WO2018221433A1 - Dérivé d'amine hétéroaryle - Google Patents

Dérivé d'amine hétéroaryle 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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Japanese (ja)
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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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    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—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
    • 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
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • A61P9/10—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.

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Abstract

L'invention concerne un nouveau composé, et un sel pharmaceutiquement acceptable de celui-ci, qui a une action de réduction de la glycémie et similaire, et qui est utile en tant que médicament thérapeutique et/ou préventif pour des maladies telles que le diabète. L'invention concerne un dérivé d'amine hétéroaryle représenté par la formule (I), ou un sel, ou un cristal de celui-ci, la formule ayant divers substituants (les significations de A, B, C, R1, R2, R3, R4, R5 et R6 dans la formule (I) sont tels que définis dans la description).
PCT/JP2018/020268 2017-05-29 2018-05-28 Dérivé d'amine hétéroaryle WO2018221433A1 (fr)

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CN115417856A (zh) * 2021-09-30 2022-12-02 成都奥睿药业有限公司 一类取代杂芳酞嗪衍生物的药学用途及其制备方法
WO2022253326A1 (fr) * 2021-06-05 2022-12-08 药捷安康(南京)科技股份有限公司 Inhibiteur de l'inflammasome nlrp3 et son utilisation
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US11618751B1 (en) 2022-03-25 2023-04-04 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives
WO2023088856A1 (fr) * 2021-11-17 2023-05-25 F. Hoffmann-La Roche Ag Inhibiteurs hétérocycliques de nlrp3
WO2023159148A3 (fr) * 2022-02-18 2023-10-05 Ptc Therapeutics, Inc. Inhibiteurs de nlrp3

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11046691B1 (en) 2018-12-10 2021-06-29 Ideaya Biosciences, Inc. 2-oxoquinazoline derivatives as methionine adenosyltransferase 2A inhibitors
US11084798B1 (en) 2018-12-10 2021-08-10 Ideaya Biosciences, Inc. 2-oxoquinazoline derivatives as methionine adenosyltransferase 2A inhibitors
US11130759B1 (en) 2018-12-10 2021-09-28 Ideaya Bioscience, Inc. 2-oxoquinazoline derivatives as methionine adenosyltransferase 2A inhibitors
WO2022253326A1 (fr) * 2021-06-05 2022-12-08 药捷安康(南京)科技股份有限公司 Inhibiteur de l'inflammasome nlrp3 et son utilisation
WO2023278438A1 (fr) * 2021-06-29 2023-01-05 Zomagen Biosciences Ltd Modulateurs de nlrp3
CN115417856A (zh) * 2021-09-30 2022-12-02 成都奥睿药业有限公司 一类取代杂芳酞嗪衍生物的药学用途及其制备方法
WO2023051761A1 (fr) * 2021-09-30 2023-04-06 成都奥睿药业有限公司 Utilisation pharmaceutique et procédé de préparation d'un dérivé d'hétéroaryl-phtalazine substitué
WO2023088856A1 (fr) * 2021-11-17 2023-05-25 F. Hoffmann-La Roche Ag Inhibiteurs hétérocycliques de nlrp3
WO2023159148A3 (fr) * 2022-02-18 2023-10-05 Ptc Therapeutics, Inc. Inhibiteurs de nlrp3
US11618751B1 (en) 2022-03-25 2023-04-04 Ventus Therapeutics U.S., Inc. Pyrido-[3,4-d]pyridazine amine derivatives useful as NLRP3 derivatives

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