3-d]ピリダジン(2.00g, 9.75mmol)、エチル　(4-アミノ-3-フルオロフェニル)アセテート(1.92g, 9.75mmol)、エタノール(30mL)を用いて、副生成物としての標記化合物(890mg, 2.40mmol, 25%)を固体として得た。
LCMS (ES): m/z 366 [M+H]+. Step 33 (a): Preparation of ethyl {4-[(4-chlorothieno [2,3-d] pyridazin-7-yl) amino] -3-fluorophenyl} acetate in the same manner as in Step 10 (a), , 7-dichlorothieno [2,3-d] pyridazine (2.00 g, 9.75 mmol), ethyl (4-amino-3-fluorophenyl) acetate (1.92 g, 9.75 mmol), ethanol (30 mL) The title compound as a product (890 mg, 2.40 mmol, 25%) was obtained as a solid.
LCMS (ES): m / z 366 [M + H] + .
工程33(b)：エチル [3-フルオロ-4-({4-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-7-イル}アミノ)フェニル]アセテートの製造
工程33(a)で得られたエチル　[3-フルオロ-4-({7-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-4-イル}アミノ)フェニル]アセテートとエチル{4-[(4-クロロチエノ[2,3-d]ピリダジン-7-イル)アミノ]-3-フルオロフェニル}アセテートの混合物(0.380g, 1.04mmol)を1,2-ジメトキシエタン(10mL)および水 (1mL)に溶解し、室温にて2-(2-メトキシエトキシ)フェニルボロン酸(0.244g, 1.25mmol)、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)・ジクロロメタン錯体(0.085g, 0.104mmol) およびりん酸三カリウム(0.441g, 2.08mmol)を加えた後、100℃で4時間攪拌した。反応液に酢酸エチルを加え、無水硫酸ナトリウムを加えた。不溶物をろ別して得られたろ液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝50/50-0/100(V/V)］にて精製し、標記化合物 (0.297g, 0.617mmol, 59%)を固体として得た。
LCMS (ES): m/z 482 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 1.28 (3H, t, J = 6.6 Hz), 3.14 (3H, s), 3.46 (3H, t, J = 5.5 Hz), 3.61 (2H, s), 4.09 (2H, t, J = 5.5 Hz), 4.18 (2H, q, J = 6.6 Hz), 7.05-7.19 (4H, m), 7.35 (1H, d, J = 5.1 Hz), 7.43-7.48 (1H, m), 7.62-7.66 (2H, m), 8.57-8.57 (1H, m). Step 33 (b): Preparation of ethyl [3-fluoro-4-({4- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-7-yl} amino) phenyl] acetate Ethyl [3-fluoro-4-({7- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-4-yl} amino) phenyl] obtained in step 33 (a) A mixture of acetate and ethyl {4-[(4-chlorothieno [2,3-d] pyridazin-7-yl) amino] -3-fluorophenyl} acetate (0.380 g, 1.04 mmol) was added to 1,2-dimethoxyethane ( 10 mL) and water (1 mL) and dissolved at room temperature with 2- (2-methoxyethoxy) phenylboronic acid (0.244 g, 1.25 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium ( II) · Dichloromethane complex (0.085 g, 0.104 mmol) and tripotassium phosphate (0.441 g, 2.08 mmol) were added, followed by stirring at 100 ° C. for 4 hours. Ethyl acetate was added to the reaction solution, and anhydrous sodium sulfate was added. The filtrate obtained by filtering insolubles was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100 (V / V)], The title compound (0.297 g, 0.617 mmol, 59%) was obtained as a solid.
LCMS (ES): m / z 482 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.28 (3H, t, J = 6.6 Hz), 3.14 (3H, s), 3.46 (3H, t, J = 5.5 Hz), 3.61 (2H, s), 4.09 (2H, t, J = 5.5 Hz), 4.18 (2H, q, J = 6.6 Hz), 7.05-7.19 (4H, m), 7.35 (1H, d, J = 5.1 Hz), 7.43-7.48 (1H , m), 7.62-7.66 (2H, m), 8.57-8.57 (1H, m).
工程33(c)：2-[3-フルオロ-4-({4-[2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-7-イル}アミノ)フェニル]アセタミドの製造
工程33(b)で得られた化合物(0.296g, 0.615mmol)をエタノール(9mL)に溶解し、室温にて1規定水酸化ナトリウム水溶液(0.922mL, 0.922mmol)を加え、室温にて2時間攪拌した。反応液に1規定塩酸水溶液(0.922mL, 0.922mmol)を加えた後、減圧濃縮した。得られた残渣を、実施例7(c)と同様にして、（ジメチルアミノ)-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ)メタンイミニウム　ヘキサフルオロホスフェート(0.257g, 0.676mmol)および 4% アンモニア－イソプロパノール溶液(0.922mL, 1.84mmol)を用いて、標記化合物(0.216g, 0.477mmol, 78%)を固体として得た。
LCMS (ES): m/z 452 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 3.13 (3H, s), 3.46 (2H, t, J = 4.5 Hz), 3.55 (2H, s), 4.09 (2H, t, J = 4.5 Hz), 5.86 (1H, br s), 6.29 (1H, br s), 6.99-7.16 (4H, m), 7.26-7.33 (1H, m), 7.45 (1H, t, J = 7.8 Hz), 7.59 (1H, d, J = 7.8 Hz), 7.64 (1H, d, J = 5.5 Hz), 8.49-8.49 (1H, m). Step 33 (c): of 2- [3-Fluoro-4-({4- [2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-7-yl} amino) phenyl] acetamide The compound (0.296 g, 0.615 mmol) obtained in production step 33 (b) is dissolved in ethanol (9 mL), 1N aqueous sodium hydroxide solution (0.922 mL, 0.922 mmol) is added at room temperature, and 2 at room temperature. Stir for hours. A 1N aqueous hydrochloric acid solution (0.922 mL, 0.922 mmol) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained residue was treated in the same manner as in Example 7 (c) using (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy. ) Methaniminium hexafluorophosphate (0.257 g, 0.676 mmol) and 4% ammonia-isopropanol solution (0.922 mL, 1.84 mmol) were used to give the title compound (0.216 g, 0.477 mmol, 78%) as a solid.
LCMS (ES): m / z 452 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 3.13 (3H, s), 3.46 (2H, t, J = 4.5 Hz), 3.55 (2H, s), 4.09 (2H, t, J = 4.5 Hz), 5.86 (1H, br s), 6.29 (1H, br s), 6.99-7.16 (4H, m), 7.26-7.33 (1H, m), 7.45 (1H, t, J = 7.8 Hz), 7.59 (1H, d, J = 7.8 Hz), 7.64 (1H, d, J = 5.5 Hz), 8.49-8.49 (1H, m).
（実施例３４）
2-(3-{[4-(4-クロロ-2-メトキシフェニル)チエノ[2,3-d]ピリダジン-7-イル]アミノ}アゼチジン-1-イル)-2-オキソアセタミド (Example 34)
2- (3-{[4- (4-Chloro-2-methoxyphenyl) thieno [2,3-d] pyridazin-7-yl] amino} azetidin-1-yl) -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
工程34(a)：3-(4-クロロ-2-メトキシベンゾイル)チオフェン-2-カルボン酸の製造
チオフェン-2-カルボン酸(2.00g, 15.6mmol)、および4-クロロ-N,2-ジメトキシ-N-メチルベンズアミド(3.58g, 15.6mmol)をテトラヒドロフラン(50mL)に溶解し、-78℃に冷却した。反応液にn-ブチルリチウム/ヘキサン溶液(1.6mol/L, 21.5ml, 34.3mmol)を20分かけて滴下した後、徐々に室温に戻して終夜攪拌した。反応液に飽和塩化アンモニウム水溶液および酢酸エチルを加え、抽出した有機層を飽和塩化アンモニウム水溶液、食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝35/65-80/20(V/V)］にて精製し、標記化合物の粗生成物(3.52g, 11.9mmol, 76.0%)を固体として得た。これ以上の精製は行わず、次の反応を行った。
LCMS (ES): m/z 296 [M+H]+. Step 34 (a): Preparation of 3- (4-chloro-2-methoxybenzoyl) thiophene-2-carboxylic acid Thiophene-2-carboxylic acid (2.00 g, 15.6 mmol) and 4-chloro-N, 2-dimethoxy -N-methylbenzamide (3.58 g, 15.6 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to -78 ° C. An n-butyllithium / hexane solution (1.6 mol / L, 21.5 ml, 34.3 mmol) was added dropwise to the reaction solution over 20 minutes, and the mixture was gradually returned to room temperature and stirred overnight. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction solution, and the extracted organic layer was washed with a saturated aqueous ammonium chloride solution and brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 35 / 65-80 / 20 (V / V)] to give a crude product of the title compound. The product (3.52 g, 11.9 mmol, 76.0%) was obtained as a solid. The following reaction was performed without further purification.
LCMS (ES): m / z 296 [M + H] + .
工程34(b)：4-(4-クロロ-2-メトキシフェニル)チエノ[2,3-d]ピリダジン-7(6H)-オンの製造
工程34(a)で得られた化合物(3.52g, 11.9mmol)、をn-ブタノール(50mL)に溶解し、ヒドラジン一水和物(1.15mL, 23.7mmol)を加えて140℃で3時間加熱攪拌した。反応液を室温に放冷後、ジエチルエーテルを加えて懸濁液を生じさせた。得られた沈殿を吸引ろ過後、真空乾燥させることで標記化合物(1.86g, 6.34mmol, 53.4%)を固体として得た。
1H NMR (CD3OD) δ (ppm) 3.79 (3H, s), 7.10-7.13 (2H, m), 7.22 (1H, d, J = 2.0 Hz), 7.38 (1H, d, J = 8.2 Hz), 8.03 (1H, d, J = 5.1 Hz). Step 34 (b): Preparation of 4- (4-chloro-2-methoxyphenyl) thieno [2,3-d] pyridazin-7 (6H) -one The compound obtained in Step 34 (a) (3.52 g, 11.9 mmol) was dissolved in n-butanol (50 mL), hydrazine monohydrate (1.15 mL, 23.7 mmol) was added, and the mixture was stirred with heating at 140 ° C. for 3 hr. The reaction solution was allowed to cool to room temperature, and diethyl ether was added to form a suspension. The obtained precipitate was suction filtered and dried in vacuo to give the title compound (1.86 g, 6.34 mmol, 53.4%) as a solid.
1 H NMR (CD 3 OD) δ (ppm) 3.79 (3H, s), 7.10-7.13 (2H, m), 7.22 (1H, d, J = 2.0 Hz), 7.38 (1H, d, J = 8.2 Hz ), 8.03 (1H, d, J = 5.1 Hz).
工程34(c)：4-(4-クロロ-2-メトキシフェニル)チエノ[2,3-d]ピリダジン-7(6H)-オンの製造
工程34(b)で得られた化合物(1.86g, 6.34mmol)を塩化ホスホリル(12.8mL, 140mmol)に溶解し、100℃で2.5時間加熱攪拌した。反応液を氷浴につけ、飽和炭酸水素ナトリウム水溶液を徐々に加えて反応を停止させた。ここに酢酸エチルを加えて有機層を抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ジクロロメタン/酢酸エチル＝100/0-35/65(V/V)］にて精製し、標記化合物(1.88g, 6.04mmol, 95.3%) を固体として得た。
1H NMR (CDCl3) δ (ppm): 3.88 (3H, s), 7.17 (1H, d, J = 1.6 Hz), 7.74-7.73 (2H, m), 8.23 (1H, d, J = 5.5 Hz). Step 34 (c): Preparation of 4- (4-chloro-2-methoxyphenyl) thieno [2,3-d] pyridazin-7 (6H) -one The compound obtained in Step 34 (b) (1.86 g, 6.34 mmol) was dissolved in phosphoryl chloride (12.8 mL, 140 mmol), and the mixture was heated and stirred at 100 ° C. for 2.5 hours. The reaction solution was placed in an ice bath, and saturated aqueous sodium hydrogen carbonate solution was gradually added to stop the reaction. Ethyl acetate was added thereto, and the organic layer was extracted, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: dichloromethane / ethyl acetate = 100 / 0-35 / 65 (V / V)] to give the title compound (1.88 g , 6.04 mmol, 95.3%) was obtained as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 3.88 (3H, s), 7.17 (1H, d, J = 1.6 Hz), 7.74-7.73 (2H, m), 8.23 (1H, d, J = 5.5 Hz ).
工程34(d)：tert-ブチル 3-{[4-(4-クロロ-2-メトキシフェニル）チエノ[2,3-d]ピリダジン-7-イル]アミノ}アゼチジン-1-カルボキシレートの製造
工程34(c)で得られた化合物(0.230g, 0.70mmol)にtert-ブチル 3-アミノアゼチジン-1-カルボキシレート(4.00mL, 23.2mmol)を加え、120℃で2時間加熱攪拌した。反応液に飽和炭酸水素ナトリウム水溶液およびジクロロメタンを加えて有機層を抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ジクロロメタン/メタノール＝100/0-90/10(V/V)］にて精製し、標記化合物の粗生成物(1.88g, 6.04mmol, 95.3%) を固体として得た。これ以上の精製は行わず、次の反応を行った。 Step 34 (d): Step of producing tert-butyl 3-{[4- (4-chloro-2-methoxyphenyl) thieno [2,3-d] pyridazin-7-yl] amino} azetidine-1-carboxylate To the compound obtained in 34 (c) (0.230 g, 0.70 mmol) was added tert-butyl 3-aminoazetidine-1-carboxylate (4.00 mL, 23.2 mmol), and the mixture was stirred with heating at 120 ° C. for 2 hr. A saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added to the reaction solution, and the organic layer was extracted, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: dichloromethane / methanol = 100 / 0-90 / 10 (V / V)] to give a crude product of the title compound. (1.88 g, 6.04 mmol, 95.3%) was obtained as a solid. The following reaction was performed without further purification.
工程34(e)：2-(3-{[4-(4-クロロ-2-メトキシフェニル)チエノ[2,3-d]ピリダジン-7-イル]アミノ｝アゼチジン-1-イル)-2-オキソアセタミドの製造
工程34(d)で得られた化合物(1.51g, 3.37mmol) をジクロロメタン(12mL)に溶解させ、トリフルオロ酢酸 (5mL)を加え室温にて2時間攪拌した。反応液を減圧下で溶媒留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ジクロロメタン/メタノール＝100/0-90/10(V/V)］にて精製し、脱保護した粗生成物 (1.94g) を得た。これをN,N,-ジメチルホルムアミド(30mL)に溶解し、オキサミン酸(0.451 g, 5.06mmol)、Ｎ，Ｎ－ジイソプロピルエチルアミン(2.31mL, 13.5mmol)、および（ジメチルアミノ）-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ)メタンイミニウム　ヘキサフルオロホスフェート(1.92g, 5.06mmol)を加え、室温にて５時間撹拌した。反応液に飽和炭酸水素ナトリウム水溶液およびジクロロメタンを加えて有機層を抽出し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をアミノシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/メタノール＝100/0-85/15(V/V)］にて精製し、標記化合物 (255mg, 0.610mmol, 18.1%) を固体として得た。
LCMS (ES): m/z 417 [M+H]+.
1H NMR (CD3OD) δ (ppm): 3.77 (3H, s), 4.15 (1H, dd, J = 11.2, 3.3 Hz), 4.54-4.65 (2H, m), 5.07-4.98 (1H, m), 7.13 (1H, dd, J = 7.8, 2.0 Hz), 7.17 (1H, d, J = 5.5 Hz), 7.22 (1H, d, J = 2.0 Hz), 7.39 (1H, d, J = 8.2 Hz), 7.94 (1H, d, J = 5.1 Hz).  Step 34 (e): 2- (3-{[4- (4-Chloro-2-methoxyphenyl) thieno [2,3-d] pyridazin-7-yl] amino} azetidin-1-yl) -2- The compound (1.51 g, 3.37 mmol) obtained in the oxoacetamide production step 34 (d) was dissolved in dichloromethane (12 mL), trifluoroacetic acid (5 mL) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: dichloromethane / methanol = 100 / 0-90 / 10 (V / V)] to remove the deprotected crude. The product (1.94g) was obtained. This was dissolved in N, N, -dimethylformamide (30 mL) and oxamic acid (0.451 g, 5.06 mmol), N, N-diisopropylethylamine (2.31 mL, 13.5 mmol), and (dimethylamino) -N, N- Dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridin-3-yloxy) methaniminium hexafluorophosphate (1.92 g, 5.06 mmol) was added, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous sodium hydrogen carbonate solution and dichloromethane were added to the reaction solution, and the organic layer was extracted, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography on amino silica gel [eluent: ethyl acetate / methanol = 100 / 0-85 / 15 (V / V)] to give the title compound (255 mg , 0.610 mmol, 18.1%) was obtained as a solid.
LCMS (ES): m / z 417 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 3.77 (3H, s), 4.15 (1H, dd, J = 11.2, 3.3 Hz), 4.54-4.65 (2H, m), 5.07-4.98 (1H, m ), 7.13 (1H, dd, J = 7.8, 2.0 Hz), 7.17 (1H, d, J = 5.5 Hz), 7.22 (1H, d, J = 2.0 Hz), 7.39 (1H, d, J = 8.2 Hz) ), 7.94 (1H, d, J = 5.1 Hz).
（実施例３５）
2-{3-[(4-{4-クロロ-2-[(2-メトキシエチル)アミノ]フェニル}チエノ[2,3-d]ピリダジン-7-イル)アミノ]アゼチジン-1-イル}-2-オキソアセタミド (Example 35)
2- {3-[(4- {4-Chloro-2-[(2-methoxyethyl) amino] phenyl} thieno [2,3-d] pyridazin-7-yl) amino] azetidin-1-yl}- 2-oxoacetamide
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078
工程35(a)：5-クロロ-2-(7-クロロチエノ[2,3-d]ピリダジン-4-イル)-N-(2-メトキシエチル）アニリンの製造
工程5(b)と同様にして、4,7-ジクロロチエノ[2,3-d]ピリダジン(800mg, 3.9mmol）、参考例6の化合物(1.2g, 3.9mmol) 、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)・ジクロロメタン錯体(320mg, 0.39mmol)、リン酸カリウムn水和物 (2.7g, 12mmol)、1,2-ジメトキシエタン(20mL)、水(0.5mL)を用いて、標記化合物(320mg, 0.90mmol, 23%)を油状物質として得た。
1H NMR (CDCl3) δ (ppm) : 3.31-3.35 (2H, m), 3.33 (3H, s), 3.57 (2H, t, J = 5.6 Hz), 6.76 (1H, dd, J = 8.3, 2.0 Hz), 6.81 (1H, d, J = 2.0 Hz), 6.89 (1H, s), 7.34 (1H, d, J = 8.3 Hz), 7.57 (1H, d, J= 5.4 Hz), 7.87 (1H, d, J = 5.4 Hz). Step 35 (a): Preparation of 5-chloro-2- (7-chlorothieno [2,3-d] pyridazin-4-yl) -N- (2-methoxyethyl) aniline as in Step 5 (b) 4,7-dichlorothieno [2,3-d] pyridazine (800 mg, 3.9 mmol), compound of Reference Example 6 (1.2 g, 3.9 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloro Using the palladium (II) -dichloromethane complex (320 mg, 0.39 mmol), potassium phosphate n hydrate (2.7 g, 12 mmol), 1,2-dimethoxyethane (20 mL), water (0.5 mL), the title compound ( 320 mg, 0.90 mmol, 23%) was obtained as an oily substance.
1 H NMR (CDCl 3 ) δ (ppm): 3.31-3.35 (2H, m), 3.33 (3H, s), 3.57 (2H, t, J = 5.6 Hz), 6.76 (1H, dd, J = 8.3, 2.0 Hz), 6.81 (1H, d, J = 2.0 Hz), 6.89 (1H, s), 7.34 (1H, d, J = 8.3 Hz), 7.57 (1H, d, J = 5.4 Hz), 7.87 (1H , d, J = 5.4 Hz).
工程35(b)：tert-ブチル 3-[(4-{4-クロロ-2-[(2-メトキシエチル)アミノ]フェニル}チエノ[2,3-d]ピリダジン-7-イル)アミノ]アゼチジン-1-カルボキシレートの製造
　工程35(a)で得られた化合物(320mg, 0.903mmol)にtert-ブチル3-アミノアゼチジンカルボキシレート(466mg, 2.71mmol)を加え、130℃で5時間攪拌した。反応液をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝100/0-50/50(V/V)］にて精製し、標記化合物(280mg, 0.571mmol, 63%) を固体として得た。
LCMS (ES): m/z 490 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 1.43 (9H, s), 3.30-3.33 (2H, m), 3.30 (3H, s), 3.55 (2H, t, J= 5.6 Hz), 3.87-3.92 (2H, m), 4.45 (2H, t, J = 8.3 Hz), 4.99-5.09 (1H, m), 6.73 (1H, dd, J = 8.1, 2.2 Hz), 6.78 (1H, d, J = 2.0 Hz), 7.26 (1H, d, J = 7.8 Hz), 7.45 (1H, d, J = 5.4 Hz), 7.67 (1H, d, J = 5.4 Hz). Step 35 (b): tert-butyl 3-[(4- {4-chloro-2-[(2-methoxyethyl) amino] phenyl} thieno [2,3-d] pyridazin-7-yl) amino] azetidine Preparation of -1-carboxylate To the compound obtained in step 35 (a) (320 mg, 0.903 mmol) was added tert-butyl 3-aminoazetidine carboxylate (466 mg, 2.71 mmol), and the mixture was stirred at 130 ° C. for 5 hours. . The reaction solution was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-50 / 50 (V / V)] to obtain the title compound (280 mg, 0.571 mmol, 63%) as a solid. .
LCMS (ES): m / z 490 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.43 (9H, s), 3.30-3.33 (2H, m), 3.30 (3H, s), 3.55 (2H, t, J = 5.6 Hz), 3.87-3.92 (2H, m), 4.45 (2H, t, J = 8.3 Hz), 4.99-5.09 (1H, m), 6.73 (1H, dd, J = 8.1, 2.2 Hz), 6.78 (1H, d, J = 2.0 Hz), 7.26 (1H, d, J = 7.8 Hz), 7.45 (1H, d, J = 5.4 Hz), 7.67 (1H, d, J = 5.4 Hz).
工程35(c)：2-{3-[(4-{4-クロロ-2-[(2-メトキシエチル)アミノ]フェニル}チエノ[2,3-d]ピリダジン-7-イル)アミノ]アゼチジン-1-イル}-2-オキソアセタミドの製造
工程5(c)と同様にして、工程35(b)で得られた化合物(180mg, 0.367mmol)、ジクロロメタン(4mL)、トリフルオロ酢酸(2mL)、オキサミン酸(65mg, 0.735mmol)、N,N-ジメチルホルムアミド(5mL)、（ジメチルアミノ)-N,N-ジメチル(3H-[1,2,3]トリアゾロ[4,5-b]ピリジン-3-イルオキシ)メタンイミニウム　ヘキサフルオロホスフェート(279mg, 0.735mmol)、N,N-ジイソプロピルアミン(0.251mL, 1.47mmol)を用いて、標記化合物(100mg, 0.217mmol, 59%) を固体として得た。
LCMS (ES): m/z 461 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 3.22-3.36 (2H, m), 3.24 (3H, s), 3.48 (2H, t, J = 5.4 Hz), 4.10-4.15 (1H, m), 4.52-4.63 (2H, m), 4.98-5.04 (2H, m), 6.75 (1H, dd, J = 8.3, 1.5 Hz), 6.82 (1H, d, J = 1.0 Hz), 7.22 (1H, d, J = 8.3 Hz), 7.32 (1H, d, J = 5.9 Hz), 7.97 (1H, dd, J = 5.4, 1.0 Hz). Step 35 (c): 2- {3-[(4- {4-chloro-2-[(2-methoxyethyl) amino] phenyl} thieno [2,3-d] pyridazin-7-yl) amino] azetidine In the same manner as in Production Step 5 (c) of 1-yl} -2-oxoacetamide, the compound obtained in Step 35 (b) (180 mg, 0.367 mmol), dichloromethane (4 mL), trifluoroacetic acid (2 mL), Oxamic acid (65 mg, 0.735 mmol), N, N-dimethylformamide (5 mL), (dimethylamino) -N, N-dimethyl (3H- [1,2,3] triazolo [4,5-b] pyridine-3 The title compound (100 mg, 0.217 mmol, 59%) was obtained as a solid using -yloxy) methaniminium hexafluorophosphate (279 mg, 0.735 mmol) and N, N-diisopropylamine (0.251 mL, 1.47 mmol).
LCMS (ES): m / z 461 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 3.22-3.36 (2H, m), 3.24 (3H, s), 3.48 (2H, t, J = 5.4 Hz), 4.10-4.15 (1H, m), 4.52-4.63 (2H, m), 4.98-5.04 (2H, m), 6.75 (1H, dd, J = 8.3, 1.5 Hz), 6.82 (1H, d, J = 1.0 Hz), 7.22 (1H, d, J = 8.3 Hz), 7.32 (1H, d, J = 5.9 Hz), 7.97 (1H, dd, J = 5.4, 1.0 Hz).
（実施例３６）
2-{(3R,4S)-4-[(4-{4-フルオロ-2-[(2-メトキシエチル)アミノ]フェニル}チエノ[2,3-d]ピリダジン-7-イル)アミノ]-3-メチルピペリジン-1-イル}-2-オキソアセタミド (Example 36)
2-{(3R, 4S) -4-[(4- {4-Fluoro-2-[(2-methoxyethyl) amino] phenyl} thieno [2,3-d] pyridazin-7-yl) amino]- 3-methylpiperidin-1-yl} -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079
工程36(a)：2,4-ジフルオロ-N-メトキシ-N-メチルベンズアミドの製造
2,4-ジフルオロ安息香酸(25g,0.16mol)をジクロロメタン(100mL)に懸濁し、氷浴下撹拌中、オキサリルクロリド(16mL, 0.19mol)、N,N-ジメチルホルムアミド(0.5mL)を加え、室温で1.5時間撹拌した。反応液を減圧下濃縮し、トルエンで一度共沸した。N,O-ジメチルヒドロキシルアミン(7.4g, 76mmol)のジクロロメタン(100mL)懸濁液を氷浴下撹拌中、N,N-ジイソプロピルエチルアミン(32mL, 0.19mol)、調整した酸クロリドのジクロロメタン(30mL)溶液を順に加え、室温にて2時間撹拌後、静置した。反応液を希塩酸に注ぎ、ジクロロメタンで3回抽出した。有機層を炭酸水素ナトリウムで洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝70/30-40/60(v/v)］で精製し、標記化合物(12g, 60mmol, 94%)を油状物として得た。
1H NMR (CDCl3) δ: 3.35 (3H, s), 3.56 (3H, br s), 6.86 (1H, dt, J=2.3, 9.4 Hz), 6.94 (1H, dt, J=2.3, 7.8 Hz), 7.45 (1H, q, J=7.8 Hz). Step 36 (a): Preparation of 2,4-difluoro-N-methoxy-N-methylbenzamide
2,4-Difluorobenzoic acid (25 g, 0.16 mol) was suspended in dichloromethane (100 mL), and oxalyl chloride (16 mL, 0.19 mol) and N, N-dimethylformamide (0.5 mL) were added while stirring in an ice bath. Stir at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure and azeotroped once with toluene. While stirring a suspension of N, O-dimethylhydroxylamine (7.4 g, 76 mmol) in dichloromethane (100 mL) in an ice bath, N, N-diisopropylethylamine (32 mL, 0.19 mol), dichloromethane of adjusted acid chloride (30 mL) The solutions were added in order, stirred at room temperature for 2 hours, and allowed to stand. The reaction solution was poured into dilute hydrochloric acid and extracted three times with dichloromethane. The organic layer was washed with sodium bicarbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 70 / 30-40 / 60 (v / v)] to give the title compound (12 g, 60 mmol, 94%) as an oil.
1H NMR (CDCl 3 ) δ: 3.35 (3H, s), 3.56 (3H, br s), 6.86 (1H, dt, J = 2.3, 9.4 Hz), 6.94 (1H, dt, J = 2.3, 7.8 Hz) , 7.45 (1H, q, J = 7.8 Hz).
工程36(b)：メチル 3-(2,4-ジフルオロベンゾイル)チオフェン-2-カルボキシレートの製造
チオフェン-2-カルボン酸(19g, 0.15mol)をテトラヒドロフラン(300mL)に溶解し、ドライアイス－アセトン浴にて-78℃に冷却中、n-ブチルリチウム-ヘキサン溶液(2.6M, 0.12L, 0.31mol)を加え、同温で１時間撹拌後、工程36(a)で得られた化合物(30g, 0.15mol)のテトラヒドロフラン(100mL)溶液を滴下した。同温で20分間撹拌後、室温で3時間撹拌した。反応液を希塩酸に注ぎ、酢酸エチルで3回抽出した。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後、減圧下濃縮した。残渣をテトラヒドロフラン(300 mL)－メタノール(50mL)に溶解し、氷浴下撹拌中、トリメチルシリルジアゾメタン溶液(2M, 82mL, 0.16mol)を滴下した。30分間撹拌後、室温に静置した。反応液に酢酸(5mL) を加え、減圧下濃縮した。残渣を炭酸水素ナトリウム水溶液に注ぎ、酢酸エチルで3回抽出した。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後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝98/2-80/20(v/v)］で精製し、標記化合物(15g, 53mmol, 36%) を固体として得た。
LCMS (ES): m/z 283 [M+H]+.
1H NMR (CDCl3) δ: 3.71 (3H, s), 6.80-6.85 (1H, m), 6.96-7.00 (1H, m), 7.17 (1H, d, J=4.9 Hz), 7.57 (1H, d, J=4.9 Hz), 7.85-7.89 (1H, m). Step 36 (b): Preparation of methyl 3- (2,4-difluorobenzoyl) thiophene-2-carboxylate Thiophene-2-carboxylic acid (19 g, 0.15 mol) was dissolved in tetrahydrofuran (300 mL) and dried ice-acetone While cooling to -78 ° C in a bath, n-butyllithium-hexane solution (2.6M, 0.12L, 0.31mol) was added, and the mixture was stirred at the same temperature for 1 hour. , 0.15 mol) in tetrahydrofuran (100 mL) was added dropwise. After stirring at the same temperature for 20 minutes, the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (300 mL) -methanol (50 mL), and trimethylsilyldiazomethane solution (2M, 82 mL, 0.16 mol) was added dropwise while stirring in an ice bath. After stirring for 30 minutes, the mixture was allowed to stand at room temperature. Acetic acid (5 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was poured into an aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 98 / 2-80 / 20 (v / v)] to give the title compound (15 g, 53 mmol, 36%) as a solid.
LCMS (ES): m / z 283 [M + H] +.
1H NMR (CDCl3) δ: 3.71 (3H, s), 6.80-6.85 (1H, m), 6.96-7.00 (1H, m), 7.17 (1H, d, J = 4.9 Hz), 7.57 (1H, d, J = 4.9 Hz), 7.85-7.89 (1H, m).
工程36(c)：メチル 3-{4-フルオロ-2-[(2-メトキシエチル)アミノ]ベンゾイル}チオフェン-2-カルボキシレートの製造
工程36(b)で得られた化合物(15g, 53mmol)を1,4-ジオキサン(150mL)に溶解し、2-メトキシエチルアミン(12mL, 0.13mol)、トリエチルアミン(18mL, 0.13mol)を加え、85℃で3時間撹拌した。反応液を減圧下濃縮し、残渣を炭酸水素ナトリウム水溶液に注ぎ、ジクロロメタンで3回抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝95/5-75/25(v/v)］で精製し、標記化合物(11g, 34mmol, 63%) を固体として得た。
LCMS (ES): m/z 338 [M+H]+.
1H NMR (CDCl3) δ: 3.44 (2H, q, J=5.5 Hz), 3.45 (3H, s), 3.70 (2H, t, J=5.5 Hz), 3.75 (3H, s), 6.14-6.19 (1H, m), 6.41 (1H, dd, J=2.3, 8.1 Hz), 7.06 (1H, d, J=5.1 Hz), 7.18 (1H, dd, J=6.6, 9.0 Hz), 7.56 (1H, d, J=5.1 Hz), 9.24 (1H, br s). Step 36 (c): Preparation of methyl 3- {4-fluoro-2-[(2-methoxyethyl) amino] benzoyl} thiophene-2-carboxylate Compound obtained in Step 36 (b) (15 g, 53 mmol) Was dissolved in 1,4-dioxane (150 mL), 2-methoxyethylamine (12 mL, 0.13 mol) and triethylamine (18 mL, 0.13 mol) were added, and the mixture was stirred at 85 ° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was poured into an aqueous sodium hydrogen carbonate solution and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 95 / 5-75 / 25 (v / v)] to obtain the title compound (11 g, 34 mmol, 63%) as a solid.
LCMS (ES): m / z 338 [M + H] +.
1H NMR (CDCl 3 ) δ: 3.44 (2H, q, J = 5.5 Hz), 3.45 (3H, s), 3.70 (2H, t, J = 5.5 Hz), 3.75 (3H, s), 6.14-6.19 ( 1H, m), 6.41 (1H, dd, J = 2.3, 8.1 Hz), 7.06 (1H, d, J = 5.1 Hz), 7.18 (1H, dd, J = 6.6, 9.0 Hz), 7.56 (1H, d , J = 5.1 Hz), 9.24 (1H, br s).
工程36(d)：4-{4-フルオロ-2-[(2-メトキシエチル)アミノ]フェニル}チエノ[2,3-d]ピリダジン-7(6H)-オンの製造
工程36(c)で得られた化合物(10g, 30mmol)をエタノール(70mL)及びテトラヒドロフラン(70mL)に溶解し、5規定水酸化ナトリウム(12mL, 60mmol) を加え、室温で4時間撹拌後、静置した。反応液に5規定塩酸(13mL, 65mmol)を加え、減圧下濃縮した。残渣を飽和食塩水に注ぎ、酢酸エチルで3回抽出した。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後、減圧下濃縮した。残渣をn-ブタノール(150mL)に溶解し、ヒドラジン水和物(4.4mL, 90mmol)を加え、140℃で4時間撹拌した。反応液を冷却し、ジエチルエーテルを加え、析出物をろ取した。母液は減圧下濃縮し、残渣にジエチルエーテルを加えて固体をろ取し、合わせて標記化合物(8.7g, 27mmol, 91%)を固体として得た。
LCMS (ES): m/z 320 [M+H]+.
1H NMR (CDCl3) δ: 3.29 (2H, q, J=5.4 Hz), 3.36 (3H, s), 3.58 (2H, t, J=5.4 Hz), 5.74 (1H, br s), 6.47-6.52 (2H, m), 7.31 (1H, dd, J=6.8, 8.3 Hz), 7.33 (1H, d, J=4.9 Hz), 7.83(1H, d, J=4.9 Hz). Step 36 (d): In production step 36 (c) of 4- {4-fluoro-2-[(2-methoxyethyl) amino] phenyl} thieno [2,3-d] pyridazin-7 (6H) -one The obtained compound (10 g, 30 mmol) was dissolved in ethanol (70 mL) and tetrahydrofuran (70 mL), 5N sodium hydroxide (12 mL, 60 mmol) was added, and the mixture was stirred at room temperature for 4 hours and allowed to stand. 5N Hydrochloric acid (13 mL, 65 mmol) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue was poured into saturated brine and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in n-butanol (150 mL), hydrazine hydrate (4.4 mL, 90 mmol) was added, and the mixture was stirred at 140 ° C. for 4 hr. The reaction solution was cooled, diethyl ether was added, and the precipitate was collected by filtration. The mother liquor was concentrated under reduced pressure, diethyl ether was added to the residue and the solid was collected by filtration and combined to obtain the title compound (8.7 g, 27 mmol, 91%) as a solid.
LCMS (ES): m / z 320 [M + H] +.
1H NMR (CDCl 3 ) δ: 3.29 (2H, q, J = 5.4 Hz), 3.36 (3H, s), 3.58 (2H, t, J = 5.4 Hz), 5.74 (1H, br s), 6.47-6.52 (2H, m), 7.31 (1H, dd, J = 6.8, 8.3 Hz), 7.33 (1H, d, J = 4.9 Hz), 7.83 (1H, d, J = 4.9 Hz).
工程36(e)：2-(7-クロロチエノ[2,3-d]ピリダジン-4-イル)-5-フルオロ-N-(2-メトキシエチル）アニリンの製造
工程36(d)で得られた化合物(9.1g, 28mmol)にオキシ塩化リン(15mL, 0.16mol)を加え、100℃で1.5時間撹拌した。反応液を氷に注ぎ、5規定水酸化ナトリウム水溶液、塩酸、硫酸にて中和し、ジクロロメタンで3回抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝98/2-60/40(v/v)］で精製し、標記化合物(8.3g, 25mmol, 86%) を固体として得た。
LCMS (ES): m/z 338 [M+H]+.
1H NMR (CDCl3) δ: 3.32-3.35 (2H, m), 3.36 (3H, s), 3.59 (2H, t, J=5.9 Hz), 6.50-6.57 (2H, m), 7.01 (1H, br s), 7.42 (1H, dd, J=6.3, 8.3 Hz), 7.61 (1H, d, J=5.4 Hz), 7.90 (1H, d, J=5.4 Hz). Step 36 (e): Obtained in Step 36 (d) of 2- (7-chlorothieno [2,3-d] pyridazin-4-yl) -5-fluoro-N- (2-methoxyethyl) aniline To the compound (9.1 g, 28 mmol) was added phosphorus oxychloride (15 mL, 0.16 mol), and the mixture was stirred at 100 ° C. for 1.5 hours. The reaction mixture was poured onto ice, neutralized with 5N aqueous sodium hydroxide, hydrochloric acid and sulfuric acid, and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 98 / 2-60 / 40 (v / v)] to give the title compound (8.3 g, 25 mmol, 86%) as a solid.
LCMS (ES): m / z 338 [M + H] +.
1H NMR (CDCl 3 ) δ: 3.32-3.35 (2H, m), 3.36 (3H, s), 3.59 (2H, t, J = 5.9 Hz), 6.50-6.57 (2H, m), 7.01 (1H, br s), 7.42 (1H, dd, J = 6.3, 8.3 Hz), 7.61 (1H, d, J = 5.4 Hz), 7.90 (1H, d, J = 5.4 Hz).
工程36(f)：tert-ブチル (3R,4S)-4-[(4-{4-フルオロ-2-[(2-メトキシエチル)アミノ]フェニル｝チエノ[2,3-d]ピリダジン-7-イル)アミノ]-3-メチルピペリジン-1-カルボキシレートおよびtert-ブチル(3R,4R)-4-[(4-{4-フルオロ-2-[(2-メトキシエチル）アミノ]フェニル｝チエノ[2,3-d]ピリダジン-7-イル)アミノ]-3-メチルピペリジン-1-カルボキシレートの製造
工程36(e)で得られた化合物(0.200g, 0.592mmol)およびtert-ブチル(3R,4S)-4-アミノ-3-メチルピペリジン-1-カルボキシレートとtert-ブチル(3R,4R)-4-アミノ-3-メチルピペリジン-1-カルボキシレートの混合物(0.317g, 1.48mmol)を150℃で8時間攪拌した。室温に冷却後、ジクロロメタンを注ぎ、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、不溶物をろ別して得られたろ液を減圧濃縮した。残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝100/0-50/50(V/V)］にて精製し、tert-ブチル(3R,4S)-4-[(4-{4-フルオロ-2-[(2-メトキシエチル)アミノ]フェニル}チエノ[2,3-d]ピリダジン-7-イル)アミノ]-3-メチルピペリジン-1-カルボキシレート(0.074 g, 0.144 mmol, 24%) およびtert-ブチル(3R,4R)-4-[(4-{4-フルオロ-2-[(2-メトキシエチル)アミノ]フェニル}チエノ[2,3-d]ピリダジン-7-イル)アミノ]-3-メチルピペリジン-1-カルボキシレート(0.025g, 0.049mmol, 8%) をそれぞれ固体として得た。
tert-ブチル(3R,4S)-4-[(4-{4-フルオロ-2-[(2-メトキシエチル)アミノ]フェニル}チエノ[2,3-d]ピリダジン-7-イル)アミノ]-3-メチルピペリジン-1-カルボキシレート
LCMS (ES): m/z 516 [M+H]+. Step 36 (f): tert-butyl (3R, 4S) -4-[(4- {4-fluoro-2-[(2-methoxyethyl) amino] phenyl} thieno [2,3-d] pyridazine-7 -Yl) amino] -3-methylpiperidine-1-carboxylate and tert-butyl (3R, 4R) -4-[(4- {4-fluoro-2-[(2-methoxyethyl) amino] phenyl} thieno Preparation of [2,3-d] pyridazin-7-yl) amino] -3-methylpiperidine-1-carboxylate Compound (0.200 g, 0.592 mmol) obtained in Step 36 (e) and tert-butyl (3R , 4S) -4-amino-3-methylpiperidine-1-carboxylate and tert-butyl (3R, 4R) -4-amino-3-methylpiperidine-1-carboxylate (0.317 g, 1.48 mmol) Stir at 150 ° C. for 8 hours. After cooling to room temperature, dichloromethane was poured, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the filtrate obtained by filtering insolubles was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-50 / 50 (V / V)], and tert-butyl (3R, 4S) -4-[(4- {4 -Fluoro-2-[(2-methoxyethyl) amino] phenyl} thieno [2,3-d] pyridazin-7-yl) amino] -3-methylpiperidine-1-carboxylate (0.074 g, 0.144 mmol, 24 %) And tert-butyl (3R, 4R) -4-[(4- {4-fluoro-2-[(2-methoxyethyl) amino] phenyl} thieno [2,3-d] pyridazin-7-yl) Amino] -3-methylpiperidine-1-carboxylate (0.025 g, 0.049 mmol, 8%) was obtained as a solid, respectively.
tert-butyl (3R, 4S) -4-[(4- {4-fluoro-2-[(2-methoxyethyl) amino] phenyl} thieno [2,3-d] pyridazin-7-yl) amino]- 3-methylpiperidine-1-carboxylate
LCMS (ES): m / z 516 [M + H] + .
tert-ブチル(3R,4R)-4-[(4-{4-フルオロ-2-[(2-メトキシエチル)アミノ]フェニル}チエノ[2,3-d]ピリダジン-7-イル)アミノ]-3-メチルピペリジン-1-カルボキシレート
LCMS (ES): m/z 516 [M+H]+. tert-butyl (3R, 4R) -4-[(4- {4-fluoro-2-[(2-methoxyethyl) amino] phenyl} thieno [2,3-d] pyridazin-7-yl) amino]- 3-methylpiperidine-1-carboxylate
LCMS (ES): m / z 516 [M + H] + .
工程36(g)：2-{(3R,4S)-4-[(4-{4-フルオロ-2-[(2-メトキシエチル)アミノ]フェニル}チエノ[2,3-d]ピリダジン-7-イル)アミノ]-3-メチルピペリジン-1-イル}-2-オキソアセタミドの製造
工程5(c)と同様にして、工程36(f)で得られたtert-ブチル(3R,4S)-4-[(4-{4-フルオロ-2-[(2-メトキシエチル）アミノ]フェニル}チエノ[2,3-d]ピリダジン-7-イル)アミノ]-3-メチルピペリジン-1-カルボキシレート(0.073g, 0.14mmol)、4規定塩酸-1,4-ジオキサン溶液(2mL)、オキサミン酸(0.015g, 0.17mmol)、O-(7-アザ-1H-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　ヘキサフルオロホスフェート(0.059g, 0.16mmol)およびトリエチルアミン(0.118mL, 0.85mmol) を用いて、標記化合物(0.059g, 0.12mmol, 86%)を固体として得た。
LCMS (ES): m/z 487 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 1.04 (3H, d, J = 4.7 Hz), 1.75-2.11 (4H, m), 2.51-2.70 (1H, m), 3.14-3.27 (1H, m), 3.33-3.74 (1H, m), 3.59 (8H, t, J = 5.5 Hz), 4.09-4.42 (1H, m), 4.46-4.65 (2H, m), 4.80 (1H, br s), 5.83 (1H, d, J = 12.1 Hz), 6.44-6.57 (2H, m), 6.74 (1H, br s), 7.10 (1H, br s), 7.28-7.36 (1H, m), 7.47 (1H, d, J = 5.1 Hz), 7.67 (1H, d, J = 5.1 Hz). Step 36 (g): 2-{(3R, 4S) -4-[(4- {4-fluoro-2-[(2-methoxyethyl) amino] phenyl} thieno [2,3-d] pyridazine-7 -Yl) amino] -3-methylpiperidin-1-yl} -2-oxoacetamide in the same manner as in Step 5 (c), tert-butyl (3R, 4S) -4 obtained in Step 36 (f) -[(4- {4-Fluoro-2-[(2-methoxyethyl) amino] phenyl} thieno [2,3-d] pyridazin-7-yl) amino] -3-methylpiperidine-1-carboxylate ( 0.073 g, 0.14 mmol), 4N hydrochloric acid-1,4-dioxane solution (2 mL), oxamic acid (0.015 g, 0.17 mmol), O- (7-aza-1H-benzotriazol-1-yl) -N, Using N, N ', N'-tetramethyluronium hexafluorophosphate (0.059 g, 0.16 mmol) and triethylamine (0.118 mL, 0.85 mmol), the title compound (0.059 g, 0.12 mmol, 86%) as a solid Obtained.
LCMS (ES): m / z 487 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.04 (3H, d, J = 4.7 Hz), 1.75-2.11 (4H, m), 2.51-2.70 (1H, m), 3.14-3.27 (1H, m) , 3.33-3.74 (1H, m), 3.59 (8H, t, J = 5.5 Hz), 4.09-4.42 (1H, m), 4.46-4.65 (2H, m), 4.80 (1H, br s), 5.83 ( 1H, d, J = 12.1 Hz), 6.44-6.57 (2H, m), 6.74 (1H, br s), 7.10 (1H, br s), 7.28-7.36 (1H, m), 7.47 (1H, d, J = 5.1 Hz), 7.67 (1H, d, J = 5.1 Hz).
（実施例３７）
4-[4-フルオロ-2-(2-メトキシエトキシ)フェニル-N-[1-(メチルスルホニル)ピペリジン-4-イル]チエノ[2,3-d]ピリダジン-7-アミン (Example 37)
4- [4-Fluoro-2- (2-methoxyethoxy) phenyl-N- [1- (methylsulfonyl) piperidin-4-yl] thieno [2,3-d] pyridazine-7-amine
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080
工程37(a)：メチル 4-フルオロ-2-メトキシベンゾエートの製造
4-フルオロ-2-ヒドロキシ安息香酸(50g, 0.32mol)をアセトン(500mL)に懸濁し、炭酸カリウム(93g, 0.67mol)、ジメチル硫酸(46mL, 0.48mol)を加え、80℃で7時間撹拌した。反応液を冷却し、不溶物をろ去後、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝100/0-70/30(v/v)］で精製し、標記化合物(49g, 0.27mol, 84%)を油状物質として得た。
1H NMR (CDCl3) δ: 3.88 (3H, s), 3.90 (3H, s), 6.66-6.70 (2H, m), 7.84-7.87 (1H, m). Step 37 (a): Production of methyl 4-fluoro-2-methoxybenzoate
Suspend 4-fluoro-2-hydroxybenzoic acid (50 g, 0.32 mol) in acetone (500 mL), add potassium carbonate (93 g, 0.67 mol) and dimethyl sulfate (46 mL, 0.48 mol), and stir at 80 ° C. for 7 hours. did. The reaction solution was cooled, insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-70 / 30 (v / v)] to give the title compound (49 g, 0.27 mol, 84%) as an oil.
1 H NMR (CDCl 3 ) δ: 3.88 (3H, s), 3.90 (3H, s), 6.66-6.70 (2H, m), 7.84-7.87 (1H, m).
工程37(b)：4-フルオロ-N,2-ジメトキシ-N-メチルベンズアミドの製造
工程37(a)で得られた化合物(49g, 0.27mol)をメタノール(500mL)に溶解し、5規定水酸化ナトリウム(80mL, 0.40mol)を加え、室温で6日間静置した。反応液に濃塩酸(35mL)を加え、減圧下濃縮した。残渣にジクロロメタンを加え、水に注ぎ、ジクロロメタンで3回抽出した。有機層を減圧下濃縮し、乾燥した。これをジクロロメタン(400mL)に懸濁し、室温で撹拌中、オキサリルクロリド(34mL, 0.40mol)、N,N-ジメチルホルムアミド(0.1mL) を加え、1時間撹拌した。反応液を減圧下濃縮し、残渣にトルエンを加え、共沸した。N,O-ジメチルヒドロキシルアミン塩酸塩(31g, 0.32mol)をジクロロメタン(300mL)に懸濁し、N,N-ジイソプロピルエチルアミン(110mL, 0.64mol)を加え、氷浴下撹拌中、調整した酸クロリドのジクロロメタン(100mL)溶液を滴下した。滴下終了後、室温で18時間撹拌した。反応液を炭酸水素ナトリウム水溶液に注ぎ、ジクロロメタンで３回抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝70/30-30/70(v/v)］で精製し、標記化合物(46g, 0.22mol, 81%)を油状物質として得た。
1H NMR (CDCl3) δ: 3.30 (3H, br s), 3.53 (3H, br s), 3.84 (3H, s), 6.65 (1H, dd, J=2.3, 11.0 Hz), 6.70 (1H, dd, J=2.3, 8.2 Hz), 7.26 (1H, dd, J=6.6, 8.2 Hz). Step 37 (b): Preparation of 4-fluoro-N, 2-dimethoxy-N-methylbenzamide The compound (49 g, 0.27 mol) obtained in Step 37 (a) was dissolved in methanol (500 mL), and 5N water was added. Sodium oxide (80 mL, 0.40 mol) was added, and the mixture was allowed to stand at room temperature for 6 days. Concentrated hydrochloric acid (35 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Dichloromethane was added to the residue, poured into water, and extracted with dichloromethane three times. The organic layer was concentrated under reduced pressure and dried. This was suspended in dichloromethane (400 mL), oxalyl chloride (34 mL, 0.40 mol) and N, N-dimethylformamide (0.1 mL) were added while stirring at room temperature, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and toluene was added to the residue and azeotroped. N, O-dimethylhydroxylamine hydrochloride (31 g, 0.32 mol) was suspended in dichloromethane (300 mL), N, N-diisopropylethylamine (110 mL, 0.64 mol) was added, and the resulting acid chloride was stirred while stirring in an ice bath. A solution of dichloromethane (100 mL) was added dropwise. After completion of dropping, the mixture was stirred at room temperature for 18 hours. The reaction solution was poured into an aqueous sodium hydrogen carbonate solution and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 70 / 30-30 / 70 (v / v)] to give the title compound (46 g, 0.22 mol, 81%) as an oil.
1H NMR (CDCl 3 ) δ: 3.30 (3H, br s), 3.53 (3H, br s), 3.84 (3H, s), 6.65 (1H, dd, J = 2.3, 11.0 Hz), 6.70 (1H, dd , J = 2.3, 8.2 Hz), 7.26 (1H, dd, J = 6.6, 8.2 Hz).
工程37(c)：3-(4-フルオロ-2-メトキシベンゾイル)チオフェン-2-カルボン酸の製造
チオフェン-2-カルボン酸(22g, 0.17mol)をテトラヒドロフラン(300mL)に懸濁し、ドライアイス－アセトン浴にて冷却中、n-ブチルリチウム-ヘキサン溶液(2.65mol/L, 130mL, 0.35mol)をシリンジにて滴下した。同温で1時間撹拌後、工程37(b)で得られた化合物(33g, 0.16mol)のテトラヒドロフラン(100mL)溶液を加えた。徐々に室温まで昇温し、一晩静置した。反応液を水に注ぎ、5規定塩酸を加えて酸性にし、酢酸エチルで3回抽出した。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後、減圧下濃縮し、標記化合物(44g, 0.16mol, 100%)を褐色油状物として得た。 Step 37 (c): Preparation of 3- (4-fluoro-2-methoxybenzoyl) thiophene-2-carboxylic acid Thiophene-2-carboxylic acid (22 g, 0.17 mol) was suspended in tetrahydrofuran (300 mL) and dried ice- While cooling in an acetone bath, n-butyllithium-hexane solution (2.65 mol / L, 130 mL, 0.35 mol) was added dropwise with a syringe. After stirring at the same temperature for 1 hour, a solution of the compound (33 g, 0.16 mol) obtained in step 37 (b) in tetrahydrofuran (100 mL) was added. The temperature was gradually raised to room temperature and allowed to stand overnight. The reaction mixture was poured into water, acidified with 5N hydrochloric acid, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (44 g, 0.16 mol, 100%) as a brown oil.
工程37(d)：4-(4-フルオロ-2-メトキシフェニル)チエノ[2,3-d]ピリダジン-7(6H)-オンの製造
工程37(c)で得られた化合物(44g, 0.16mol)をn-ブタノール(400mL)に溶解し、ヒドラジン水和物(15mL, 0.31mol)を加え、140℃で5時間撹拌した。反応液を室温に冷却し、減圧下濃縮した。残渣にジエチルエーテルを加え、析出物をろ取し、標記化合物(5.5g, 20mmol, 13%)を固体として得た。
1H NMR (CDCl3) δ: 3.78 (3H, s), 6.77 (1H, dd, J=2.3, 10.6 Hz), 6.81 (1H, td, J=2.3, 8.3 Hz), 7.05 (1H, d, J=5.1 Hz), 7.39 (1H, dd, J=6.7, 8.3 Hz), 7.77 (1H, d, J=5.1 Hz). Step 37 (d): Preparation of 4- (4-fluoro-2-methoxyphenyl) thieno [2,3-d] pyridazin-7 (6H) -one The compound obtained in Step 37 (c) (44 g, 0.16 mol) was dissolved in n-butanol (400 mL), hydrazine hydrate (15 mL, 0.31 mol) was added, and the mixture was stirred at 140 ° C. for 5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitate was collected by filtration to give the title compound (5.5 g, 20 mmol, 13%) as a solid.
1H NMR (CDCl 3 ) δ: 3.78 (3H, s), 6.77 (1H, dd, J = 2.3, 10.6 Hz), 6.81 (1H, td, J = 2.3, 8.3 Hz), 7.05 (1H, d, J = 5.1 Hz), 7.39 (1H, dd, J = 6.7, 8.3 Hz), 7.77 (1H, d, J = 5.1 Hz).
工程37(e)：7-クロロ-4-(4-フルオロ-2-メトキシフェニル)チエノ[2,3-d]ピリダジンの製造
工程37(d)で得られた化合物(7.0g, 25mmol)にオキシ塩化リン(15mL, 0.16mol)を加え、90℃で3時間撹拌した。反応液を氷に注ぎ、5規定水酸化ナトリウムで中和した。ジクロロメタンを加えて分液し、水層はさらにジクロロメタンで2回抽出した。有機層を炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。標記化合物(7.1g, 24mmol, 95%)を固体として得た。
LCMS (ES): m/z 295 [M+H]+.
1H NMR (CDCl3) δ: 3.76 (3H, s), 6.80 (1H, dd, J=2.4, 10.7 Hz), 6.86 (1H, td, J=2.0, 8.3 Hz), 7.28 (1H, d, J=5.4 Hz), 7.56 (1H, dd, J=6.8, 8.3 Hz), 7.82 (1H, d, J=5.4 Hz). Step 37 (e): Preparation of 7-chloro-4- (4-fluoro-2-methoxyphenyl) thieno [2,3-d] pyridazine The compound obtained in Step 37 (d) (7.0 g, 25 mmol) Phosphorus oxychloride (15 mL, 0.16 mol) was added, and the mixture was stirred at 90 ° C. for 3 hr. The reaction mixture was poured onto ice and neutralized with 5N sodium hydroxide. Dichloromethane was added for liquid separation, and the aqueous layer was further extracted twice with dichloromethane. The organic layer was washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound (7.1 g, 24 mmol, 95%) was obtained as a solid.
LCMS (ES): m / z 295 [M + H] +.
1H NMR (CDCl 3 ) δ: 3.76 (3H, s), 6.80 (1H, dd, J = 2.4, 10.7 Hz), 6.86 (1H, td, J = 2.0, 8.3 Hz), 7.28 (1H, d, J = 5.4 Hz), 7.56 (1H, dd, J = 6.8, 8.3 Hz), 7.82 (1H, d, J = 5.4 Hz).
工程37(f)：2-(7-クロロチエノ[2,3-d]ピリダジン-4-イル)-5-フルオロフェノールの製造
工程37(e)で得られた化合物(7.1g, 24mmol)をジクロロメタン(120mL)に溶解し、氷浴下撹拌中、ボロントリブロミド(25g, 0.10mol)のジクロロメタン(80mL)溶液を滴下した。滴下終了後、室温で1.5時間撹拌し、反応液を氷冷した飽和炭酸水素ナトリウム水溶液に徐々に加えた。ジクロロメタン－メタノールで3回抽出し、有機層を無水硫酸ナトリウムで乾燥後、減圧下濃縮し、標記化合物(7.0g, 24mmol, 100%)を固体として得た。
LCMS (ES): m/z 281 [M+H]+.
1H NMR (CDCl3) δ: 6.76-6.80 (1H, m), 6.88-6.92 (1H, m), 7.87 (1H, dd, J=6.3, 8.8 Hz), 7.96 (1H, d, J=5.4 Hz), 8.06 (1H, d, J=5.4 Hz). Step 37 (f): Preparation of 2- (7-chlorothieno [2,3-d] pyridazin-4-yl) -5-fluorophenol The compound obtained in Step 37 (e) (7.1 g, 24 mmol) was dissolved in dichloromethane. A solution of boron tribromide (25 g, 0.10 mol) in dichloromethane (80 mL) was added dropwise while stirring in an ice bath. After completion of the dropwise addition, the mixture was stirred at room temperature for 1.5 hours, and the reaction solution was gradually added to an ice-cooled saturated aqueous sodium bicarbonate solution. The mixture was extracted 3 times with dichloromethane-methanol, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (7.0 g, 24 mmol, 100%) as a solid.
LCMS (ES): m / z 281 [M + H] +.
1H NMR (CDCl 3 ) δ: 6.76-6.80 (1H, m), 6.88-6.92 (1H, m), 7.87 (1H, dd, J = 6.3, 8.8 Hz), 7.96 (1H, d, J = 5.4 Hz ), 8.06 (1H, d, J = 5.4 Hz).
工程37(g)：7-クロロ-4-[4-フルオロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジンの製造
工程37(f)で得られた化合物(3.0 g, 11 mmol)をトルエン(30mL)に懸濁し、2-メトキシエタノール(1.0mL, 13mmol)、トリフェニルホスフィン(3.4g, 13mmol)、ジ-tert-ブチル　アゾジカルボキシレート(3.0g, 13mmol)を加え、室温で2.5時間撹拌した。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［溶出溶媒：ヘキサン/酢酸エチル＝86/14-20/80(v/v)］で精製し、標記化合物(3.6g, 11mmol, 100%)を固体として得た。 Step 37 (g): Preparation of 7-chloro-4- [4-fluoro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazine Compound (3.0) obtained in Step 37 (f) g, 11 mmol) suspended in toluene (30 mL), 2-methoxyethanol (1.0 mL, 13 mmol), triphenylphosphine (3.4 g, 13 mmol), di-tert-butyl azodicarboxylate (3.0 g, 13 mmol) And stirred at room temperature for 2.5 hours. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 86 / 14-20 / 80 (v / v)] to give the title compound (3.6 g, 11 mmol, 100%). Obtained as a solid.
工程37(h)：tert-ブチル 4-({4-[4-フルオロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-7-イル}アミノ)ピペリジン-1-カルボキシレートの製造
工程37(g)で得られた化合物(3.62g, 10.7mmol)、tert-ブチル 4-アミノピペリジン-1-カルボキシレート(6.42g, 32.0mmol)を150℃で13時間撹拌した。反応液を室温に冷却し、シリカゲルカラムクロマトグラフィー [溶出溶媒：ヘキサン/酢酸エチル=22/78-0/100(V/V)] で精製し、標記化合物(2.33g, 4.64mmol, 43%)を得た。
1H NMR (CDCl3) δ (ppm) : 1.48 (9H, s), 2.22-2.32 (1H, m), 2.90-3.15 (1H, m), 3.14 (3H, s), 3.43-3.51 (1H, m), 4.03-4.36 (3H, m), 4.54 (1H, br s), 6.75-6.86 (2H, m), 7.26-7.28 (1H, m), 7.56-7.58 (2H, m). Step 37 (h): tert-butyl 4-({4- [4-fluoro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-7-yl} amino) piperidine-1- The compound (3.62 g, 10.7 mmol) obtained in the carboxylate production step 37 (g) and tert-butyl 4-aminopiperidine-1-carboxylate (6.42 g, 32.0 mmol) were stirred at 150 ° C. for 13 hours. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 22 / 78-0 / 100 (V / V)] to give the title compound (2.33 g, 4.64 mmol, 43%) Got.
1 H NMR (CDCl 3 ) δ (ppm): 1.48 (9H, s), 2.22-2.32 (1H, m), 2.90-3.15 (1H, m), 3.14 (3H, s), 3.43-3.51 (1H, m), 4.03-4.36 (3H, m), 4.54 (1H, br s), 6.75-6.86 (2H, m), 7.26-7.28 (1H, m), 7.56-7.58 (2H, m).
工程37(i)：4-[4-フルオロ-2-(2-メトキシエトキシ)フェニル]-N-(ピペリジン-4-イル)チエノ[2,3-d]ピリダジン-7-アミン　塩酸塩の製造
工程37(h)で得られた化合物(2.33g, 4.64mmol)を1,4-ジオキサン(10mL)に溶解し、4規定塩酸－ジオキサン溶液(10mL)を加え、室温で1時間撹拌した。反応液を減圧下濃縮し、1,4-ジオキサンで共沸した。得られた残渣は精製せず、そのまま次の反応に用いた。 Step 37 (i): Preparation of 4- [4-Fluoro-2- (2-methoxyethoxy) phenyl] -N- (piperidin-4-yl) thieno [2,3-d] pyridazin-7-amine hydrochloride The compound (2.33 g, 4.64 mmol) obtained in step 37 (h) was dissolved in 1,4-dioxane (10 mL), 4N hydrochloric acid-dioxane solution (10 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure and azeotroped with 1,4-dioxane. The obtained residue was used for the next reaction without purification.
工程37(j)：4-[4-フルオロ-2-(2-メトキシエトキシ)フェニル-N-[1-(メチルスルホニル)ピペリジン-4-イル]チエノ[2,3-d]ピリダジン-7-アミンの製造
工程37(i)で得られた化合物(100mg, 0.228mmol)をN,N-ジメチルホルムアミド(3mL)に溶解し、トリエチルアミン(0.089mL, 1.21mmol)、メタンスルホニルクロリド(0.018mL, 0.232mmol)、N,N-ジメチルアミノピリジン(26mg, 0.213mmol)を加え、室温で4時間撹拌後、静置した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー [溶出溶媒：酢酸エチル/メタノール=100/0-90/10 (V/V)］で精製後、ジクロロメタン、ジイソプロピルエーテルを加えて不溶物をろ取し、標記化合物(54mg, 0.11mmol, 49%)を固体として得た。
LCMS (ES): m/z 481 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 1.68-1.79 (2H, m), 2.44 (2H, d, J=10.2 Hz), 2.84 (3H, s), 2.92 (2H, td, J=2.3, 12.1 Hz), 3.15 (3H, s), 3.48 (2H, t, J=4.7 Hz), 3.90 (2H, d, J=12.1 Hz), 4.07 (2H, t, J=4.7 Hz), 4.49-4.57 (1H, m), 6.77-6.86 (2H, m), 7.26-7.28 (1H, m), 7.56-7.62 (2H, m). Step 37 (j): 4- [4-Fluoro-2- (2-methoxyethoxy) phenyl-N- [1- (methylsulfonyl) piperidin-4-yl] thieno [2,3-d] pyridazine-7- The compound obtained in the amine production step 37 (i) (100 mg, 0.228 mmol) was dissolved in N, N-dimethylformamide (3 mL), triethylamine (0.089 mL, 1.21 mmol), methanesulfonyl chloride (0.018 mL, 0.232 mmol). mmol) and N, N-dimethylaminopyridine (26 mg, 0.213 mmol) were added, and the mixture was stirred at room temperature for 4 hours and allowed to stand. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: ethyl acetate / methanol = 100 / 0-90 / 10 (V / V)], dichloromethane and diisopropyl ether were added, and the insoluble material was collected by filtration to give the title compound (54 mg , 0.11 mmol, 49%) as a solid.
LCMS (ES): m / z 481 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.68-1.79 (2H, m), 2.44 (2H, d, J = 10.2 Hz), 2.84 (3H, s), 2.92 (2H, td, J = 2.3, 12.1 Hz), 3.15 (3H, s), 3.48 (2H, t, J = 4.7 Hz), 3.90 (2H, d, J = 12.1 Hz), 4.07 (2H, t, J = 4.7 Hz), 4.49-4.57 (1H, m), 6.77-6.86 (2H, m), 7.26-7.28 (1H, m), 7.56-7.62 (2H, m).
（実施例３８）
2-[(3S)-3-({4-[4-クロロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-7-イル}アミノ)ピロリジン-1-イル]-2-オキソアセタミド (Example 38)
2-[(3S) -3-({4- [4-Chloro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-7-yl} amino) pyrrolidin-1-yl] -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000081
工程38(a)：5-クロロ-2-(7-クロロチエノ[2,3-d]ピリダジン-4-イル)フェノールの製造
工程34(c)で得られた化合物(18g, 59mmol)をジクロロメタン(300mL)に懸濁し、氷浴下撹拌中、ボロントリブロミド(50g, 0.20mol)のジクロロメタン(150mL)溶液を滴下した。室温で2時間撹拌後、反応液を氷浴下、炭酸水素ナトリウム水溶液に注ぎ、1.5時間撹拌した。分液ロートに移し、ジクロロメタン－メタノールで3回抽出し、有機層を無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣にジエチルエーテルを加えて不溶物をろ取し、標記化合物(18g, 59mmol, 100%)を固体として得た。
LCMS (ES): m/z 297 [M+H]+.
1H NMR (DMSO-d6) δ: 6.51 (1H, s), 7.05 (1H, dd, J=2.0, 7.8 Hz), 7.08 (1H, d, J=2.0 Hz), 7.45-7.47 (2H, m), 8.35 (1H, d, J=5.4 Hz). Step 38 (a): Preparation of 5-chloro-2- (7-chlorothieno [2,3-d] pyridazin-4-yl) phenol The compound obtained in Step 34 (c) (18 g, 59 mmol) was dissolved in dichloromethane ( The solution was suspended in 300 mL), and a solution of boron tribromide (50 g, 0.20 mol) in dichloromethane (150 mL) was added dropwise while stirring in an ice bath. After stirring at room temperature for 2 hours, the reaction solution was poured into an aqueous sodium hydrogen carbonate solution in an ice bath and stirred for 1.5 hours. The mixture was transferred to a separatory funnel and extracted three times with dichloromethane-methanol. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Diethyl ether was added to the residue, and the insoluble material was collected by filtration to give the title compound (18 g, 59 mmol, 100%) as a solid.
LCMS (ES): m / z 297 [M + H] +.
1H NMR (DMSO-d 6 ) δ: 6.51 (1H, s), 7.05 (1H, dd, J = 2.0, 7.8 Hz), 7.08 (1H, d, J = 2.0 Hz), 7.45-7.47 (2H, m ), 8.35 (1H, d, J = 5.4 Hz).
工程38(b)：7-クロロ-4-[4-クロロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジンの製造
工程38(a)で得られた化合物(17g, 58mmol)をN,N-ジメチルホルムアミド(150mL)に溶解し、2-ブロモエチルメチルエーテル(3.5mL, 64mmol)、炭酸カリウム(6.8g, 87mmol)を加え、70℃で8時間撹拌した。反応液を減圧下濃縮し、残渣に水を加え、酢酸エチルで抽出した。有機層を水、食塩水で順に洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝90/10-50/50(v/v)］で精製し、標記化合物(3.9g, 11mmol, 34%)を固体として得た。
1H NMR (CDCl3) δ: 3.14 (3H, s), 3.46 (2H, t, J=4.7 Hz), 4.10 (2H, t, J=4.7 Hz), 7.09 (1H, d, J=2.0 Hz), 7.16 (1H, dd, J=2.0, 8.2 Hz), 7.37 (1H, d, J=5.5 Hz), 7.56 (1H, d, J=8.2 Hz), 7.81 (1H, d, J=5.5 Hz). Step 38 (b): Preparation of 7-chloro-4- [4-chloro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazine Compound (17g) obtained in Step 38 (a) 58 mmol) was dissolved in N, N-dimethylformamide (150 mL), 2-bromoethyl methyl ether (3.5 mL, 64 mmol) and potassium carbonate (6.8 g, 87 mmol) were added, and the mixture was stirred at 70 ° C. for 8 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-50 / 50 (v / v)] to give the title compound (3.9 g, 11 mmol, 34%) as a solid.
1H NMR (CDCl 3 ) δ: 3.14 (3H, s), 3.46 (2H, t, J = 4.7 Hz), 4.10 (2H, t, J = 4.7 Hz), 7.09 (1H, d, J = 2.0 Hz) , 7.16 (1H, dd, J = 2.0, 8.2 Hz), 7.37 (1H, d, J = 5.5 Hz), 7.56 (1H, d, J = 8.2 Hz), 7.81 (1H, d, J = 5.5 Hz) .
工程38(c)：tert-ブチル-(3S)-3-({4-[4-クロロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-7-イル}アミノ)ピロリジン-1-カルボキシレートの製造
工程38(b)で得られた化合物(250mg, 0.704mmol）、(3S)-1-(tert-ブトキシカルボニル）-3-アミノピロリジン(0.38mL, 1.98mmol)を150℃で9時間撹拌した。反応液をシリカゲルカラムクロマトグラフィー [溶出溶媒：ヘキサン/酢酸エチル=43/57-22/78(V/V)］で精製し、標記化合物(267mg, 0.528mmol, 71%)を油状物として得た。
1H NMR (CDCl3) δ (ppm) : 1.47 (9H, s), 2.35-2.45 (1H, m), 3.15 (3H, s), 3.48 (2H, t, J=4.5 Hz), 3.47-3.66 (3H, m), 3.82-3.96 (1H, m), 4.08 (2H, t, J=4.5 Hz), 4.56 (1H, br s), 4.98-5.05 (1H, m), 7.05 (1H, d, J=2.0 Hz), 7.12 (1H, dd, J=2.0, 8.2 Hz), 7.27 (1H, d, J=6.2 Hz), 7.56 (1H, d, J=8.2 Hz), 7.59 (1H, d, J=6.2 Hz). Step 38 (c): tert-butyl- (3S) -3-({4- [4-chloro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-7-yl} amino ) Preparation of pyrrolidine-1-carboxylate (38 mg, 0.704 mmol), (3S) -1- (tert-butoxycarbonyl) -3-aminopyrrolidine (0.38 mL, 1.98 mmol) Was stirred at 150 ° C. for 9 hours. The reaction solution was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 43 / 57-22 / 78 (V / V)] to give the title compound (267 mg, 0.528 mmol, 71%) as an oil. .
1 H NMR (CDCl 3 ) δ (ppm): 1.47 (9H, s), 2.35-2.45 (1H, m), 3.15 (3H, s), 3.48 (2H, t, J = 4.5 Hz), 3.47-3.66 (3H, m), 3.82-3.96 (1H, m), 4.08 (2H, t, J = 4.5 Hz), 4.56 (1H, br s), 4.98-5.05 (1H, m), 7.05 (1H, d, J = 2.0 Hz), 7.12 (1H, dd, J = 2.0, 8.2 Hz), 7.27 (1H, d, J = 6.2 Hz), 7.56 (1H, d, J = 8.2 Hz), 7.59 (1H, d, J = 6.2 Hz).
工程38(d)：2-[(3S)-3-({4-[4-クロロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-7-イル}アミノ)ピロリジン-1-イル]-2-オキソアセタミドの製造
工程5(c)と同様にして、工程38(c)で得られた化合物(267mg, 0.528mmol) を1,4-ジオキサン(2mL)に溶解し、4規定塩酸-ジオキサン溶液(2mL)を加え、室温で1時間撹拌した。反応液を減圧下濃縮し、残渣をN,N-ジメチルホルムアミド(5mL)に溶解し、オキサミン酸(69mg, 0.78mmol)、O-(7-アザ-1H-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　ヘキサフルオロホスフェート(295mg, 0.775mmol)、N,N-ジイソプロピルエチルアミン(0.27mL, 1.59mmol) を加え、室温で19時間撹拌した。反応液に水を加え、酢酸エチルで3回抽出した。有機層を飽和炭酸水素ナトリウム水溶液、飽和食塩水で順に洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をアミノシリカゲルカラムクロマトグラフィー [溶出溶媒：酢酸エチル/メタノール=97/3-88/12(V/V)］ で精製後、酢酸エチル、ジイソプロピルエーテルを加えて不溶物をろ取し、標記化合物(117mg, 0.246mmol, 47%)を固体として得た。
1H NMR (DMSO-d6) δ (ppm) : 2.17-2.48 (2H, m), 3.13 (3H, s), 3.47 (2H, t, J=4.5 Hz), 3.62-3.80 (2H, m), 3.92-4.10 (2H, m), 4.11 (2H, t, J=4.5 Hz), 4.29 (1H, dd, J=6.3, 12.1 Hz), 7.13-7.16 (1H, m), 7.21-7.23 (2H, m), 7.43 (1H, dd, J=1.2, 7.8 Hz), 7.90 (1H, d, J=6.2 Hz). Step 38 (d): 2-[(3S) -3-({4- [4-Chloro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-7-yl} amino) Pyrrolidin-1-yl] -2-oxoacetamide In the same manner as in Step 5 (c), the compound (267 mg, 0.528 mmol) obtained in Step 38 (c) was dissolved in 1,4-dioxane (2 mL). 4N hydrochloric acid-dioxane solution (2 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in N, N-dimethylformamide (5 mL), oxamic acid (69 mg, 0.78 mmol), O- (7-aza-1H-benzotriazol-1-yl) -N , N, N ′, N′-Tetramethyluronium hexafluorophosphate (295 mg, 0.775 mmol) and N, N-diisopropylethylamine (0.27 mL, 1.59 mmol) were added, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography [eluent: ethyl acetate / methanol = 97 / 3-88 / 12 (V / V)], ethyl acetate and diisopropyl ether were added, and the insoluble material was collected by filtration to give the title compound. (117 mg, 0.246 mmol, 47%) was obtained as a solid.
1 H NMR (DMSO-d 6 ) δ (ppm): 2.17-2.48 (2H, m), 3.13 (3H, s), 3.47 (2H, t, J = 4.5 Hz), 3.62-3.80 (2H, m) , 3.92-4.10 (2H, m), 4.11 (2H, t, J = 4.5 Hz), 4.29 (1H, dd, J = 6.3, 12.1 Hz), 7.13-7.16 (1H, m), 7.21-7.23 (2H , m), 7.43 (1H, dd, J = 1.2, 7.8 Hz), 7.90 (1H, d, J = 6.2 Hz).
（実施例３９）
2-[(3R,4S)-4-({4-[4-クロロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-7-イル}アミノ)-3-フルオロピペリジン-1-イル]-2-オキソアセタミド (Example 39)
2-[(3R, 4S) -4-({4- [4-Chloro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-7-yl} amino) -3-fluoro Piperidin-1-yl] -2-oxoacetamide
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000082
工程39(a)：tert-ブチル (3R,4S)-4-({4-[4-クロロ-2-(2-メトキシエトキシ)フェニル］チエノ[2,3-d]ピリダジン-7-イル}アミノ)-3-フルオロピペリジン-1-カルボキシレートの製造
工程38(b)で得られた化合物(0.124g, 0.349mmol)、tert-ブチル(3R,4S)-4-アミノ-3-フルオロピペリジン-1-カルボキシレート(0.152g, 0.698mmol)およびN,N-ジイソプロピルエチルアミン(0.182mL, 1.05mmol)の混合物を、150℃で4時間攪拌した。反応液を室温に冷却後、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝50/50-0/100(V/V)］にて精製し、標記化合物(0.021g, 0.039mmol, 11%)を固体として得た。
1H NMR (CDCl3) δ (ppm) : 1.49 (9H, s), 1.83-2.13 (2H, m), 2.81-3.12 (1H, m), 3.15 (3H, s), 3.47 (2H, t, J = 4.9 Hz), 4.08 (2H, t, J = 4.9 Hz), 4.17-4.89 (4H, m), 5.03 (1H, d, J = 49.3 Hz), 7.05 (1H, d, J = 2.0 Hz), 7.12 (1H, dd, J = 8.2, 2.0 Hz), 7.27 (1H, d, J = 5.1 Hz), 7.54 (1H, d, J = 8.2 Hz), 7.61 (1H, d, J = 5.1 Hz). Step 39 (a): tert-butyl (3R, 4S) -4-({4- [4-chloro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-7-yl} Amino) -3-fluoropiperidine-1-carboxylate Compound (0.124 g, 0.349 mmol) obtained in Step 38 (b), tert-butyl (3R, 4S) -4-amino-3-fluoropiperidine- A mixture of 1-carboxylate (0.152 g, 0.698 mmol) and N, N-diisopropylethylamine (0.182 mL, 1.05 mmol) was stirred at 150 ° C. for 4 hours. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100 (V / V)] to give the title compound (0.021 g, 0.039 mmol, 11% ) Was obtained as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 1.49 (9H, s), 1.83-2.13 (2H, m), 2.81-3.12 (1H, m), 3.15 (3H, s), 3.47 (2H, t, J = 4.9 Hz), 4.08 (2H, t, J = 4.9 Hz), 4.17-4.89 (4H, m), 5.03 (1H, d, J = 49.3 Hz), 7.05 (1H, d, J = 2.0 Hz) , 7.12 (1H, dd, J = 8.2, 2.0 Hz), 7.27 (1H, d, J = 5.1 Hz), 7.54 (1H, d, J = 8.2 Hz), 7.61 (1H, d, J = 5.1 Hz) .
工程39(b)：2-[(3R,4S)-4-({4-[4-クロロ-2-(2-メトキシエトキシ)フェニル]チエノ[2,3-d]ピリダジン-7-イル}アミノ)-3-フルオロピペリジン-1-イル]-2-オキソアセタミドの製造
工程5(c)と同様にして、工程39(a)で得られた化合物(0.021g, 0.039mmol)、4規定塩酸-1,4-ジオキサン溶液(0.5mL)、オキサミン酸(0.004g, 0.05mmol)、O-(7-アザ-1H-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　ヘキサフルオロホスフェート(0.016g, 0.043mmol)およびトリエチルアミン (0.033mL, 0.24mmol)を用いて、標記化合物(0.012g, 0.02 mmol, 60%)を固体として得た。
LCMS (ES): m/z 508 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 1.95-2.27 (2H, m), 2.94-3.28 (2H, m), 3.08 (3H, s), 3.36-3.67 (1H, m), 3.47 (2H, t, J = 4.5 Hz), 4.13 (2H, t, J = 4.5 Hz), 4.17-4.53 (1H, m), 4.59-4.85 (2H, m), 5.15 (1H, dd, J = 48.7, 24.4 Hz), 7.14 (1H, dd, J = 8.2, 2.0 Hz), 7.20-7.27 (2H, m), 7.42 (1H, dd, J = 8.2, 1.2 Hz), 8.26 (1H, dd, J = 5.5, 1.2 Hz). Step 39 (b): 2-[(3R, 4S) -4-({4- [4-Chloro-2- (2-methoxyethoxy) phenyl] thieno [2,3-d] pyridazin-7-yl} Amino) -3-fluoropiperidin-1-yl] -2-oxoacetamide In the same manner as in Step 5 (c), the compound obtained in Step 39 (a) (0.021 g, 0.039 mmol), 4N hydrochloric acid- 1,4-dioxane solution (0.5 mL), oxamic acid (0.004 g, 0.05 mmol), O- (7-aza-1H-benzotriazol-1-yl) -N, N, N ′, N′-tetramethyl The title compound (0.012 g, 0.02 mmol, 60%) was obtained as a solid using uronium hexafluorophosphate (0.016 g, 0.043 mmol) and triethylamine (0.033 mL, 0.24 mmol).
LCMS (ES): m / z 508 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 1.95-2.27 (2H, m), 2.94-3.28 (2H, m), 3.08 (3H, s), 3.36-3.67 (1H, m), 3.47 (2H , t, J = 4.5 Hz), 4.13 (2H, t, J = 4.5 Hz), 4.17-4.53 (1H, m), 4.59-4.85 (2H, m), 5.15 (1H, dd, J = 48.7, 24.4 Hz), 7.14 (1H, dd, J = 8.2, 2.0 Hz), 7.20-7.27 (2H, m), 7.42 (1H, dd, J = 8.2, 1.2 Hz), 8.26 (1H, dd, J = 5.5, 1.2 Hz).
（実施例４０）
2-(4-{[8-フルオロ-1-(4-フルオロ-2-メトキシフェニル)2-オキソ-1,2-ジヒドロキナゾリン-4-イル]アミノ}-3-メチルフェニル)アセタミド (Example 40)
2- (4-{[8-Fluoro-1- (4-fluoro-2-methoxyphenyl) 2-oxo-1,2-dihydroquinazolin-4-yl] amino} -3-methylphenyl) acetamide
Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083
工程40(a)：2,3-ジフルオロ-N-[(4-フルオロ-2-メトキシフェニル)カルバモイル]ベンザミドの製造
2,3-ジフルオロベンズアミド(2.0g, 13mmol)を1,2-ジクロロエタン(20 mL)に溶解し、オキサリルクロリド(1.6 mL, 2.4 mmol)を加え、90℃で3時間攪拌した。反応液を濃縮し、得られた残渣を1,4-ジオキサン(100 mL)に溶解した。反応液に、4-フルオロ-2-メトキシアニリン(1.8g, 13mmol)を加え、室温で5時間攪拌した。反応液に水を加えて、析出した固体をろ取し、50℃で減圧乾燥した。得られた粗生成物(2.1g)は精製することなく次の反応に使用した。 Step 40 (a): Preparation of 2,3-difluoro-N-[(4-fluoro-2-methoxyphenyl) carbamoyl] benzamide
2,3-Difluorobenzamide (2.0 g, 13 mmol) was dissolved in 1,2-dichloroethane (20 mL), oxalyl chloride (1.6 mL, 2.4 mmol) was added, and the mixture was stirred at 90 ° C. for 3 hr. The reaction mixture was concentrated, and the resulting residue was dissolved in 1,4-dioxane (100 mL). 4-Fluoro-2-methoxyaniline (1.8 g, 13 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration and dried at 50 ° C. under reduced pressure. The obtained crude product (2.1 g) was used in the next reaction without purification.
工程40(b)：8-フルオロ-1-(4-フルオロ-2-メトキシフェニル)キナゾリン-2,4(1H,3H)-ジオンの製造
工程40(a)で得られた化合物(2.1g)をN,N-ジメチルホルムアミド(15mL)に懸濁させ、水素化ナトリウム(0.57g, 14mmol)を加え、70℃で5時間攪拌した。反応液に、１規定塩酸を加え、析出した固体をろ取し、水で洗浄した。得られた固体を50℃で減圧乾燥し、標記化合物の粗生成物(2.23g)を得た。得られた固体は精製することなく次の反応に使用した。
LCMS (ES): m/z 305 [M+H]+. Step 40 (b): Preparation of 8-fluoro-1- (4-fluoro-2-methoxyphenyl) quinazoline-2,4 (1H, 3H) -dione Compound (2.1 g) obtained in Step 40 (a) Was suspended in N, N-dimethylformamide (15 mL), sodium hydride (0.57 g, 14 mmol) was added, and the mixture was stirred at 70 ° C. for 5 hr. 1N Hydrochloric acid was added to the reaction mixture, and the precipitated solid was collected by filtration and washed with water. The obtained solid was dried under reduced pressure at 50 ° C. to obtain a crude product (2.23 g) of the title compound. The obtained solid was used for the next reaction without purification.
LCMS (ES): m / z 305 [M + H] + .
工程40(c)：4-(エチルスルファニル)-8-フルオロ-1-(4-フルオロ-2-メトキシフェニル)キナゾリン-2(1H)-オンの製造
工程40(b)で得られた化合物(2.23g)に、ピリジン(20mL)と1,3-ジチオキソジホスファチアン　1,3-ジスルフィド(4.3g, 19mmol)を加え、110℃で10時間攪拌した。反応液を室温まで冷却し、１規定塩酸を加え、析出した固体をろ取し、酢酸エチルで洗浄後、50℃で減圧乾燥した。得られた固体をテトラヒドロフラン(20mL)、水(20mL)に溶解し、炭酸カリウム(5.07g, 36.7mmol)、ヨードエタン(1.17mL, 14.7mmol)を加え、室温で5時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧下で溶媒を留去し、標記化合物の粗生成物(2.0g)を得た。得られた固体は精製することなく次の反応に使用した。
LCMS (ES): m/z 349 [M+H]+. Step 40 (c): Preparation of 4- (ethylsulfanyl) -8-fluoro-1- (4-fluoro-2-methoxyphenyl) quinazolin-2 (1H) -one Compound obtained in Step 40 (b) ( Pyridine (20 mL) and 1,3-dithioxodiphosphatian 1,3-disulfide (4.3 g, 19 mmol) were added to 2.23 g), and the mixture was stirred at 110 ° C. for 10 hours. The reaction mixture was cooled to room temperature, 1N hydrochloric acid was added, the precipitated solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure at 50 ° C. The obtained solid was dissolved in tetrahydrofuran (20 mL) and water (20 mL), potassium carbonate (5.07 g, 36.7 mmol) and iodoethane (1.17 mL, 14.7 mmol) were added, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (2.0 g) of the title compound. The obtained solid was used for the next reaction without purification.
LCMS (ES): m / z 349 [M + H] + .
工程40(d)：2-(4-{[8-フルオロ-1-(4-フルオロ-2-メトキシフェニル)2-オキソ-1,2-ジヒドロキナゾリン-4-イル]アミノ}-3-メチルフェニル)アセタミドの製造
工程29(e)と同様にして、工程40(c)で得られた化合物(75mg, 0.22mmol)と、2-(4-アミノ-3-メチルフェニル)アセタミド(106mg, 0.65mmol)、酢酸(3mL)を用いて、標記化合物(80mg, 0.18mmol, 83%)を固体として得た。
LCMS (ES): m/z 451 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 2.28 (3H, s), 3.49 (2H, s), 3.72 (3H, s), 6.72 (1H, td, J = 8.4, 2.6 Hz), 6.89 (1H, dt, J = 12.4, 4.6 Hz), 7.16-7.40 (6H, m), 8.06 (1H, d, J = 8.3 Hz). Step 40 (d): 2- (4-{[8-Fluoro-1- (4-fluoro-2-methoxyphenyl) 2-oxo-1,2-dihydroquinazolin-4-yl] amino} -3-methyl (Phenyl) acetamide In the same manner as in Step 29 (e), the compound obtained in Step 40 (c) (75 mg, 0.22 mmol) and 2- (4-amino-3-methylphenyl) acetamide (106 mg, 0.65 mmol) and acetic acid (3 mL) were used to obtain the title compound (80 mg, 0.18 mmol, 83%) as a solid.
LCMS (ES): m / z 451 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 2.28 (3H, s), 3.49 (2H, s), 3.72 (3H, s), 6.72 (1H, td, J = 8.4, 2.6 Hz), 6.89 ( 1H, dt, J = 12.4, 4.6 Hz), 7.16-7.40 (6H, m), 8.06 (1H, d, J = 8.3 Hz).
（実施例４１）
2-(4-{[1-(4-クロロ-2-メトキシフェニル)-7-フルオロ-2-オキソ-1,2-ジヒドロキナゾリン-4-イル]アミノ}-3-メチルフェニル)アセタミド (Example 41)
2- (4-{[1- (4-Chloro-2-methoxyphenyl) -7-fluoro-2-oxo-1,2-dihydroquinazolin-4-yl] amino} -3-methylphenyl) acetamide
Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000084
工程41(a)：メチル 2-[(4-クロロ-2-メトキシフェニル)アミノ]-4-フルオロベンゾエートの製造
メチル 2-アミノ-4-フルオロ-ベンゾエート(1.50g, 8.87mmol)、および1-ブロモ-4-クロロ-2-メトキシベンゼン(2.06g, 9.31mmol)を1,4-ジオキサン(30mL)に溶解し、酢酸パラジウム(0.205g, 0.887mmol)、炭酸セシウム(4.05g, 12.4mmol)、およびジシクロヘキシル-[3,6-ジメトキシ-2-(2,4,6-トリイソプロピルフェニル)フェニル]ホスフィン(Brettphos)(0.952g, 1.77mmol)を加え、窒素雰囲気下100℃にて4時間加熱攪拌した。反応液に水および酢酸エチルを加え、有機層を抽出し食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下溶媒を留去し、得られた残渣をシリカカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝100/0-30/70(V/V)］にて精製し、標記化合物(3.55g, 8.93mmol, 100%)を固体として得た。
1H NMR (CDCl3) δ (ppm): 3.88 (3H, s), 3.90 (3H, s), 6.41-6.46 (1H, m), 6.81 (1H, dd, J = 12.1, 2.3 Hz), 6.93-6.96 (2H, m), 7.30 (1H, d, J = 8.6 Hz), 7.97 (1H, dd, J = 9.0, 6.7 Hz), 9.55 (1H, s).  Step 41 (a): Preparation of methyl 2-[(4-chloro-2-methoxyphenyl) amino] -4-fluorobenzoate Methyl 2-amino-4-fluoro-benzoate (1.50 g, 8.87 mmol), and 1- Bromo-4-chloro-2-methoxybenzene (2.06 g, 9.31 mmol) dissolved in 1,4-dioxane (30 mL), palladium acetate (0.205 g, 0.887 mmol), cesium carbonate (4.05 g, 12.4 mmol), And dicyclohexyl- [3,6-dimethoxy-2- (2,4,6-triisopropylphenyl) phenyl] phosphine (Brettphos) (0.952 g, 1.77 mmol) were added, and the mixture was heated and stirred at 100 ° C. for 4 hours under a nitrogen atmosphere. did. Water and ethyl acetate were added to the reaction solution, and the organic layer was extracted, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica kagel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-30 / 70 (V / V)] to give the title compound (3.55 g , 8.93 mmol, 100%) was obtained as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 3.88 (3H, s), 3.90 (3H, s), 6.41-6.46 (1H, m), 6.81 (1H, dd, J = 12.1, 2.3 Hz), 6.93 -6.96 (2H, m), 7.30 (1H, d, J = 8.6 Hz), 7.97 (1H, dd, J = 9.0, 6.7 Hz), 9.55 (1H, s).
工程41(b)：1-(4-クロロ-2-メトキシフェニル)-7-フルオロキナゾリン-2,4(1H,3H)-ジオンの製造
工程41(a)で得られた化合物(3.546g, 8.931mmol)をテトラヒドロフラン／酢酸エチル混合溶媒(30mL/30 mL)に溶解し、-15℃に冷却後、N-(オキソメチレン)スルファニルクロリド(1.90g, 13.4mmol)を10分かけて滴下し同温で20分間撹拌した。反応液に水(10mL)を加えて反応を停止させ、徐々に室温に戻した。5％水酸化ナトリウム水溶液(50 mL)を加えた後、酢酸エチルを加えて有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、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［溶出溶媒：ジクロロメタン/メタノール＝95/5-90/10(V/V)］にて精製し、標記化合物(2.02g, 6.29mmol, 70.4%) を固体として得た。
1H NMR (CD3OD) δ (ppm): 3.81 (3H, s), 6.25 (1H, dd, J = 10.6, 2.3 Hz), 7.07-7.02 (1H, m), 7.20 (1H, dd, J = 8.2, 2.3 Hz), 7.33-7.36 (2H, m), 8.18 (1H, dd, J = 8.8, 6.1 Hz). Step 41 (b): Preparation of 1- (4-chloro-2-methoxyphenyl) -7-fluoroquinazoline-2,4 (1H, 3H) -dione The compound obtained in Step 41 (a) (3.546 g, 8.931 mmol) was dissolved in a tetrahydrofuran / ethyl acetate mixed solvent (30 mL / 30 mL), cooled to -15 ° C, and N- (oxomethylene) sulfanyl chloride (1.90 g, 13.4 mmol) was added dropwise over 10 minutes. Stir at warm for 20 minutes. Water (10 mL) was added to the reaction solution to stop the reaction, and the temperature was gradually returned to room temperature. 5% Aqueous sodium hydroxide solution (50 mL) was added, ethyl acetate was added, the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: dichloromethane / methanol = 95 / 5-90 / 10 (V / V)] to give the title compound (2.02 g, 6.29 mmol, 70.4%) as a solid. Obtained.
1 H NMR (CD 3 OD) δ (ppm): 3.81 (3H, s), 6.25 (1H, dd, J = 10.6, 2.3 Hz), 7.07-7.02 (1H, m), 7.20 (1H, dd, J = 8.2, 2.3 Hz), 7.33-7.36 (2H, m), 8.18 (1H, dd, J = 8.8, 6.1 Hz).
工程41(c)：1-(4-クロロ-2-メトキシフェニル)-4-(エチルスルファニル)-7-フルオロキナゾリン-2(1H)-オンの製造
工程41(b)で得られた化合物(2.02g, 6.29mmol)をピリジン(30mL)に溶解し、五硫化二りん(1.68g, 7.54mmol)を加え、120℃にて5時間加熱撹拌した。反応液を減圧下、溶媒留去して得られた残渣に酢酸エチルを加えて希釈し、有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、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［溶出溶媒：ヘキサン/酢酸エチル＝90/10-50/50(V/V)］にて精製し、粗生成物(2.12g)を得た。これをテトラヒドロフラン／水(5mL/5mL)に溶解させ、ヨードエタン(2.45g, 15.7mmol)および炭酸カリウム(4.34g, 31.4mmol)を加え、室温にて終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、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［溶出溶媒：ヘキサン/酢酸エチル＝90/10-50/50(V/V)］にて精製し、標記化合物(1.80g, 4.34mmol, 78.5%)を固体として得た。
1H NMR (CDCl3) δ (ppm): 1.45 (3H, t, J = 7.4 Hz), 3.36-3.44 (2H, m), 3.76 (3H, s), 6.24-6.27 (1H, m), 6.92-6.87 (1H, m), 7.11-7.19 (3H, m), 7.99 (1H, dd, J = 8.8, 5.7 Hz). Step 41 (c): Preparation of 1- (4-chloro-2-methoxyphenyl) -4- (ethylsulfanyl) -7-fluoroquinazolin-2 (1H) -one Compound obtained in Step 41 (b) ( 2.02 g, 6.29 mmol) was dissolved in pyridine (30 mL), diphosphorus pentasulfide (1.68 g, 7.54 mmol) was added, and the mixture was heated with stirring at 120 ° C. for 5 hours. The reaction solution was evaporated under reduced pressure to dilute the residue obtained by adding ethyl acetate, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-50 / 50 (V / V)] to give a crude product (2.12 g). This was dissolved in tetrahydrofuran / water (5 mL / 5 mL), iodoethane (2.45 g, 15.7 mmol) and potassium carbonate (4.34 g, 31.4 mmol) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-50 / 50 (V / V)] to give the title compound (1.80 g, 4.34 mmol, 78.5%) as a solid Got as.
1 H NMR (CDCl 3 ) δ (ppm): 1.45 (3H, t, J = 7.4 Hz), 3.36-3.44 (2H, m), 3.76 (3H, s), 6.24-6.27 (1H, m), 6.92 -6.87 (1H, m), 7.11-7.19 (3H, m), 7.99 (1H, dd, J = 8.8, 5.7 Hz).
工程41(d)：2-(4-{[1-(4-クロロ-2-メトキシフェニル)-7-フルオロ-2-オキソ-1,2-ジヒドロキナゾリン-4-イル]アミノ}-3-メチルフェニル)アセタミドの製造
工程41(c)で得られた化合物(100mg, 0.274mmol)を酢酸(2mL)に溶解し2-(4-アミノ-3-メチル－フェニル)アセタミド(50mg, 0.30mmol)を加え、135℃にて1.5時間撹拌した。反応液に酢酸エチルを加えて有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、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［溶出溶媒：ジクロロメタン/メタノール＝100/0-90/10(V/V)］にて精製し、標記化合物(84.3mg, 0.181mmol, 65.9%)を固体として得た。
LCMS (ES): m/z 450 [M+H]+.
1H NMR (CD3OD) δ (ppm): 2.30 (3H, s), 3.52 (2H, s), 3.77 (3H, s), 6.30 (1H, d, J = 7.8 Hz), 7.30-7.08 (7H, m), 8.32 (1H, dd, J = 8.6, 5.5 Hz).  Step 41 (d): 2- (4-{[1- (4-Chloro-2-methoxyphenyl) -7-fluoro-2-oxo-1,2-dihydroquinazolin-4-yl] amino} -3- Methylphenyl) acetamide Compound (100 mg, 0.274 mmol) obtained in Step 41 (c) was dissolved in acetic acid (2 mL) to give 2- (4-amino-3-methyl-phenyl) acetamide (50 mg, 0.30 mmol) And stirred at 135 ° C. for 1.5 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: dichloromethane / methanol = 100 / 0-90 / 10 (V / V)] to give the title compound (84.3 mg, 0.181 mmol, 65.9%) as a solid Obtained.
LCMS (ES): m / z 450 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 2.30 (3H, s), 3.52 (2H, s), 3.77 (3H, s), 6.30 (1H, d, J = 7.8 Hz), 7.30-7.08 ( 7H, m), 8.32 (1H, dd, J = 8.6, 5.5 Hz).
（実施例４２）
2-[4-({7-フルオロ-1-[4-フルオロ-2-(ピリジン-2-イルメトキシ)フェニル]-2-オキソ-1,2-ジヒドロキナゾリン-4-イル}アミノ)-3-メチルフェニル)アセタミド (Example 42)
2- [4-({7-Fluoro-1- [4-fluoro-2- (pyridin-2-ylmethoxy) phenyl] -2-oxo-1,2-dihydroquinazolin-4-yl} amino) -3- Methylphenyl) acetamide
Figure JPOXMLDOC01-appb-C000085
Figure JPOXMLDOC01-appb-C000085
工程42(a)：メチル 4-フルオロ-2-[(4-フルオロ-2-メトキシフェニル)アミノ]ベンゾエートの製造
メチル 2-アミノ-4-フルオロ-ベンゾエート(5.00g, 29.6mmol)、および1-ブロモ-4-フルオロ-2-メトキシベンゼン(6.36g, 31.0mmol)を1,4-ジオキサン(100mL)に溶解し、酢酸パラジウム(0.342g, 0.148mmol)、炭酸セシウム(13.5g, 41.4mmol)、およびジシクロヘキシル-[3,6-ジメトキシ-2-(2,4,6-トリイソプロピルフェニル)フェニル]ホスフィン(Brettphos)(1.59g, 2.96mmol)を加え、窒素雰囲気下100℃にて4.5時間加熱攪拌した。減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝100/0-20/80(V/V)］にて精製し、標記化合物(7.91g, 21.3mmol, 72.1%)を固体として得た。
1H NMR (CDCl3) δ (ppm): 3.84 (3H, s), 3.90 (3H, s), 6.37-6.41 (1H, m), 6.61-6.72 (3H, m), 7.26-7.29 (1H, m), 7.96 (1H, dd, J = 9.0, 6.7 Hz), 9.38 (1H, s).  Step 42 (a): Preparation of methyl 4-fluoro-2-[(4-fluoro-2-methoxyphenyl) amino] benzoate Methyl 2-amino-4-fluoro-benzoate (5.00 g, 29.6 mmol), and 1- Bromo-4-fluoro-2-methoxybenzene (6.36 g, 31.0 mmol) dissolved in 1,4-dioxane (100 mL), palladium acetate (0.342 g, 0.148 mmol), cesium carbonate (13.5 g, 41.4 mmol), And dicyclohexyl- [3,6-dimethoxy-2- (2,4,6-triisopropylphenyl) phenyl] phosphine (Brettphos) (1.59 g, 2.96 mmol) were added, and the mixture was heated and stirred at 100 ° C. for 4.5 hours under a nitrogen atmosphere. did. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-20 / 80 (V / V)] to give the title compound (7.91 g, 21.3 mmol, 72.1%) was obtained as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 3.84 (3H, s), 3.90 (3H, s), 6.37-6.41 (1H, m), 6.61-6.72 (3H, m), 7.26-7.29 (1H, m), 7.96 (1H, dd, J = 9.0, 6.7 Hz), 9.38 (1H, s).
工程42(b)：7-フルオロ-1-(4-フルオロ-2-メトキシフェニル)キナゾリン-2,4(1H,3H)-ジオンの製造
工程42(a)で得られた化合物(7.91g, 27.0mmol)をテトラヒドロフラン／酢酸エチル混合溶媒(60mL/60mL)に溶解し、-15℃に冷却後、N-(オキソメチレン)スルファニルクロリド(4.10g, 29.0mmol)を10分かけて滴下し同温で40分間撹拌した。反応液に水(10mL)を加えて反応を停止させ、徐々に室温に戻した。5％水酸化ナトリウム水溶液(100 mL)を加えて終夜撹拌後、60℃に昇温して4時間加熱撹拌した。室温に放冷したのち生じた懸濁液を吸引ろ過し、固体をろ取した。ろ液に酢酸エチルを加えて有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、減圧下溶媒を留去した。得られた固体とろ取した固体を合わせて真空乾燥させ、標記化合物(8.48g, 27.9mmol, 100%)を固体として得た。
1H NMR (CD3OD) δ (ppm): 3.81 (3H, s), 6.26 (1H, dd, J = 10.2, 2.3 Hz), 6.88-6.91 (2H, m), 6.98 (1H, ddd, J = 9.4, 7.0, 1.6 Hz), 7.27-7.30 (1H, m), 8.25 (1H, dd, J = 8.6, 6.3 Hz), 8.32 (1H, br s). Step 42 (b): Preparation of 7-fluoro-1- (4-fluoro-2-methoxyphenyl) quinazoline-2,4 (1H, 3H) -dione The compound obtained in Step 42 (a) (7.91 g, 27.0 mmol) was dissolved in a tetrahydrofuran / ethyl acetate mixed solvent (60 mL / 60 mL), cooled to -15 ° C, and N- (oxomethylene) sulfanyl chloride (4.10 g, 29.0 mmol) was added dropwise over 10 minutes at the same temperature. For 40 minutes. Water (10 mL) was added to the reaction solution to stop the reaction, and the temperature was gradually returned to room temperature. 5% Aqueous sodium hydroxide solution (100 mL) was added and the mixture was stirred overnight, then heated to 60 ° C. and stirred with heating for 4 hours. The resulting suspension was allowed to cool to room temperature, and the resulting suspension was filtered with suction, and the solid was collected by filtration. Ethyl acetate was added to the filtrate, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid and the collected solid were combined and dried under vacuum to obtain the title compound (8.48 g, 27.9 mmol, 100%) as a solid.
1 H NMR (CD 3 OD) δ (ppm): 3.81 (3H, s), 6.26 (1H, dd, J = 10.2, 2.3 Hz), 6.88-6.91 (2H, m), 6.98 (1H, ddd, J = 9.4, 7.0, 1.6 Hz), 7.27-7.30 (1H, m), 8.25 (1H, dd, J = 8.6, 6.3 Hz), 8.32 (1H, br s).
工程42(c)：4-(エチルスルファニル)-7-フルオロキナゾリン-1-(4-フルオロ-2-メトキシフェニル)-2(1H)-オンの製造
工程42(b)で得られた化合物(8.25g, 27.1mmol)をピリジン(60mL)に溶解し、五硫化二りん(7.23g, 32.5mmol)を加え、120℃にて5時間加熱撹拌した。反応液を減圧下、溶媒留去して得られた残渣に酢酸エチルを加えて希釈し、有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、減圧下溶媒を留去し、粗生成物のチオカルボニル体(7.2g）を得た。これをテトラヒドロフラン／水混合溶媒(60mL/30mL)に溶解させ、ヨードエタン(12.7g, 81.3mmol)および炭酸カリウム(18.7g, 135mmol)を加え、室温にて終夜撹拌した。反応混合物に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、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［溶出溶媒：ヘキサン/酢酸エチル＝85/15-50/50(V/V)］にて精製し、標記化合物(5.86g, 16.8mmol, 75.3%)を固体として得た。
1H NMR (CDCl3) δ (ppm): 1.45 (3H, t, J = 7.4 Hz), 3.36-3.44 (2H, m), 3.75 (3H, s), 6.25 (1H, dd, J = 10.6, 2.3 Hz), 6.83-7.00 (3H, m), 7.21 (1H, dd, J = 9.2, 6.1 Hz), 7.99 (1H, dd, J = 9.0, 5.9 Hz). Step 42 (c): Preparation of 4- (ethylsulfanyl) -7-fluoroquinazolin-1- (4-fluoro-2-methoxyphenyl) -2 (1H) -one The compound obtained in Step 42 (b) ( 8.25 g, 27.1 mmol) was dissolved in pyridine (60 mL), diphosphorus pentasulfide (7.23 g, 32.5 mmol) was added, and the mixture was heated with stirring at 120 ° C. for 5 hours. The reaction solution was evaporated under reduced pressure to dilute the residue obtained by adding ethyl acetate, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. A crude product thiocarbonyl (7.2 g) was obtained. This was dissolved in a tetrahydrofuran / water mixed solvent (60 mL / 30 mL), iodoethane (12.7 g, 81.3 mmol) and potassium carbonate (18.7 g, 135 mmol) were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 85 / 15-50 / 50 (V / V)] to give the title compound (5.86 g, 16.8 mmol, 75.3%) as a solid Got as.
1 H NMR (CDCl 3 ) δ (ppm): 1.45 (3H, t, J = 7.4 Hz), 3.36-3.44 (2H, m), 3.75 (3H, s), 6.25 (1H, dd, J = 10.6, 2.3 Hz), 6.83-7.00 (3H, m), 7.21 (1H, dd, J = 9.2, 6.1 Hz), 7.99 (1H, dd, J = 9.0, 5.9 Hz).
工程42(d)：4-(エチルスルファニル)-7-フルオロ-1-(4-フルオロ-2-ヒドロキシフェニル)キナゾリン-2(1H)-オンの製造
工程42(c)で得られた化合物(0.833g, 2.39mmol)をジクロロエタン(30mL)に溶解し、0℃に冷却後、三臭化ホウ素／ジクロロメタン溶液(1.0M, 3.00mL, 3.00mmol)を滴下した後、1.5時間加熱還流撹拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えた後、酢酸エチルを加えて有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、減圧下溶媒を留去した。得られた粗生成物をジクロロメタン／ヘキサンにて固化させ、生じた固体を吸引ろ過して真空乾燥させることで、標記化合物(0.830g, 2.39mmol, 100%)を固体として得た。
1H NMR (CDCl3) δ (ppm): 1.45 (3H, t, J = 7.4 Hz), 3.38 (2H, q, J = 7.3 Hz), 6.37 (1H, dd, J = 10.2, 2.3 Hz), 6.79-6.83 (2H, m), 7.11-7.07 (1H, m), 7.23-7.27 (1H, m), 8.14 (1H, dd, J = 9.0, 5.9 Hz). Step 42 (d): Preparation of 4- (ethylsulfanyl) -7-fluoro-1- (4-fluoro-2-hydroxyphenyl) quinazolin-2 (1H) -one Compound obtained in Step 42 (c) ( 0.833 g, 2.39 mmol) was dissolved in dichloroethane (30 mL), cooled to 0 ° C., boron tribromide / dichloromethane solution (1.0 M, 3.00 mL, 3.00 mmol) was added dropwise, and the mixture was heated to reflux with stirring for 1.5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, ethyl acetate was added, the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was solidified with dichloromethane / hexane, and the resulting solid was suction filtered and vacuum dried to obtain the title compound (0.830 g, 2.39 mmol, 100%) as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 1.45 (3H, t, J = 7.4 Hz), 3.38 (2H, q, J = 7.3 Hz), 6.37 (1H, dd, J = 10.2, 2.3 Hz), 6.79-6.83 (2H, m), 7.11-7.07 (1H, m), 7.23-7.27 (1H, m), 8.14 (1H, dd, J = 9.0, 5.9 Hz).
工程42(e)：4-(エチルスルファニル)-7-フルオロ-1-[4-フルオロ-2-(ピリジン-2-イルメトキシ)フェニル]キナゾリン-2(1H)-オンの製造
工程42(d)で得られた化合物(90mg, 0.27mmol)をトルエン(5mL)に溶解し、2-ピリジルメタノール(59mg, 0.54mmol)、1,1’-(アゾジカルボニル）ジピペリジン(135mg, 0.54mmol)、およびトリ-n-ブチルホスフィン(0.134mL, 0.54mmol)を加えて終夜撹拌した。反応液に水および酢酸エチルを加えて有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、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［溶出溶媒：ヘキサン/酢酸エチル＝85/15-60/40(V/V)］にて精製し、標記化合物(111mg, 0.26mmol, 97%)を固体として得た。
1H NMR (CDCl3) δ (ppm): 1.46 (3H, t, J = 7.4 Hz), 3.37-3.48 (2H, m), 5.20 (2H, s), 6.33 (1H, dd, J = 10.4, 2.5 Hz), 6.79-6.95 (4H, m), 7.18 (1H, t, J = 6.3 Hz), 7.23 (1H, t, J = 2.9 Hz), 7.61 (1H, td, J = 7.7, 1.7 Hz), 8.01 (1H, dd, J = 9.0, 5.5 Hz), 8.52 (1H, d, J = 4.7 Hz). Step 42 (e): Step 42 (d) for the production of 4- (ethylsulfanyl) -7-fluoro-1- [4-fluoro-2- (pyridin-2-ylmethoxy) phenyl] quinazolin-2 (1H) -one The compound (90 mg, 0.27 mmol) obtained in 1 was dissolved in toluene (5 mL), 2-pyridylmethanol (59 mg, 0.54 mmol), 1,1 ′-(azodicarbonyl) dipiperidine (135 mg, 0.54 mmol), and Tri-n-butylphosphine (0.134 mL, 0.54 mmol) was added and stirred overnight. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 85 / 15-60 / 40 (V / V)] to give the title compound (111 mg, 0.26 mmol, 97%) as a solid Obtained.
1 H NMR (CDCl 3 ) δ (ppm): 1.46 (3H, t, J = 7.4 Hz), 3.37-3.48 (2H, m), 5.20 (2H, s), 6.33 (1H, dd, J = 10.4, 2.5 Hz), 6.79-6.95 (4H, m), 7.18 (1H, t, J = 6.3 Hz), 7.23 (1H, t, J = 2.9 Hz), 7.61 (1H, td, J = 7.7, 1.7 Hz) , 8.01 (1H, dd, J = 9.0, 5.5 Hz), 8.52 (1H, d, J = 4.7 Hz).
工程42(f)：2-[4-({7-フルオロ-1-[4-フルオロ-2-(ピリジン-2-イルメトキシ)フェニル]-2-オキソ-1,2-ジヒドロキナゾリン-4-イル}アミノ)-3-メチルフェニル)アセタミドの製造
工程41(d)と同様の手順に従い、工程42(e)で得られた化合物(111mg, 0.26mmol)、2-(4-アミノ-3-メチル-フェニル)アセタミド(50mg, 0.30mmol)および酢酸(2mL)を用いて標記化合物(90mg, 0.17mmol, 65%)を固体として得た。
LCMS (ES): m/z 527 [M+H]+.
1H NMR (CDCl3) δ (ppm): 2.09 (3H, s), 2.19 (3H, s), 3.57 (2H, s), 5.22 (2H, s), 5.51-5.61 (2H, br m), 6.22 (1H, dd, J = 10.4, 2.2 Hz), 6.84-6.88 (3H, m), 6.92-6.97 (1H, m), 7.13-7.16 (2H, m), 7.19-7.22 (2H, m), 7.28-7.32 (1H, m), 7.61-7.57 (1H, m), 7.71 (1H, br s), 8.44 (1H, dd, J = 9.0, 6.3 Hz), 8.55 (1H, d, J = 4.7 Hz). Step 42 (f): 2- [4-({7-Fluoro-1- [4-fluoro-2- (pyridin-2-ylmethoxy) phenyl] -2-oxo-1,2-dihydroquinazolin-4-yl } Preparation of amino) -3-methylphenyl) acetamide According to the same procedure as in Step 41 (d), the compound obtained in Step 42 (e) (111 mg, 0.26 mmol), 2- (4-amino-3-methyl The title compound (90 mg, 0.17 mmol, 65%) was obtained as a solid using -phenyl) acetamide (50 mg, 0.30 mmol) and acetic acid (2 mL).
LCMS (ES): m / z 527 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 2.09 (3H, s), 2.19 (3H, s), 3.57 (2H, s), 5.22 (2H, s), 5.51-5.61 (2H, br m), 6.22 (1H, dd, J = 10.4, 2.2 Hz), 6.84-6.88 (3H, m), 6.92-6.97 (1H, m), 7.13-7.16 (2H, m), 7.19-7.22 (2H, m), 7.28-7.32 (1H, m), 7.61-7.57 (1H, m), 7.71 (1H, br s), 8.44 (1H, dd, J = 9.0, 6.3 Hz), 8.55 (1H, d, J = 4.7 Hz ).
（実施例４３）
1-(4-クロロ-2-エトキシフェニル)-7-フルオロ-4-{[2-メチル-3-(2-オキソイミダゾリジン-1-イル)フェニル]アミノ}キナゾリン-2(1H)-オン (Example 43)
1- (4-Chloro-2-ethoxyphenyl) -7-fluoro-4-{[2-methyl-3- (2-oxoimidazolidin-1-yl) phenyl] amino} quinazolin-2 (1H) -one
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086
工程43(a)：1-(4-クロロ-2-ヒドロキシフェニル)-4-(エチルスルファニル)-7-フルオロキナゾリン-2(1H)-オンの製造
工程41(c)で得られた化合物(8.51g, 23.3mmol)を1,2-ジクロロエタン(85.1ml)に溶解させ、三臭化ホウ素／ジクロロメタン溶液(1.0 Mジクロロメタン, 28.0ml, 28.0mmol)を室温にて少量ずつ加え、80℃で14時間攪拌した。反応液を飽和炭酸水素ナトリウム水溶液(200ml)に注ぎ込んで中和し、ジクロロメタン／イソプロピルアルコール(=4/1)混合液で(200mlで3回)抽出し、有機層を合わせ、混合液量を150mlまで減圧濃縮した後に、ジエチルエーテル（150ml）を加えて生じた沈殿をろ取し、減圧乾燥することで標記化合物(6.89g, 19.6mmol, 84%)を固体として得た。
LCMS (ES): m/z 351 [M+H]+.
1H NMR (CDCl3) δ(ppm): 1.27 (3H, t, J = 7.2 Hz), 2.27 (3H, s), 3.83 (6H, s), 4.18 (2H, q, J = 7.2 Hz), 4.55 (2H, s), 5.91-5.92 (1H, m), 6.06-6.07 (1H, m), 6.64 (2H, d, J = 8.3 Hz), 7.28 (1H, s), 7.30 (1H, t, J = 8.3 Hz). 1H NMR (DMSO-D6) δ(ppm): 1.40 (3H, t, J = 7.2 Hz), 3.34 (2H, q, J = 23.6 Hz), 6.34 (1H, dd, J = 10.8, 2.5 Hz), 7.09 (1H, dd, J = 8.6, 2.3 Hz), 7.13 (1H, d, J = 2.6 Hz), 7.19 (1H, td, J = 8.6, 2.3 Hz), 7.36 (1H, d, J = 8.6 Hz), 8.10 (1H, dd, J = 9.0, 5.9 Hz), 10.46 (1H, s). Step 43 (a): Preparation of 1- (4-chloro-2-hydroxyphenyl) -4- (ethylsulfanyl) -7-fluoroquinazolin-2 (1H) -one The compound obtained in Step 41 (c) ( 8.51 g, 23.3 mmol) was dissolved in 1,2-dichloroethane (85.1 ml), and a boron tribromide / dichloromethane solution (1.0 M dichloromethane, 28.0 ml, 28.0 mmol) was added in portions at room temperature. Stir for hours. The reaction mixture was neutralized by pouring into saturated aqueous sodium hydrogen carbonate (200 ml), extracted with a dichloromethane / isopropyl alcohol (= 4/1) mixture (3 times with 200 ml), the organic layers were combined, and the amount of the mixture was 150 ml. After concentration under reduced pressure, diethyl ether (150 ml) was added and the resulting precipitate was collected by filtration and dried under reduced pressure to give the title compound (6.89 g, 19.6 mmol, 84%) as a solid.
LCMS (ES): m / z 351 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.27 (3H, t, J = 7.2 Hz), 2.27 (3H, s), 3.83 (6H, s), 4.18 (2H, q, J = 7.2 Hz), 4.55 (2H, s), 5.91-5.92 (1H, m), 6.06-6.07 (1H, m), 6.64 (2H, d, J = 8.3 Hz), 7.28 (1H, s), 7.30 (1H, t, 1 H NMR (DMSO-D 6 ) δ (ppm): 1.40 (3H, t, J = 7.2 Hz), 3.34 (2H, q, J = 23.6 Hz), 6.34 (1H, dd, J = 10.8, 2.5 Hz), 7.09 (1H, dd, J = 8.6, 2.3 Hz), 7.13 (1H, d, J = 2.6 Hz), 7.19 (1H, td, J = 8.6, 2.3 Hz), 7.36 ( 1H, d, J = 8.6 Hz), 8.10 (1H, dd, J = 9.0, 5.9 Hz), 10.46 (1H, s).
工程43(b)：1-(4-クロロ-2-エトキシフェニル)-4-(エチルスルファニル)-7-フルオロキナゾリン-2(1H)-オンの製造
工程43(a)で得られた化合物(1.89g, 5.39mmol)をN,N-ジメチルホルムアミド(37.8ml)に溶解させ、炭酸カリウム(2.23g, 16.2mmol)および、ヨードエタン(0.646ml, 8.08mmol)を加えて室温で終夜攪拌した。反応混合液を減圧濃縮し、残渣に飽和塩化アンモニウム水溶液(150ml)を加え、沈殿をろ取して減圧乾燥することで、標記化合物(1.25g, 3.30mmol, 61%)を固体として得た。
1H NMR (CDCl3) δ(ppm): 1.20 (3H, t, J = 7.0 Hz), 1.46 (3H, t, J = 7.0 Hz), 3.34-3.49 (2H, m), 3.99-4.08 (2H, m), 6.90 (1H, ddd, J = 9.6, 7.2, 1.8 Hz), 7.11 (1H, dd, J = 10.2, 2.0 Hz), 7.18 (1H, d, J = 7.8 Hz), 7.99 (1H, dd, J = 9.0, 5.9 Hz). Step 43 (b): Preparation of 1- (4-chloro-2-ethoxyphenyl) -4- (ethylsulfanyl) -7-fluoroquinazolin-2 (1H) -one The compound obtained in Step 43 (a) ( 1.89 g, 5.39 mmol) was dissolved in N, N-dimethylformamide (37.8 ml), potassium carbonate (2.23 g, 16.2 mmol) and iodoethane (0.646 ml, 8.08 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, saturated aqueous ammonium chloride solution (150 ml) was added to the residue, the precipitate was collected by filtration and dried under reduced pressure to give the title compound (1.25 g, 3.30 mmol, 61%) as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 1.20 (3H, t, J = 7.0 Hz), 1.46 (3H, t, J = 7.0 Hz), 3.34-3.49 (2H, m), 3.99-4.08 (2H , m), 6.90 (1H, ddd, J = 9.6, 7.2, 1.8 Hz), 7.11 (1H, dd, J = 10.2, 2.0 Hz), 7.18 (1H, d, J = 7.8 Hz), 7.99 (1H, dd, J = 9.0, 5.9 Hz).
工程43(c)：1-(4-クロロ-2-エトキシフェニル)-7-フルオロ-4-{[2-メチル-3-(2-オキソイミダゾリジン-1-イル)フェニル]アミノ}キナゾリン-2(1H)-オンの製造
工程43(b)で得られた化合物(100mg, 0.264mmol)、1-(3-アミノ-2-メチルフェニル)イミダゾリジン-2-オン(50mg, 0.264mmol)の酢酸(3.00ml)溶液を120℃で1時間攪拌した。反応混合液を減圧濃縮し、分取用薄層クロマトグラフィー(Silicagel 70 PF254Plate-Wako, 3枚, ジクロロメタン／メタノール＝9／1)にて精製することで、標記化合物(78.7mg, 0.155mmol, 58.7%)を固体として得た。
LCMS (ES): m/z 508 [M+H]+
1H NMR (DMSO-D6) δ(ppm) : 1.09 (3H, t, J = 7.0 Hz), 1.91 (3H, s), 3.47 (2H, t, J = 7.8 Hz), 3.80 (2H, t, J = 7.8 Hz), 4.05-4.12 (2H, m), 6.24 (1H, d, J= 10.6 Hz), 6.71 (1H, br s), 7.16-7.39 (6H, m), 8.48 (1H, br s), 9.97 (1H, br s). 
（実施例４４）
2-{4-[(1-{4-クロロ-2-[(3-フルオロピリジン-2-イル)メトキシ]フェニル}-2-オキソ-1,2-ジヒドロキナゾリン-4-イル)アミノ]-3-メチルフェニル}アセタミド Step 43 (c): 1- (4-Chloro-2-ethoxyphenyl) -7-fluoro-4-{[2-methyl-3- (2-oxoimidazolidin-1-yl) phenyl] amino} quinazoline- Preparation of 2 (1H) -one Step 43 (b) (100 mg, 0.264 mmol), 1- (3-amino-2-methylphenyl) imidazolidin-2-one (50 mg, 0.264 mmol) The acetic acid (3.00 ml) solution was stirred at 120 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure and purified by preparative thin layer chromatography (Silicagel 70 PF 254 Plate-Wako, 3 plates, dichloromethane / methanol = 9/1) to give the title compound (78.7 mg, 0.155 mmol , 58.7%) was obtained as a solid.
LCMS (ES): m / z 508 [M + H] +
1 H NMR (DMSO-D 6 ) δ (ppm): 1.09 (3H, t, J = 7.0 Hz), 1.91 (3H, s), 3.47 (2H, t, J = 7.8 Hz), 3.80 (2H, t , J = 7.8 Hz), 4.05-4.12 (2H, m), 6.24 (1H, d, J = 10.6 Hz), 6.71 (1H, br s), 7.16-7.39 (6H, m), 8.48 (1H, br s), 9.97 (1H, br s).
(Example 44)
2- {4-[(1- {4-Chloro-2-[(3-fluoropyridin-2-yl) methoxy] phenyl} -2-oxo-1,2-dihydroquinazolin-4-yl) amino]- 3-methylphenyl} acetamide
Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087
工程44(a)：メチル 2-[(4-クロロ-2-メトキシフェニル)アミノ]ベンゾエートの製造
1-ブロモ-4-クロロ-2-メトキシベンゼン(10.0g, 45.0mmol)を1,4-ジオキサン(250mL)に溶解し、メチル2-アミノベンゾエート(6.8g, 45.0mmol)、酢酸パラジウム(II)(0.50g, 2.2mmol)、ジシクロヘキシル[3,6-ジメトキシ-2’,4’,6’-トリ(プロパン-2-イル)ビフェニル-2-イル]ホスファン(2.4g, 4.5mmol)、炭酸セシウム(21.0g, 63.0mmol)を加え、100℃で12時間攪拌した。反応液中の不溶物を酢酸エチルを用いてろ別し、母液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝100/0-75/25(V/V)］にて精製し、標記化合物 (13.1g, 45.0mmol, 100%) を油状物質として得た。
LCMS (ES): m/z 292 [M+H]+. Step 44 (a): Preparation of methyl 2-[(4-chloro-2-methoxyphenyl) amino] benzoate
1-Bromo-4-chloro-2-methoxybenzene (10.0 g, 45.0 mmol) dissolved in 1,4-dioxane (250 mL), methyl 2-aminobenzoate (6.8 g, 45.0 mmol), palladium (II) acetate (0.50 g, 2.2 mmol), dicyclohexyl [3,6-dimethoxy-2 ′, 4 ′, 6′-tri (propan-2-yl) biphenyl-2-yl] phosphane (2.4 g, 4.5 mmol), cesium carbonate (21.0 g, 63.0 mmol) was added, and the mixture was stirred at 100 ° C. for 12 hours. Insolubles in the reaction solution were filtered off using ethyl acetate, the mother liquor was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-75 / 25 (V / V)] to give the title compound (13.1 g, 45.0 mmol, 100%) as an oil.
LCMS (ES): m / z 292 [M + H] + .
工程44(b)：1-(4-クロロ-2-メトキシフェニル)キナゾリン-2,4(1H,3H)-ジオンの製造
工程44(a)で得られた化合物(13.1g, 45.0mmol)をテトラヒドロフラン(100mL)、酢酸エチル(50mL)に溶解した。反応液を-15℃に冷却し、サルファイソシアナチドイルクロリド(9.55g, 67.5mmol)を加え、室温で１時間攪拌した。反応液を0℃に冷却し、水(50mL)を加えた。発泡が終了したのを確認後、5規定水酸化ナトリウム水溶液(60 mL)を加え、室温に昇温し、5時間攪拌した。反応液を0℃に冷却し、5規定塩酸(70mL)を加え、析出した固体をろ取し、酢酸エチルで洗浄し、得られた固体を50℃で減圧乾燥し、標記化合物(15.0g, 49.6mmol, 100%)を固体として得た。
1H NMR (CDCl3) δ (ppm) : 3.74 (3H, s), 6.53 (1H, d, J = 8.3 Hz), 7.10 (2H, td, J = 8.5, 2.0 Hz), 7.20 (1H, d, J = 8.3 Hz), 7.24 (1H, d, J = 7.8 Hz), 7.47 (1H, td, J = 7.8, 1.3 Hz), 8.19 (1H, dd, J = 7.8, 1.5 Hz), 8.50 (1H, s). Step 44 (b): Preparation of 1- (4-chloro-2-methoxyphenyl) quinazoline-2,4 (1H, 3H) -dione The compound (13.1 g, 45.0 mmol) obtained in Step 44 (a) Dissolved in tetrahydrofuran (100 mL) and ethyl acetate (50 mL). The reaction solution was cooled to −15 ° C., sulfa isocyanatoyl chloride (9.55 g, 67.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was cooled to 0 ° C. and water (50 mL) was added. After confirming the completion of foaming, 5N aqueous sodium hydroxide solution (60 mL) was added, and the mixture was warmed to room temperature and stirred for 5 hours. The reaction solution was cooled to 0 ° C., 5N hydrochloric acid (70 mL) was added, the precipitated solid was collected by filtration, washed with ethyl acetate, and the obtained solid was dried under reduced pressure at 50 ° C. to give the title compound (15.0 g, 49.6 mmol, 100%) was obtained as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 3.74 (3H, s), 6.53 (1H, d, J = 8.3 Hz), 7.10 (2H, td, J = 8.5, 2.0 Hz), 7.20 (1H, d , J = 8.3 Hz), 7.24 (1H, d, J = 7.8 Hz), 7.47 (1H, td, J = 7.8, 1.3 Hz), 8.19 (1H, dd, J = 7.8, 1.5 Hz), 8.50 (1H , s).
工程44(c)：1-(4-クロロ-2-メトキシフェニル)-4-(エチルスルファニル)キナゾリン-2(1H)-オンの製造
工程29(c)および、工程43(b)と同様にして、工程44(b)で得られた化合物(15.0g, 49.6mmol)、ピリジン(200mL)と五硫化二りん(11.0g, 49.6mmol)、テトラヒドロフラン(200mL)、水(100mL)、炭酸カリウム(20.7g, 150mmol)、ヨードエタン(8.0mL, 100mmol)を用いて、標記化合物(12.6g, 36.4mmol, 73%)を固体として得た。
1H NMR (CDCl3) δ (ppm) : 1.43 (3H, t, J = 7.3 Hz), 3.39 (2H, dq, J = 14.9, 5.0 Hz), 3.72 (3H, s), 6.56 (1H, d, J = 8.8 Hz), 7.09 (2H, td, J = 7.1, 2.1 Hz), 7.16 (2H, tt, J = 7.1, 1.6 Hz), 7.43-7.47 (1H, m), 7.96 (1H, dd, J = 7.8, 1.5 Hz). Step 44 (c): Preparation of 1- (4-chloro-2-methoxyphenyl) -4- (ethylsulfanyl) quinazolin-2 (1H) -one as in Step 29 (c) and Step 43 (b) The compound obtained in step 44 (b) (15.0 g, 49.6 mmol), pyridine (200 mL) and diphosphorus pentasulfide (11.0 g, 49.6 mmol), tetrahydrofuran (200 mL), water (100 mL), potassium carbonate ( 20.7 g, 150 mmol) and iodoethane (8.0 mL, 100 mmol) were used to obtain the title compound (12.6 g, 36.4 mmol, 73%) as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 1.43 (3H, t, J = 7.3 Hz), 3.39 (2H, dq, J = 14.9, 5.0 Hz), 3.72 (3H, s), 6.56 (1H, d , J = 8.8 Hz), 7.09 (2H, td, J = 7.1, 2.1 Hz), 7.16 (2H, tt, J = 7.1, 1.6 Hz), 7.43-7.47 (1H, m), 7.96 (1H, dd, J = 7.8, 1.5 Hz).
工程44(d)：1-(4-クロロ-2-ヒドロキシフェニル)-4-(エチルスルファニル)キナゾリン-2(1H)-オン
工程43(a)と同様にして、工程44(c)で得られた化合物(12.6g, 36.4mmol)、ジクロロエタン(100mL)に溶解し、三臭化ホウ素／ジクロロメタン溶液(1.0M, 50mL, 50mmol)を加え、80℃で5時間攪拌した。反応液に三臭化ホウ素／ジクロロメタン溶液(1.0M, 50mL, 50mmol)を追加し、さらに5時間攪拌した。0℃に冷却した飽和炭酸水素ナトリウム水溶液に反応液を加え、析出した固体をろ取し、酢酸エチル、ヘキサンで洗浄し、標記化合物(8.0g, 24mmol, 66%)を得た。母液をジクロロメタンで抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、標記化合物(3.0g, 9.0mmol, 25%) を固体として得た。 Step 44 (d): 1- (4-Chloro-2-hydroxyphenyl) -4- (ethylsulfanyl) quinazolin-2 (1H) -one Obtained in Step 44 (c) in the same manner as Step 43 (a) The obtained compound (12.6 g, 36.4 mmol) was dissolved in dichloroethane (100 mL), boron tribromide / dichloromethane solution (1.0 M, 50 mL, 50 mmol) was added, and the mixture was stirred at 80 ° C. for 5 hr. Boron tribromide / dichloromethane solution (1.0 M, 50 mL, 50 mmol) was added to the reaction solution, and the mixture was further stirred for 5 hours. The reaction solution was added to a saturated aqueous sodium hydrogen carbonate solution cooled to 0 ° C., and the precipitated solid was collected by filtration and washed with ethyl acetate and hexane to obtain the title compound (8.0 g, 24 mmol, 66%). The mother liquor was extracted with dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (3.0 g, 9.0 mmol, 25%) as a solid.
工程44(e)：1-{4-クロロ-2-[(3-フルオロピリジン-2-イル)メトキシ]フェニル}-4-(エチルスルファニル)キナゾリン-2(1H)-オンの製造
(3-フルオロピリジン-2-イル)メタノール(764mg, 6.01mmol)をジクロロメタン(50mL)に溶解し、トリエチルアミン(2.08mL, 15.0mmol)を加えた。反応液を0℃に冷却した後、メタンスルホニルクロリド(0.702mL, 9.01mmol)を加え、30分間攪拌した。反応液に水を加え、有機層を無水硫酸マグネシウムで乾燥した後、減圧下で溶媒を留去した。得られた残渣に、工程44(d)で得られた化合物(1.00g, 3.00mmol)、炭酸セシウム(2.94g, 9.01mmol)、N,N-ジメチルホルムアミド(15mL)を加え、80℃で30分間攪拌し、その後、室温で更に3時間攪拌した。反応液に酢酸エチルを加えて不溶物をろ別し、減圧下でろ液から溶媒を留去し、得られた残渣をシカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝50/50-0/100(V/V)］にて精製し、粗製の標記化合物(1.4g, 3.2mmol, 100%)を固体として得た。 Step 44 (e): Preparation of 1- {4-chloro-2-[(3-fluoropyridin-2-yl) methoxy] phenyl} -4- (ethylsulfanyl) quinazolin-2 (1H) -one
(3-Fluoropyridin-2-yl) methanol (764 mg, 6.01 mmol) was dissolved in dichloromethane (50 mL), and triethylamine (2.08 mL, 15.0 mmol) was added. After the reaction solution was cooled to 0 ° C., methanesulfonyl chloride (0.702 mL, 9.01 mmol) was added and stirred for 30 minutes. Water was added to the reaction solution, and the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. To the obtained residue, the compound obtained in Step 44 (d) (1.00 g, 3.00 mmol), cesium carbonate (2.94 g, 9.01 mmol), N, N-dimethylformamide (15 mL) were added, and the mixture was stirred at 80 ° C. for 30 minutes. The mixture was stirred for 3 minutes, and then further stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction solution, the insoluble material was filtered off, the solvent was distilled off from the filtrate under reduced pressure, and the resulting residue was subjected to silica gel column chromatography [elution solvent: hexane / ethyl acetate = 50 / 50-0. / 100 (V / V)] to give the crude title compound (1.4 g, 3.2 mmol, 100%) as a solid.
工程44(f)：2-{4-[(1-{4-クロロ-2-[(3-フルオロピリジン-2-イル)メトキシ]フェニル}-2-オキソ-1,2-ジヒドロキナゾリン-4-イル)アミノ]-3-メチルフェニル}アセタミドの製造
工程43(c)と同様にして、工程44(e)で得られた化合物(250mg, 0.566mmol)、2-(4-アミノ-3-メチルフェニル）アセタミド(111mg, 0.679mmol)、酢酸(2mL)を用いて、標記化合物(100mg, 0.184mmol, 32%)を固体として得た。
LCMS (ES): m/z 544 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 2.20 (3H, s), 3.49 (2H, s), 5.20 (2H, s), 6.54 (1H, d, J = 8.8 Hz), 7.15-7.17 (2H, m), 7.24 (4H, dd, J = 18.1, 7.3 Hz), 7.35 (1H, dd, J = 8.8, 4.4 Hz), 7.47 (3H, dt, J = 24.4, 7.4 Hz), 8.15 (1H, d, J = 7.8 Hz), 8.24 (1H, d, J = 4.9 Hz). Step 44 (f): 2- {4-[(1- {4-chloro-2-[(3-fluoropyridin-2-yl) methoxy] phenyl} -2-oxo-1,2-dihydroquinazoline-4 -Yl) amino] -3-methylphenyl} acetamide In the same manner as in Step 43 (c), the compound (250 mg, 0.566 mmol) obtained in Step 44 (e), 2- (4-amino-3- The title compound (100 mg, 0.184 mmol, 32%) was obtained as a solid using methylphenyl) acetamide (111 mg, 0.679 mmol) and acetic acid (2 mL).
LCMS (ES): m / z 544 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 2.20 (3H, s), 3.49 (2H, s), 5.20 (2H, s), 6.54 (1H, d, J = 8.8 Hz), 7.15-7.17 ( 2H, m), 7.24 (4H, dd, J = 18.1, 7.3 Hz), 7.35 (1H, dd, J = 8.8, 4.4 Hz), 7.47 (3H, dt, J = 24.4, 7.4 Hz), 8.15 (1H , d, J = 7.8 Hz), 8.24 (1H, d, J = 4.9 Hz).
（実施例４５）
2-[4-({7-フルオロ-1-[4-フルオロ-2-(1,3-チアゾール-2-イルメトキシ)フェニル]-2-オキソ-1,2-ジヒドロキナゾリン-4-イル}アミノ)-3-メチルフェニル]アセタミド (Example 45)
2- [4-({7-Fluoro-1- [4-fluoro-2- (1,3-thiazol-2-ylmethoxy) phenyl] -2-oxo-1,2-dihydroquinazolin-4-yl} amino ) -3-Methylphenyl] acetamide
Figure JPOXMLDOC01-appb-C000088
Figure JPOXMLDOC01-appb-C000088
工程45(a)：メチル 2-アミノ-4-フルオロベンゾエートの製造
2-アミノ-4-フルオロ安息香酸(25.0g, 161mmol)をメタノール(750mL)に溶解し、塩化チオニル(81.8mL, 1.13mol)を加え、加熱還流下、48時間攪拌した。減圧下で溶媒を留去し、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルを加えて抽出した。有機層を3回飽和炭酸水素ナトリウム水で洗浄し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去し、標記化合物(23.3g, 138mmol, 86%)を固体として得た。
1H NMR (CDCl3) δ (ppm) : 3.86 (3H, s), 5.87 (2H, s), 6.30-6.38 (2H, m), 7.86 (1H, dd, J = 8.8, 6.8 Hz). Step 45 (a): Preparation of methyl 2-amino-4-fluorobenzoate
2-Amino-4-fluorobenzoic acid (25.0 g, 161 mmol) was dissolved in methanol (750 mL), thionyl chloride (81.8 mL, 1.13 mol) was added, and the mixture was stirred for 48 hours with heating under reflux. The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and ethyl acetate was added for extraction. The organic layer was washed 3 times with saturated aqueous sodium hydrogen carbonate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (23.3 g, 138 mmol, 86%) as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 3.86 (3H, s), 5.87 (2H, s), 6.30-6.38 (2H, m), 7.86 (1H, dd, J = 8.8, 6.8 Hz).
工程45(b)：メチル 4-フルオロ-2-[(4-フルオロ-2-メトキシフェニル)アミノ]ベンゾエートの製造
工程45(a)で得られた化合物(23.3g, 138mmol)を1,4-ジオキサン(400mL)に溶解し、2-ブロモ-5-フルオロアニソール(28.3g, 138mmol)、酢酸パラジウム(II)(1.55g, 6.89mmol)、ジシクロヘキシル[3,6-ジメトキシ-2’,4’,6’-トリ(プロパン-2-イル)ビフェニル-2-イル］ホスファン(7.40g, 13.8mmol)、炭酸セシウム(112g, 345mmol)を加え、加熱還流下、13時間攪拌した。反応混合物に水を加え、酢酸エチルを加えて抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル=100/0-0/100(V/V)］にて精製し、標記化合物(45.3g, 154mmol, 100%)を固体として得た。
1H NMR (CDCl3) δ (ppm) : 3.84 (3H, s), 3.90 (3H, s), 6.39 (1H, ddd, J = 9.6, 7.2, 1.8 Hz), 6.59-6.73 (3H, m), 7.24-7.30 (1H, m), 7.96 (1H, dd, J = 9.0, 6.7 Hz), 9.38 (1H, br s). Step 45 (b): Production of methyl 4-fluoro-2-[(4-fluoro-2-methoxyphenyl) amino] benzoate The compound obtained in Step 45 (a) (23.3 g, 138 mmol) was converted to 1,4- Dissolved in dioxane (400 mL), 2-bromo-5-fluoroanisole (28.3 g, 138 mmol), palladium (II) acetate (1.55 g, 6.89 mmol), dicyclohexyl [3,6-dimethoxy-2 ′, 4 ′, 6'-Tri (propan-2-yl) biphenyl-2-yl] phosphane (7.40 g, 13.8 mmol) and cesium carbonate (112 g, 345 mmol) were added, and the mixture was stirred for 13 hours under heating to reflux. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-0 / 100 (V / V)] to give the title compound (45.3 g , 154 mmol, 100%) was obtained as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 3.84 (3H, s), 3.90 (3H, s), 6.39 (1H, ddd, J = 9.6, 7.2, 1.8 Hz), 6.59-6.73 (3H, m) , 7.24-7.30 (1H, m), 7.96 (1H, dd, J = 9.0, 6.7 Hz), 9.38 (1H, br s).
工程45(c)：7-フルオロ-1-(4-フルオロ-2-メトキシフェニル)キナゾリン-2,4(1H,3H)-ジオンの製造
工程45(b)で得られた化合物(45.3g, 154mmol)をテトラヒドロフラン(500mL)と酢酸エチル(250mL)の混合溶媒に溶解し、-15℃でクロロスルホニルイソシアネート(20.0mL, 231mmol)を加え、-15℃で1時間攪拌した。水(100mL)を加え、0℃にて10分間攪拌し、5規定水酸化ナトリウム水溶液(300mL)を加え、室温にて13時間攪拌した。反応混合物を酢酸エチルで2回抽出し、水層に飽和塩化アンモニウム水溶液を加え、酢酸エチルで2回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下にて溶媒を留去して得られた固体を、ヘキサンで洗浄し、減圧下乾燥し、標記化合物(50.9g, 167mmol, 100％)を固体として得た。
1H NMR (CDCl3) δ (ppm) : 3.78 (3H, s), 6.23 (1H, dd, J = 10.2, 2.3 Hz), 6.83-7.00 (4H, m), 8.22 (1H, dd, J = 8.8, 6.1 Hz). Step 45 (c): Preparation of 7-fluoro-1- (4-fluoro-2-methoxyphenyl) quinazoline-2,4 (1H, 3H) -dione The compound obtained in Step 45 (b) (45.3 g, 154 mmol) was dissolved in a mixed solvent of tetrahydrofuran (500 mL) and ethyl acetate (250 mL), chlorosulfonyl isocyanate (20.0 mL, 231 mmol) was added at -15 ° C, and the mixture was stirred at -15 ° C for 1 hour. Water (100 mL) was added, and the mixture was stirred at 0 ° C. for 10 min, 5N aqueous sodium hydroxide solution (300 mL) was added, and the mixture was stirred at room temperature for 13 hr. The reaction mixture was extracted twice with ethyl acetate, saturated aqueous ammonium chloride solution was added to the aqueous layer, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solid obtained by distilling off the solvent under reduced pressure was washed with hexane and dried under reduced pressure to obtain the title compound (50.9 g, 167 mmol, 100%) as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 3.78 (3H, s), 6.23 (1H, dd, J = 10.2, 2.3 Hz), 6.83-7.00 (4H, m), 8.22 (1H, dd, J = (8.8, 6.1 Hz).
工程45(d)：4-(エチルスルファニル)-7-フルオロ-1-(4-フルオロ-2-メトキシフェニル)キナゾリン-2(1H)-オンの製造
工程45(c)で得られた化合物(50.9g, 167mmol)、をピリジン(850mL)に溶解し、五硫化二りん(39.0g, 176mmol)を加え、加熱還流下、8時間攪拌した。減圧下で溶媒を留去し、水を加えた。固体をろ取し、ろ液を酢酸エチルで3回抽出し、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去し、先にろ取した固体と合わせた。この固体をテトラヒドロフラン(600mL)と水(300mL)の混合溶媒に溶解し、炭酸カリウム(69.3g, 502mmol)、ヨードエタン(26.8mL, 335mmol)を加え、室温にて20時間攪拌した。反応液に水を加え、酢酸エチルで2回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去して得られた残渣をろ取し、ジイソプロピルエーテルで洗浄し、固体を減圧下で乾燥した。ろ液を減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル=100/0-40/60-20/80(V/V)］にて精製し、ろ取した固体と合わせて標記化合物(33.5g, 96.2mmol, 58%)を固体として得た。
1H NMR (CDCl3) δ (ppm) : 1.45 (3H, t, J = 7.2 Hz), 3.36-3.46 (2H, m), 3.75 (3H, s), 6.25 (1H, dd, J = 10.6, 2.3 Hz), 6.81-6.92 (3H, m), 7.21 (1H, dd, J = 9.4, 5.8 Hz), 7.98 (1H, dd, J = 8.8, 5.8 Hz). Step 45 (d): Preparation of 4- (ethylsulfanyl) -7-fluoro-1- (4-fluoro-2-methoxyphenyl) quinazolin-2 (1H) -one Compound obtained in Step 45 (c) ( 50.9 g, 167 mmol) was dissolved in pyridine (850 mL), diphosphorus pentasulfide (39.0 g, 176 mmol) was added, and the mixture was stirred with heating under reflux for 8 hours. The solvent was distilled off under reduced pressure, and water was added. The solid was collected by filtration, and the filtrate was extracted three times with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and combined with the solid collected earlier. This solid was dissolved in a mixed solvent of tetrahydrofuran (600 mL) and water (300 mL), potassium carbonate (69.3 g, 502 mmol) and iodoethane (26.8 mL, 335 mmol) were added, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was collected by filtration, washed with diisopropyl ether, and the solid was dried under reduced pressure. The filtrate was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-40 / 60-20 / 80 (V / V)]. The title compound (33.5 g, 96.2 mmol, 58%) was obtained as a solid in combination with the solid collected by filtration.
1 H NMR (CDCl 3 ) δ (ppm): 1.45 (3H, t, J = 7.2 Hz), 3.36-3.46 (2H, m), 3.75 (3H, s), 6.25 (1H, dd, J = 10.6, 2.3 Hz), 6.81-6.92 (3H, m), 7.21 (1H, dd, J = 9.4, 5.8 Hz), 7.98 (1H, dd, J = 8.8, 5.8 Hz).
工程45(e)：4-(エチルスルファニル)-7-フルオロ-1-(4-フルオロ-2-ヒドロキシフェニル)キナゾリン-2(1H)-オンの製造
工程45(d)で得られた化合物(31.5g, 90.5mmol)を1,2-ジクロロエタン(450mL)に溶解し、三臭化ホウ素／ジクロロメタン溶液(1.0M, 113mL, 113mmol)を加え、80℃で3時間攪拌した。0℃で飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去し、得られた固体をジイソプロピルエーテルで洗浄し、標記化合物(30.2g, 90.3mmol, 99%)を固体として得た。
1H NMR (DMSO-D6) δ (ppm): 1.37 (3H, t, J = 7.4 Hz), 3.29 (2H, q, J = 7.4 Hz), 3.64 (1H, br s), 6.28 (1H, dd, J = 10.6, 2.4 Hz), 6.83-6.92 (2H, m), 7.16 (1H, td, J = 8.7, 2.4 Hz), 7.33 (1H, dd, J = 8.4, 6.5 Hz), 8.06 (1H, dd, J = 9.0, 5.9 Hz). Step 45 (e): Preparation of 4- (ethylsulfanyl) -7-fluoro-1- (4-fluoro-2-hydroxyphenyl) quinazolin-2 (1H) -one Compound obtained in Step 45 (d) ( 31.5 g, 90.5 mmol) was dissolved in 1,2-dichloroethane (450 mL), boron tribromide / dichloromethane solution (1.0 M, 113 mL, 113 mmol) was added, and the mixture was stirred at 80 ° C. for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added at 0 ° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting solid was washed with diisopropyl ether to obtain the title compound (30.2 g, 90.3 mmol, 99%) as a solid.
1 H NMR (DMSO-D 6 ) δ (ppm): 1.37 (3H, t, J = 7.4 Hz), 3.29 (2H, q, J = 7.4 Hz), 3.64 (1H, br s), 6.28 (1H, dd, J = 10.6, 2.4 Hz), 6.83-6.92 (2H, m), 7.16 (1H, td, J = 8.7, 2.4 Hz), 7.33 (1H, dd, J = 8.4, 6.5 Hz), 8.06 (1H , dd, J = 9.0, 5.9 Hz).
工程45(f)：4-(エチルスルファニル)-7-フルオロ-1-[4-フルオロ-2-(1,3-チアゾール-2-イルメトキシ)フェニル]キナゾリン-2(1H)-オンの製造
工程45(e)で得られた化合物(200mg, 0.598mmol)をN,N-ジメチルフォルムアミド(10mL)に溶解し、2-(クロロメチル)-1,3-チアゾール(95.9mg, 0.718mmol)、炭酸カリウム(124mg, 0.897mmol)を加え、80℃で12時間攪拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去し、得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル=100/0－0/100(V/V)］にて精製し、標記化合物(213mg, 0.494mmol, 83%)を油状物質として得た。
1H NMR (CDCl3) δ (ppm) : 1.46 (3H, t, J = 7.4 Hz), 3.38-3.46 (2H, m), 5.36 (2H, s), 6.26 (1H, t, J = 9.8 Hz), 6.86-7.00 (3H, m), 7.19-7.40 (3H, m), 7.69-7.75 (1H, m). Step 45 (f): Step of producing 4- (ethylsulfanyl) -7-fluoro-1- [4-fluoro-2- (1,3-thiazol-2-ylmethoxy) phenyl] quinazolin-2 (1H) -one Compound (200 mg, 0.598 mmol) obtained in 45 (e) was dissolved in N, N-dimethylformamide (10 mL), and 2- (chloromethyl) -1,3-thiazole (95.9 mg, 0.718 mmol) was obtained. Potassium carbonate (124 mg, 0.897 mmol) was added and stirred at 80 ° C. for 12 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-0 / 100 (V / V)] to give the title compound (213 mg , 0.494 mmol, 83%) was obtained as an oily substance.
1 H NMR (CDCl 3 ) δ (ppm): 1.46 (3H, t, J = 7.4 Hz), 3.38-3.46 (2H, m), 5.36 (2H, s), 6.26 (1H, t, J = 9.8 Hz ), 6.86-7.00 (3H, m), 7.19-7.40 (3H, m), 7.69-7.75 (1H, m).
工程45(g)：2-[4-({7-フルオロ-1-[4-フルオロ-2-(1,3-チアゾール-2-イルメトキシ)フェニル]-2-オキソ-1,2-ジヒドロキナゾリン-4-イル}アミノ)-3-メチルフェニル]アセタミドの製造
工程45(f)で得た4-(エチルスルファニル)-7-フルオロ-1-[4-フルオロ-2-(1,3-チアゾール-2-イルメトキシ)フェニル]キナゾリン-2(1H)-オン(106mg, 0.246mmol)を酢酸(4mL)、1,2-ジメトキシエタン(8mL)の混合溶媒に溶解し、2-(4-アミノ-3-メチルフェニル)アセタミド(44.4mg, 0.270mmol)を加え、加熱還流下、9時間攪拌した。減圧下で溶媒を留去し、得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/メタノール=100/0-80/20(V/V)］にて精製した。再度、シリカゲルカラムクロマトグラフィー［NHシリカゲル、溶出溶媒：酢酸エチル/メタノール=100/0－80/20(V/V)］にて精製し、標記化合物(67mg, 0.13mmol, 51%)を固体として得た。
LCMS (ES): m/z 534 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 2.14 (3H, s), 3.52 (2H, s), 5.37 (1H, d, J = 13.3 Hz), 5.42 (1H, d, J = 13.3 Hz), 6.33 (1H, d, J = 8.3 Hz), 6.98 (1H, td, J = 8.3, 2.6 Hz), 7.06-7.14 (2H, m), 7.16-7.29 (3H, m), 7.37 (1H, t, J = 7.4 Hz), 7.52 (1H, d, J = 3.1 Hz), 7.72 (1H, d, J = 3.1 Hz), 8.33 (1H, dd, J = 8.8, 5.7 Hz). Step 45 (g): 2- [4-({7-fluoro-1- [4-fluoro-2- (1,3-thiazol-2-ylmethoxy) phenyl] -2-oxo-1,2-dihydroquinazoline 4- (Ethylsulfanyl) -7-fluoro-1- [4-fluoro-2- (1,3-thiazole) obtained in Preparation Step 45 (f) of 4--4-yl} amino) -3-methylphenyl] acetamide 2-ylmethoxy) phenyl] quinazolin-2 (1H) -one (106 mg, 0.246 mmol) was dissolved in a mixed solvent of acetic acid (4 mL) and 1,2-dimethoxyethane (8 mL) to give 2- (4-amino- 3-Methylphenyl) acetamide (44.4 mg, 0.270 mmol) was added, and the mixture was stirred for 9 hours under heating to reflux. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [elution solvent: ethyl acetate / methanol = 100 / 0-80 / 20 (V / V)]. Purify again by silica gel column chromatography [NH silica gel, elution solvent: ethyl acetate / methanol = 100 / 0-80 / 20 (V / V)] to obtain the title compound (67 mg, 0.13 mmol, 51%) as a solid. Obtained.
LCMS (ES): m / z 534 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 2.14 (3H, s), 3.52 (2H, s), 5.37 (1H, d, J = 13.3 Hz), 5.42 (1H, d, J = 13.3 Hz) , 6.33 (1H, d, J = 8.3 Hz), 6.98 (1H, td, J = 8.3, 2.6 Hz), 7.06-7.14 (2H, m), 7.16-7.29 (3H, m), 7.37 (1H, t , J = 7.4 Hz), 7.52 (1H, d, J = 3.1 Hz), 7.72 (1H, d, J = 3.1 Hz), 8.33 (1H, dd, J = 8.8, 5.7 Hz).
（実施例４６）
2-(4-{[1-(4-クロロ-2-メトキシフェニル）-2-オキソ-1,2-ジヒドロチエノ[3,2-d]ピリミジン-4-イル]アミノ}-3-メチルフェニル)アセタミド (Example 46)
2- (4-{[1- (4-Chloro-2-methoxyphenyl) -2-oxo-1,2-dihydrothieno [3,2-d] pyrimidin-4-yl] amino} -3-methylphenyl) Acetamide
Figure JPOXMLDOC01-appb-C000089
Figure JPOXMLDOC01-appb-C000089
工程46(a)：メチル 3-[(4-クロロ-2-メトキシフェニル)アミノ]チオフェン-2-カルボキシレートの製造
メチル 3-アミノチオフェン-2-カルボキシレート(25.0g, 159mmol)、および1-ブロモ-4-クロロ-2-メトキシベンゼン(35.9g, 162mmol) を1,4-ジオキサン(500mL)に溶解し、酢酸パラジウム(1.84g, 7.95mmol)、炭酸セシウム(72.5g, 223mmol)、およびジシクロヘキシル-[3,6-ジメトキシ-2-(2,4,6-トリイソプロピルフェニル)フェニル]ホスフィン(Bretphos)(8.54g, 15.9mmol)を加え、窒素雰囲気下16時間加熱還流攪拌した。反応液に水を加え、不溶物をろ別した後、ろ液に酢酸エチルを加え、有機層を抽出し食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。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［溶出溶媒：ヘキサン/酢酸エチル＝90/10-60/40(V/V)］にて精製し、標記化合物(42.4g, 142mmol, 89.5%) を油状物質として得た。
1H NMR (CDCl3) δ (ppm) : 3.88 (3H, s), 3.91 (3H, s), 6.89-6.92 (2H, m), 7.13 (1H, d, J = 5.5 Hz), 7.23 (1H, d, J = 8.2 Hz), 7.40 (1H, d, J = 5.5 Hz), 8.89 (1H, br s). Step 46 (a): Preparation of methyl 3-[(4-chloro-2-methoxyphenyl) amino] thiophene-2-carboxylate Methyl 3-aminothiophene-2-carboxylate (25.0 g, 159 mmol), and 1- Bromo-4-chloro-2-methoxybenzene (35.9 g, 162 mmol) dissolved in 1,4-dioxane (500 mL), palladium acetate (1.84 g, 7.95 mmol), cesium carbonate (72.5 g, 223 mmol), and dicyclohexyl -[3,6-Dimethoxy-2- (2,4,6-triisopropylphenyl) phenyl] phosphine (Bretphos) (8.54 g, 15.9 mmol) was added, and the mixture was heated to reflux with stirring in a nitrogen atmosphere for 16 hours. Water was added to the reaction solution, insoluble matter was filtered off, ethyl acetate was added to the filtrate, the organic layer was extracted, washed with brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-60 / 40 (V / V)] to give the title compound (42.4 g, 142 mmol, 89.5%) as an oil.
1 H NMR (CDCl 3 ) δ (ppm): 3.88 (3H, s), 3.91 (3H, s), 6.89-6.92 (2H, m), 7.13 (1H, d, J = 5.5 Hz), 7.23 (1H , d, J = 8.2 Hz), 7.40 (1H, d, J = 5.5 Hz), 8.89 (1H, br s).
工程46(b)：1-(4-クロロ-2-メトキシフェニル)チエノ[3,2-d]ピリミジン-2,4(1H,3H)-ジオンの製造
工程41(b)と同様にして、工程46(a)で得られた化合物(42.4g, 142mmol)、N-(オキソメチレン)スルファニルクロリド(18.4mL, 214mmol)を用いて反応を行うことで、標記化合物(39.2g, 127mmol, 89.2%)を固体として得た。
1H NMR (CD3OD) δ (ppm): 1.45 (3H, t, J = 7.4 Hz), 3.40 (2H, q, J = 7.3 Hz), 3.80 (4H, s), 6.48 (1H, d, J = 5.5 Hz), 7.17 (1H, dd, J = 8.4, 2.2 Hz), 7.31 (1H, d, J = 2.0 Hz), 7.36 (1H, d, J = 8.6 Hz), 7.92 (1H, d, J = 5.5 Hz).  Step 46 (b): In the same manner as in Step 41 (b) for producing 1- (4-chloro-2-methoxyphenyl) thieno [3,2-d] pyrimidine-2,4 (1H, 3H) -dione, The title compound (39.2 g, 127 mmol, 89.2%) was obtained by carrying out the reaction using the compound (42.4 g, 142 mmol) obtained in step 46 (a) and N- (oxomethylene) sulfanyl chloride (18.4 mL, 214 mmol). ) Was obtained as a solid.
1 H NMR (CD 3 OD) δ (ppm): 1.45 (3H, t, J = 7.4 Hz), 3.40 (2H, q, J = 7.3 Hz), 3.80 (4H, s), 6.48 (1H, d, J = 5.5 Hz), 7.17 (1H, dd, J = 8.4, 2.2 Hz), 7.31 (1H, d, J = 2.0 Hz), 7.36 (1H, d, J = 8.6 Hz), 7.92 (1H, d, J = 5.5 Hz).
工程46(c)：1-(4-クロロ-2-メトキシフェニル)-4-(エチルスルファニル)チエノ[3,2-d]ピリミジン-2(1H)-オンの製造
工程41(c)と同様にして、工程46(b)で得られた化合物(4.72g, 15.3mmol)を用いて反応を行うことで、標記化合物 (5.29g, 15.0mmol, 98.2%)を固体として得た。
LCMS (ES): m/z 308 [M+H]+.
1H NMR (CDCl3) δ (ppm): 1.45 (3H, t, J = 7.4 Hz), 3.37-3.49 (2H, m), 3.78 (3H, s), 6.36 (1H, d, J = 5.1 Hz), 7.08-7.10 (2H, m), 7.24 (1H, d, J = 8.6 Hz), 7.53 (1H, d, J = 5.1 Hz). Step 46 (c): Same as Step 41 (c) for the preparation of 1- (4-chloro-2-methoxyphenyl) -4- (ethylsulfanyl) thieno [3,2-d] pyrimidin-2 (1H) -one Then, the title compound (5.29 g, 15.0 mmol, 98.2%) was obtained as a solid by performing the reaction using the compound (4.72 g, 15.3 mmol) obtained in step 46 (b).
LCMS (ES): m / z 308 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.45 (3H, t, J = 7.4 Hz), 3.37-3.49 (2H, m), 3.78 (3H, s), 6.36 (1H, d, J = 5.1 Hz ), 7.08-7.10 (2H, m), 7.24 (1H, d, J = 8.6 Hz), 7.53 (1H, d, J = 5.1 Hz).
工程46(d)：2-(4-{[1-(4-クロロ-2-メトキシフェニル)-2-オキソ-1,2-ジヒドロチエノ[3,2-d]ピリミジン-4-イル]アミノ}-3-メチルフェニル)アセタミドの製造
工程41(d)と同様にして、工程46(c)で得られた化合物(100mg, 0.283mmol)、2-(4-アミノ-3-メチル-フェニル)アセタミド(56mg, 0.34mmol)を用いて反応を行うことで、標記化合物(23mg, 0.051mmol, 18%)を固体として得た。
LCMS (ES): m/z 454 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 2.28 (3H, d, J = 8.2 Hz), 3.54 (2H, s), 3.79 (3H, s), 6.34-6.37 (1H, m), 7.13 (1H, dd, J = 8.2, 2.0 Hz), 7.22-7.31 (5H, m), 7.77-7.72 (1H, m).  Step 46 (d): 2- (4-{[1- (4-Chloro-2-methoxyphenyl) -2-oxo-1,2-dihydrothieno [3,2-d] pyrimidin-4-yl] amino} 3-methylphenyl) acetamide In the same manner as in Step 41 (d), the compound obtained in Step 46 (c) (100 mg, 0.283 mmol), 2- (4-amino-3-methyl-phenyl) acetamide The reaction was carried out using (56 mg, 0.34 mmol) to obtain the title compound (23 mg, 0.051 mmol, 18%) as a solid.
LCMS (ES): m / z 454 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 2.28 (3H, d, J = 8.2 Hz), 3.54 (2H, s), 3.79 (3H, s), 6.34-6.37 (1H, m), 7.13 ( 1H, dd, J = 8.2, 2.0 Hz), 7.22-7.31 (5H, m), 7.77-7.72 (1H, m).
（実施例４７）
2-{4-[(1-{4-クロロ-2-[(5-フルオロピリジン-2-イル)メトキシ]フェニル}-2-オキソ-1,2-ジヒドロチエノ[3,2-d]ピリミジン-4-イル)アミノ]-3-メチルフェニル}アセタミド (Example 47)
2- {4-[(1- {4-Chloro-2-[(5-fluoropyridin-2-yl) methoxy] phenyl} -2-oxo-1,2-dihydrothieno [3,2-d] pyrimidine- 4-yl) amino] -3-methylphenyl} acetamide
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090
工程47(a)：(5-フルオロピリジン-2-イル)メチル　メタンスルホネートの製造
(5-フルオロ-2-ピリジル)メタノール(1.18g, 9.28mmol)をジクロロメタン(5mL)に溶解し、0℃に冷却後、トリエチルアミン(1.93mL, 13.9mmol)、メタンスルホニルクロリド(0.904mL, 11.6mmol)を滴下し同温で20分間撹拌した。反応液に1規定塩酸(10mL）を加えて反応を停止させ、酢酸エチルを加えた。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、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［溶出溶媒：ヘキサン/酢酸エチル＝60/40-40/60(V/V)］にて精製し、標記化合物 (1.64g, 7.97mmol, 85.8%) を油状物質として得た。
1H NMR (CDCl3) δ (ppm) : 3.11 (3H, s), 5.43 (2H, d, J = 2.0 Hz), 7.37-7.41 (1H, m), 7.51-7.47 (1H, m), 8.47-8.48 (1H, m). Step 47 (a): Preparation of (5-fluoropyridin-2-yl) methyl methanesulfonate
(5-Fluoro-2-pyridyl) methanol (1.18 g, 9.28 mmol) was dissolved in dichloromethane (5 mL), cooled to 0 ° C., triethylamine (1.93 mL, 13.9 mmol), methanesulfonyl chloride (0.904 mL, 11.6 mmol). ) Was added dropwise and stirred at the same temperature for 20 minutes. 1N hydrochloric acid (10 mL) was added to the reaction solution to stop the reaction, and ethyl acetate was added. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 60 / 40-40 / 60 (V / V)] to give the title compound (1.64 g, 7.97 mmol, 85.8%) as an oil Obtained as material.
1 H NMR (CDCl 3 ) δ (ppm): 3.11 (3H, s), 5.43 (2H, d, J = 2.0 Hz), 7.37-7.41 (1H, m), 7.51-7.47 (1H, m), 8.47 -8.48 (1H, m).
工程47(b)：1-(4-クロロ-2-ヒドロキシフェニル)-4-(エチルスルファニル)チエノ[3,2-d]ピリミジン-2(1H)-オンの製造
工程42(a)と同様にして、工程46(c)で得られた化合物(4.50g, 12.8mmol)、三臭化ホウ素／ジクロロメタン溶液(1.0M, 15.3mL, 15.3mmol)を用いて反応を行うことで、標記化合物 (3.91g, 11.5mmol, 90.5%)を固体として得た。
1H NMR (CD3OD) δ (ppm) : 1.46 (3H, t, J = 7.4 Hz), 3.43 (2H, q, J = 7.4 Hz), 6.56-6.54 (1H, m), 7.03 (1H, dd, J = 8.4, 2.2 Hz), 7.08 (1H, d, J = 2.3 Hz), 7.29 (1H, d, J = 8.2 Hz), 7.98 (1H, d, J = 5.5 Hz). Step 47 (b): Similar to Step 42 (a) for the production of 1- (4-chloro-2-hydroxyphenyl) -4- (ethylsulfanyl) thieno [3,2-d] pyrimidin-2 (1H) -one The reaction was carried out using the compound obtained in step 46 (c) (4.50 g, 12.8 mmol) and boron tribromide / dichloromethane solution (1.0 M, 15.3 mL, 15.3 mmol) to give the title compound ( 3.91 g, 11.5 mmol, 90.5%) was obtained as a solid.
1 H NMR (CD 3 OD) δ (ppm): 1.46 (3H, t, J = 7.4 Hz), 3.43 (2H, q, J = 7.4 Hz), 6.56-6.54 (1H, m), 7.03 (1H, dd, J = 8.4, 2.2 Hz), 7.08 (1H, d, J = 2.3 Hz), 7.29 (1H, d, J = 8.2 Hz), 7.98 (1H, d, J = 5.5 Hz).
工程47(c)：1-{4-クロロ-2-[(5-フルオロピリジン-2-イル)メトキシ]フェニル}-4-(エチルスルファニル)チエノ[3,2-d]ピリミジン-2(1H)-オンの製造
工程42(b)と同様にして、工程47(b)で得られた化合物(9.27g, 27.4mmol)、工程47(a)で得られた化合物(8.42g, 41.0mmol)を用いて反応を行うことで、標記化合物(11.1g, 24.8mmol, 90.5%)を固体として得た。
LCMS (ES): m/z 448 [M+H]+.
1H NMR (CDCl3) δ (ppm): 1.46 (3H, t, J = 7.4 Hz), 3.39-3.51 (2H, m), 5.19 (2H, s), 6.43 (1H, d, J = 5.1 Hz), 7.04 (1H, d, J = 2.3 Hz), 7.11 (1H, dd, J = 8.2, 2.0 Hz), 7.28 (1H, d, J = 5.1 Hz), 7.32-7.39 (2H, m), 7.55 (1H, d, J = 5.1 Hz), 8.38 (1H, d, J = 2.3 Hz).  Step 47 (c): 1- {4-Chloro-2-[(5-fluoropyridin-2-yl) methoxy] phenyl} -4- (ethylsulfanyl) thieno [3,2-d] pyrimidine-2 (1H In the same manner as in Step 42 (b) for the production of) -one, the compound obtained in Step 47 (b) (9.27 g, 27.4 mmol), the compound obtained in Step 47 (a) (8.42 g, 41.0 mmol) To give the title compound (11.1 g, 24.8 mmol, 90.5%) as a solid.
LCMS (ES): m / z 448 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.46 (3H, t, J = 7.4 Hz), 3.39-3.51 (2H, m), 5.19 (2H, s), 6.43 (1H, d, J = 5.1 Hz ), 7.04 (1H, d, J = 2.3 Hz), 7.11 (1H, dd, J = 8.2, 2.0 Hz), 7.28 (1H, d, J = 5.1 Hz), 7.32-7.39 (2H, m), 7.55 (1H, d, J = 5.1 Hz), 8.38 (1H, d, J = 2.3 Hz).
工程47(d)：2-{4-[(1-{4-クロロ-2-[(5-フルオロピリジン-2-イル)メトキシ]フェニル}-2-オキソ-1,2-ジヒドロチエノ[3,2-d]ピリミジン-4-イル)アミノ]-3-メチルフェニル}アセタミドの製造
工程41(d)と同様にして、工程47(c)で得られた化合物(158mg, 0.353mmol)、2-(4-アミノ-3-メチル-フェニル)アセタミド(64mg, 0.39mmol)を用いて反応を行うことで、標記化合物 (138mg, 0.251mmol, 71.1%)を固体として得た。
LCMS (ES): m/z 550 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 2.26 (3H, s), 3.54 (2H, s), 5.14-5.22 (2H, m), 6.42 (1H, br s), 7.18 (1H, dd, J = 8.4, 2.2 Hz), 7.23-7.31 (5H, m), 7.38 (1H, d, J = 8.2 Hz), 7.50 (1H, td, J = 8.6, 2.7 Hz), 7.77 (1H, br s), 8.39 (1H, d, J = 3.1 Hz). Step 47 (d): 2- {4-[(1- {4-chloro-2-[(5-fluoropyridin-2-yl) methoxy] phenyl} -2-oxo-1,2-dihydrothieno [3, 2-d] pyrimidin-4-yl) amino] -3-methylphenyl} acetamide In the same manner as in Step 41 (d), the compound (158 mg, 0.353 mmol) obtained in Step 47 (c), 2- Reaction was carried out using (4-amino-3-methyl-phenyl) acetamide (64 mg, 0.39 mmol) to obtain the title compound (138 mg, 0.251 mmol, 71.1%) as a solid.
LCMS (ES): m / z 550 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 2.26 (3H, s), 3.54 (2H, s), 5.14-5.22 (2H, m), 6.42 (1H, br s), 7.18 (1H, dd, J = 8.4, 2.2 Hz), 7.23-7.31 (5H, m), 7.38 (1H, d, J = 8.2 Hz), 7.50 (1H, td, J = 8.6, 2.7 Hz), 7.77 (1H, br s) , 8.39 (1H, d, J = 3.1 Hz).
（実施例４８）
2-{3-[(1-{4-クロロ-2-[(5-フルオロピリジン-2-イル)メトキシ]フェニル}-2-オキソ-1,2-ジヒドロチエノ[3,2-d]チエノ-4-イル)アミノ]-2-メチルフェノキシ}アセタミド (Example 48)
2- {3-[(1- {4-Chloro-2-[(5-fluoropyridin-2-yl) methoxy] phenyl} -2-oxo-1,2-dihydrothieno [3,2-d] thieno- 4-yl) amino] -2-methylphenoxy} acetamide
Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091
工程48(a)：プロパン-2-イル (2-メチル-3-ニトロフェノキシ)アセテートの製造
2-メチル-3-ニトロ－フェノール(0.500g, 3.27mmol)をN,N-ジメチルホルムアミド(5mL)に溶解し、ナトリウム tert-ブトキシド(0.320g, 3.33mmol)、イソプロピルブロモアセテート(0.507ml, 3.92mmol)を加えて終夜撹拌した。反応液に水および酢酸エチルを加えて有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、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［溶出溶媒：ヘキサン/酢酸エチル＝100/0-80/20(V/V)］にて精製し、標記化合物 (762mg, 3.01mmol, 92.2%) を固体として得た。
1H NMR (CDCl3) δ (ppm): 1.27 (6H, t, J = 4.5 Hz), 2.45 (3H, s), 4.67 (2H, s), 5.08-5.15 (1H, m), 6.92 (1H, d, J = 8.2 Hz), 7.26-7.23 (1H, m), 7.46 (1H, d, J = 8.2 Hz). Step 48 (a): Preparation of propan-2-yl (2-methyl-3-nitrophenoxy) acetate
2-Methyl-3-nitro-phenol (0.500 g, 3.27 mmol) is dissolved in N, N-dimethylformamide (5 mL), sodium tert-butoxide (0.320 g, 3.33 mmol), isopropyl bromoacetate (0.507 ml, 3.92 mmol). mmol) was added and stirred overnight. Water and ethyl acetate were added to the reaction mixture, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-80 / 20 (V / V)] to give the title compound (762 mg, 3.01 mmol, 92.2%) as a solid Obtained.
1 H NMR (CDCl 3 ) δ (ppm): 1.27 (6H, t, J = 4.5 Hz), 2.45 (3H, s), 4.67 (2H, s), 5.08-5.15 (1H, m), 6.92 (1H , d, J = 8.2 Hz), 7.26-7.23 (1H, m), 7.46 (1H, d, J = 8.2 Hz).
工程48(b)：プロパン-2-イル (3-アミノ-2-メチルフェノキシ)アセテートの製造
工程48(a)で得られた化合物(0.762g, 3.01mmol)をエタノール(15mL)に溶解し、10% パラジウム－炭素(0.25g)を加え、水素雰囲気下室温で2.5時間撹拌した。触媒をろ去し、ろ液を減圧下濃縮し、標記化合物(0.635g, 2.84mmol, 94.5%) を固体として得た。
1H NMR (CDCl3) δ (ppm): 1.27 (6H, d, J = 6.3 Hz), 2.12 (3H, s), 3.64 (2H, br s), 4.57 (2H, s), 5.10-5.16 (1H, m), 6.20 (1H, d, J = 8.2 Hz), 6.38 (1H, d, J = 7.8 Hz), 6.94 (1H, t, J = 7.4 Hz). Step 48 (b): Preparation of propan-2-yl (3-amino-2-methylphenoxy) acetate The compound obtained in Step 48 (a) (0.762 g, 3.01 mmol) was dissolved in ethanol (15 mL). 10% Palladium-carbon (0.25 g) was added, and the mixture was stirred at room temperature for 2.5 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (0.635 g, 2.84 mmol, 94.5%) as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 1.27 (6H, d, J = 6.3 Hz), 2.12 (3H, s), 3.64 (2H, br s), 4.57 (2H, s), 5.10-5.16 ( 1H, m), 6.20 (1H, d, J = 8.2 Hz), 6.38 (1H, d, J = 7.8 Hz), 6.94 (1H, t, J = 7.4 Hz).
工程48(c)：プロパン-2-イル {3-[(1-{4-クロロ-2-[(5-フルオロピリジン-2-イル)メトキシ]フェニル}-2-オキソ-1,2-ジヒドロチエノ[3,2-d]ピリミジン-4-イル)アミノ]-2-メチルフェノキシ}アセテートの製造
工程41(d)と同様にして、工程47(c)で得られた化合物(130mg, 0.290mmol)、工程48(b)で得られた化合物(80mg, 0.358mmol)を用いて反応を行うことで、標記化合物(176mg, 0.289mmol, 99.6%)を固体として得た。
LCMS (ES): m/z 609 [M+H]+. Step 48 (c): Propan-2-yl {3-[(1- {4-chloro-2-[(5-fluoropyridin-2-yl) methoxy] phenyl} -2-oxo-1,2-dihydrothieno [3,2-d] pyrimidin-4-yl) amino] -2-methylphenoxy} acetate In the same manner as in Step 41 (d), the compound obtained in Step 47 (c) (130 mg, 0.290 mmol) The title compound (176 mg, 0.289 mmol, 99.6%) was obtained as a solid by performing a reaction using the compound (80 mg, 0.358 mmol) obtained in Step 48 (b).
LCMS (ES): m / z 609 [M + H] + .
工程48(d)：2-{3-[(1-{4-クロロ-2-[(5-フルオロピリジン-2-イル)メトキシ]フェニル}-2-オキソ-1,2-ジヒドロチエノ[3,2-d]チエノ-4-イル)アミノ]-2-メチルフェノキシ}アセタミドの製造
工程48(c)で得られた化合物(0.176g, 0.289mmol)をメタノール(1mL)に溶解し、5規定水酸化ナトリウム水溶液(2mL)を加えて室温で終夜撹拌した。反応液に1規定塩酸を加えて中和し、反応液に10％メタノール／ジクロロメタン混合溶媒を加えた。有機層を飽和食塩水で洗浄後、硫酸マグネシウムで乾燥させ、減圧下溶媒を留去し、カルボン酸粗生成物(143 mg)を得た。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝60/40-40/60(V/V)］にて精製し、標記化合物(1.64g, 7.97mmol, 85.8%) を油状物質として得た。これをN,N-ジメチルホルムアミド(3mL)に溶解し、2Mアンモニア／イソプロパノール溶液(1.00mL, 2.00mmol)、N,N-ジイソプロピルエチルアミン(0.130mL, 0.757mmol)、O-(7-アザ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ホスファート(125mg, 0.328mmol)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およびジクロロメタンを加えて分液し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をアミノシリカゲルカラムクロマトグラフィー［溶出溶媒：ジクロロメタン/メタノール＝100/0-90/10(V/V)］にて精製し、標記化合物 (82mg, 0.15mmol, 57%) を固体として得た。 Step 48 (d): 2- {3-[(1- {4-chloro-2-[(5-fluoropyridin-2-yl) methoxy] phenyl} -2-oxo-1,2-dihydrothieno [3, 2-d] thieno-4-yl) amino] -2-methylphenoxy} acetamide The compound (0.176 g, 0.289 mmol) obtained in step 48 (c) was dissolved in methanol (1 mL), and 5N Aqueous sodium oxide (2 mL) was added and stirred overnight at room temperature. The reaction solution was neutralized with 1N hydrochloric acid, and a 10% methanol / dichloromethane mixed solvent was added to the reaction solution. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give a crude carboxylic acid product (143 mg). The obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 60 / 40-40 / 60 (V / V)] to give the title compound (1.64 g, 7.97 mmol, 85.8%) as an oil Obtained as material. This is dissolved in N, N-dimethylformamide (3 mL), 2M ammonia / isopropanol solution (1.00 mL, 2.00 mmol), N, N-diisopropylethylamine (0.130 mL, 0.757 mmol), O- (7-azabenzotriazole 1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate (125 mg, 0.328 mmol) was added, and the mixture was stirred at room temperature for 4 hours. To the reaction solution are added a saturated aqueous sodium hydrogen carbonate solution and dichloromethane, and the mixture is separated, and the organic layer is washed with a saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography [elution solvent: dichloromethane / methanol = 100 / 0-90 / 10 (V / V)] to give the title compound (82 mg, 0.15 mmol, 57%) was obtained as a solid.
 LCMS (ES): m/z 566 [M+H]+.
1H NMR (CDCl3) δ (ppm): 2.14-2.21 (3H, m), 4.55-4.58 (2H, m), 5.18-5.20 (2H, m), 5.77-5.83 (1H, br m), 6.31 (1H, dd, J = 18.6, 5.3 Hz), 6.55 (1H, br s), 6.63 (1H, d, J = 8.2 Hz), 6.86-6.98 (1H, m), 7.04-7.13 (2H, m), 7.17-7.24 (1H, m), 7.28-7.47 (3H, m), 8.39-8.42 (1H, m). LCMS (ES): m / z 566 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 2.14-2.21 (3H, m), 4.55-4.58 (2H, m), 5.18-5.20 (2H, m), 5.77-5.83 (1H, br m), 6.31 (1H, dd, J = 18.6, 5.3 Hz), 6.55 (1H, br s), 6.63 (1H, d, J = 8.2 Hz), 6.86-6.98 (1H, m), 7.04-7.13 (2H, m) , 7.17-7.24 (1H, m), 7.28-7.47 (3H, m), 8.39-8.42 (1H, m).
（実施例４９）
メチル(3-{[1-(4-クロロ-2-エトキシフェニル)-2-オキソ-1,2-ジヒドロチエノ[3,2-d]ピリミジン-4-イル]アミノ}-2-メチルフェニル)カーバメート (Example 49)
Methyl (3-{[1- (4-chloro-2-ethoxyphenyl) -2-oxo-1,2-dihydrothieno [3,2-d] pyrimidin-4-yl] amino} -2-methylphenyl) carbamate
Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-C000092
工程49(a)：1-(4-クロロ-2-ヒドロキシフェニル)-4-(エチルスルファニル)チエノ[3,2-d]ピリミジン-2(1H)-オンの製造
工程43(a)と同様にして、工程46(c)で得られた化合物(11.5g, 32.6mmol)を用いて、標記化合物9.27g, 27.4mmol, 84%）を得た。
1H NMR (DMSO-D6) δ(ppm): 1.38 (3H, t, J = 7.4 Hz), 3.31 (2H, q, J = 7.4 Hz), 6.49 (1H, d, J = 5.6 Hz), 7.02 (1H, dd, J = 8.6, 2.3 Hz), 7.08 (1H, d, J = 2.3 Hz), 7.36 (1H, d, J = 8.6 Hz), 8.04 (1H, d, J = 5.5 Hz), 10.49 (1H, s). Step 49 (a): Preparation of 1- (4-chloro-2-hydroxyphenyl) -4- (ethylsulfanyl) thieno [3,2-d] pyrimidin-2 (1H) -one as in Step 43 (a) The title compound (9.27 g, 27.4 mmol, 84%) was obtained using the compound obtained in step 46 (c) (11.5 g, 32.6 mmol).
1 H NMR (DMSO-D 6 ) δ (ppm): 1.38 (3H, t, J = 7.4 Hz), 3.31 (2H, q, J = 7.4 Hz), 6.49 (1H, d, J = 5.6 Hz), 7.02 (1H, dd, J = 8.6, 2.3 Hz), 7.08 (1H, d, J = 2.3 Hz), 7.36 (1H, d, J = 8.6 Hz), 8.04 (1H, d, J = 5.5 Hz), 10.49 (1H, s).
工程49(b)：1-(4-クロロ-2-エトキシフェニル)-4-(エチルスルファニル)チエノ[3,2-d]ピリミジン-2(1H)-オンの製造
工程49(b)で得られた化合物(10.0g, 29.5mmol)をN,N-ジメチルホルムアミド(200mL)に溶解し、炭酸カリウム(8.16g, 59.0mmol)および、ヨードエタン(3.54ml, 44.3mmol) を加え、室温で終夜攪拌した。反応混合液を減圧濃縮し、残渣を酢酸エチル(400ml)に溶解し、飽和塩化アンモニウム水溶液で洗浄した。有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた濃縮残渣をヘキサンで洗浄し、減圧濃縮することで、標記化合物(10.8g, 99.9%）を固体として得た。
1H NMR (CDCl3) δ(ppm): 1.23 (3H, t, J = 7.0 Hz), 1.46 (3H, t, J = 7.4 Hz), 3.37-3.53 (2H, m), 3.98-4.11 (2H, m), 6.38 (1H, d, J= 5.5 Hz), 7.07 (1H, s), 7.08 (1H, dd, J= 7.4, 2.3 Hz), 7.23-7.26 (1H, m), 7.53 (1H, d, J = 5.5 Hz). Step 49 (b): 1- (4-Chloro-2-ethoxyphenyl) -4- (ethylsulfanyl) thieno [3,2-d] pyrimidin-2 (1H) -one obtained in Step 49 (b) The obtained compound (10.0 g, 29.5 mmol) was dissolved in N, N-dimethylformamide (200 mL), potassium carbonate (8.16 g, 59.0 mmol) and iodoethane (3.54 ml, 44.3 mmol) were added, and the mixture was stirred at room temperature overnight. did. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (400 ml) and washed with saturated aqueous ammonium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained concentrated residue was washed with hexane and concentrated under reduced pressure to obtain the title compound (10.8 g, 99.9%) as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 1.23 (3H, t, J = 7.0 Hz), 1.46 (3H, t, J = 7.4 Hz), 3.37-3.53 (2H, m), 3.98-4.11 (2H , m), 6.38 (1H, d, J = 5.5 Hz), 7.07 (1H, s), 7.08 (1H, dd, J = 7.4, 2.3 Hz), 7.23-7.26 (1H, m), 7.53 (1H, d, J = 5.5 Hz).
工程49(c)：メチル(3-{[1-(4-クロロ-2-エトキシフェニル)-2-オキソ-1,2-ジヒドロチエノ[3,2-d]ピリミジン-4-イル]アミノ}-2-メチルフェニル)カーバメートの製造
工程49(b)で得た1-(4-クロロ-2-エトキシフェニル)-4-(エチルスルファニル)チエノ[3,2-d]ピリミジン-2(1H)-オン(100mg, 0.272mmol)およびメチル N-(3-アミノ-2-メチルフェニル)カーバメート(49.1mg, 0.273mmol)の酢酸 (3．00mL)混合液を80℃で9時間攪拌した。反応混合液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/メタノール＝100／0－90／10(V/V)]で精製することで、標記化合物（94.9mg, 0.196mmol, 72%）を固体物質として得た。
LCMS (ES): m/z 485 [M+H]+
1H NMR (DMSO-D6) δ(ppm): 1.07 (3H, t, J = 7.0 Hz), 2.04 (3H, s), 3.33 (3H, s), 4.00-4.08 (2H, m), 6.29 (1H, br s), 7.10 (2H, dd, J = 8.6, 2.3 Hz), 7.20 (1H, t, J = 7.8 Hz), 7.30 (2H, d, J = 2.3 Hz), 7.33 (1H, t, J = 8.6 Hz), 7.81 (1H, br s), 8.99 (1H, s). Step 49 (c): Methyl (3-{[1- (4-chloro-2-ethoxyphenyl) -2-oxo-1,2-dihydrothieno [3,2-d] pyrimidin-4-yl] amino}- 1- (4-Chloro-2-ethoxyphenyl) -4- (ethylsulfanyl) thieno [3,2-d] pyrimidine-2 (1H)-obtained in Step 49 (b) of 2-methylphenyl) carbamate A mixture of ON (100 mg, 0.272 mmol) and methyl N- (3-amino-2-methylphenyl) carbamate (49.1 mg, 0.273 mmol) in acetic acid (3.00 mL) was stirred at 80 ° C. for 9 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: ethyl acetate / methanol = 100 / 0-90 / 10 (V / V)] to give the title compound (94.9 mg , 0.196 mmol, 72%) was obtained as a solid material.
LCMS (ES): m / z 485 [M + H] +
1 H NMR (DMSO-D 6 ) δ (ppm): 1.07 (3H, t, J = 7.0 Hz), 2.04 (3H, s), 3.33 (3H, s), 4.00-4.08 (2H, m), 6.29 (1H, br s), 7.10 (2H, dd, J = 8.6, 2.3 Hz), 7.20 (1H, t, J = 7.8 Hz), 7.30 (2H, d, J = 2.3 Hz), 7.33 (1H, t , J = 8.6 Hz), 7.81 (1H, br s), 8.99 (1H, s).
（実施例５０）
1-{4-クロロ-2-[(5-フルオロピリジン-2-イル)メトキシ]フェニル}-4-{[(2S,4S)-2-メチル-1-(メチルスルフォニル)ピペリジン-4-イル]アミノ}チエノ[3,2-d]ピリミジン-2(1H)-オン (Example 50)
1- {4-Chloro-2-[(5-fluoropyridin-2-yl) methoxy] phenyl} -4-{[(2S, 4S) -2-methyl-1- (methylsulfonyl) piperidin-4-yl ] Amino} thieno [3,2-d] pyrimidin-2 (1H) -one
Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-C000093
工程50(a)：tert-ブチル (2S,4S)-4-[(1-{4-クロロ-2-[(5-フルオロピリジン-2-イル)メトキシ]フェニル}-2-オキソ-1,2-ジヒドロチエノ[3,2-d]ピリミジン-4-イル)アミノ]-2-メチルピペリジン-1-カルボキシレートの製造
工程47(c)で得られた化合物(194mg)、tert-ブチル (2S,4S)-4-アミノ-2-メチルピペリジン-1-カルボキシレート(278 mg)を150℃で撹拌した。8時間後攪拌を停止し、室温に静置した。反応液をシリカゲルカラムクロマトグラフィー [溶出溶媒：酢酸エチル/メタノール＝100/0－95/5(V/V)］ で精製し、標記化合物(180mg) を得た。
1H NMR (CDCl3) δ: 1.30 (3H, d, J=6.8 Hz), 1.46 (9H, s), 1.70-1.80 (2H, m), 2.08-2.18 (2H, m), 3.20-3.28 (1H, m), 3.84-3.91 (1H, m), 4.18-4.25 (1H, m), 4.70 (1H, nr s), 5.19 (2H, s), 6.43 (2H, d, J=5.1 Hz), 6.99-7.02 (1H, m), 7.06-7.18 (1H, m), 7.30-7.37 (2H, m), 7.43-7.48 (2H, m), 8.37 (1H, d, J=2.7 Hz).
 
工程50(b)：1-{4-クロロ-2-[(5-フルオロピリジン-2-イル)メトキシ]フェニル}-4-{[(2S,4S)-2-メチル-1-(メチルスルフォニル)ピペリジン-4-イル]アミノ}チエノ[3,2-d]ピリミジン-2(1H)-オンの製造
工程50(a)で得られた化合物(180mg)を1,4-ジオキサン(3mL)に溶解し、4規定塩酸-1,4-ジオキサン溶液(3mL)を加え、室温で1時間撹拌した。反応液を減圧下濃縮し、残渣を1,4-ジオキサンで共沸した。これをN,N-ジメチルホルムアミド(3mL)に溶解し、トリエチルアミン(0.21mL)、メタンスルホニルクロリド(0.026mL)を加え、室温で10時間撹拌後、静置した。反応液に水を加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー ［溶出溶媒：酢酸エチル/メタノール=100/0－91/9(V/V)］で精製後、ジクロロメタン－ジイソプロピルエーテルを加えて不溶物を濾取し、標記化合物(101mg)を固体として得た。
LCMS (ES): m/z 578 [M+H]+.
1H NMR (CDCl3) δ: 1.72 (3H, d, J=6.3 Hz), 1.51-1.53 (2H, m), 1.66-1.76 (1H, m), 2.15-2.25 (1H, m), 2.92 (3H, s), 2.96-3.04 (1H, m), 3.42-3.48 (1H, m), 4.93-4.99 (1H, m), 4.70 (1H, br s), 5.19 (2H, s), 6.42 (1H, d, J=5.5 Hz), 7.00 (1H, d, J=2.0 Hz), 7.07-7.19 (1H, m), 7.24-7.28 (1H, m), 7.31-7.35 (1H, m), 7.40-7.44 (1H, m), 7.48 (1H, d, J=5.5 Hz), 8.38 (1H, d, J=2.3 Hz). Step 50 (a): tert-butyl (2S, 4S) -4-[(1- {4-chloro-2-[(5-fluoropyridin-2-yl) methoxy] phenyl} -2-oxo-1, 2-Dihydrothieno [3,2-d] pyrimidin-4-yl) amino] -2-methylpiperidine-1-carboxylate Compound (194 mg) obtained in Step 47 (c), tert-butyl (2S, 4S) -4-Amino-2-methylpiperidine-1-carboxylate (278 mg) was stirred at 150 ° C. Stirring was stopped after 8 hours and allowed to stand at room temperature. The reaction solution was purified by silica gel column chromatography [eluent: ethyl acetate / methanol = 100 / 0-95 / 5 (V / V)] to obtain the title compound (180 mg).
1 H NMR (CDCl 3 ) δ: 1.30 (3H, d, J = 6.8 Hz), 1.46 (9H, s), 1.70-1.80 (2H, m), 2.08-2.18 (2H, m), 3.20-3.28 ( 1H, m), 3.84-3.91 (1H, m), 4.18-4.25 (1H, m), 4.70 (1H, nr s), 5.19 (2H, s), 6.43 (2H, d, J = 5.1 Hz), 6.99-7.02 (1H, m), 7.06-7.18 (1H, m), 7.30-7.37 (2H, m), 7.43-7.48 (2H, m), 8.37 (1H, d, J = 2.7 Hz).

Step 50 (b): 1- {4-Chloro-2-[(5-fluoropyridin-2-yl) methoxy] phenyl} -4-{[(2S, 4S) -2-methyl-1- (methylsulfonyl) ) Piperidin-4-yl] amino} thieno [3,2-d] pyrimidin-2 (1H) -one compound (180 mg) obtained in Step 50 (a) was converted to 1,4-dioxane (3 mL). After dissolution, 4N hydrochloric acid-1,4-dioxane solution (3 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure, and the residue was azeotroped with 1,4-dioxane. This was dissolved in N, N-dimethylformamide (3 mL), triethylamine (0.21 mL) and methanesulfonyl chloride (0.026 mL) were added, and the mixture was stirred at room temperature for 10 hours and allowed to stand. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: ethyl acetate / methanol = 100 / 0-91 / 9 (V / V)], dichloromethane-diisopropyl ether was added and the insoluble material was collected by filtration to give the title compound (101 mg ) Was obtained as a solid.
LCMS (ES): m / z 578 [M + H] + .
1 H NMR (CDCl 3 ) δ: 1.72 (3H, d, J = 6.3 Hz), 1.51-1.53 (2H, m), 1.66-1.76 (1H, m), 2.15-2.25 (1H, m), 2.92 ( 3H, s), 2.96-3.04 (1H, m), 3.42-3.48 (1H, m), 4.93-4.99 (1H, m), 4.70 (1H, br s), 5.19 (2H, s), 6.42 (1H , d, J = 5.5 Hz), 7.00 (1H, d, J = 2.0 Hz), 7.07-7.19 (1H, m), 7.24-7.28 (1H, m), 7.31-7.35 (1H, m), 7.40- 7.44 (1H, m), 7.48 (1H, d, J = 5.5 Hz), 8.38 (1H, d, J = 2.3 Hz).
（実施例５１）
1-(4-クロロ-2-エトキシフェニル)-4-{[2-メチル-3-(2-オキソイミダゾリジン-1-イル)フェニル]アミノ}チエノ[3,2-d]ピリミジン-2(1H)-オン (Example 51)
1- (4-Chloro-2-ethoxyphenyl) -4-{[2-methyl-3- (2-oxoimidazolidin-1-yl) phenyl] amino} thieno [3,2-d] pyrimidine-2 ( 1H) -ON
Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000094
工程49(c)と同様にして、メチル N-(3-アミノ-2-メチルフェニル)カーバメートの代わりに1-(3-アミノ-2-メチルフェニル)イミダゾリジン-2-オン(52.1mg, 0.273mmol)を用いて標記化合物(48.9mg, 0.0986mmol, 36%)を固体として得た。
1H NMR (CDCl3) δ: 1.23-1.30 (3H, m), 2.18 (3/2H, s), 2.22 (3/2H, s), 3.61-3.66 (2H, m), 3.83-3.88 (2H, m), 3.99-4.10 (2H, m), 4.75-4.78 (1H, m), 6.23 (1/2H, d, J = 5.5 Hz), 6.28 (1/2H, d, J = 5.5 Hz), 6.89-8.13 (8H, m). In the same manner as in step 49 (c), 1- (3-amino-2-methylphenyl) imidazolidin-2-one (52.1 mg, 0.273) was used instead of methyl N- (3-amino-2-methylphenyl) carbamate. mmol) to give the title compound (48.9 mg, 0.0986 mmol, 36%) as a solid.
1 H NMR (CDCl 3 ) δ: 1.23-1.30 (3H, m), 2.18 (3 / 2H, s), 2.22 (3 / 2H, s), 3.61-3.66 (2H, m), 3.83-3.88 (2H , m), 3.99-4.10 (2H, m), 4.75-4.78 (1H, m), 6.23 (1 / 2H, d, J = 5.5 Hz), 6.28 (1 / 2H, d, J = 5.5 Hz), 6.89-8.13 (8H, m).
（実施例５２）
1-(3-{[1-(4-クロロ-2-エトキシフェニル)-2-オキソ-1,2-ジヒドロチエノ[3,2-d]ピリミジン-4-イル]アミノ}-2-メチルフェニル)イミダゾリジン-2,4-ジオン (Example 52)
1- (3-{[1- (4-chloro-2-ethoxyphenyl) -2-oxo-1,2-dihydrothieno [3,2-d] pyrimidin-4-yl] amino} -2-methylphenyl) Imidazolidine-2,4-dione
Figure JPOXMLDOC01-appb-C000095
Figure JPOXMLDOC01-appb-C000095
工程49(c)と同様にして、1-(4-クロロ-2-エトキシフェニル)-4-(エチルスルファニル)チエノ[3,2-d]ピリミジン-2(1H)-オン(80.0mg, 0.218mmol)、酢酸(1.50mL)、1-(3-アミノ-2-メチルフェニル)イミダゾリジン-2,4-ジオン(100mg, 0.436mmol)を用いて、標記化合物(50.0mg, 0.0980mmol, 45%)を固体として得た。
LCMS (ES): m/z 510 [M+H]+.
1H NMR (DMSO-D6) δ (ppm) : 1.02-1.09 (3H, m), 2.02-2.05 (3H, m), 3.96-4.10 (2H, m), 4.31 (1H, s), 4.33-4.38 (1H, m), 7.06-7.44 (8H, m), 9.38 (1H, s), 11.04 (1H, s). Analogous to step 49 (c), 1- (4-chloro-2-ethoxyphenyl) -4- (ethylsulfanyl) thieno [3,2-d] pyrimidin-2 (1H) -one (80.0 mg, 0.218 mmol), acetic acid (1.50 mL), 1- (3-amino-2-methylphenyl) imidazolidine-2,4-dione (100 mg, 0.436 mmol), and the title compound (50.0 mg, 0.0980 mmol, 45% ) Was obtained as a solid.
LCMS (ES): m / z 510 [M + H] + .
1 H NMR (DMSO-D 6 ) δ (ppm): 1.02-1.09 (3H, m), 2.02-2.05 (3H, m), 3.96-4.10 (2H, m), 4.31 (1H, s), 4.33- 4.38 (1H, m), 7.06-7.44 (8H, m), 9.38 (1H, s), 11.04 (1H, s).
（実施例５３）
3-(3-{[1-(4-クロロ-2-エトキシフェニル)-2-オキソ-1,2-ジヒドロチエノ[3,2-d]ピリミジン-4-イル]アミノ}-6-フルオロ-2-メチルフェニル)イミダゾリジン-2,4-ジオン (Example 53)
3- (3-{[1- (4-Chloro-2-ethoxyphenyl) -2-oxo-1,2-dihydrothieno [3,2-d] pyrimidin-4-yl] amino} -6-fluoro-2 -Methylphenyl) imidazolidine-2,4-dione
Figure JPOXMLDOC01-appb-C000096
Figure JPOXMLDOC01-appb-C000096
工程49(c)と同様にして、メチル N-(3-アミノ-2-メチルフェニル)カーバメートの代わりに3-(3-アミノ-6-フルオロ-2-メチルフェニル)イミダゾリジン-2,4-ジオン(60.8mg, 0.273mmol)を用いて標記化合物(96.7mg, 0.183mmol, 67%)を固体として得た。
LCMS (ES): m/z 528 [M+H]+
1H NMR (DMSO-D6) δ(ppm): 1.07 (3H, t, J = 7.0 Hz), 2.00 (3H, s), 3.99-4.09 (2H, m), 4.24 (2H, s), 6.30 (1H, br s), 7.11 (1H, dd, J = 8.2, 2.3 Hz), 7.22-7.40 (4H, m), 7.84 (1H, br s), 8.47 (1H, s). Similar to step 49 (c), instead of methyl N- (3-amino-2-methylphenyl) carbamate, 3- (3-amino-6-fluoro-2-methylphenyl) imidazolidine-2,4- Dione (60.8 mg, 0.273 mmol) was used to obtain the title compound (96.7 mg, 0.183 mmol, 67%) as a solid.
LCMS (ES): m / z 528 [M + H] +
1 H NMR (DMSO-D 6 ) δ (ppm): 1.07 (3H, t, J = 7.0 Hz), 2.00 (3H, s), 3.99-4.09 (2H, m), 4.24 (2H, s), 6.30 (1H, br s), 7.11 (1H, dd, J = 8.2, 2.3 Hz), 7.22-7.40 (4H, m), 7.84 (1H, br s), 8.47 (1H, s).
（実施例５４）
1-(4-クロロ-2-エトキシフェニル)-4-{[2-メチル-3-(5-オキソ-1,5-ジヒドロ-4H-1,2,4-トリアゾール-4-イル)フェニル]アミノ}チエノ[3,2-d]ピリミジン-2(1H)-オン (Example 54)
1- (4-Chloro-2-ethoxyphenyl) -4-{[2-methyl-3- (5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl) phenyl] Amino} thieno [3,2-d] pyrimidin-2 (1H) -one
Figure JPOXMLDOC01-appb-C000097
Figure JPOXMLDOC01-appb-C000097
工程49(c)と同様にして、メチル N-(3-アミノ-2-メチルフェニル)カーバメートの代わりに4-(3-アミノ-2-メチルフェニル)-2,4-ジヒドロ-3H-1,2,4-トリアゾール-3-オン(51.8mg, 0.273mmol)を用いて標記化合物(91.0mg, 0.184mmol, 67%)を固体として得た。
LCMS (ES): m/z 495 [M+H]+
1H NMR (DMSO-D6) δ(ppm): 1.08 (3H, t, J = 7.0 Hz), 1.84 (3H, s), 4.01-4.09 (2H, m), 6.30 (1H, d, J= 5.1 Hz), 7.11 (1H, dd, J = 8.2, 2.0 Hz), 7.18-7.38 (5H, m), 7.82 (1H, br s), 8.06 (1H, s), 11.90 (1H, s). In the same manner as in step 49 (c), instead of methyl N- (3-amino-2-methylphenyl) carbamate, 4- (3-amino-2-methylphenyl) -2,4-dihydro-3H-1, The title compound (91.0 mg, 0.184 mmol, 67%) was obtained as a solid using 2,4-triazol-3-one (51.8 mg, 0.273 mmol).
LCMS (ES): m / z 495 [M + H] +
1 H NMR (DMSO-D 6 ) δ (ppm): 1.08 (3H, t, J = 7.0 Hz), 1.84 (3H, s), 4.01-4.09 (2H, m), 6.30 (1H, d, J = 5.1 Hz), 7.11 (1H, dd, J = 8.2, 2.0 Hz), 7.18-7.38 (5H, m), 7.82 (1H, br s), 8.06 (1H, s), 11.90 (1H, s).
（実施例５５）
2-(4-{[1-(4-フルオロ-2-メトキシフェニル)-2-オキソ-1,2-ジヒドロチエノ[2,3-d]ピリミジン-4-イル]アミノ}-3-メチルフェニル)アセタミド (Example 55)
2- (4-{[1- (4-Fluoro-2-methoxyphenyl) -2-oxo-1,2-dihydrothieno [2,3-d] pyrimidin-4-yl] amino} -3-methylphenyl) Acetamide
Figure JPOXMLDOC01-appb-C000098
Figure JPOXMLDOC01-appb-C000098
工程55(a)：メチル 2-[(4-フルオロ-2-メトキシフェニル)アミノ]チオフェン-3-カルボキシレートの製造
メチル2-アミノチオフェン-3-カルボキシレート(3.00g, 19.1mmol)を1,4-ジオキサン(100mL)に溶解し、1-ブロモ-4-フルオロ-2-メトキシベンゼン(3.91g, 19.1mmol)、酢酸パラジウム(II)(214mg, 0.954mmol)、(9,9-ジメチル-9H-キサンテン-4,5-ジイル)ビス(ジフェニルホスファン)(1.10g, 1.91mmol)、炭酸セシウム(12.4g, 38.2mmol)を加え、加熱還流下、8時間撹拌した。水を加え、セライトろ過を行い、ろ液を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去し、得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル=70/30(V/V)］にて精製し、標記化合物(4.65g, 16.5mmol, 87%)を固体として得た。
1H NMR (CDCl3) δ (ppm): 3.88 (3H, s), 3.95 (3H, s), 6.32 (1H, d, J = 5.8 Hz), 6.66-6.73 (2H, m), 7.16 (1H, d, J = 4.7 Hz), 7.47 (1H, dd, J = 8.8, 5.8 Hz), 10.03 (1H, br s). Step 55 (a): Preparation of methyl 2-[(4-fluoro-2-methoxyphenyl) amino] thiophene-3-carboxylate Methyl 2-aminothiophene-3-carboxylate (3.00 g, 19.1 mmol) Dissolved in 4-dioxane (100 mL), 1-bromo-4-fluoro-2-methoxybenzene (3.91 g, 19.1 mmol), palladium (II) acetate (214 mg, 0.954 mmol), (9,9-dimethyl-9H -Xanthene-4,5-diyl) bis (diphenylphosphane) (1.10 g, 1.91 mmol) and cesium carbonate (12.4 g, 38.2 mmol) were added, and the mixture was stirred with heating under reflux for 8 hours. Water was added, celite filtration was performed, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 70/30 (V / V)] to give the title compound (4.65 g, 16.5 mmol). , 87%) as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 3.88 (3H, s), 3.95 (3H, s), 6.32 (1H, d, J = 5.8 Hz), 6.66-6.73 (2H, m), 7.16 (1H , d, J = 4.7 Hz), 7.47 (1H, dd, J = 8.8, 5.8 Hz), 10.03 (1H, br s).
工程55(b)：4-(エチルスルファニル)-1-(4-フルオロ-2-メトキシフェニル)チエノ[2,3-d]ピリミジン-2(1H)オンの製造
工程55(a)で得られた化合物(4.64g, 16.5mmol)をテトラヒドロフラン(100mL)、酢酸エチル(50.0mL)の混合溶媒に溶解し、-15℃にて、クロロスルホニルイソシアネート(2.14mL, 24.8mmol)を加え、-15℃で30分攪拌した。水を加えて10分攪拌し、5規定水酸化ナトリウム水溶液を加え、室温で18時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、反応混合物を酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去した。残渣をピリジン(150mL)に溶解し、五硫化二りん(5.51g, 24.8mmol)を加え、加熱還流下、8時間撹拌した。減圧下で溶媒を留去し、水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去した。残渣をテトラヒドロフラン(100mL)、水(50.0mL)に溶解し、炭酸カリウム(4.56g, 33.0mmol)、ヨードエタン(2.64mL, 33.0mmol)を加え、室温にて18時間攪拌した。水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下で溶媒を留去し、得られた残渣を、シリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル=100/0-0/100(V/V)］にて精製し、標記化合物(2.06g, 6.12mmol, 37%)を固体として得た。
1H NMR (CDCl3) δ (ppm): 1.44 (3H, t, J = 7.4 Hz), 3.34-3.45 (2H, m), 3.79 (3H, s), 6.77-6.85 (3H, m), 7.16 (1H, d, J = 5.9 Hz), 7.29-7.36 (1H, m). Step 55 (b): Obtained in Step 55 (a) for the preparation of 4- (ethylsulfanyl) -1- (4-fluoro-2-methoxyphenyl) thieno [2,3-d] pyrimidin-2 (1H) one. The compound (4.64 g, 16.5 mmol) was dissolved in a mixed solvent of tetrahydrofuran (100 mL) and ethyl acetate (50.0 mL), chlorosulfonyl isocyanate (2.14 mL, 24.8 mmol) was added at -15 ° C, and -15 ° C For 30 minutes. Water was added and stirred for 10 minutes, 5N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was dissolved in pyridine (150 mL), diphosphorus pentasulfide (5.51 g, 24.8 mmol) was added, and the mixture was stirred with heating under reflux for 8 hr. The solvent was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL) and water (50.0 mL), potassium carbonate (4.56 g, 33.0 mmol) and iodoethane (2.64 mL, 33.0 mmol) were added, and the mixture was stirred at room temperature for 18 hours. Water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-0 / 100 (V / V)] to give the title compound (2.06 g, 6.12 mmol, 37%) was obtained as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 1.44 (3H, t, J = 7.4 Hz), 3.34-3.45 (2H, m), 3.79 (3H, s), 6.77-6.85 (3H, m), 7.16 (1H, d, J = 5.9 Hz), 7.29-7.36 (1H, m).
工程55(c)：2-(4-{[1-(4-フルオロ-2-メトキシフェニル)-2-オキソ-1,2-ジヒドロチエノ[2,3-d]ピリミジン-4-イル]アミノ}-3-メチルフェニル)アセタミドの製造
工程55(b)で得られた化合物(50.0mg, 0.149mmol)を、酢酸(2.00mL)、1,2-ジメトキシエタン(4.00mL)の混合溶媒に溶解し、2-(4-アミノ-3-メチルフェニル)アセタミド(26.9mg, 0.164mmol)を加え、加熱還流下、8時間撹拌した。減圧下で溶媒を留去して得られた残渣を、シリカゲルカラムクロマトグラフィー［NHシリカゲル、溶出溶媒：酢酸エチル/メタノール=80/20(V/V)］にて精製し、標記化合物(64.0mg, 0.146mmol, 98%)を固体として得た。
LCMS (ES): m/z 439 [M+H]+.
1H NMR (CDCl3) δ (ppm): 2.21 (3H, s), 3.49 (2H, s), 3.83 (3H, s), 6.77-6.86 (2H, m), 7.09-7.21 (4H, m), 7.46 (1H, d, J = 5.8 Hz), 7.50-7.53 (1H, m). Step 55 (c): 2- (4-{[1- (4-Fluoro-2-methoxyphenyl) -2-oxo-1,2-dihydrothieno [2,3-d] pyrimidin-4-yl] amino} -3-Methylphenyl) acetamide The compound (50.0 mg, 0.149 mmol) obtained in step 55 (b) was dissolved in a mixed solvent of acetic acid (2.00 mL) and 1,2-dimethoxyethane (4.00 mL). 2- (4-amino-3-methylphenyl) acetamide (26.9 mg, 0.164 mmol) was added, and the mixture was stirred with heating under reflux for 8 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography [NH silica gel, elution solvent: ethyl acetate / methanol = 80/20 (V / V)] to give the title compound (64.0 mg , 0.146 mmol, 98%) was obtained as a solid.
LCMS (ES): m / z 439 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 2.21 (3H, s), 3.49 (2H, s), 3.83 (3H, s), 6.77-6.86 (2H, m), 7.09-7.21 (4H, m) , 7.46 (1H, d, J = 5.8 Hz), 7.50-7.53 (1H, m).
（実施例５６）
2-(4-{[1-(4-クロロ-2-メトキシフェニル)-2-オキソ-1,2-ジヒドロピロロ[1,2-a][1,3,5]トリアジン-4-イル]アミノ}-3-メチルフェニル)アセタミド (Example 56)
2- (4-{[1- (4-Chloro-2-methoxyphenyl) -2-oxo-1,2-dihydropyrrolo [1,2-a] [1,3,5] triazin-4-yl] Amino} -3-methylphenyl) acetamide
Figure JPOXMLDOC01-appb-C000099
Figure JPOXMLDOC01-appb-C000099
工程56(a)：N-(4-クロロ-2-メトキシフェニル)-4,4-ジメトキシブタンチオアミドの製造
マグネシウム(7.65g, 315mmol)をテトラヒドロフラン(350mL)に懸濁し、3-クロロ-1,1-ジメトキシプロパン(38.2g, 276mmol)を滴下し、1時間攪拌し、(3,3-ジメトキシプロピル)マグネシウムクロリドを調製した。4-クロロ-1-イソチオシアナト-2-メトキシベンゼン(39.3g, 197mmol)のテトラヒドロフラン(150mL)に溶解した溶液を0℃に冷却し、先ほど調製した(3,3-ジメトキシプロピル)マグネシウムブロミドを滴下した。滴下後、室温まで昇温し、5時間攪拌した。反応液に、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝95/5-40/60(V/V)］にて精製し、標記化合物 (49.4g, 163mmol, 83%) を固体として得た。
1H NMR (CDCl3) δ: 2.15 (2H, td, J = 7.3, 5.6 Hz), 2.87 (2H, t, J = 7.3 Hz), 3.35 (6H, s), 3.88 (3H, s), 4.43 (1H, t, J= 5.6 Hz), 6.89 (1H, d, J = 2.2 Hz), 6.95 (1H, dd, J = 8.5, 2.2 Hz), 8.92 (1H, d, J = 8.5 Hz), 9.28 (1H, s). Step 56 (a): Preparation of N- (4-chloro-2-methoxyphenyl) -4,4-dimethoxybutanethioamide Magnesium (7.65 g, 315 mmol) was suspended in tetrahydrofuran (350 mL), and 3-chloro-1, 1-Dimethoxypropane (38.2 g, 276 mmol) was added dropwise and stirred for 1 hour to prepare (3,3-dimethoxypropyl) magnesium chloride. A solution of 4-chloro-1-isothiocyanato-2-methoxybenzene (39.3 g, 197 mmol) dissolved in tetrahydrofuran (150 mL) was cooled to 0 ° C., and (3,3-dimethoxypropyl) magnesium bromide prepared earlier was added dropwise. . After dropping, the temperature was raised to room temperature and stirred for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 95 / 5-40 / 60 (V / V)] to give the title compound (49.4 g , 163 mmol, 83%) as a solid.
1 H NMR (CDCl 3 ) δ: 2.15 (2H, td, J = 7.3, 5.6 Hz), 2.87 (2H, t, J = 7.3 Hz), 3.35 (6H, s), 3.88 (3H, s), 4.43 (1H, t, J = 5.6 Hz), 6.89 (1H, d, J = 2.2 Hz), 6.95 (1H, dd, J = 8.5, 2.2 Hz), 8.92 (1H, d, J = 8.5 Hz), 9.28 (1H, s).
工程56(b)：メチル(4-クロロ-2-メトキシフェニル)(4,4-ジメトキシブタンチオイル)カルバメートの製造
水素化ナトリウム(8.05g, 211mmol)をテトラヒドロフラン(100mL)に懸濁し、0℃にて工程56(a)で得られた化合物(49.5g, 163mmol)のテトラヒドロフラン(200mL)溶液を滴下した。滴下後、0℃で10分間攪拌した後、メチルクロロホルメート(20.0g, 211mmol)のテトラヒドロフラン(100mL)溶液を滴下した。30分攪拌後、反応液を塩化アンモニウム水溶液に加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣は精製を行わず、そのまま次の反応に使用した。
1H NMR (CDCl3) δ: 2.08-2.19 (2H, m), 3.33 (6H, s), 3.39-3.48 (2H, m), 3.71 (3H, s), 3.75 (3H, s), 4.48 (1H, t, J = 5.6 Hz), 6.92 (1H, d, J = 1.5 Hz), 6.94-6.96 (2H, m). Step 56 (b): Preparation of methyl (4-chloro-2-methoxyphenyl) (4,4-dimethoxybutanethioyl) carbamate Sodium hydride (8.05 g, 211 mmol) was suspended in tetrahydrofuran (100 mL) and treated at 0 ° C. Then, a solution of the compound (49.5 g, 163 mmol) obtained in step 56 (a) in tetrahydrofuran (200 mL) was added dropwise. After dropping, the mixture was stirred at 0 ° C. for 10 minutes, and then a solution of methyl chloroformate (20.0 g, 211 mmol) in tetrahydrofuran (100 mL) was added dropwise. After stirring for 30 minutes, the reaction solution was added to an aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was used for the next reaction without purification.
1 H NMR (CDCl 3 ) δ: 2.08-2.19 (2H, m), 3.33 (6H, s), 3.39-3.48 (2H, m), 3.71 (3H, s), 3.75 (3H, s), 4.48 ( 1H, t, J = 5.6 Hz), 6.92 (1H, d, J = 1.5 Hz), 6.94-6.96 (2H, m).
工程56(c)：1-(4-クロロ-2-メトキシフェニル)-6-(3,3-ジメトキシプロピル)-4-(エチルスルファニル)-1,3,5-トリアジン-2(1H)-オンの製造
チオウレア(16.1g, 212mmol)をエタノール(120mL)に懸濁し、ヨードエタン(43.2g, 277mmol)を加えて、65℃で5時間攪拌し、エチル　カルバミミドチオエートを調製した。工程56(b)で得られた化合物(59.0g, 163mmol)をエタノール(400mL)に溶解し、0℃に冷却後、先ほど調製したエチル　カルバミミドチオエートを加えた。反応液を室温にして、トリエチルアミン(56.5mL, 408mmol)を加え、室温で2時間攪拌した。反応液を減圧下濃縮し、得られた残渣に水を加え、ジクロロメタンで抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝80/20-40/60(V/V)］にて精製し、標記化合物 (47.8g, 120mmol, 73%) を油状物質として得た。
LCMS (ES): m/z 400 [M+H]+.
1H NMR (CDCl3) δ: 1.37 (3H, t, J = 7.3 Hz), 1.86-1.98 (2H, m), 2.31 (2H, t, J = 7.3 Hz), 3.13 (2H, qd, J = 7.3, 2.3 Hz), 3.22 (6H, s), 3.80 (3H, s), 4.28 (1H, t, J = 5.4 Hz), 7.01-7.11 (3H, m). Step 56 (c): 1- (4-chloro-2-methoxyphenyl) -6- (3,3-dimethoxypropyl) -4- (ethylsulfanyl) -1,3,5-triazine-2 (1H)- Preparation of ON Thiourea (16.1 g, 212 mmol) was suspended in ethanol (120 mL), iodoethane (43.2 g, 277 mmol) was added, and the mixture was stirred at 65 ° C. for 5 hours to prepare ethyl carbamidimide thioate. The compound (59.0 g, 163 mmol) obtained in step 56 (b) was dissolved in ethanol (400 mL), cooled to 0 ° C., and ethyl carbamimidothioate prepared earlier was added. The reaction mixture was brought to room temperature, triethylamine (56.5 mL, 408 mmol) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [eluent: hexane / ethyl acetate = 80 / 20-40 / 60 (V / V)] To obtain the title compound (47.8 g, 120 mmol, 73%) as an oily substance.
LCMS (ES): m / z 400 [M + H] + .
1 H NMR (CDCl 3 ) δ: 1.37 (3H, t, J = 7.3 Hz), 1.86-1.98 (2H, m), 2.31 (2H, t, J = 7.3 Hz), 3.13 (2H, qd, J = 7.3, 2.3 Hz), 3.22 (6H, s), 3.80 (3H, s), 4.28 (1H, t, J = 5.4 Hz), 7.01-7.11 (3H, m).
工程56(d)：1-(4-クロロ-2-メトキシフェニル)-4-(エチルスルファニル)ピロロ[1,2-a][1,3,5]トリアジン-2(1H)-オンの製造
工程56(c)で得られた化合物(5.41g, 13.5mmol)をジクロロメタン(40.0mL)に溶解し、0℃に冷却後、トリフルオロ酢酸(10.0mL)/水(10.0mL)の混合液を滴下し、5時間攪拌した。ジクロロメタンを用いて抽出し、有機層に飽和炭酸水素ナトリウム水溶液を加え中和した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をテトラヒドロフラン(60.0mL)に溶解し、水冷下攪拌中に、3,3,3-トリエチル-1-(メトキシカルボニル)ジアザチアン-3-イウム-1-イド2,2-ジオキシド(Burgess試薬、3.22g, 13.5mmol)を加え、室温で3時間攪拌した。反応液に、飽和食塩水を加え、酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝70/30-40/60(V/V)］にて精製し、標記化合物 (2.36g, 7.03mmol, 52%) を固体として得た。
LCMS (ES): m/z 336 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 1.46 (3H, t, J = 7.3 Hz), 3.34-3.46 (2H, m), 3.77 (3H, s), 5.08 (1H, dd, J = 3.4, 1.5 Hz), 6.36 (1H, t, J = 3.4 Hz), 6.84 (1H, dd, J = 3.4, 1.5 Hz), 7.02-7.07 (2H, m), 7.23-7.28 (1H, m). Step 56 (d): Preparation of 1- (4-chloro-2-methoxyphenyl) -4- (ethylsulfanyl) pyrrolo [1,2-a] [1,3,5] triazin-2 (1H) -one The compound obtained in step 56 (c) (5.41 g, 13.5 mmol) is dissolved in dichloromethane (40.0 mL), cooled to 0 ° C., and then mixed with trifluoroacetic acid (10.0 mL) / water (10.0 mL). The solution was added dropwise and stirred for 5 hours. Extraction was performed using dichloromethane, and the organic layer was neutralized by adding a saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in tetrahydrofuran (60.0 mL), and while stirring under water cooling, 3,3,3-triethyl-1- (methoxycarbonyl) diazathian-3-ium-1 -Id 2,2-dioxide (Burgess reagent, 3.22 g, 13.5 mmol) was added and stirred at room temperature for 3 hours. To the reaction solution was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 70 / 30-40 / 60 (V / V)] to give the title compound (2.36 g , 7.03 mmol, 52%) as a solid.
LCMS (ES): m / z 336 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.46 (3H, t, J = 7.3 Hz), 3.34-3.46 (2H, m), 3.77 (3H, s), 5.08 (1H, dd, J = 3.4, 1.5 Hz), 6.36 (1H, t, J = 3.4 Hz), 6.84 (1H, dd, J = 3.4, 1.5 Hz), 7.02-7.07 (2H, m), 7.23-7.28 (1H, m).
工程56(e)：2-(4-{[1-(4-クロロ-2-メトキシフェニル)-2-オキソ-1,2-ジヒドロピロロ[1,2-a][1,3,5]トリアジン-4-イル]アミノ}-3-メチルフェニル)アセタミドの製造
工程56(d)で得られた化合物(105mg, 0.312mmol)を、酢酸(1.00mL)に溶解し、2-(4-アミノ-3-メチルフェニル)アセタミド(77.0mg, 0.469mmol)を加え、135℃で4時間攪拌した。反応液を減圧下、濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/メタノール＝100/0-70/30(V/V)］にて精製し、標記化合物(40.0mg, 0.292mmol, 29%) を固体として得た。
LCMS (ES): m/z 438 [M+H]+.
1H NMR (DMSO-D6) δ (ppm) : 2.22 (3H, s), 3.72 (3H, s), 4.94 (2H, d, J = 2.0 Hz), 6.40 (1H, s), 6.88 (1H, s), 7.09-7.36 (7H, m), 7.48 (2H, s), 9.81 (1H, s). Step 56 (e): 2- (4-{[1- (4-chloro-2-methoxyphenyl) -2-oxo-1,2-dihydropyrrolo [1,2-a] [1,3,5] Triazin-4-yl] amino} -3-methylphenyl) acetamide The compound (105 mg, 0.312 mmol) obtained in Step 56 (d) was dissolved in acetic acid (1.00 mL) to give 2- (4-amino -3-Methylphenyl) acetamide (77.0 mg, 0.469 mmol) was added, and the mixture was stirred at 135 ° C. for 4 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by silica gel column chromatography [elution solvent: ethyl acetate / methanol = 100 / 0-70 / 30 (V / V)] to give the title compound (40.0 mg , 0.292 mmol, 29%) was obtained as a solid.
LCMS (ES): m / z 438 [M + H] + .
1 H NMR (DMSO-D 6 ) δ (ppm): 2.22 (3H, s), 3.72 (3H, s), 4.94 (2H, d, J = 2.0 Hz), 6.40 (1H, s), 6.88 (1H , s), 7.09-7.36 (7H, m), 7.48 (2H, s), 9.81 (1H, s).
（実施例５７）
2-[4-({1-[4-フルオロ-2-(テトラヒドロ-2H-ピラン-2-イルメトキシ)フェニル]-2-オキソ-1,2-ジヒドロピロロ[1,2-a][1,3,5]トリアジン-4-イル}アミノ)-3-メチルフェニル]アセタミド (Example 57)
2- [4-({1- [4-Fluoro-2- (tetrahydro-2H-pyran-2-ylmethoxy) phenyl] -2-oxo-1,2-dihydropyrrolo [1,2-a] [1, 3,5] triazin-4-yl} amino) -3-methylphenyl] acetamide
Figure JPOXMLDOC01-appb-C000100
Figure JPOXMLDOC01-appb-C000100
工程57(a)：N-(4-フルオロ-2-メトキシフェニル)-4,4-ジメトキシブタンチオアミドの製造
工程56(a)と同様にして、4-フルオロ-1-イソチオシアナト-2-メトキシベンゼン(64.8g, 354mmol)、3-ブロモ-1,1-ジメトキシプロパン(90.7g, 496mmol)、マグネシウム(13.8g, 566mmol)、テトラヒドロフラン(900mL)を用いて、標記化合物(57.0g, 198mmol, 56%)を油状物質として得た。
LCMS (ES): m/z 288 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 2.15 (2H, td, J = 7.2, 5.9 Hz), 2.86 (2H, t, J = 7.2 Hz), 3.34 (6H, s), 3.86 (3H, s), 4.43 (1H, t, J= 5.5 Hz), 6.62-6.69 (2H, m), 8.78 (1H, dd, J = 8.8, 6.1 Hz), 9.19 (1H, s). Step 57 (a): Preparation of N- (4-fluoro-2-methoxyphenyl) -4,4-dimethoxybutanethioamide As in Step 56 (a), 4-fluoro-1-isothiocyanato-2-methoxybenzene (64.8 g, 354 mmol), 3-bromo-1,1-dimethoxypropane (90.7 g, 496 mmol), magnesium (13.8 g, 566 mmol), tetrahydrofuran (900 mL) were used to give the title compound (57.0 g, 198 mmol, 56% ) Was obtained as an oil.
LCMS (ES): m / z 288 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 2.15 (2H, td, J = 7.2, 5.9 Hz), 2.86 (2H, t, J = 7.2 Hz), 3.34 (6H, s), 3.86 (3H, s ), 4.43 (1H, t, J = 5.5 Hz), 6.62-6.69 (2H, m), 8.78 (1H, dd, J = 8.8, 6.1 Hz), 9.19 (1H, s).
工程57(b)：1-(4-フルオロ-2-メトキシフェニル)-4-(エチルスルファニル）ピロロ[1,2-a][1,3,5]トリアジン-2(1H)-オンの製造
工程56(b)、(c)、(d)と同様にして、工程57(a)で得られた化合物(57.3g, 199mmol)、水素化ナトリウム(11.4g, 299mmol)、メチルクロロホルメート(37.7g, 399mmol)、テトラヒドロフラン(500mL)、エチル　カルバミミドチオエート(48.4g, 208mmol)、トリエチルアミン(27.5mL, 198mmol)、ジクロロメタン(300mL)、トリフルオロ酢酸(10mL)/水(10mL)、3,3,3-トリエチル-1-(メトキシカルボニル)ジアザチアン-3-イウム-1-イド2,2-ジオキシド(Burgess試薬、17.0g, 71.0mmol)、テトラヒドロフラン(300mL)を用いて、標記化合物(3.20g, 10.0mmol, 5%)を得た。
LCMS (ES): m/z 320 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 1.46 (3H, t, J = 7.6 Hz), 3.35-3.43 (2H, m), 3.76 (3H, s), 5.07 (1H, dd, J = 3.7, 1.7 Hz), 6.36 (1H, t, J = 3.7 Hz), 6.72-6.81 (2H, m), 6.84-6.85 (1H, m), 7.28 (1H, dd, J = 8.5, 6.1 Hz). Step 57 (b): Preparation of 1- (4-fluoro-2-methoxyphenyl) -4- (ethylsulfanyl) pyrrolo [1,2-a] [1,3,5] triazin-2 (1H) -one In the same manner as in steps 56 (b), (c), and (d), the compound obtained in step 57 (a) (57.3 g, 199 mmol), sodium hydride (11.4 g, 299 mmol), methyl chloroformate ( 37.7 g, 399 mmol), tetrahydrofuran (500 mL), ethyl carbamidimide thioate (48.4 g, 208 mmol), triethylamine (27.5 mL, 198 mmol), dichloromethane (300 mL), trifluoroacetic acid (10 mL) / water (10 mL), 3 , 3,3-triethyl-1- (methoxycarbonyl) diazathian-3-ium-1-id 2,2-dioxide (Burgess reagent, 17.0 g, 71.0 mmol), tetrahydrofuran (300 mL), and the title compound (3.20 g, 10.0 mmol, 5%).
LCMS (ES): m / z 320 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.46 (3H, t, J = 7.6 Hz), 3.35-3.43 (2H, m), 3.76 (3H, s), 5.07 (1H, dd, J = 3.7, 1.7 Hz), 6.36 (1H, t, J = 3.7 Hz), 6.72-6.81 (2H, m), 6.84-6.85 (1H, m), 7.28 (1H, dd, J = 8.5, 6.1 Hz).
工程57(c)：4-(エチルスルファニル)-1-(4-フルオロ-2-ヒドロキシフェニル)ピロロ[1,2-a][1,3,5]トリアジン-2(1H)-オンの製造
工程R1(e)と同様にして、工程57(b)で得られた化合物(3.20g, 10.0mmol)、三臭化ホウ素／17%ジクロロメタン溶液(1.90mL, 20.0mmol)、ジクロロメタン(100mL)を用いて、標記化合物(1.90g, 6.20mmol, 62%)を固体として得た。
LCMS (ES): m/z 306 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 1.47 (2H, t, J = 7.3 Hz), 3.39 (1H, q, J = 7.3 Hz), 5.17 (1H, dd, J = 3.5, 1.6 Hz), 6.46 (1H, t, J = 3.5 Hz), 6.69 (2H, dt, J = 18.6, 6.7 Hz), 7.02 (1H, dd, J = 3.5, 1.6 Hz), 7.25 (1H, dd, J = 8.6, 6.3 Hz). Step 57 (c): Preparation of 4- (ethylsulfanyl) -1- (4-fluoro-2-hydroxyphenyl) pyrrolo [1,2-a] [1,3,5] triazin-2 (1H) -one In the same manner as in Step R1 (e), the compound obtained in Step 57 (b) (3.20 g, 10.0 mmol), boron tribromide / 17% dichloromethane solution (1.90 mL, 20.0 mmol), dichloromethane (100 mL) were added. Used to give the title compound (1.90 g, 6.20 mmol, 62%) as a solid.
LCMS (ES): m / z 306 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 1.47 (2H, t, J = 7.3 Hz), 3.39 (1H, q, J = 7.3 Hz), 5.17 (1H, dd, J = 3.5, 1.6 Hz) , 6.46 (1H, t, J = 3.5 Hz), 6.69 (2H, dt, J = 18.6, 6.7 Hz), 7.02 (1H, dd, J = 3.5, 1.6 Hz), 7.25 (1H, dd, J = 8.6 , 6.3 Hz).
工程57(d)：4-(エチルスルファニル)-1-[4-フルオロ-2-(テトラヒドロ-2H-ピラン-2-イルメトキシ)フェニル]ピロロ[1,2-a][1,3,5]トリアジン-2(1H)-オンの製造
工程16(a)と同様にして、工程57(c)で得られた化合物(100mg, 0.328mmol)と2-(ブロモメチル)テトラヒドロ-2H-ピラン(117mg, 0.655mmol)、炭酸セシウム(320mg, 0.983mmol)、N,N-ジメチルホルムアミド(1.50mL)を用いて、標記化合物(14.0mg, 0.0347mmol, 11%)を油状物質として得た。
LCMS (ES): m/z 404 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 1.13-1.24 (1H, m), 1.34-1.56 (4H, m), 1.45 (3H, t, J = 7.3 Hz), 1.69-1.82 (1H, m), 3.32-3.42 (1H, m), 3.40 (2H, q, J = 7.3 Hz), 3.48-3.54 (1H, m), 3.81-3.91 (2H, m), 3.96-4.04 (1H, m), 5.06-5.13 (1H, m), 6.33-6.37 (1H, m), 6.73-6.78 (1H, m), 6.82-6.86 (2H, m), 7.26-7.30 (1H, m). Step 57 (d): 4- (Ethylsulfanyl) -1- [4-fluoro-2- (tetrahydro-2H-pyran-2-ylmethoxy) phenyl] pyrrolo [1,2-a] [1,3,5] Preparation of triazin-2 (1H) -one In the same manner as in Step 16 (a), the compound (100 mg, 0.328 mmol) obtained in Step 57 (c) and 2- (bromomethyl) tetrahydro-2H-pyran (117 mg, 0.655 mmol), cesium carbonate (320 mg, 0.983 mmol) and N, N-dimethylformamide (1.50 mL) were used to obtain the title compound (14.0 mg, 0.0347 mmol, 11%) as an oily substance.
LCMS (ES): m / z 404 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.13-1.24 (1H, m), 1.34-1.56 (4H, m), 1.45 (3H, t, J = 7.3 Hz), 1.69-1.82 (1H, m) , 3.32-3.42 (1H, m), 3.40 (2H, q, J = 7.3 Hz), 3.48-3.54 (1H, m), 3.81-3.91 (2H, m), 3.96-4.04 (1H, m), 5.06 -5.13 (1H, m), 6.33-6.37 (1H, m), 6.73-6.78 (1H, m), 6.82-6.86 (2H, m), 7.26-7.30 (1H, m).
工程57(e)：2-[4-({1-[4-フルオロ-2-(テトラヒドロ-2H-ピラン-2-イルメトキシ)フェニル]-2-オキソ-1,2-ジヒドロピロロ[1,2-a][1,3,5]トリアジン-4-イル}アミノ)-3-メチルフェニル]アセタミドの製造
工程57(d)で得られた化合物(14.0mg, 0.0347mmol)をジメチルスルホキシド(0.300mL)に溶解し、2-(4-アミノ-3-メチルフェニル)アセタミド(8.00mg, 0.0520mmol)を加え、120℃で5時間攪拌した。反応液をアミノシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/メタノール＝100/0-50/50(V/V)］にて精製し、標記化合物 (10.0mg, 0.0200mmol, 57%) を固体として得た。
LCMS (ES): m/z 506 [M+H]+.
1H NMR(CDCl3) δ(ppm) : 1.14-1.27 (1H, m), 1.37-1.56 (4H, m), 1.73-1.81 (1H, m), 2.19 (3H, s), 3.29-3.37 (1H, m), 3.45-3.57 (1H, m), 3.54 (2H, s), 3.80-3.85 (1H, m), 3.86-3.92 (1H, m), 3.95-4.02 (1H, m), 5.09-5.13 (1H, m), 6.24-6.27 (1H, m), 6.72-6.88 (3H, m), 7.10-7.19 (2H, m), 7.27-7.35 (2H, m). Step 57 (e): 2- [4-({1- [4-Fluoro-2- (tetrahydro-2H-pyran-2-ylmethoxy) phenyl] -2-oxo-1,2-dihydropyrrolo [1,2 -a] [1,3,5] triazin-4-yl} amino) -3-methylphenyl] acetamide The compound (14.0 mg, 0.0347 mmol) obtained in Step 57 (d) was converted to dimethyl sulfoxide (0.300 mL). ), 2- (4-amino-3-methylphenyl) acetamide (8.00 mg, 0.0520 mmol) was added, and the mixture was stirred at 120 ° C. for 5 hours. The reaction solution was purified by column chromatography on amino silica gel [eluent: ethyl acetate / methanol = 100 / 0-50 / 50 (V / V)] to give the title compound (10.0 mg, 0.0200 mmol, 57%) as a solid. Obtained.
LCMS (ES): m / z 506 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.14-1.27 (1H, m), 1.37-1.56 (4H, m), 1.73-1.81 (1H, m), 2.19 (3H, s), 3.29-3.37 ( 1H, m), 3.45-3.57 (1H, m), 3.54 (2H, s), 3.80-3.85 (1H, m), 3.86-3.92 (1H, m), 3.95-4.02 (1H, m), 5.09- 5.13 (1H, m), 6.24-6.27 (1H, m), 6.72-6.88 (3H, m), 7.10-7.19 (2H, m), 7.27-7.35 (2H, m).
（実施例５８）
2-{4-[(1-{4-フルオロ-2-[(3-フルオロピリジン-2-イル）メトキシ］フェニル}-2-オキソ-1,2-ジヒドロピロロ[1,2-a][1,3,5]トリアジン-4-イル)アミノ]-3-メチルフェニル}アセタミド (Example 58)
2- {4-[(1- {4-Fluoro-2-[(3-fluoropyridin-2-yl) methoxy] phenyl} -2-oxo-1,2-dihydropyrrolo [1,2-a] [ 1,3,5] triazin-4-yl) amino] -3-methylphenyl} acetamide
Figure JPOXMLDOC01-appb-C000101
Figure JPOXMLDOC01-appb-C000101
工程58(a)：4-(エチルスルファニル)-1-{4-フルオロ-2-[(3-フルオロピリジン-2-イル)メトキシ]フェニル}ピロロ[1,2-a][1,3,5]トリアジン-2(1H)-オンの製造
(3-フルオロピリジン-2-イル）メタノール(200mg, 1.57mmol)をジクロロメタン(25.0mL)に溶解し、トリエチルアミン(0.454mL, 3.28mmol)を加えた。反応液を0℃に冷却した後、メタンスルホニルクロリド(0.153mL, 1.97mmol)を加え、30分間攪拌した。反応液に水を加え、有機層を無水硫酸マグネシウムで乾燥した後、減圧下で溶媒を留去した。得られた残渣に、工程57(c)で得られた化合物(200mg, 0.655mmol)、炭酸セシウム(640mg, 1.97mmol)、N,N-ジメチルホルムアミド(5.00mL)を加え、70℃で2時間攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝50/50-0/100(V/V)］にて精製し、標記化合物(119mg, 0.287mmol, 43%) を油状物質として得た。
LCMS (ES): m/z 415 [M+H]+. Step 58 (a): 4- (Ethylsulfanyl) -1- {4-fluoro-2-[(3-fluoropyridin-2-yl) methoxy] phenyl} pyrrolo [1,2-a] [1,3, 5] Manufacture of triazine-2 (1H) -one
(3-Fluoropyridin-2-yl) methanol (200 mg, 1.57 mmol) was dissolved in dichloromethane (25.0 mL), and triethylamine (0.454 mL, 3.28 mmol) was added. After the reaction solution was cooled to 0 ° C., methanesulfonyl chloride (0.153 mL, 1.97 mmol) was added and stirred for 30 minutes. Water was added to the reaction solution, and the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. To the obtained residue, the compound obtained in step 57 (c) (200 mg, 0.655 mmol), cesium carbonate (640 mg, 1.97 mmol), N, N-dimethylformamide (5.00 mL) were added, and 70 ° C. for 2 hours. Stir. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 50 / 50-0 / 100 (V / V)] to give the title compound (119 mg, 0.287 mmol, 43%) was obtained as an oil.
LCMS (ES): m / z 415 [M + H] + .
工程58(b)：2-{4-[(1-{4-フルオロ-2-[(3-フルオロピリジン-2-イル)メトキシ]フェニル}-2-オキソ-1,2-ジヒドロピロロ[1,2-a][1,3,5]トリアジン-4-イル)アミノ]-3-メチルフェニル}アセタミドの製造
工程57(e)と同様にして、工程58(a)で得られた化合物(119mg, 0.369mmol)、2-(4-アミノ-3-メチルフェニル)アセタミド(90.0mg, 0.554mmol)、ジメチルスルホキシド(0.300mL)を用いて、標記化合物(80.0mg, 0.150mmol, 41%)を固体として得た。
LCMS (ES): m/z 517 [M+H]+.
1H NMR (CD3OD) δ (ppm) : 2.16 (0.9H, s), 2.28 (2.1H, s), 3.54 (2H, s), 4.99 (0.3H, s), 5.03 (0.7H, s), 5.26-5.35 (2H, m), 6.26 (0.3H, t, J= 3.5 Hz), 6.46 (0.7H, t, J = 3.5 Hz), 6.84-6.94 (1H, m), 7.11-7.50 (7H, m), 7.58 (1H, t, J = 8.8 Hz), 8.32-8.38 (1H, m). Step 58 (b): 2- {4-[(1- {4-fluoro-2-[(3-fluoropyridin-2-yl) methoxy] phenyl} -2-oxo-1,2-dihydropyrrolo [1 , 2-a] [1,3,5] triazin-4-yl) amino] -3-methylphenyl} acetamide In the same manner as in Step 57 (e), the compound obtained in Step 58 (a) ( 119 mg, 0.369 mmol), 2- (4-amino-3-methylphenyl) acetamide (90.0 mg, 0.554 mmol), dimethyl sulfoxide (0.300 mL), and the title compound (80.0 mg, 0.150 mmol, 41%) Obtained as a solid.
LCMS (ES): m / z 517 [M + H] + .
1 H NMR (CD 3 OD) δ (ppm): 2.16 (0.9H, s), 2.28 (2.1H, s), 3.54 (2H, s), 4.99 (0.3H, s), 5.03 (0.7H, s ), 5.26-5.35 (2H, m), 6.26 (0.3H, t, J = 3.5 Hz), 6.46 (0.7H, t, J = 3.5 Hz), 6.84-6.94 (1H, m), 7.11-7.50 ( 7H, m), 7.58 (1H, t, J = 8.8 Hz), 8.32-8.38 (1H, m).
（参考例Ｒ１）
2-(4-クロロ-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル)フェノール (Reference Example R1)
2- (4-Chloro-6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl) phenol
Figure JPOXMLDOC01-appb-C000102
Figure JPOXMLDOC01-appb-C000102
工程R1(a)：メチル2-{[(トリフルオロメチル)スルホニル］オキシ｝シクロペンタ－１－エン－１－カルボキシレートの製造
2-オキソシクロペンタンカルボン酸メチル(50g, 352mmol)をジクロロメタン(450mL)に溶解し、N,N-ジイソプロピルエチルアミン (250mL, 1.41mol)を加え、-78℃に冷却した。反応液に、無水トリフルオロメタンスルホン酸(65mL, 390mmol)を滴下した後、0℃まで昇温して2時間攪拌した。反応液に飽和塩化アンモニウム水溶液(30mL)を加え、酢酸エチルを加えて抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝90/10-50/50(V/V)］にて精製し、標記化合物(92g, 336mmol, 95%)を油状物質として得た。
1H NMR (CDCl3) δ (ppm): 1.96-2.03 (2H, m), 2.66-2.75 (4H, m), 3.77 (3H, s) Step R1 (a): Preparation of methyl 2-{[(trifluoromethyl) sulfonyl] oxy} cyclopent-1-ene-1-carboxylate
Methyl 2-oxocyclopentanecarboxylate (50 g, 352 mmol) was dissolved in dichloromethane (450 mL), N, N-diisopropylethylamine (250 mL, 1.41 mol) was added, and the mixture was cooled to -78 ° C. Trifluoromethanesulfonic anhydride (65 mL, 390 mmol) was added dropwise to the reaction solution, and then the mixture was heated to 0 ° C. and stirred for 2 hours. Saturated aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, ethyl acetate was added for extraction, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-50 / 50 (V / V)] to give the title compound (92 g, 336 mmol, 95%) was obtained as an oil.
1 H NMR (CDCl 3 ) δ (ppm): 1.96-2.03 (2H, m), 2.66-2.75 (4H, m), 3.77 (3H, s)
工程R1(b)：メチル2-{[(トリフルオロメチル)スルホニル]オキシ}シクロペンタ-1-エン-1-カルボキシレートの製造
2-メトキシベンズアルデヒド(25.9g, 190mmol)をクロロホルム(500mL)に溶解し、トリメチルシリルシアニド(18.9g, 190mmol)とトリエチルアミン(29.0mL, 207mmol)を加え、50℃で4時間攪拌した。反応液を濃縮し、得られた残渣をテトラヒドロフラン(350mL)で希釈し、工程R1(a)で得られた化合物(46.0g, 190mmol)を加え、-78℃に冷却した。反応液にビス（テトラメチルシリル）アミドカリウム・テトラヒドロフラン溶液(1規定、200mL, 200mmol)をゆっくりと滴下し、同温で30分間攪拌した。その後、-10℃まで昇温した後、反応液にテトラ-n-ブチルアンモニウムフルオリド・テトラヒドロフラン溶液(1規定、200ml, 200mmol)を加え、0℃で1時間攪拌した。反応液に水を加え、酢酸エチルを加えて抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー[溶出溶媒：ヘキサン/酢酸エチル＝90/10-60/40(V/V)]にて精製し、標記化合物(40.2g, 154mmol, 81%)を固体として得た。
LCMS (ES): m/z 261 [M+H]+.
1H NMR (CDCl3) δ (ppm) : 1.98-2.06 (2H, m), 2.72 (2H, tt, J= 7.8, 2.3 Hz), 2.83 (2H, tt, J= 7.6, 2.4 Hz), 3.41 (3H, s), 3.80 (3H, s), 6.91 (1H, d, J = 8.3 Hz), 7.01 (1H, dd, J = 11.7, 4.4 Hz), 7.44-7.47 (1H, m), 7.79 (1H, dd, J = 7.8, 2.0 Hz). Step R1 (b): Preparation of methyl 2-{[(trifluoromethyl) sulfonyl] oxy} cyclopent-1-ene-1-carboxylate
2-Methoxybenzaldehyde (25.9 g, 190 mmol) was dissolved in chloroform (500 mL), trimethylsilylcyanide (18.9 g, 190 mmol) and triethylamine (29.0 mL, 207 mmol) were added, and the mixture was stirred at 50 ° C. for 4 hours. The reaction mixture was concentrated, the resulting residue was diluted with tetrahydrofuran (350 mL), the compound obtained in Step R1 (a) (46.0 g, 190 mmol) was added, and the mixture was cooled to −78 ° C. To the reaction solution, a bis (tetramethylsilyl) amido potassium / tetrahydrofuran solution (1N, 200 mL, 200 mmol) was slowly added dropwise, followed by stirring at the same temperature for 30 minutes. Thereafter, the temperature was raised to −10 ° C., tetra-n-butylammonium fluoride / tetrahydrofuran solution (1N, 200 ml, 200 mmol) was added to the reaction solution, and the mixture was stirred at 0 ° C. for 1 hour. Water was added to the reaction liquid, ethyl acetate was added for extraction, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-60 / 40 (V / V)] to give the title compound (40.2 g , 154 mmol, 81%) as a solid.
LCMS (ES): m / z 261 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 1.98-2.06 (2H, m), 2.72 (2H, tt, J = 7.8, 2.3 Hz), 2.83 (2H, tt, J = 7.6, 2.4 Hz), 3.41 (3H, s), 3.80 (3H, s), 6.91 (1H, d, J = 8.3 Hz), 7.01 (1H, dd, J = 11.7, 4.4 Hz), 7.44-7.47 (1H, m), 7.79 ( 1H, dd, J = 7.8, 2.0 Hz).
工程R1(c)：4-(2-メトキシフェニル)-2,5,6,7-テトラヒドロ-1H-シクロペンタ[d]ピリダジン-1-オンの製造
工程R1(b)で得られた化合物(40. 2g, 154mmol)をエタノール(350mL)に溶解し、ヒドラジン2塩酸塩(45g, 334mmol)を加え、110℃で14時間加熱攪拌した。反応液を濃縮後、水、ジクロロメタンを加えて抽出し有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、得られた残渣に酢酸エチル、ジクロロメタンを加え、析出した固体をろ取した。得られた固体を、減圧下、50℃で加熱乾燥し、標記化合物(16g, 63mmol, 44%) を得た。
1H NMR (DMSO-D6) δ (ppm): 1.94 (2H, t, J = 7.6 Hz), 2.60 (2H, t, J = 7.6 Hz), 2.73 (2H, t, J = 7.6 Hz), 3.75 (3H, s), 7.00 (1H, t, J = 7.3 Hz), 7.10 (1H, d, J = 8.3 Hz), 7.21 (1H, dd, J = 7.3, 1.5 Hz), 7.40-7.43 (1H, m), 12.88 (1H, s). Step R1 (c): Preparation of 4- (2-methoxyphenyl) -2,5,6,7-tetrahydro-1H-cyclopenta [d] pyridazin-1-one Compound (40) obtained in Step R1 (b) 2 g, 154 mmol) was dissolved in ethanol (350 mL), hydrazine dihydrochloride (45 g, 334 mmol) was added, and the mixture was stirred with heating at 110 ° C. for 14 hr. The reaction mixture was concentrated, extracted with water and dichloromethane, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, ethyl acetate and dichloromethane were added to the resulting residue, and the precipitated solid was collected by filtration. The obtained solid was dried by heating at 50 ° C. under reduced pressure to obtain the title compound (16 g, 63 mmol, 44%).
1 H NMR (DMSO-D 6 ) δ (ppm): 1.94 (2H, t, J = 7.6 Hz), 2.60 (2H, t, J = 7.6 Hz), 2.73 (2H, t, J = 7.6 Hz), 3.75 (3H, s), 7.00 (1H, t, J = 7.3 Hz), 7.10 (1H, d, J = 8.3 Hz), 7.21 (1H, dd, J = 7.3, 1.5 Hz), 7.40-7.43 (1H m), 12.88 (1H, s).
工程R1(d)：1-クロロ-4-(2-メトキシフェニル)-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジンの製造
工程R1(c)で得られた化合物(133g, 126mmol)にオキシ塩化リン(50mL)を加え、80℃で2時間加熱攪拌した。氷水に反応液を加えた後、5規定水酸化ナトリウム水溶液を用いて中和した。ジクロロメタンを加えて抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、析出した固体を酢酸エチル、ヘキサンを用いてろ取し、減圧下50℃で加熱乾燥し、標記化合物 (33.3 g, 126 mmol, 100%) を固体として得た。
LCMS (ES): m/z 261 [M+H]+.
1H NMR (CDCl3): 2.14 (2H, quint, J=7.6 Hz), 2.93 (2H, t, J=7.6 Hz), 3.09 (2H, t, J=7.6 Hz), 3.74 (3H, s), 7.00 (1H, d, J=7.8 Hz), 7.10 (1H, td, J=1.0, 7.8 Hz), 7.44-7.47 (2H, m). Step R1 (d): Preparation of 1-chloro-4- (2-methoxyphenyl) -6,7-dihydro-5H-cyclopenta [d] pyridazine To the compound (133 g, 126 mmol) obtained in Step R1 (c) Phosphorus oxychloride (50 mL) was added, and the mixture was stirred with heating at 80 ° C. for 2 hr. The reaction solution was added to ice water and then neutralized with 5N aqueous sodium hydroxide solution. Dichloromethane was added for extraction, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated solid was collected by filtration with ethyl acetate and hexane, and dried by heating at 50 ° C. under reduced pressure to obtain the title compound (33.3 g, 126 mmol, 100%) as a solid.
LCMS (ES): m / z 261 [M + H] + .
1 H NMR (CDCl 3 ): 2.14 (2H, quint, J = 7.6 Hz), 2.93 (2H, t, J = 7.6 Hz), 3.09 (2H, t, J = 7.6 Hz), 3.74 (3H, s) , 7.00 (1H, d, J = 7.8 Hz), 7.10 (1H, td, J = 1.0, 7.8 Hz), 7.44-7.47 (2H, m).
工程R1(e)：2-(4-クロロ-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-1-イル)フェノールの製造
工程R1(d)で得られた化合物(3.1g, 11.9mmol)をジクロロメタン(30mL)に溶解し、ボラントリブロミド（17%ジクロロメタン溶液、15mL, 15mmol)を加え、室温で5時間攪拌した。反応液に少量のメタノールを加えた後、飽和炭酸水素ナトリウム水溶液を加えた。ジクロロメタン、酢酸エチルで抽出し、有機層を無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、析出した固体を酢酸エチル、ヘキサンを用いてろ取し、減圧下50℃で加熱乾燥し、標記化合物(2.8g, 11.4mmol, 95%) を固体として得た。
LCMS (ES): m/z 247 [M+H]+. Step R1 (e): Preparation of 2- (4-chloro-6,7-dihydro-5H-cyclopenta [d] pyridazin-1-yl) phenol The compound obtained in Step R1 (d) (3.1 g, 11.9 mmol) ) Was dissolved in dichloromethane (30 mL), borane tribromide (17% dichloromethane solution, 15 mL, 15 mmol) was added, and the mixture was stirred at room temperature for 5 hours. A small amount of methanol was added to the reaction solution, and then a saturated aqueous sodium hydrogen carbonate solution was added. Extraction was performed with dichloromethane and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated solid was collected by filtration using ethyl acetate and hexane, and dried by heating at 50 ° C. under reduced pressure to obtain the title compound (2.8 g, 11.4 mmol, 95%) as a solid.
LCMS (ES): m / z 247 [M + H] + .
（参考例Ｒ２）
N-(2-メトキシエチル)-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン (Reference Example R2)
N- (2-methoxyethyl) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline
Figure JPOXMLDOC01-appb-C000103
Figure JPOXMLDOC01-appb-C000103
工程R2(a)：2-メトキシ-N-[2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル]アセタミドの製造
2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン(1.15g, 5.25mmol)をアセトニトリル(20mL)に溶解し、炭酸カリウム(1.45g, 10.5mmol)とメトキシアセチルクロリド(600mg, 5.51mmol)を加え、室温で3時間攪拌した。不溶物をろ別した後、ろ液を減圧下濃縮し、粗製の標記化合物を油状物質として得た。得られた化合物は精製することなく、次の反応に使用した。 Step R2 (a): Preparation of 2-methoxy-N- [2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] acetamide
2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (1.15 g, 5.25 mmol) was dissolved in acetonitrile (20 mL) and potassium carbonate (1.45 g, 10.5 mmol) and methoxyacetyl chloride (600 mg, 5.51 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the crude title compound as an oil. The obtained compound was used for the next reaction without purification.
工程R2(b)：N-(2-メトキシエチル)-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリンの製造
工程R2(a)で得られた化合物をテトラヒドロフラン(50mL)で希釈した後、1規定ボラン・テトラヒドロフラン溶液(36.8mL, 36.8mmol)を加え、7時間加熱還流した。反応液を室温まで冷却した後、少量のメタノールを加えた。反応液を減圧下濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル＝100/0-70/30(V/V)］にて精製し、標記化合物 (350mg, 1.00mmol, 33%) を固体として得た。
1H NMR(CDCl3)δ(ppm): 1.31 (12H, s), 3.26-3.32 (2H, m), 3.39 (3H, s), 3.59-3.62 (2H, m), 6.09 (1H, s), 6.54 (1H, d, J = 8.3 Hz), 6.60 (1H, td, J = 7.3, 2.3 Hz), 7.24-7.29 (1H, m), 7.59 (1H, dd, J= 7.3, 2.0 Hz). Step R2 (b): N- (2-methoxyethyl) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline in the production step R2 (a) The obtained compound was diluted with tetrahydrofuran (50 mL), 1N borane / tetrahydrofuran solution (36.8 mL, 36.8 mmol) was added, and the mixture was heated to reflux for 7 hr. After cooling the reaction solution to room temperature, a small amount of methanol was added. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-70 / 30 (V / V)] to give the title compound (350 mg, 1.00 mmol, 33%) as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 1.31 (12H, s), 3.26-3.32 (2H, m), 3.39 (3H, s), 3.59-3.62 (2H, m), 6.09 (1H, s) , 6.54 (1H, d, J = 8.3 Hz), 6.60 (1H, td, J = 7.3, 2.3 Hz), 7.24-7.29 (1H, m), 7.59 (1H, dd, J = 7.3, 2.0 Hz).
（参考例Ｒ３）
2-(4-クロロチエノ[2,3-d]ピリダジン-7-イル)フェノール (Reference Example R3)
2- (4-Chlorothieno [2,3-d] pyridazin-7-yl) phenol
Figure JPOXMLDOC01-appb-C000104
Figure JPOXMLDOC01-appb-C000104
工程R3(a)：2-(2-メトキシベンゾイル)チオフェン-3-カルボン酸の製造
2-クロロチオフェン-3-カルボン酸(21.5g, 168mmol) をテトラヒドロフラン(230mL)に溶解し、-78℃に冷却した後、n-ブチルリチルム・ヘキサン溶液(2.69mol/L, 137mL, 369mmol) を30分間かけて滴下した。同温で15分間撹拌後、N,2-ジメトキシ-N-メチルベンザミド(32.8g, 168mmol)をテトラヒドロフラン(100mL)に溶解した溶液を滴下した。滴下後、室温で2時間撹拌し、1規定塩酸に注ぎ、酢酸エチルで3回抽出した。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後、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/メタノール＝100/0-80/20(V/V)］にて精製し、標記化合物(50.9g, 194mmol, 100%) を油状物質として得た。
1H NMR (CDCl3) δ (ppm): 3.78 (3H, s), 7.03 (2H, dt, J = 16.4, 7.7 Hz), 7.40 (1H, dd, J= 7.6, 1.7 Hz), 7.54 (1H, dt, J= 10.9, 4.1 Hz), 7.66 (1H, d, J= 4.9 Hz), 7.93 (1H, d, J = 5.4 Hz). Step R3 (a): Preparation of 2- (2-methoxybenzoyl) thiophene-3-carboxylic acid
2-Chlorothiophene-3-carboxylic acid (21.5 g, 168 mmol) was dissolved in tetrahydrofuran (230 mL), cooled to −78 ° C., and then n-butyllithyl hexane solution (2.69 mol / L, 137 mL, 369 mmol) was added to 30 Added dropwise over a period of minutes. After stirring at the same temperature for 15 minutes, a solution of N, 2-dimethoxy-N-methylbenzamide (32.8 g, 168 mmol) dissolved in tetrahydrofuran (100 mL) was added dropwise. After dropping, the mixture was stirred at room temperature for 2 hours, poured into 1N hydrochloric acid, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [elution solvent: ethyl acetate / methanol = 100 / 0-80 / 20 (V / V)] to give the title compound (50.9 g, 194 mmol, 100%) as an oily substance. Got as.
1 H NMR (CDCl 3 ) δ (ppm): 3.78 (3H, s), 7.03 (2H, dt, J = 16.4, 7.7 Hz), 7.40 (1H, dd, J = 7.6, 1.7 Hz), 7.54 (1H , dt, J = 10.9, 4.1 Hz), 7.66 (1H, d, J = 4.9 Hz), 7.93 (1H, d, J = 5.4 Hz).
工程R3(b)：7-(2-メトキシフェニル)チエノ[2,3-d]ピリダジン-4(5H)-オンの製造
工程R3(a)で得られた化合物(43g, 164mmol) をブタノール(250mL)に懸濁し、ヒドラジン1水和物(20mL, 412mmol) を加えて、140℃で2時間撹拌した反応液を室温に冷却し、減圧下濃縮した。得られた残渣にジエチルエーテルを加え、不溶物を濾取した。母液は減圧下濃縮し、希塩酸に注ぎ、ジクロロメタンで3回抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/ジクロロメタン＝0/100-50/50(V/V)］にて精製し、標記化合物(37.3g, 144mmol, 88%)を固体として得た。 Step R3 (b): Preparation of 7- (2-methoxyphenyl) thieno [2,3-d] pyridazin-4 (5H) -one The compound (43 g, 164 mmol) obtained in Step R3 (a) was converted to butanol ( 250 ml), hydrazine monohydrate (20 mL, 412 mmol) was added, and the reaction solution stirred at 140 ° C. for 2 hours was cooled to room temperature and concentrated under reduced pressure. Diethyl ether was added to the obtained residue, and the insoluble material was collected by filtration. The mother liquor was concentrated under reduced pressure, poured into dilute hydrochloric acid, and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: ethyl acetate / dichloromethane = 0 / 100-50 / 50 (V / V)] to obtain the title compound (37.3 g, 144 mmol, 88%) as a solid.
工程R3(c)：4-クロロ-7-(2-メトキシフェニル)チエノ[2,3-d]ピリダジンの製造
工程R3(b)で得られた化合物(20.2g, 78.4mmol)にオキシ塩化リン(20mL)を加え、100℃で撹拌した。4時間後、反応液を室温に冷却し、氷に注いだ。5規定水酸化ナトリウム水溶液を徐々に加えて中和し、ジクロロメタンで3回抽出した。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後、減圧下濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：酢酸エチル/ジクロロメタン＝0/100-30/70(V/V)］にて精製後、エーテルで洗浄し、標記化合物 (20g, 72.3mmol, 92%) を固体として得た。
1H NMR (CDCl3) δ (ppm): 3.79 (3H, s), 7.06 (1H, d, J = 8.3 Hz), 7.10-7.14 (1H, m), 7.49-7.52 (1H, m), 7.59-7.60 (2H, m), 7.86 (1H, d, J = 5.4 Hz). Step R3 (c): Preparation of 4-chloro-7- (2-methoxyphenyl) thieno [2,3-d] pyridazine The compound obtained in Step R3 (b) (20.2 g, 78.4 mmol) was added to phosphorus oxychloride. (20 mL) was added and stirred at 100 ° C. After 4 hours, the reaction was cooled to room temperature and poured onto ice. A 5N aqueous sodium hydroxide solution was gradually added to neutralize, and the mixture was extracted 3 times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: ethyl acetate / dichloromethane = 0 / 100-30 / 70 (V / V)], then washed with ether to give the title compound (20 g, 72.3 mmol, 92 %) As a solid.
1 H NMR (CDCl 3 ) δ (ppm): 3.79 (3H, s), 7.06 (1H, d, J = 8.3 Hz), 7.10-7.14 (1H, m), 7.49-7.52 (1H, m), 7.59 -7.60 (2H, m), 7.86 (1H, d, J = 5.4 Hz).
工程R3(d)：2-(4-クロロチエノ[2,3-d]ピリダジン-7-イル)フェノールの製造
工程R1(e)と同様にして、工程R3(c)で得られた化合物(15g, 54.2mmol)、ジクロロメタン(15mL)、トリブロモボラン・ジクロロメタン溶液(1規定、100mL, 100mmol)を用いて、標記化合物(14.2g, 54.2mmol, 100%)を固体として得た。
LCMS (ES): m/z 263 [M+H]+.
1H NMR (CDCl3)δ(ppm): 7.04-7.07 (1H, m), 7.16 (1H, d, J= 8.3 Hz), 7.43 (1H, td, J = 7.7, 1.6 Hz), 7.70 (0.3H, d, J= 5.4 Hz), 7.73 (0.7H, d, J = 5.4 Hz), 8.06 (1H, dd, J = 5.4, 2.9 Hz), 8.11 (1H, dd, J = 7.8, 1.5 Hz). Step R3 (d): Preparation of 2- (4-chlorothieno [2,3-d] pyridazin-7-yl) phenol In the same manner as in Step R1 (e), the compound (15 g) obtained in Step R3 (c) The title compound (14.2 g, 54.2 mmol, 100%) was obtained as a solid using dichloromethane (15 mL), tribromoborane / dichloromethane solution (1N, 100 mL, 100 mmol).
LCMS (ES): m / z 263 [M + H] + .
1 H NMR (CDCl 3 ) δ (ppm): 7.04-7.07 (1H, m), 7.16 (1H, d, J = 8.3 Hz), 7.43 (1H, td, J = 7.7, 1.6 Hz), 7.70 (0.3 H, d, J = 5.4 Hz), 7.73 (0.7H, d, J = 5.4 Hz), 8.06 (1H, dd, J = 5.4, 2.9 Hz), 8.11 (1H, dd, J = 7.8, 1.5 Hz) .
（参考例Ｒ４）
1-(2-メトキシフェニル)-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-4-アミン (Reference Example R4)
1- (2-methoxyphenyl) -6,7-dihydro-5H-cyclopenta [d] pyridazin-4-amine
Figure JPOXMLDOC01-appb-C000105
Figure JPOXMLDOC01-appb-C000105
工程R4(a)：2-(2-メトキシベンゾイル)シクロペンテン-1-カルボニトリル の製造
トリエチルアミン(30mL, 0.22mol)をクロロホルム(180mL)に加え、氷浴下撹拌中、2-メトキシベンゾイルクロリド(16mL, 0.11mol) のクロロホルム(20mL) 溶液を滴下した。氷浴下１時間撹拌後、トリメチルシリルシアニド(22mL, 0.16mol) を加え、氷浴下30分間撹拌後、室温で2時間撹拌した。反応液にトリフルオロ酢酸(32.5mL, 0.44mol) を加え、室温で1時間撹拌後、反応液を飽和炭酸水素ナトリウム水溶液に注ぎ、ジクロロメタンで3回抽出した。有機層を無水硫酸ナトリウムで乾燥後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー ［溶出溶媒：ヘキサン/酢酸エチル=100/0-30/70 (v/v)］で精製し、標記化合物(18g, 0.078mol, 71%) を固体として得た。
1H NMR (CDCl3) δ (ppm): 2.05-2.11 (2H, m), 2.78-2.83 (2H, m), 2.86-2.90 (2H, m), 3.85 (3H, s), 6.97 (1H, d, J=7.6 Hz), 7.06 (1H, t, J=7.6 Hz), 7.47 (1H, dd, J=1.7, 7.6 Hz), 7.52 (1H, dd, J=1.7, 7.6 Hz). Step R4 (a): Preparation of 2- (2-methoxybenzoyl) cyclopentene-1-carbonitrile Triethylamine (30 mL, 0.22 mol) was added to chloroform (180 mL), and 2-methoxybenzoyl chloride (16 mL) was stirred in an ice bath. , 0.11 mol) in chloroform (20 mL) was added dropwise. After stirring in an ice bath for 1 hour, trimethylsilylcyanide (22 mL, 0.16 mol) was added, stirred in an ice bath for 30 minutes, and then stirred at room temperature for 2 hours. Trifluoroacetic acid (32.5 mL, 0.44 mol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted three times with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-30 / 70 (v / v)] to obtain the title compound (18 g, 0.078 mol, 71%) as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 2.05-2.11 (2H, m), 2.78-2.83 (2H, m), 2.86-2.90 (2H, m), 3.85 (3H, s), 6.97 (1H, d, J = 7.6 Hz), 7.06 (1H, t, J = 7.6 Hz), 7.47 (1H, dd, J = 1.7, 7.6 Hz), 7.52 (1H, dd, J = 1.7, 7.6 Hz).
工程R4(b)：1-(2-メトキシフェニル)-6,7-ジヒドロ-5H-シクロペンタ[d]ピリダジン-4-アミンの製造
工程R4(a)で得られた化合物(18g, 78mmol)をエタノール(200mL)に溶解し、ヒドラジン水和物(7.6mL, 0.16mol)、5規定塩酸(40mL, 0.20mol)を加え、加熱還流した。1.5時間後、ヒドラジン二塩酸塩(8.2g, 78mmol)を加え、さらに5時間加熱還流した。反応液を室温に冷却し、減圧下濃縮した。残渣を水酸化ナトリウム水溶液に注ぎ、ジクロロメタンで4回抽出した。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後、減圧下濃縮した。残渣にジクロロメタン－ジエチルエーテルを加えて不溶物を濾取し、標記化合物(15g, 61mmol, 78%)を固体として得た。
1H NMR (CDCl3)δ(ppm): 2.11 (2H, quint, J=7.8 Hz), 2.80 (2H, t, J=7.8 Hz), 2.88 (2H, t, J=7.8 Hz), 3.76 (3H, s), 6.94 (1H, d, J=7.8 Hz), 7.02 (1H, td, J=1.0, 7.8 Hz), 7.47 (1H, dd, J=1.7, 7.6 Hz), 7.52 (1H, dd, J=1.7, 7.6 Hz). Step R4 (b): Production of 1- (2-methoxyphenyl) -6,7-dihydro-5H-cyclopenta [d] pyridazin-4-amine The compound (18 g, 78 mmol) obtained in Step R4 (a) was prepared. After dissolving in ethanol (200 mL), hydrazine hydrate (7.6 mL, 0.16 mol) and 5N hydrochloric acid (40 mL, 0.20 mol) were added, and the mixture was heated to reflux. After 1.5 hours, hydrazine dihydrochloride (8.2 g, 78 mmol) was added, and the mixture was further heated to reflux for 5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was poured into aqueous sodium hydroxide and extracted four times with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Dichloromethane-diethyl ether was added to the residue, and insoluble matter was collected by filtration to obtain the title compound (15 g, 61 mmol, 78%) as a solid.
1 H NMR (CDCl 3 ) δ (ppm): 2.11 (2H, quint, J = 7.8 Hz), 2.80 (2H, t, J = 7.8 Hz), 2.88 (2H, t, J = 7.8 Hz), 3.76 ( 3H, s), 6.94 (1H, d, J = 7.8 Hz), 7.02 (1H, td, J = 1.0, 7.8 Hz), 7.47 (1H, dd, J = 1.7, 7.6 Hz), 7.52 (1H, dd , J = 1.7, 7.6 Hz).
（参考例Ｒ５）
エチル 2-(4-アミノ-2,3-ジフルオロフェニル)アセテート (Reference Example R5)
Ethyl 2- (4-amino-2,3-difluorophenyl) acetate
Figure JPOXMLDOC01-appb-C000106
Figure JPOXMLDOC01-appb-C000106
工程R5(a)：ジメチル 2-(2,3-ジフルオロ-4-ニトロフェニル)プロパンジオエート の製造
ジメチル 2-クロロプロパンジオエート(7.2mL, 56mmol)、1,2,3-トリフルオロ-4-ニトロベンゼン(5.0g, 28mmol)をテトラヒドロフラン(80mL)に溶解し、氷浴下撹拌中、1,8-ジアザビシクロ[5.4.0]ウンデセン(8.4mL, 56mmol) を加えた。滴下終了後、室温で17時間撹拌した。反応液を希塩酸に注ぎ、酢酸エチルで3回抽出した。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後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル=100/0-75/25 (v/v)］で精製し、標記化合物(3.2g, 11mmol, 39%)を油状物質として得た。
1H NMR (CDCl3) δ (ppm): 3.82 (6H, s), 5.06 (1H, s), 7.46-7.50 (1H, m), 7.87-7.91 (1H, m). Step R5 (a): Preparation of dimethyl 2- (2,3-difluoro-4-nitrophenyl) propanedioate Dimethyl 2-chloropropanedioate (7.2 mL, 56 mmol), 1,2,3-trifluoro-4- Nitrobenzene (5.0 g, 28 mmol) was dissolved in tetrahydrofuran (80 mL), and 1,8-diazabicyclo [5.4.0] undecene (8.4 mL, 56 mmol) was added while stirring in an ice bath. After completion of dropping, the mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-75 / 25 (v / v)] to obtain the title compound (3.2 g, 11 mmol, 39%) as an oily substance.
1 H NMR (CDCl 3 ) δ (ppm): 3.82 (6H, s), 5.06 (1H, s), 7.46-7.50 (1H, m), 7.87-7.91 (1H, m).
工程R5(b)：ジメチル 2-(4-アミノ-2,3-ジフルオロフェニル)プロパンジオエート の製造
工程R5(a)で得られた化合物(3.2g, 11mmol)をエタノール(100mL)に溶解し、10%パラジウム－炭素(0.60g)を加え、水素雰囲気下、室温で4時間撹拌した。触媒を濾去し、濾液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル=90/10-60/40 (v/v)］で精製し、標記化合物(2.4 g, 9.3mmol, 85%)を油状物質として得た。
1H NMR (CDCl3) δ (ppm): 3.78 (6H, s), 4.86 (1H, s), 6.52-6.56 (1H, m), 6.97-7.01 (1H, m). Step R5 (b): Preparation of dimethyl 2- (4-amino-2,3-difluorophenyl) propanedioate The compound (3.2 g, 11 mmol) obtained in Step R5 (a) was dissolved in ethanol (100 mL). , 10% palladium-carbon (0.60 g) was added, and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 90 / 10-60 / 40 (v / v)] to give the title compound (2.4 g, 9.3 mmol, 85%) as an oil. .
1 H NMR (CDCl 3 ) δ (ppm): 3.78 (6H, s), 4.86 (1H, s), 6.52-6.56 (1H, m), 6.97-7.01 (1H, m).
工程R5(c)：エチル 2-(4-アミノ-2,3-ジフルオロフェニル)アセテートの製造
工程R5(b)で得られた化合物(2.4g, 9.3mmol) をエタノール(30mL) に溶解し、5規定水酸化ナトリウム水溶液(2.4mL, 12mmol)を加え、90℃で3.5時間撹拌した。反応液を室温に冷却し、5規定塩酸(2.4mL, 12mmol)を加え、減圧下濃縮した。残渣に水を加え、酢酸エチルで3回抽出した。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後、減圧下濃縮した。残渣をエタノール(30mL)に溶解し、濃塩酸(1mL)を加え、90℃で1時間撹拌した。反応液を室温に冷却し、減圧下濃縮した。残渣に酢酸エチルを加え、炭酸水素ナトリウム水溶液に注ぎ、酢酸エチルで3回抽出した。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後、減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル=100/0-70/30 (v/v)］で精製し、標記化合物(1.1g, 5.0mmol, 54%)を油状物質として得た。
1H NMR (CDCl3)δ(ppm): 1.47 (3H, t, J=7.7 Hz), 3.56 (2H, s), 3.78 (2H, br s), 4.26 (2H, q, J=7.7 Hz), 6.49 (1H, td, J=2.0, 8.1 Hz), 6.76 (1H, td, J=2.0, 8.1 Hz). Step R5 (c): Preparation of ethyl 2- (4-amino-2,3-difluorophenyl) acetate The compound obtained in Step R5 (b) (2.4 g, 9.3 mmol) was dissolved in ethanol (30 mL). 5N Aqueous sodium hydroxide solution (2.4 mL, 12 mmol) was added, and the mixture was stirred at 90 ° C. for 3.5 hr. The reaction mixture was cooled to room temperature, 5N hydrochloric acid (2.4 mL, 12 mmol) was added, and the mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (30 mL), concentrated hydrochloric acid (1 mL) was added, and the mixture was stirred at 90 ° C. for 1 hr. The reaction solution was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate was added to the residue, poured into an aqueous sodium hydrogen carbonate solution, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-70 / 30 (v / v)] to obtain the title compound (1.1 g, 5.0 mmol, 54%) as an oily substance. .
1 H NMR (CDCl 3 ) δ (ppm): 1.47 (3H, t, J = 7.7 Hz), 3.56 (2H, s), 3.78 (2H, br s), 4.26 (2H, q, J = 7.7 Hz) , 6.49 (1H, td, J = 2.0, 8.1 Hz), 6.76 (1H, td, J = 2.0, 8.1 Hz).
（参考例Ｒ６）
5-クロロ-N-(2-メトキシエチル)-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン (Reference Example R6)
5-Chloro-N- (2-methoxyethyl) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline
Figure JPOXMLDOC01-appb-C000107
Figure JPOXMLDOC01-appb-C000107
工程R6(a)：5-クロロ-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリンの製造
2-ブロモ-5-クロロアニリン(3.0g, 14.5mmol)を1,4-ジオキサン(50mL)に溶解し、[1,1’-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)・ジクロロメタン錯体(590mg, 0.73mmol)、トリエチルアミン(8.0mL, 58mmol)、ピナコールボラン(5.6g, 44mmol)を加え、100℃で5時間攪拌した。反応液に水を加え、酢酸エチルで抽出後、有機層を減圧下濃縮し、残渣をシリカゲルカラムクロマトグラフィー［溶出溶媒：ヘキサン/酢酸エチル=100/0-70/30 (v/v)］で精製し、標記化合物(1.1g, 5.0mmol, 54%)を油状物質として得た。
1H NMR (CDCl3) δ(ppm): 1.34 (12H, t, J = 3.9 Hz), 4.81 (2H, s), 6.58 (1H, d, J = 1.5 Hz), 6.63 (1H, dd, J = 7.8, 1.5 Hz), 7.51 (1H, d, J = 7.8 Hz). Step R6 (a): Preparation of 5-chloro-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline
2-Bromo-5-chloroaniline (3.0 g, 14.5 mmol) dissolved in 1,4-dioxane (50 mL), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) / dichloromethane complex (590 mg, 0.73 mmol), triethylamine (8.0 mL, 58 mmol) and pinacol borane (5.6 g, 44 mmol) were added, and the mixture was stirred at 100 ° C. for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane / ethyl acetate = 100 / 0-70 / 30 (v / v)]. Purification gave the title compound (1.1 g, 5.0 mmol, 54%) as an oil.
1 H NMR (CDCl 3 ) δ (ppm): 1.34 (12H, t, J = 3.9 Hz), 4.81 (2H, s), 6.58 (1H, d, J = 1.5 Hz), 6.63 (1H, dd, J = 7.8, 1.5 Hz), 7.51 (1H, d, J = 7.8 Hz).
工程R6(b)：5-クロロ-N-(2-メトキシエチル)-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル）アニリンの製造
工程R2(b)と同様にして、工程R6(a)で得られた化合物(1.0g, 3.9mmol)を用いて、標記化合物(1.2g, 3.9mmol, 100%)を油状物質として得た。 Step R6 (b): Step R2 for producing 5-chloro-N- (2-methoxyethyl) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline In the same manner as in (b), the title compound (1.2 g, 3.9 mmol, 100%) was obtained as an oily substance using the compound (1.0 g, 3.9 mmol) obtained in Step R6 (a).
（参考例Ｒ７）
5-フルオロ-N-(2-メトキシエチル)-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリン (Reference Example R7)
5-Fluoro-N- (2-methoxyethyl) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline
Figure JPOXMLDOC01-appb-C000108
Figure JPOXMLDOC01-appb-C000108
工程R7(a)：5-フルオロ-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリンの製造
工程R6(a)と同様にして、2-ブロモ-5-フルオロアニリン(6.1g, 32mmol)を用いて、標記化合物(5.4g, 23mmol, 71%)を油状物質として得た。
1H NMR (CDCl3) δ: 1.31 (12H, s), 4.84 (2H, s), 6.24 (1H, dd, J = 11.7, 2.4 Hz), 6.33 (1H, td, J = 8.4, 2.3 Hz), 7.54 (1H, t, J = 8.1 Hz). Step R7 (a): Preparation of 5-fluoro-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline in the same manner as in Step R6 (a), 2 -Bromo-5-fluoroaniline (6.1 g, 32 mmol) was used to give the title compound (5.4 g, 23 mmol, 71%) as an oil.
1 H NMR (CDCl 3 ) δ: 1.31 (12H, s), 4.84 (2H, s), 6.24 (1H, dd, J = 11.7, 2.4 Hz), 6.33 (1H, td, J = 8.4, 2.3 Hz) , 7.54 (1H, t, J = 8.1 Hz).
工程R7(b)：5-フルオロ-N-(2-メトキシエチル）-2-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)アニリンの製造
工程R6(b)と同様にして、工程R7(a)で得られた化合物(5.4g, 23mmol)を用いて、標記化合物(1.9g, 6.3mmol, 27%)を油状物質として得た。 Step R7 (b): Step R6 for producing 5-fluoro-N- (2-methoxyethyl) -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline In the same manner as in (b), the title compound (1.9 g, 6.3 mmol, 27%) was obtained as an oily substance using the compound (5.4 g, 23 mmol) obtained in Step R7 (a).
＜試験例１＞Zucker diabetic fattyラットを用いた経口糖負荷試験
　雄性Zucker diabetic fattyラット(ZDFラット、10週令)に飼料(FR-2、株式会社船橋農場)を1週間以上自由摂取させ予備飼育した後、一晩絶食し、経口糖負荷試験に用いた。ZDFラットへの投与液として、被験化合物濃度が2.5mg/mlとした0.5％メチルセルロース(和光純薬工業(株))溶液(0.5％MC)、又は92mg/mL CAPTISOL（CYDEX）溶液（SBE-β-CyD）を調製した。各群5匹のZDFラットに対し、被験化合物投与量が10mg/kgとなるよう、調整した投与液を4ml/kg用量で強制経口投与した。対照群は、4ml/kg用量の0.5％メチルセルロース溶液あるいはSBE-β-CyDを経口投与した。経口糖負荷として、被験化合物投与30分後にグルコース溶液(大塚糖液50％:(株)大塚製薬工業)を2g/kgの用量で強制経口投与した。 <Test Example 1> Oral glucose tolerance test using Zucker diabetic fatty rats Male Zucker diabetic fatty rats (ZDF rats, 10 weeks old) are allowed to freely ingest feed (FR-2, Funabashi Farm Co., Ltd.) for 1 week or longer. And then fasted overnight and used for oral glucose tolerance test. As an administration solution to ZDF rats, 0.5% methylcellulose (Wako Pure Chemical Industries, Ltd.) solution (0.5% MC) with a test compound concentration of 2.5 mg / ml, or 92 mg / mL CAPTISOL (CYDEX) solution (SBE-β -CyD) was prepared. For each group of 5 ZDF rats, the adjusted administration solution was forcibly orally administered at a dose of 4 ml / kg so that the test compound dose was 10 mg / kg. The control group was orally administered with a 4 ml / kg dose of 0.5% methylcellulose solution or SBE-β-CyD. As an oral glucose load, a glucose solution (Otsuka sugar solution 50%: Otsuka Pharmaceutical Co., Ltd.) was forcibly orally administered at a dose of 2 g / kg 30 minutes after administration of the test compound.
　被験化合物投与直前（T0）、被験化合物投与25分後(T1)、経口糖負荷30分後(T2)、60分後(T3)、120分後(T4)および180分後(T5)に、ラットの尾静脈より採血を行い、血糖測定器（アキュチェックアビバ：ロシュ・ダイアグノスティックス(株）)にて血糖値を測定した。また、T1血糖値は化合物投与30分後の糖負荷直前値として解析した。下記式より、血糖値曲線下面積を求め、対照群からの血糖低下率（％）を算出し、表１に示した。 Immediately before test compound administration (T0), 25 minutes after test compound administration (T1), 30 minutes after oral glucose load (T2), 60 minutes (T3), 120 minutes (T4) and 180 minutes (T5), Blood was collected from the tail vein of the rat, and the blood glucose level was measured with a blood glucose meter (Accucheck Aviva: Roche Diagnostics). The T1 blood glucose level was analyzed as the value immediately before glucose load 30 minutes after compound administration. The area under the blood glucose level curve was determined from the following formula, and the blood glucose lowering rate (%) from the control group was calculated and shown in Table 1.
　血糖値曲線下面積＝[（T0血糖値＋T1血糖値）×30]÷2 ＋[（T1血糖値＋T2血糖値）×30]÷2 
＋[（T2血糖値＋T3血糖値）×30]÷2＋[（T3血糖値＋T4血糖値）×60]÷2 ＋[（T4血糖値＋T5血糖値）×60]÷2 
　血糖低下率（％）＝[１－(被験化合物投与群血糖値曲線下面積／対照群血糖値曲線下面積)]×100 Area under the blood glucose level curve = [(T0 blood sugar level + T1 blood sugar level) x 30] ÷ 2 + [(T1 blood sugar level + T2 blood sugar level) x 30] ÷ 2
+ [(T2 blood sugar level + T3 blood sugar level) x 30] ÷ 2 + [(T3 blood sugar level + T4 blood sugar level) x 60] ÷ 2 + [(T4 blood sugar level + T5 blood sugar level) x 60] ÷ 2
Blood glucose reduction rate (%) = [1- (Area under test compound administration group blood glucose level curve / Area under control group blood glucose level curve)] × 100
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000109
＜試験例２＞　BKS.Cg-Dock7m+/+Leprdb/Jマウスを用いた経口負荷試験
　雄性BKS.Cg-Dock7m+/+Leprdb/Jマウス（db/dbマウス、6週令)に飼料(FR-2、株式会社船橋農場)を1週間以上自由摂取させ予備飼育した後、2時間絶食し、被験化合物負荷試験に用いた。db/dbマウスへの投与液として、被験化合物濃度が1mg/mlあるいは3mg/mlの0.5％メチルセルロース（和光純薬工業(株)）溶液(0.5％MC)を調製した。各群5匹のdb/dbマウスに対し、被験化合物投与量が10mg/kgあるいは30mg/kgとなるよう、調整した投与液を10ml/kg用量で強制経口投与した。対照群には、0.5％メチルセルロース溶液を、10ml/kg用量で強制経口投与した。 <Test Example 2> Oral loading test using BKS.Cg-Dock7m + / + Leprdb / J mice Male BKS.Cg-Dock7m + / + Leprdb / J mice (db / db mice, 6 weeks old) were fed (FR-2 , Funabashi Farm Co., Ltd.) was allowed to ingest freely for more than a week, preliminarily raised, fasted for 2 hours, and used for the test compound loading test. As a solution for administration to db / db mice, 0.5% methylcellulose (Wako Pure Chemical Industries, Ltd.) solution (0.5% MC) having a test compound concentration of 1 mg / ml or 3 mg / ml was prepared. For each group of 5 db / db mice, the adjusted administration solution was forcibly orally administered at a dose of 10 ml / kg so that the test compound dose was 10 mg / kg or 30 mg / kg. In the control group, 0.5% methylcellulose solution was orally administered by gavage at a dose of 10 ml / kg.
　被験化合物投与直前（T0）、被験化合物投与30分後(T1)、60分後(T2)、120分後(T3)、および240分後(T4)に、マウスの尾静脈より採血を行い、血糖測定器(アキュチェックアビバ：ロシュ・ダイアグノスティックス（株）)にて血糖値を測定した。下記式より、血糖値曲線下面積を求め、対照群からの血糖低下率（％）を算出し、表２－１、２－２に示した。 Immediately before test compound administration (T0), 30 minutes after test compound administration (T1), 60 minutes (T2), 120 minutes (T3), and 240 minutes (T4), blood is collected from the tail vein of the mouse, The blood glucose level was measured with a blood glucose meter (Accu Check Aviva: Roche Diagnostics). From the following formula, the area under the blood glucose level curve was obtained, and the blood glucose lowering rate (%) from the control group was calculated and shown in Tables 2-1 and 2-2.
　血糖値曲線下面積＝[（T0血糖値＋T1血糖値）×30]÷2 ＋[（T1血糖値＋T2血糖値）×30]÷2 
＋[（T2血糖値＋T3血糖値）×60]÷2＋[（T3血糖値＋T4血糖値）×120]÷2 
　血糖低下率（％）＝[１－(被験化合物投与群血糖値曲線下面積／対照群血糖値曲線下面積)]×100 Area under the blood glucose level curve = [(T0 blood sugar level + T1 blood sugar level) x 30] ÷ 2 + [(T1 blood sugar level + T2 blood sugar level) x 30] ÷ 2
+ [(T2 blood sugar level + T3 blood sugar level) x 60] ÷ 2 + [(T3 blood sugar level + T4 blood sugar level) x 120] ÷ 2
Blood glucose reduction rate (%) = [1- (Area under test compound administration group blood glucose level curve / Area under control group blood glucose level curve)] × 100
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000111
   　 
 
Figure JPOXMLDOC01-appb-T000111
   　 
 

Claims (12)

  1. 一般式(I)
    Figure JPOXMLDOC01-appb-C000001
     ［式中、
    環Aは、ベンゼン環または二環性ベンゾ複素環を示し、
    環Bは、環内に窒素原子を2つ含む一環性または二環性の環を示し、
    該二環性の環はさらに、窒素原子、酸素原子及び硫黄原子からなる群から選ばれる1または2以上の原子を環内に含んでいてもよく、
    環Cは、ベンゼン環または4～6員の飽和含窒素複素環を示し、
    R1は、水素原子またはハロゲン原子を示し、
    R2は、環Aがベンゼン環である場合に2位の位置に結合する置換基であって、下記Z群より独立に選ばれる1または2以上の基によって置換されていてもよいC1-C6アルキル基、下記Z群より独立に選ばれる1または2以上の基によって置換されていてもよいC1-C6アルコキシ基、下記Z群より独立に選ばれる1または2以上の基によって置換されていてもよいモノC1-C6アルキルアミノ基、-[O-(CH2)2]m-X-Qまたは-O-(CH2)n-X-Qを示し、
    mは1または2の整数を示し、
    nは1、2、3または4の整数を示し、
    XはO、NHまたはNHC=Oを示し、
    QはC1-C6アルキル基、C1-C6アルコキシ基またはモノC1-C6アルキルアミノ基を示し、
    R3は、水素原子またはハロゲン原子を示し、
    R4、R5およびR6は、それぞれ独立に、水素原子、ハロゲン原子、下記Y群より独立に選ばれる1または2以上の基によって置換されていてもよいC1-C6アルキル基、下記Y群より独立に選ばれる1または2以上の基によって置換されていてもよいC1-C6アルコキシ基、下記Y群より独立に選ばれる1または2以上の基によって置換されていてもよいモノC1-C6アルキルアミノ基、C1-C6アルキルスルホニル基、または下記のいずれかの基
    Figure JPOXMLDOC01-appb-C000002
     を示す。］
    で表される化合物またはその薬学上許容される塩。
    Z群：C1-C6アルコキシ基、モノC1-C6アルキルアミノ基、ジC1-C6アルキルアミノ基、フェニル基（該フェニル基は、ハロゲン原子、カルボキシ基及びC1-C6アルキル基からなる群より独立に選ばれる1または2の基で置換されていてもよい）、及び4～6員の飽和もしくは不飽和の複素環基（該複素環基は、ハロゲン原子、カルボキシ基及びC1-C6アルキル基からなる群より独立に選ばれる1または2の基で置換されていてもよい）。
    Y群：オキソ基、C1-C6アルコキシ基、及びカルバモイル基。     Formula (I)
    Figure JPOXMLDOC01-appb-C000001
     [Where:
    Ring A represents a benzene ring or a bicyclic benzoheterocycle,
    Ring B represents a unitary or bicyclic ring containing two nitrogen atoms in the ring,
    The bicyclic ring may further contain one or more atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom in the ring,
    Ring C represents a benzene ring or a 4- to 6-membered saturated nitrogen-containing heterocycle,
    R 1 represents a hydrogen atom or a halogen atom,
    R 2 is a substituent which the ring A is bonded to the position of the 2-position in the case of a benzene ring, one or more of which may be substituted by a group C 1 independently selected from the following group Z - C 6 alkyl group, C 1 -C 6 alkoxy group optionally substituted by one or more groups independently selected from the following group Z, substituted by one or more groups independently selected from the following group Z which may be mono-C 1 -C 6 alkylamino group, - [O- (CH 2) 2] mXQ or -O- (CH 2) shows the NXQ,
    m represents an integer of 1 or 2,
    n represents an integer of 1, 2, 3 or 4,
    X represents O, NH or NHC = O;
    Q represents a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group or a mono C 1 -C 6 alkylamino group,
    R 3 represents a hydrogen atom or a halogen atom,
    R 4 , R 5 and R 6 are each independently a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group optionally substituted by one or more groups independently selected from the following group Y, A C 1 -C 6 alkoxy group optionally substituted by one or more groups independently selected from the Y group, a mono group optionally substituted by one or more groups independently selected from the following Y group C 1 -C 6 alkylamino group, C 1 -C 6 alkylsulfonyl group, or any of the following groups
    Figure JPOXMLDOC01-appb-C000002
     Indicates. ]
    Or a pharmaceutically acceptable salt thereof.
    Group Z: C 1 -C 6 alkoxy group, mono C 1 -C 6 alkylamino group, di C 1 -C 6 alkylamino group, phenyl group (the phenyl group is a halogen atom, a carboxy group, and C 1 -C 6 An optionally substituted 1 or 2 group selected from the group consisting of alkyl groups), and a 4-6 membered saturated or unsaturated heterocyclic group (the heterocyclic group is a halogen atom, a carboxy group) And optionally substituted by 1 or 2 groups independently selected from the group consisting of C 1 -C 6 alkyl groups).
    Group Y: an oxo group, a C 1 -C 6 alkoxy group, and a carbamoyl group.
  2. 前記式(I)において、下記の部分構造式(I-1)
    Figure JPOXMLDOC01-appb-C000003
     が、下記群
    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-I000005
    のいずれかである請求項１に記載の化合物またはその薬学上許容される塩。     In the above formula (I), the following partial structural formula (I-1)
    Figure JPOXMLDOC01-appb-C000003
     But the following group
    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-I000005
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  3. 前記式(I)中において、下記の部分構造式(I-2)
    Figure JPOXMLDOC01-appb-C000006
     が、下記式(II)
    Figure JPOXMLDOC01-appb-C000007
     ［式中、
    環Dは、ベンゼン環、ピロール環、フラン環、チオフェン環、シクロペンテン環、またはジヒドロフラン環を示し、
    R3は、水素原子またはハロゲン原子を示す。］
    で表される基である請求項１または２に記載の化合物またはその薬学上許容される塩。     In the above formula (I), the following partial structural formula (I-2)
    Figure JPOXMLDOC01-appb-C000006
     Is represented by the following formula (II)
    Figure JPOXMLDOC01-appb-C000007
     [Where:
    Ring D represents a benzene ring, a pyrrole ring, a furan ring, a thiophene ring, a cyclopentene ring, or a dihydrofuran ring,
    R 3 represents a hydrogen atom or a halogen atom. ]
    The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
  4. 前記式(I)中の部分構造式(I-2)が、
    下記群
    Figure JPOXMLDOC01-appb-C000008
     のいずれかである請求項１または２に記載の化合物またはその薬学上許容される塩。     The partial structural formula (I-2) in the formula (I) is
    Following group
    Figure JPOXMLDOC01-appb-C000008
     The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
  5. 前記式(I)中の部分構造式(I-2)が、
    下記式(III)
    Figure JPOXMLDOC01-appb-C000009
    ［式中、
    環Eは、ベンゼン環、ピロール環、またはチオフェン環を示し、
    R3は、水素原子またはハロゲン原子を示す。］
    で表される基である請求項１または２に記載の化合物またはその薬学上許容される塩。     The partial structural formula (I-2) in the formula (I) is
    The following formula (III)
    Figure JPOXMLDOC01-appb-C000009
    [Where:
    Ring E represents a benzene ring, a pyrrole ring, or a thiophene ring,
    R 3 represents a hydrogen atom or a halogen atom. ]
    The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
  6. 前記式(I)中の部分構造式(I-2)が、
    下記群
    Figure JPOXMLDOC01-appb-C000010
     のいずれかである請求項１または２に記載の化合物またはその薬学上許容される塩。     The partial structural formula (I-2) in the formula (I) is
    Following group
    Figure JPOXMLDOC01-appb-C000010
     The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
  7. 前記式(I)において、下記の部分構造式(I-3)
    Figure JPOXMLDOC01-appb-C000011
     が、下記群
    Figure JPOXMLDOC01-appb-C000012
     のいずれかである請求項１から６のいずれか１項に記載の化合物またはその薬学上許容される塩。     In the above formula (I), the following partial structural formula (I-3)
    Figure JPOXMLDOC01-appb-C000011
     But the following group
    Figure JPOXMLDOC01-appb-C000012
     The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.
  8. 請求項１～７のいずれか１項に記載の化合物またはその薬学上許容される塩を有効成分として含有する血糖降下剤。 A hypoglycemic agent comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.
  9. 請求項１～７のいずれか１項に記載の化合物またはその薬学上許容される塩を有効成分として含有する医薬。 A medicament comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.
  10. 糖尿病、食後過血糖症、耐糖能障害、糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、高脂血症、動脈硬化症、血栓性疾患、肥満、高血圧、浮腫、インスリン抵抗性、不安定糖尿病、インスリノーマまたは高インスリン血症の治療若しくは予防のための、請求項９に記載の医薬。 Diabetes, postprandial hyperglycemia, glucose intolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, hyperlipidemia, arteriosclerosis, thrombotic disease, obesity, hypertension, edema, insulin resistance, non The medicament according to claim 9, for the treatment or prevention of stable diabetes, insulinoma or hyperinsulinemia.
  11. 医薬組成物を製造するための、請求項１～７のいずれか一項に記載の化合物またはその薬学上許容される塩の使用。 Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition.
  12. 請求項１～７のいずれか一項に記載の化合物またはその薬学上許容される塩の薬理的な有効量を哺乳動物に投与することを特徴とする糖尿病の治療方法。 A method for treating diabetes, comprising administering to a mammal a pharmacologically effective amount of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.
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WO2022253326A1 (en) * 2021-06-05 2022-12-08 药捷安康(南京)科技股份有限公司 Nlrp3 inflammasome inhibitor and application thereof
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