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WO2018181345A1 - Composé hétérocyclique - Google Patents

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Publication number
WO2018181345A1
WO2018181345A1 PCT/JP2018/012481 JP2018012481W WO2018181345A1 WO 2018181345 A1 WO2018181345 A1 WO 2018181345A1 JP 2018012481 W JP2018012481 W JP 2018012481W WO 2018181345 A1 WO2018181345 A1 WO 2018181345A1
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Prior art keywords
group
optionally substituted
ethyl
methyl
aromatic heterocyclic
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PCT/JP2018/012481
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English (en)
Japanese (ja)
Inventor
北崎　智幸
西川　洋一
藤本　卓也
修 久保
佐々木　実
朝人 喜名
幸恵 森本
史朗 菊池
浩行 高田
雄二 石地
信幸 ▲高▼倉
実 生駒
佐藤　健二郎
山下　徹
健 山▲崎▼
浩史 渡部
重充 松本
英人 福士
直義 野口
亮磨 原
俊威 小林
前川　毅志
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Takeda Pharmaceutical Co Ltd
Scohia Pharma Inc
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Takeda Pharmaceutical Co Ltd
Scohia Pharma Inc
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Publication of WO2018181345A1 publication Critical patent/WO2018181345A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
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    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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    • 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
    • C07D401/06—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 carbon chain containing only aliphatic carbon 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
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D403/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems

Definitions

  • the present invention has an effect of activating nuclear factor erythroid 2-related factor ⁇ ⁇ ⁇ 2 (sometimes abbreviated as “Nrf2” in the present specification) and is associated with oxidative stress, particularly hepatitis (for example, non-alcoholic Steatohepatitis (NASH)), cardiovascular disease (eg, heart failure or pulmonary arterial hypertension), lung disease (eg, chronic obstructive pulmonary disease (COPD)), kidney disease (eg, chronic kidney disease (CKD)) Acute kidney injury (AKI)), central nervous system diseases (eg Parkinson's disease), mitochondrial diseases (eg Friedreich's ataxia, mitochondrial myopathy), autoimmune diseases (eg multiple sclerosis), etc.
  • Nrf2 nuclear factor erythroid 2-related factor ⁇ ⁇ ⁇ 2
  • oxidative stress particularly hepatitis (for example, non-alcoholic Steatohepatitis (NASH)), cardiovascular disease (eg, heart failure or pulmonary arterial hypertension), lung disease (eg, chronic
  • Oxidative stress is a state in which an excessive oxidation reaction has an adverse effect on a living body due to an unbalanced oxidation / antioxidation balance, and has been shown to be closely related to the formation of various pathological conditions.
  • the living body has a defense mechanism against oxidative stress, and the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) plays a central role in this mechanism.
  • Nrf2 binds to Keap1 (Kelch-like ECH-associated protein 1) in the steady state, and its intracellular concentration is kept low due to degradation regulation by proteosome. However, Nrf2 is dissociated from Keap1 when subjected to some oxidative stress.
  • Nrf2 activator is expected to exert a strong antioxidant effect by activating the Nrf2-Keap1 system.
  • Nrf2 activators include a type that modifies the Cys residue of Keap1 and a type that inhibits protein-protein interaction of Nrf2-Keap1, both of which are known to activate Nrf2 (Non-Patent Documents) 2).
  • Nrf2 activators are considered to be effective in preventing or treating various oxidative stress-related diseases.
  • liver diseases such as non-alcoholic steatohepatitis (NASH)
  • lung diseases such as obstructive pulmonary disease (COPD)
  • kidney diseases chronic kidney disease (CKD), acute kidney injury (AKI), etc.)
  • Heart disease heart failure, pulmonary arterial hypertension, etc.
  • central nervous system disease Parkinson disease, Alzheimer disease, etc.
  • mitochondrial disease Feriedreich ataxia, mitochondrial myopathy, etc.
  • autoimmune disease multiple sclerosis, etc.
  • eye diseases age-related macular degeneration, etc.
  • Non-patent Document 4 Bardoxolone methyl (CDDO-Me), which activates Nrf2 by modifying the Cyap residue of Keap1, has been shown to improve renal function in large-scale clinical trials of CKD patients with diabetic nephropathy. The clinical trial was discontinued early due to serious side effects such as the onset of heart failure (Non-patent Document 4).
  • a low molecular weight compound that inhibits the protein-protein interaction of Nrf2-Keap1 is expected to show efficacy in the above oxidative stress diseases by activating Nrf2 by a mechanism different from that of CDDO-Me.
  • Nrf2 regulators The following compounds are known as Nrf2 regulators.
  • Patent Document 1 the following formula (I):
  • Patent Document 1 Is useful for the treatment of respiratory diseases such as COPD and asthma, and non-respiratory diseases such as chronic kidney disease and acute kidney injury.
  • respiratory diseases such as COPD and asthma
  • non-respiratory diseases such as chronic kidney disease and acute kidney injury.
  • Patent Document 2 the following formula (I):
  • Nrf2 activating action and involve oxidative stress, particularly hepatitis (eg non-alcoholic steatohepatitis (NASH)), cardiovascular disease (eg heart failure or pulmonary arterial hypertension) ), Lung disease (eg, chronic obstructive pulmonary disease (COPD)), kidney disease (eg, chronic kidney disease (CKD) or acute kidney injury (AKI)), central nervous system disease (eg, Parkinson's disease), mitochondria
  • NASH non-alcoholic steatohepatitis
  • COPD chronic obstructive pulmonary disease
  • kidney disease eg, chronic kidney disease (CKD) or acute kidney injury (AKI)
  • central nervous system disease eg, Parkinson's disease
  • a compound represented by the following formula (I) has an Nrf2 activating action, and therefore a disease involving oxidative stress, particularly hepatitis (for example, Non-alcoholic steatohepatitis (NASH), cardiovascular disease (eg, heart failure or pulmonary arterial hypertension), lung disease (eg, chronic obstructive pulmonary disease (COPD)), kidney disease (eg, chronic kidney disease) (CKD) or acute kidney injury (AKI)), central nervous system diseases (eg Parkinson's disease), mitochondrial diseases (eg Friedreich ataxia, mitochondrial myopathy), autoimmune diseases (eg multiple sclerosis), etc.
  • NASH Non-alcoholic steatohepatitis
  • COPD chronic obstructive pulmonary disease
  • CKD chronic kidney disease
  • AKI acute kidney injury
  • central nervous system diseases eg Parkinson's disease
  • mitochondrial diseases eg Friedreich ataxia, mitochondrial myopathy
  • autoimmune diseases eg multiple sclerosis
  • R 1 represents an optionally substituted alkyl group
  • R 2 and R 3 each independently represents a hydrogen atom or an optionally substituted alkyl group
  • R 4 represents an optionally substituted cyclic group or an optionally substituted alkyl group
  • Ring A represents an optionally substituted benzene ring
  • Ring B is a benzene ring or a pyridine ring
  • X represents —CO— or —SO 2 —
  • Y represents a bond, —O— or —N (—Ry) —
  • Ry represents a hydrogen atom or a substituent
  • n represents 1 or 2.
  • compound (I) Or a salt thereof (hereinafter also referred to as compound (I)).
  • R 1 is a C 1-6 alkyl group
  • R 2 and R 3 are each independently a hydrogen atom or a C 1-6 alkyl group
  • R 4 is (1) (a) a halogen atom, (b) a cyano group, (c) an optionally halogenated C 1-6 alkyl group, (d) (i) a halogen atom, (ii) a C 6-14 aryl group, and (iii) a C 1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from a C 3-10 cycloalkyl group, (e) a C 1-6 alkylsulfonyl group, (f) a C 6-14 aryl group, (g) a C 6-14 aryloxy group, (h) a 3- to 14-membered non-aromatic heterocyclic group, (i) pentafluorosulfanyl (-SF 5 ), and (j) 1 to 3 substituents selected from C 3-10
  • a medicament comprising the compound according to the above [1] or a salt thereof.
  • the medicament according to [8] above which is an Nrf2 activator.
  • the medicament according to [8] above which is a prophylactic or therapeutic agent for hepatitis, cardiovascular disease, lung disease, kidney disease, central nervous system disease, mitochondrial disease, or autoimmune disease.
  • the compound or a salt thereof according to the above [1] for use in the prevention or treatment of hepatitis, cardiovascular disease, lung disease, kidney disease, central nervous system disease, mitochondrial disease, or autoimmune disease.
  • a method for activating Nrf2 in a mammal which comprises administering an effective amount of the compound or salt thereof described in [1] to the mammal.
  • diseases having an excellent Nrf2 activation action and involving oxidative stress particularly hepatitis (eg, non-alcoholic steatohepatitis (NASH)), cardiovascular disease (eg, heart failure or pulmonary artery) Hypertension), lung disease (eg, chronic obstructive pulmonary disease (COPD)), kidney disease (eg, chronic kidney disease (CKD) or acute kidney injury (AKI)), central nervous system disease (eg, Parkinson's disease)
  • hepatitis eg, non-alcoholic steatohepatitis (NASH)
  • cardiovascular disease eg, heart failure or pulmonary artery
  • lung disease eg, chronic obstructive pulmonary disease (COPD)
  • kidney disease eg, chronic kidney disease (CKD) or acute kidney injury (AKI)
  • central nervous system disease eg, Parkinson's disease
  • mitochondrial diseases eg, Friedreich's ataxia, mitochondrial myopathy
  • autoimmune diseases eg, multiple sclerosis
  • each substituent has the following definition.
  • examples of the “halogen atom” include fluorine, chlorine, bromine and iodine.
  • examples of the “C 1-6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl.
  • Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2- Difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-tri Examples include fluoropentyl, hexyl, and 6,6,6-trifluorohexyl.
  • examples of the “C 2-6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3- Examples include methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
  • examples of the “C 2-6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- Examples include pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl.
  • examples of the “C 3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, and bicyclo [2.2. 2] Octyl, bicyclo [3.2.1] octyl, and adamantyl.
  • the "optionally halogenated C 3-10 also be cycloalkyl group", for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 3- A 10 cycloalkyl group.
  • examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • examples of the “C 3-10 cycloalkenyl group” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • examples of the “C 6-14 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl.
  • examples of the “C 7-16 aralkyl group” include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.
  • examples of the “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • the "optionally halogenated C 1-6 alkoxy group” for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1-6 An alkoxy group is mentioned.
  • Examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyl.
  • Examples include oxy and hexyloxy.
  • examples of the “C 3-10 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.
  • examples of the “C 1-6 alkylthio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
  • the "optionally halogenated C 1-6 alkylthio group optionally" for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1-6 An alkylthio group is mentioned.
  • examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio.
  • examples of the “C 1-6 alkyl-carbonyl group” include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2- Examples include dimethylpropanoyl, hexanoyl, and heptanoyl.
  • examples of the “ optionally halogenated C 1-6 alkyl-carbonyl group” include C 1 optionally having 1 to 7, preferably 1 to 5 halogen atoms.
  • a -6 alkyl-carbonyl group is mentioned. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
  • examples of the “C 1-6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, Examples include pentyloxycarbonyl and hexyloxycarbonyl.
  • examples of the “C 6-14 aryl-carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl.
  • examples of the “C 7-16 aralkyl-carbonyl group” include phenylacetyl and phenylpropionyl.
  • examples of the “5- to 14-membered aromatic heterocyclic carbonyl group” include nicotinoyl, isonicotinoyl, thenoyl and furoyl.
  • examples of the “3- to 14-membered non-aromatic heterocyclic carbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.
  • examples of the “mono- or di-C 1-6 alkyl-carbamoyl group” include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, N-ethyl-N-methylcarbamoyl.
  • examples of the “mono- or di-C 7-16 aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl.
  • examples of the “C 1-6 alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl and tert-butylsulfonyl.
  • the "optionally halogenated C 1-6 alkyl sulfonyl group” for example, 1 to 7, preferably which may have 1 to 5 halogen atoms C 1- 6 alkylsulfonyl group is mentioned.
  • examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, hexylsulfonyl.
  • examples of the “C 6-14 arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.
  • examples of the “substituent” include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, and a substituted group.
  • An optionally substituted amino group an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl ( SH) group and optionally substituted silyl group.
  • examples of the “hydrocarbon group” include, for example, a C 1-6 alkyl group, a C 2-6 alkenyl group, Examples thereof include a C 2-6 alkynyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 6-14 aryl group, and a C 7-16 aralkyl group.
  • examples of the “optionally substituted hydrocarbon group” include a hydrocarbon group which may have a substituent selected from the following substituent group A.
  • substituent group A (1) a halogen atom, (2) Nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) an optionally halogenated C 1-6 alkoxy group, (7) C 6-14 aryloxy group (eg, phenoxy, naphthoxy), (8) C 7-16 aralkyloxy group (eg, benzyloxy), (9) 5- to 14-membered aromatic heterocyclic oxy group (eg, pyridyloxy), (10) 3 to 14-membered non-aromatic heterocyclic oxy group (eg, morpholinyloxy, piperidinyloxy), (11) C 1-6 alkyl-carbonyloxy group (eg, acetoxy, propanoyloxy), (12) C 6-14 aryl-carbony
  • the number of the substituents in the “optionally substituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
  • examples of the “heterocyclic group” include, for example, a nitrogen atom, a sulfur atom and a ring atom other than a carbon atom.
  • an aromatic heterocyclic group (ii) a non-aromatic heterocyclic group, and (iii) a 7 to 10-membered heterocyclic bridge group each containing 1 to 4 heteroatoms selected from oxygen atoms .
  • the “aromatic heterocyclic group” (including the “5- to 14-membered aromatic heterocyclic group”) is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing 1 to 4 heteroatoms is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing 1 to 4 heteroatoms is, for example, selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring-constituting atom.
  • Suitable examples of the “aromatic heterocyclic group” include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1 5-, 6-membered monocyclic aromatic heterocyclic groups such as 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl; Benzothiophenyl, benzofuranyl, benzoimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyri
  • non-aromatic heterocyclic group examples include, for example, a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom 3 to 14-membered (preferably 4 to 10-membered) non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from Suitable examples of the “non-aromatic heterocyclic group” include aziridinyl, oxiranyl, thiylyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolidinyl, pyra
  • preferable examples of the “7 to 10-membered heterocyclic bridged ring group” include quinuclidinyl and 7-azabicyclo [2.2.1] heptanyl.
  • examples of the “nitrogen-containing heterocyclic group” include those containing at least one nitrogen atom as a ring-constituting atom among the “heterocyclic groups”.
  • examples of the “optionally substituted heterocyclic group” include a heterocyclic group which may have a substituent selected from the substituent group A described above.
  • the number of substituents in the “optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
  • acyl group is, for example, “1 selected from a halogen atom, an optionally halogenated C 1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group, and a carbamoyl group.
  • the “acyl group” also includes a hydrocarbon-sulfonyl group, a heterocyclic-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocyclic-sulfinyl group.
  • the hydrocarbon-sulfonyl group is a sulfonyl group to which a hydrocarbon group is bonded
  • the heterocyclic-sulfonyl group is a sulfonyl group to which a heterocyclic group is bonded
  • the hydrocarbon-sulfinyl group is a hydrocarbon group.
  • a sulfinyl group to which is bonded and a heterocyclic-sulfinyl group mean a sulfinyl group to which a heterocyclic group is bonded.
  • the “acyl group” a formyl group, a carboxy group, a C 1-6 alkyl-carbonyl group, a C 2-6 alkenyl-carbonyl group (eg, crotonoyl), a C 3-10 cycloalkyl-carbonyl group ( Examples, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 cycloalkenyl-carbonyl group (eg, 2-cyclohexenecarbonyl), C 6-14 aryl-carbonyl group, C 7-16 aralkyl- Carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered
  • Diallylcarbamoyl mono- or di-C 3-10 cycloalkyl-carbamoyl group (eg, cyclopropylcarbamoyl), mono- or di-C 6-14 aryl-carbamoyl group (eg, phenylcarbamoyl), mono- or Di-C 7-16 aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (eg, pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C 1-6 alkyl-thiocarbamoyl group (eg, methylthio) Carbamoyl, N-ethyl-N-methyl Okarubamoiru), mono - or di -C 2-6 alkenyl - thiocarbamoyl group (e.g., diallyl thio carbamoyl), mono - or di cycl
  • examples of the “optionally substituted amino group” include, for example, a “C 1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent group A” C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7 -16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl Groups, mono- or di-C 1-6 alkyl-carbamoyl groups, mono- or di-C 7-16 aralkyl-carbamoyl groups, C 1-6 alkylsulfonyl groups and C 6- And an amino
  • Suitable examples of the optionally substituted amino group include an amino group, a mono- or di- (optionally halogenated C 1-6 alkyl) amino group (eg, methylamino, trifluoromethylamino, Dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 alkenylamino groups (eg, diallylamino), mono- or di-C 3-10 cycloalkylamino groups (eg, Cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 arylamino group (eg, phenylamino), mono- or di-C 7-16 aralkylamino group (eg, benzylamino, dibenzylamino), mono - or di - (optionally halogenated C 1-6 alkyl) - carbonyl amino group (e.g., a Chiru
  • examples of the “optionally substituted carbamoyl group” include, for example, a “C 1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent group A” C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7 -16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di -C 1-6 alkyl - carbamoyl group and mono- - or di -C 7-16 aralkyl - 1 or 2 substituents selected from a carbamoyl group
  • Suitable examples of the optionally substituted carbamoyl group include a carbamoyl group, a mono- or di-C 1-6 alkyl-carbamoyl group, a mono- or di-C 2-6 alkenyl-carbamoyl group (eg, diallylcarbamoyl group).
  • Mono- or di-C 3-10 cycloalkyl-carbamoyl groups eg cyclopropylcarbamoyl, cyclohexylcarbamoyl
  • mono- or di-C 6-14 aryl-carbamoyl groups eg phenylcarbamoyl
  • mono- or Di-C 7-16 aralkyl-carbamoyl group mono- or di-C 1-6 alkyl-carbonyl-carbamoyl group (eg acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 aryl-carbonyl-carbamoyl Groups (eg, benzoylcarbamoyl)
  • a 5- to 14-membered aromatic heterocyclic carbamoyl group eg, pyridylcarbamoyl
  • pyridylcarbamoyl pyridylcarb
  • examples of the “optionally substituted thiocarbamoyl group” include, for example, “C 1-6 alkyl each optionally having 1 to 3 substituents selected from Substituent Group A” Group, C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group, C 7-16 aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono - or di -C 1-6 alkyl - carbamoyl group and mono- - or di -C 7-16 aralkyl - one or two location selected from a carbamoyl
  • thiocarbamoyl group which may be substituted include a thiocarbamoyl group, a mono- or di-C 1-6 alkyl-thiocarbamoyl group (eg, methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthio).
  • examples of the “optionally substituted sulfamoyl group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”.
  • the optionally substituted sulfamoyl group include sulfamoyl group, mono- or di-C 1-6 alkyl-sulfamoyl group (eg, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethyl).
  • examples of the “optionally substituted hydroxy group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”.
  • Suitable examples of the optionally substituted hydroxy group include a hydroxy group, a C 1-6 alkoxy group, a C 2-6 alkenyloxy group (eg, allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy).
  • C 3-10 cycloalkyloxy group eg, cyclohexyloxy
  • C 6-14 aryloxy group eg, phenoxy, naphthyloxy
  • C 7-16 aralkyloxy group eg, benzyloxy, phenethyloxy
  • C 1-6 alkyl-carbonyloxy group eg, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy
  • C 6-14 aryl-carbonyloxy group eg, benzoyloxy
  • C 7-16 aralkyl- A carbonyloxy group eg benzylcarbonyloxy)
  • 5 to 14-membered aromatic heterocyclic carbonyloxy group e.g., nicotinoyl oxy
  • 3 to 14-membered non-aromatic heterocyclic carbonyloxy group e.g., piperidinylcarbonyl oxy
  • examples of the “optionally substituted sulfanyl group” include a “C 1-6 alkyl group optionally having 1 to 3 substituents selected from the substituent group A”.
  • C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 6-14 aryl group, C 7-16 aralkyl group, C 1-6 alkyl-carbonyl group, C 6-14 aryl-carbonyl group and 5 to Examples thereof include a sulfanyl group optionally having a substituent selected from a 14-membered aromatic heterocyclic group and a halogenated sulfanyl group.
  • the optionally substituted sulfanyl group include a sulfanyl (—SH) group, a C 1-6 alkylthio group, a C 2-6 alkenylthio group (eg, allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10 cycloalkylthio group (eg, cyclohexylthio), C 6-14 arylthio group (eg, phenylthio, naphthylthio), C 7-16 aralkylthio group (eg, benzylthio, phenethylthio), C 1-6 alkyl-carbonylthio group (eg, acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 aryl-carbonylthio group (eg, benzoylthio), 5-
  • examples of the “optionally substituted silyl group” include a “C 1-6 alkyl group each optionally having 1 to 3 substituents selected from the substituent group A”
  • a silyl group optionally having 1 to 3 substituents selected from a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group and a C 7-16 aralkyl group ” Can be mentioned.
  • Preferable examples of the optionally substituted silyl group include a tri-C 1-6 alkylsilyl group (eg, trimethylsilyl, tert-butyl (dimethyl) silyl).
  • examples of the “hydrocarbon ring” include a C 6-14 aromatic hydrocarbon ring, a C 3-10 cycloalkane, and a C 3-10 cycloalkene.
  • examples of the “C 6-14 aromatic hydrocarbon ring” include benzene and naphthalene.
  • examples of “C 3-10 cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.
  • examples of “C 3-10 cycloalkene” include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene.
  • examples of the “heterocycle” include aromatic heterocycles each containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom. Non-aromatic heterocycles may be mentioned.
  • the “aromatic heterocycle” is, for example, a 5- to 14-membered member containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom ( Preferred is a 5- to 10-membered aromatic heterocyclic ring.
  • Suitable examples of the “aromatic heterocycle” include thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadi 5- to 6-membered monocyclic aromatic heterocycle such as azole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazol
  • non-aromatic heterocyclic ring is, for example, a 3 to 14 member containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom as a ring constituent atom. (Preferably 4 to 10 membered) non-aromatic heterocycle.
  • non-aromatic heterocycle examples include aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline.
  • examples of the “nitrogen-containing heterocycle” include those containing at least one nitrogen atom as a ring-constituting atom among the “heterocycle”.
  • examples of the “C 6-14 aromatic hydrocarbon ring” also include anthracene, phenanthrene, and acenaphthylene.
  • R 1 represents an optionally substituted alkyl group.
  • the “alkyl group” of the “optionally substituted alkyl group” represented by R 1 includes, for example, a C 1-6 alkyl group, and preferably a C 1-3 alkyl group.
  • the “alkyl group” of the “optionally substituted alkyl group” represented by R 1 may be substituted with a substituent selected from the above-mentioned substituent group A, for example, and the number of substituents is, for example, 1 to 5 (preferably 1 to 3). When the number of substituents is 2 or more, each substituent may be the same or different.
  • R 1 is preferably an optionally substituted C 1-6 alkyl group (eg, methyl, ethyl).
  • R 1 is more preferably a C 1-6 alkyl group (eg, methyl, ethyl).
  • R 1 is more preferably a C 1-3 alkyl group (eg, methyl, ethyl).
  • R 1 is particularly preferably methyl.
  • R 2 and R 3 each independently represent a hydrogen atom or an optionally substituted alkyl group.
  • the “alkyl group” of the “optionally substituted alkyl group” represented by R 2 or R 3 includes, for example, a C 1-6 alkyl group, preferably a C 1-3 alkyl group.
  • the “alkyl group” of the “optionally substituted alkyl group” represented by R 2 or R 3 may be substituted with a substituent selected from the above-mentioned substituent group A, for example, and the number of substituents Is, for example, 1 to 5 (preferably 1 to 3). When the number of substituents is 2 or more, each substituent may be the same or different.
  • R 2 and R 3 are preferably each independently a hydrogen atom or an optionally substituted C 1-6 alkyl group (eg, methyl).
  • R 2 and R 3 are more preferably each independently a hydrogen atom or a C 1-6 alkyl group (eg, methyl).
  • R 2 and R 3 are particularly preferably both hydrogen atoms.
  • R 2 is preferably a hydrogen atom, and R 3 is a hydrogen atom or an optionally substituted C 1-6 alkyl group (eg, methyl).
  • R 2 is a hydrogen atom, and R 3 is a hydrogen atom or a C 1-6 alkyl group (eg, methyl).
  • R 2 is a hydrogen atom, and R 3 is a hydrogen atom or a C 1-3 alkyl group (eg, methyl).
  • R 4 represents an optionally substituted cyclic group or an optionally substituted alkyl group.
  • the “cyclic group” of the “optionally substituted cyclic group” represented by R 4 includes a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 6-14 aryl group, an aromatic heterocyclic ring Group, non-aromatic heterocyclic group and the like.
  • the C 3-10 cycloalkyl group may be condensed with a benzene ring, and examples of such a condensed group include tetrahydronaphthyl and dihydroindenyl.
  • the C 6-14 aryl group may be condensed with a C 3-10 cycloalkane ring (preferably a C 5-6 cycloalkane ring (eg, cyclopentane, cyclohexane)). , Tetrahydronaphthyl and dihydroindenyl.
  • the aromatic heterocyclic group is preferably a 5- to 14-membered aromatic heterocyclic group, more preferably a 5- to 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl) or an 8- to 14-membered condensed poly group.
  • a cyclic (preferably bicyclic or tricyclic) aromatic heterocyclic group eg, indazolyl, indolyl, benzimidazolyl, benzotriazolyl, benzothienyl, benzofuryl).
  • the aromatic heterocyclic group is preferably a 5- to 14-membered aromatic heterocyclic group, more preferably a 5- to 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl, Thiazolyl, oxazolyl, pyrazolyl, triazolyl, thienyl) or 8- to 14-membered condensed polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic group (eg, indazolyl, indolyl, benzimidazolyl, benzotriazolyl, benzothienyl) , Benzofuryl).
  • a 5- to 14-membered aromatic heterocyclic group eg, pyridyl, Thiazolyl, oxazolyl, pyrazolyl, triazolyl, thienyl
  • 8- to 14-membered condensed polycyclic preferably bicyclic or tricyclic
  • aromatic heterocyclic group eg, indazoly
  • the non-aromatic heterocyclic group is preferably a 3- to 14-membered non-aromatic heterocyclic group, more preferably a 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, oxetanyl, tetrahydropyrani group).
  • a 9 to 14 membered fused polycyclic (preferably 2 or 3 ring) non-aromatic heterocyclic group eg, dihydrocumenyl, dihydrobenzofuryl, dihydrobenzodioxepinyl, tetrahydroquinolyl, tetrahydroiso
  • Quinolyl indolinyl, dihydrobenzodioxinyl, dihydrobenzoxazinyl, dihydrobenzoxazepinyl.
  • the non-aromatic heterocyclic group may be a spiro ring, and examples of the spiro ring include spiro [1-benzofuran-2,1′-cyclopropane] -yl, spiro [1-benzofuran-2,1 '-Cyclohexane] -yl, tetrahydro-3H-spiro [1-benzofuran-2,4'-pyran] -yl, spiro [1-benzofuran-2,1'-cyclopentane] -yl, dihydrospiro [1,4 -Benzoxazine-2,1′-cyclobutane] -yl.
  • the “cyclic group” of the “optionally substituted cyclic group” represented by R 4 may be substituted with a substituent selected from the above-described substituent group A, and the number of substituents is, for example, 1 to 5 (preferably 1 to 3). When the number of substituents is 2 or more, each substituent may be the same or different.
  • the “alkyl group” of the “optionally substituted alkyl group” represented by R 4 may be substituted with, for example, a substituent selected from the substituent group A described above, and the number of substituents is, for example, 1 to 5 (preferably 1 to 3). When the number of substituents is 2 or more, each substituent may be the same or different.
  • R 4 is, preferably, (1) condensed with an optionally substituted C 3-10 cycloalkane ring (preferably a C 5-6 cycloalkane ring (eg, cyclopentane, cyclohexane)) optionally substituted with oxo;
  • a C 6-14 aryl group eg, phenyl, naphthyl, tetrahydronaphthyl, dihydroindenyl
  • an optionally substituted C 3-10 cycloalkyl group optionally condensed with a benzene ring eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, dihydroindenyl
  • an optionally substituted 5- to 14-membered aromatic heterocyclic group preferably a 5- to 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl), 8- to 14
  • R 4 is more preferably (1) an optionally substituted C 3-10 cycloalkyl group optionally condensed with a benzene ring (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, dihydroindenyl), (2) an optionally substituted 5- to 14-membered aromatic heterocyclic group (preferably a 5- to 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl), 8- to 14-membered condensed polycyclic (preferably Is an aromatic heterocyclic group (eg, indazolyl, indolyl, benzimidazolyl, benzotriazolyl, benzothienyl, benzofuryl)), (3) an optionally substituted 3- to 14-membered non-aromatic heterocyclic group (preferably a 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg
  • R 4 is more preferably (1) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (b) a cyano group, (c) an optionally halogenated C 1-6 alkyl group (eg, methyl, ethyl, propyl, tert-butyl, trifluoromethyl), (d) (i) a halogen atom (eg, fluorine atom), (ii) a C 6-14 aryl group (eg, phenyl), and (iii) a C 3-10 cycloalkyl group (eg, cyclopropyl).
  • a halogen atom eg, fluorine atom, chlorine atom, bromine atom
  • a cyano group e.g, an optionally halogenated C 1-6 alkyl group (eg, methyl, ethyl, propyl, tert-butyl, trifluoromethyl)
  • a C 1-6 alkoxy group (eg, methoxy, ethoxy, tert-butoxy) optionally substituted by 1 to 3 substituents selected from: (e) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl), (f) a C 6-14 aryl group (eg, phenyl), (g) a C 6-14 aryloxy group (eg, phenoxy), (h) a 3- to 14-membered non-aromatic heterocyclic group (preferably a 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, morpholinyl)), (i) pentafluorosulfanyl (—SF 5 ), and (j) a C 3-10 cycloalkyl group (eg, cyclopropyl, cyclobutyl) A C 3-10 cycloalkane ring (preferably a C 5-6 cycloalkane ring (eg,
  • R 4 is more preferably (1) 1 to 3 C 1-6 alkyl groups (e.g., ethyl, propyl) optionally substituted by, C 5-6 cycloalkane ring (e.g., cyclohexane) optionally a fused C 6 A -14 aryl group (eg, phenyl, tetrahydronaphthyl), (2) (a) a cyano group, (b) C 1-6 alkyl group (eg, methyl, ethyl), and (c) C 1-6 alkoxy group (eg, methoxy) A 5- to 14-membered aromatic heterocyclic group (preferably an 8- to 14-membered condensed polycyclic (preferably 2- or 3-cyclic) aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Ring groups (eg, indazolyl, indolyl)), (3) (a) a C 1-6 alkyl group (eg, methyl, ethy
  • R 4 is preferably (1) condensed with an optionally substituted C 3-10 cycloalkane ring (preferably a C 5-6 cycloalkane ring (eg, cyclopentane, cyclohexane)) optionally substituted with oxo;
  • a C 6-14 aryl group eg, phenyl, naphthyl, tetrahydronaphthyl, dihydroindenyl
  • an optionally substituted C 3-10 cycloalkyl group optionally condensed with a benzene ring eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, dihydroindenyl
  • an optionally substituted 5- to 14-membered aromatic heterocyclic group preferably a 5- to 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl, thiazolyl
  • R 4 is more preferably (1) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (b) a cyano group, (c) an optionally halogenated C 1-6 alkyl group (eg, methyl, ethyl, propyl, tert-butyl, trifluoromethyl), (d) (i) a halogen atom (eg, fluorine atom), (ii) a C 6-14 aryl group (eg, phenyl), and (iii) a C 3-10 cycloalkyl group (eg, cyclopropyl).
  • a halogen atom eg, fluorine atom, chlorine atom, bromine atom
  • a cyano group e.g, an optionally halogenated C 1-6 alkyl group (eg, methyl, ethyl, propyl, tert-butyl, trifluoromethyl)
  • a C 1-6 alkoxy group (eg, methoxy, ethoxy, tert-butoxy) optionally substituted by 1 to 3 substituents selected from: (e) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl), (f) a C 6-14 aryl group (eg, phenyl), (g) a C 6-14 aryloxy group (eg, phenoxy), (h) a 3- to 14-membered non-aromatic heterocyclic group (preferably a 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, morpholinyl)), (i) pentafluorosulfanyl (—SF 5 ), and (j) a C 3-10 cycloalkyl group (eg, cyclopropyl, cyclobutyl) A C 3-10 cycloalkane ring (preferably a C 5-6 cycloalkane ring (eg,
  • a 5- to 14-membered aromatic heterocyclic group (preferably a 5- to 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl, thiazolyl, oxazolyl) which may be substituted with 1 to 3 substituents selected from , Pyrazolyl, triazolyl, thienyl), 8- to 14-membered condensed polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic group (eg, indazolyl, indolyl, benzimidazolyl, benzotriazolyl, benzothienyl, benzofuryl) ), (4) (a) a halogen atom (eg, fluorine atom, bromine atom), (b) a C 1-6 alkyl group (eg, methyl, ethyl, propyl) optionally substituted with 1 to 3 C 3-10 cycloalkyl groups (eg, cyclopropyl), (c) a C
  • R 4 is more preferably (1) (a) a C 1-6 alkyl group (eg, ethyl, propyl), (b) a halogen atom (eg, fluorine atom), and (c) a C 1-6 alkoxy group (eg, methoxy) A C 6-14 aryl group (eg, phenyl, tetrahydronaphthyl) optionally condensed with a C 5-6 cycloalkane ring (eg, cyclohexane), which may be substituted with 1 to 3 substituents selected from ), (2) (a) a cyano group, (b) a halogen atom (eg, fluorine atom), (c) C 1-6 alkyl group (eg, methyl, ethyl), and (d) C 1-6 alkoxy group (eg, methoxy) A 5- to 14-membered aromatic heterocyclic group (preferably a 5- to 6-membered monocyclic aromatic
  • R 4 is even more preferably (1) (a) a C 1-6 alkyl group (eg, ethyl, propyl), (b) a halogen atom (eg, fluorine atom), and (c) a C 1-6 alkoxy group (eg, methoxy)
  • R 4 is more preferably (1) (a) a halogen atom (eg, fluorine atom), (b) C 1-6 alkyl group (eg, methyl, ethyl), and (c) C 1-6 alkoxy group (eg, methoxy)
  • a C 6-14 aryl group eg, phenyl
  • R 4 optionally substituted with 1 to 3 substituents selected from: (2) (a) a halogen atom (eg, fluorine atom), (b) a hydroxy group, (c) an optionally halogenated C 1-6 alkyl group (eg, methyl, ethyl, trifluoromethyl), (d) C 1-6 alkoxy group (eg, methoxy), and (e) C 3-10 cycloalkyl group (eg, cyclopropyl) 5- to 14-membered aromatic heterocyclic group (preferably 5- to 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl,
  • R 4 is even more preferably (1) (a) a halogen atom (eg, fluorine atom), (b) a C 1-6 alkyl group (eg, ethyl), and (c) a C 1-6 alkoxy group (eg, methoxy) A C 6-14 aryl group (eg, phenyl) optionally substituted with 1 to 3 substituents selected from: (2) (a) a halogen atom (eg, fluorine atom), and (b) a C 1-6 alkyl group (eg, methyl, ethyl) 5- to 14-membered aromatic heterocyclic group (preferably 5- to 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl, thiazolyl, pyrazolyl), which may be substituted with 1 to 3 substituents selected from )) It is.
  • a halogen atom eg, fluorine atom
  • C 1-6 alkyl group eg, eth
  • R 4 is still more preferably (1) (a) a halogen atom (eg, fluorine atom), (b) a C 1-6 alkyl group (eg, ethyl), and (c) a C 1-6 alkoxy group (eg, methoxy)
  • a phenyl group optionally substituted by 1 to 3 substituents selected from: (2) a pyridyl group optionally substituted by 1 to 3 C 1-6 alkyl groups (eg, methyl, ethyl), (3) a thiazolyl group optionally substituted by 1 or 2 C 1-6 alkyl groups (eg, methyl, ethyl), or (4) (a) a halogen atom (eg, fluorine atom), and (b) a C 1-6 alkyl group (eg, methyl, ethyl) A pyrazolyl group which may be substituted with 1 to 3 substituents selected from: (2) a pyridyl group optionally substituted
  • Ring A represents an optionally substituted benzene ring.
  • the “benzene ring” of the “optionally substituted benzene ring” represented by ring A may be further substituted with, for example, a substituent selected from the substituent group A described above, and the number of substituents is For example, 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.
  • the substitution positions are the positions a and b of the following arrows.
  • the position selected from is included.
  • Ring A is preferably (a) a C 1-6 alkyl group (eg, methyl), and (b) a C 1-6 alkoxy group (eg, methoxy).
  • a benzene ring which may be further substituted with 1 to 3 substituents selected from
  • Ring A is more preferably (a) a C 1-6 alkyl group (eg, methyl), and (b) a C 1-6 alkoxy group (eg, methoxy).
  • the substitution position on the benzene ring is the position a or b of the arrow.
  • ring A is more preferably (a) a C 1-6 alkyl group (eg, methyl), and (b) a C 1-6 alkoxy group (eg, methoxy).
  • a benzene ring further substituted with 1 or 2 substituents selected from
  • the substitution positions on the benzene ring are the positions a and b of the arrows.
  • the position is selected from
  • ring A is more preferably (a) a C 1-6 alkyl group (eg, methyl), and (b) a C 1-6 alkoxy group (eg, methoxy).
  • a benzene ring further substituted with
  • the substitution positions on the benzene ring are the positions a and b of the arrows.
  • R a represents a hydrogen atom or a C 1-6 alkyl group
  • R b represents a hydrogen atom or a C 1-6 alkoxy group
  • R 1 has the same meaning as described above.
  • R a is preferably a C 1-6 alkyl group (eg, methyl), and more preferably methyl.
  • R b is preferably a C 1-6 alkoxy group (eg, methoxy), and more preferably methoxy.
  • Ring B represents a benzene ring or a pyridine ring.
  • ring B is a benzene ring or a pyridine ring, the following partial structures are exemplified.
  • Ring B is preferably a benzene ring.
  • X represents —CO— or —SO 2 —. X is preferably —CO—.
  • Y represents a bond, —O— or —N (—Ry) —
  • Ry represents a hydrogen atom or a substituent.
  • Y is —N (—Ry) —
  • Ry is preferably a C 1-6 alkyl group (eg, methyl).
  • Y is preferably a bond, —O— or —N (—Ry) — (wherein Ry is a C 1-6 alkyl group (eg, methyl)). Y is more preferably a bond or —O—. Y is particularly preferably a bond.
  • the combination of —Y—X— is preferably —CO—, —O—CO—, —N (—Ry) —CO— (wherein Ry is as defined above) or —SO 2 —. It is.
  • the combination of —Y—X— is more preferably —CO—, —O—CO—, —N (—Ry) —CO— (wherein Ry is a C 1-6 alkyl group (eg, methyl) Or —SO 2 —.
  • the combination of —YX— is more preferably —CO— or —O—CO—.
  • the combination of —Y—X— is particularly preferably —CO—.
  • n 1 or 2. n is preferably 1.
  • Preferred examples of compound (I) include the following compounds or salts thereof.
  • R 1 is an optionally substituted C 1-6 alkyl group (eg, methyl, ethyl);
  • R 2 and R 3 are each independently a hydrogen atom or an optionally substituted C 1-6 alkyl group (eg, methyl) (preferably R 2 is a hydrogen atom, and R 3 Is a hydrogen atom or an optionally substituted C 1-6 alkyl group (eg, methyl));
  • R 4 is (1) condensed with an optionally substituted C 3-10 cycloalkane ring (preferably a C 5-6 cycloalkane ring (eg, cyclopentane, cyclohexane)) optionally substituted with oxo;
  • a C 6-14 aryl group eg, phenyl, naphthyl, tetrahydronaphthyl, dihydroindenyl
  • an optionally substituted C 3-10 cycloalkyl group optionally condensed with a benzene ring e
  • R 1 is a C 1-6 alkyl group (eg, methyl, ethyl);
  • R 2 and R 3 are each independently a hydrogen atom or a C 1-6 alkyl group (eg, methyl) (preferably, R 2 is a hydrogen atom and R 3 is a hydrogen atom or C 1-6 alkyl group (eg, methyl));
  • R 4 is (1) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (b) a cyano group, (c) an optionally halogenated C 1-6 alkyl group (eg, methyl, ethyl, propyl, tert-butyl, trifluoromethyl), (d) (i) a halogen atom (eg, fluorine atom), (ii) a C 6-14 aryl group (eg, phenyl), and (iii) a C 3-10 cycloalkyl group (eg,
  • a C 1-6 alkoxy group (eg, methoxy, ethoxy, tert-butoxy) optionally substituted by 1 to 3 substituents selected from: (e) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl), (f) a C 6-14 aryl group (eg, phenyl), (g) a C 6-14 aryloxy group (eg, phenoxy), (h) a 3- to 14-membered non-aromatic heterocyclic group (preferably a 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, morpholinyl)), (i) pentafluorosulfanyl (—SF 5 ), and (j) a C 3-10 cycloalkyl group (eg, cyclopropyl, cyclobutyl) A C 3-10 cycloalkane ring (preferably a C 5-6 cycloalkane ring (eg,
  • Ring B is a benzene ring
  • X is —CO— or —SO 2 —
  • Y is a bond, —O— or —N (—Ry) — (wherein Ry is a C 1-6 alkyl group (eg, methyl)) (the combination of —YX— , —CO—, —O—CO—, —N (—Ry) —CO— (wherein Ry is a C 1-6 alkyl group (eg, methyl)) or —SO 2 —.
  • n is 1 or 2; Compound (I).
  • R 1 is a C 1-3 alkyl group (eg, methyl, ethyl); R 2 and R 3 are both hydrogen atoms; R 4 is (1) 1 to 3 C 1-6 alkyl groups (e.g., ethyl, propyl) optionally substituted by, C 5-6 cycloalkane ring (e.g., cyclohexane) optionally a fused C 6 A -14 aryl group (eg, phenyl, tetrahydronaphthyl), (2) (a) a cyano group, (b) C 1-6 alkyl group (eg, methyl, ethyl), and (c) C 1-6 alkoxy group (eg, methoxy) A 5- to 14-membered aromatic heterocyclic group (preferably an 8- to 14-membered condensed polycyclic (preferably 2- or 3-cyclic) aromatic heterocyclic group which may be substituted with 1 to 3 substituents selected from Ring groups (e
  • Ring B is a benzene ring
  • X is —CO—
  • Y is a bond or —O— (the combination of —Y—X— is —CO— or —O—CO—)
  • n is 1 or 2.
  • R 1 is an optionally substituted C 1-6 alkyl group (eg, methyl, ethyl);
  • R 2 and R 3 are each independently a hydrogen atom or an optionally substituted C 1-6 alkyl group (eg, methyl) (preferably R 2 is a hydrogen atom, and R 3 Is a hydrogen atom or an optionally substituted C 1-6 alkyl group (eg, methyl));
  • R 4 is (1) condensed with an optionally substituted C 3-10 cycloalkane ring (preferably a C 5-6 cycloalkane ring (eg, cyclopentane, cyclohexane)) optionally substituted with oxo;
  • a C 6-14 aryl group eg, phenyl, naphthyl, tetrahydronaphthyl, dihydroindenyl
  • an optionally substituted C 3-10 cycloalkyl group optionally condensed with a benzene ring e
  • R 1 is a C 1-6 alkyl group (eg, methyl, ethyl);
  • R 2 and R 3 are each independently a hydrogen atom or a C 1-6 alkyl group (eg, methyl) (preferably, R 2 is a hydrogen atom and R 3 is a hydrogen atom or C 1-6 alkyl group (eg, methyl));
  • R 4 is (1) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (b) a cyano group, (c) an optionally halogenated C 1-6 alkyl group (eg, methyl, ethyl, propyl, tert-butyl, trifluoromethyl), (d) (i) a halogen atom (eg, fluorine atom), (ii) a C 6-14 aryl group (eg, phenyl), and (iii) a C 3-10 cycloalkyl group (eg,
  • a C 1-6 alkoxy group (eg, methoxy, ethoxy, tert-butoxy) optionally substituted by 1 to 3 substituents selected from: (e) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl), (f) a C 6-14 aryl group (eg, phenyl), (g) a C 6-14 aryloxy group (eg, phenoxy), (h) a 3- to 14-membered non-aromatic heterocyclic group (preferably a 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, morpholinyl)), (i) pentafluorosulfanyl (—SF 5 ), and (j) a C 3-10 cycloalkyl group (eg, cyclopropyl, cyclobutyl) A C 3-10 cycloalkane ring (preferably a C 5-6 cycloalkane ring (eg,
  • a 5- to 14-membered aromatic heterocyclic group (preferably a 5- to 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl, thiazolyl, oxazolyl) which may be substituted with 1 to 3 substituents selected from , Pyrazolyl, triazolyl, thienyl), 8- to 14-membered condensed polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic group (eg, indazolyl, indolyl, benzimidazolyl, benzotriazolyl, benzothienyl, benzofuryl) ), (4) (a) a halogen atom (eg, fluorine atom, bromine atom), (b) a C 1-6 alkyl group (eg, methyl, ethyl, propyl) optionally substituted with 1 to 3 C 3-10 cycloalkyl groups (eg, cyclopropyl), (c) a C
  • Ring B is a benzene ring
  • X is —CO— or —SO 2 —
  • Y is a bond, —O— or —N (—Ry) — (wherein Ry is a C 1-6 alkyl group (eg, methyl)) (the combination of —YX— , —CO—, —O—CO—, —N (—Ry) —CO— (wherein Ry is a C 1-6 alkyl group (eg, methyl)) or —SO 2 —.
  • n is 1 or 2; Compound (I).
  • R 1 is a C 1-3 alkyl group (eg, methyl, ethyl); R 2 and R 3 are both hydrogen atoms; R 4 is (1) (a) a C 1-6 alkyl group (eg, ethyl, propyl), (b) a halogen atom (eg, fluorine atom), and (c) a C 1-6 alkoxy group (eg, methoxy)
  • a C 6-14 aryl group eg, phenyl, tetrahydronaphthyl
  • optionally condensed with a C 5-6 cycloalkane ring eg, cyclohexane
  • C 5-6 cycloalkane ring eg, cyclohexane
  • Ring B is a benzene ring
  • X is —CO—
  • Y is a bond or —O— (the combination of —Y—X— is —CO— or —O—CO—)
  • n is 1 or 2.
  • R 1 is a C 1-3 alkyl group (eg, methyl, ethyl); R 2 and R 3 are both hydrogen atoms; R 4 is (1) (a) a C 1-6 alkyl group (eg, ethyl, propyl), (b) a halogen atom (eg, fluorine atom), and (c) a C 1-6 alkoxy group (eg, methoxy)
  • R 4 is (1) (a) a C 1-6 alkyl group (eg, ethyl, propyl), (b) a halogen atom (eg, fluorine atom), and (c) a C 1-6 alkoxy group (eg, methoxy)
  • Ring B is a benzene ring
  • X is —CO—
  • Y is a bond or —O— (the combination of —Y—X— is —CO— or —O—CO—)
  • n is 1 or 2.
  • R a is a hydrogen atom or a C 1-6 alkyl group (eg, methyl); R b is a hydrogen atom or a C 1-6 alkoxy group (eg, methoxy); and R 1 is a C 1-6 alkyl group (eg, methyl, ethyl).
  • R 2 and R 3 are each independently a hydrogen atom or a C 1-6 alkyl group (eg, methyl) (preferably, R 2 is a hydrogen atom and R 3 is a hydrogen atom or C 1-6 alkyl group (eg, methyl));
  • R 4 is (1) (a) a halogen atom (eg, fluorine atom, chlorine atom, bromine atom), (b) a cyano group, (c) an optionally halogenated C 1-6 alkyl group (eg, methyl, ethyl, propyl, tert-butyl, trifluoromethyl), (d) (i) a halogen atom (eg, fluorine atom), (ii) a C 6-14 aryl group (eg, phenyl), and (iii) a C 3-10 cycloalkyl group (eg, cyclopropyl).
  • a halogen atom eg, fluorine atom, chlorine
  • a C 1-6 alkoxy group (eg, methoxy, ethoxy, tert-butoxy) optionally substituted by 1 to 3 substituents selected from: (e) a C 1-6 alkylsulfonyl group (eg, methylsulfonyl), (f) a C 6-14 aryl group (eg, phenyl), (g) a C 6-14 aryloxy group (eg, phenoxy), (h) a 3- to 14-membered non-aromatic heterocyclic group (preferably a 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, morpholinyl)), (i) pentafluorosulfanyl (—SF 5 ), and (j) a C 3-10 cycloalkyl group (eg, cyclopropyl, cyclobutyl) A C 3-10 cycloalkane ring (preferably a C 5-6 cycloalkane ring (eg,
  • a 5- to 14-membered aromatic heterocyclic group (preferably a 5- to 6-membered monocyclic aromatic heterocyclic group (eg, pyridyl, thiazolyl, oxazolyl) which may be substituted with 1 to 3 substituents selected from , Pyrazolyl, triazolyl, thienyl), 8- to 14-membered condensed polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic group (eg, indazolyl, indolyl, benzimidazolyl, benzotriazolyl, benzothienyl, benzofuryl) ), (4) (a) a halogen atom (eg, fluorine atom, bromine atom), (b) a C 1-6 alkyl group (eg, methyl, ethyl, propyl) optionally substituted with 1 to 3 C 3-10 cycloalkyl groups (eg, cyclopropyl), (c) a C
  • R a is a C 1-6 alkyl group (eg, methyl); R b is a C 1-6 alkoxy group (eg, methoxy); and R 1 is a C 1-6 alkyl group (eg, methyl).
  • R 2 and R 3 are both hydrogen atoms;
  • R 4 is (1) (a) a halogen atom (eg, fluorine atom), (b) C 1-6 alkyl group (eg, methyl, ethyl), and (c) C 1-6 alkoxy group (eg, methoxy)
  • a C 6-14 aryl group (eg, phenyl) optionally substituted with 1 to 3 substituents selected from: (2) (a) a halogen atom (eg, fluorine atom), (b) a hydroxy group, (c) an optionally halogenated C 1-6 alkyl group (eg, methyl, ethyl, trifluoromethyl), (d) C 1-6 alkoxy
  • R a is a C 1-6 alkyl group (eg, methyl); R b is a C 1-6 alkoxy group (eg, methoxy); and R 1 is a C 1-6 alkyl group (eg, methyl).
  • R 2 and R 3 are both hydrogen atoms;
  • R 4 is (1) (a) a halogen atom (eg, fluorine atom), (b) a C 1-6 alkyl group (eg, ethyl), and (c) a C 1-6 alkoxy group (eg, methoxy)
  • a C 6-14 aryl group (eg, phenyl) optionally substituted with 1 to 3 substituents selected from: (2) (a) a halogen atom (eg, fluorine atom), and (b) a C 1-6 alkyl group (eg, methyl, ethyl) 5- to 14-membered aromatic heterocyclic group (preferably 5- to 6-membered monocyclic aromatic heterocyclic
  • R a is a C 1-6 alkyl group (eg, methyl); R b is a C 1-6 alkoxy group (eg, methoxy); and R 1 is a C 1-6 alkyl group (eg, methyl).
  • R 2 and R 3 are both hydrogen atoms;
  • R 4 is (1) (a) a halogen atom (eg, fluorine atom), (b) a C 1-6 alkyl group (eg, ethyl), and (c) a C 1-6 alkoxy group (eg, methoxy)
  • compound (I) include, for example, the compounds of Examples 1 to 258 or salts thereof.
  • salts include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids, and the like.
  • metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; and aluminum salt.
  • salt with organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-dibenzyl.
  • Examples include salts with ethylenediamine.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.
  • Preferable examples of the salt with organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene Examples thereof include sulfonic acid and salts with p-toluenesulfonic acid.
  • salt with basic amino acid examples include salts with arginine, lysine and ornithine, and preferable examples of the salt with acidic amino acid include salts with aspartic acid and glutamic acid. It is done. Of these, pharmaceutically acceptable salts are preferred.
  • inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts), alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts), ammonium salts
  • a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, oxalic acid
  • salts with organic acids such as tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • compound (I) has isomers such as tautomers, optical isomers, stereoisomers, positional isomers, rotational isomers, any one isomer and mixture are also included in the compound of the present invention. Is done. Furthermore, when compound (I) has an optical isomer, an optical isomer resolved from a racemate is also encompassed in compound (I).
  • Compound (I) may be a crystal, and it is included in compound (I) regardless of whether the crystal form is a single crystal form or a crystal form mixture.
  • Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • co-crystals or co-crystal salts are two or more unique at room temperature, each with different physical properties (eg structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a solid.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • Compound (I) may be a solvate (for example, hydrate) or a non-solvate (for example, non-hydrate), and both are included in compound (I).
  • a deuterium converter obtained by converting 1 H into 2 H (D) is also encompassed in compound (I).
  • a compound labeled or substituted with an isotope (eg, 3 H, 11 C, 14 C, 18 F, 35 S, 125 I) and the like is also encompassed in compound (I).
  • a compound labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) used in Positron Emission Tomography (PET), and can be useful in fields such as medical diagnosis.
  • PET tracer used in Positron Emission Tomography
  • the raw materials and reagents used in each step in the following production method and the obtained compound may each form a salt.
  • Examples of such salts include those similar to the salts of the aforementioned compound of the present invention.
  • the compound obtained in each step is a free compound, it can be converted into a target salt by a method known per se.
  • the compound obtained in each step is a salt, it can be converted into a free form or other types of desired salts by a method known per se.
  • the compound obtained in each step remains in the reaction solution or is obtained as a crude product and can be used in the next reaction.
  • the compound obtained in each step is concentrated from the reaction mixture according to a conventional method. , Crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography and the like, and can be isolated and / or purified.
  • the reaction time may vary depending on the reagent and solvent to be used, but unless otherwise specified, is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.
  • the reaction temperature may vary depending on the reagent and solvent to be used, but is usually ⁇ 78 ° C. to 300 ° C., preferably ⁇ 78 ° C. to 150 ° C. unless otherwise specified.
  • the pressure may vary depending on the reagent and solvent used, but unless otherwise specified, is usually 1 to 20 atmospheres, preferably 1 to 3 atmospheres.
  • a Microwave synthesizer such as an initiator manufactured by Biotage may be used.
  • the reaction temperature may vary depending on the reagent and solvent to be used, but unless otherwise specified, is usually room temperature to 300 ° C., preferably 50 ° C. to 250 ° C.
  • the reaction time may vary depending on the reagent and solvent to be used, but unless otherwise specified, is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.
  • the reagent is used in an amount of 0.5 equivalent to 20 equivalents, preferably 0.8 equivalent to 5 equivalents, relative to the substrate.
  • the reagent is used in an amount of 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate.
  • the reagent also serves as a reaction solvent, the amount of solvent is used as the reagent.
  • these reactions are performed without solvent or dissolved or suspended in a suitable solvent.
  • the solvent include the solvents described in the examples or the following.
  • Alcohols methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc .
  • Ethers diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc .
  • Aromatic hydrocarbons chlorobenzene, toluene, xylene, etc .
  • Saturated hydrocarbons cyclohexane, hexane, etc .
  • Amides N, N-dimethylformamide, N-methylpyrrolidone, etc .
  • Halogenated hydrocarbons dichloromethane, carbon tetrachloride, etc .
  • Nitriles acetonitrile, etc.
  • Sulfoxides dimethyl sulfoxide and the like; Aromatic organic bases: pyridine, etc .; Acid anhydrides: acetic anhydride, etc .; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc .; Inorganic acids: hydrochloric acid, sulfuric acid, etc .; Esters: ethyl acetate and the like; Ketones: acetone, methyl ethyl ketone, etc .; water. Two or more of the above solvents may be mixed and used at an appropriate ratio.
  • Inorganic bases sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, etc .
  • Organic bases triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0]- 7-undecene, imidazole, piperidine and the like;
  • Metal alkoxides sodium ethoxide, potassium tert-butoxide and the like;
  • Alkali metal hydrides sodium hydride, etc .;
  • Metal amides sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc .
  • Organic lithiums n-butyllithium and the like.
  • an acid or an acidic catalyst is used in the reaction in each step, for example, the following acids and acidic catalysts, or acids and acidic catalysts described in the examples are used.
  • Inorganic acids hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc .
  • Organic acids acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc .
  • Lewis acid boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride and the like.
  • reaction in each step is a method known per se, for example, the 5th edition Experimental Chemistry Course, Volumes 13 to 19 (Edited by The Chemical Society of Japan); New Experimental Chemistry Course, Volumes 14 to 15 (Japan) Chemistry Association); Fine Organic Chemistry Revised 2nd Edition (LF Tietze, Th. Eicher, Nanedo); Revised Organic Name Reaction, its mechanism and points (by Hideo Togo, Kodansha); ORGANIC SYNTHES Collective Volume I-VII ( John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Expert Procedures (by Jie JackORD, OX) NIVERSITY publication); Comprehensive Heterocyclic Chemistry III, Vol. 1 to Vol.
  • the protection or deprotection reaction of the functional group is carried out according to a method known per se, for example, “Protective Groups in Organic Synthesis, 4th Ed.” (Theodora W. Greene, Peter G. M., et al., Wiley-Interscience). The method described in Thimeme's 2004 “Protecting Groups 3rd Ed.” (By PJ Kocienski) or the like, or the method described in the examples.
  • protecting groups for hydroxyl groups such as alcohol and phenolic hydroxyl groups
  • ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether and tetrahydropyranyl ether
  • carboxylate-type protecting groups such as acetate Sulfonic acid ester type protecting groups such as methanesulfonic acid ester
  • carbonate ester type protecting groups such as tert-butyl carbonate.
  • the protecting group for the carbonyl group of the aldehyde include an acetal-type protecting group such as dimethylacetal; and a cyclic acetal-type protecting group such as 1,3-dioxane.
  • Examples of the protecting group for the carbonyl group of the ketone include a ketal-type protecting group such as dimethyl ketal; a cyclic ketal-type protecting group such as 1,3-dioxane; an oxime-type protecting group such as O-methyloxime; and N, N-dimethyl And hydrazone-type protecting groups such as hydrazone.
  • Examples of the protecting group for carboxyl group include ester-type protecting groups such as methyl ester; amide-type protecting groups such as N, N-dimethylamide.
  • thiol-protecting group examples include ether-type protecting groups such as benzylthioether; ester-type protecting groups such as thioacetate ester, thiocarbonate, and thiocarbamate.
  • protecting groups for amino groups and aromatic heterocycles such as imidazole, pyrrole and indole include carbamate-type protecting groups such as benzylcarbamate; amide-type protecting groups such as acetamide; alkylamines such as N-triphenylmethylamine Type protecting groups, and sulfonamide type protecting groups such as methanesulfonamide.
  • the protecting group can be removed by a method known per se, for example, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (for example, trimethylsilyl iodide). And trimethylsilyl bromide) or a reduction method.
  • a method known per se for example, acid, base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (for example, trimethylsilyl iodide). And trimethylsilyl bromide) or a reduction method.
  • the reducing agent used is lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride
  • Metal hydrides such as hydrogenated triacetoxyboron tetramethylammonium; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid;
  • a catalyst such as palladium-carbon or a Lindlar catalyst.
  • the oxidizing agent used includes peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, tert-butyl hydroperoxide; tetrabutylammonium perchlorate, etc.
  • mCPBA m-chloroperbenzoic acid
  • hydrogen peroxide hydrogen peroxide
  • tert-butyl hydroperoxide hydrogen peroxide
  • tetrabutylammonium perchlorate etc.
  • Perchlorates Chlorates such as sodium chlorate; Chlorites such as sodium chlorite; Periodates such as sodium periodate; High-valent iodine reagents such as iodosylbenzene; Manganese dioxide; Reagents having manganese such as potassium permanganate; Leads such as lead tetraacetate; Reagents having chromium such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagent; N-bromosuccinimide (NBS) ), Etc .; oxygen; ozone; sulfur trioxide / pyridine complex; Of osmium; like 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ); selenium dioxide.
  • PCC pyridinium chlorochromate
  • PDC pyridinium dichromate
  • NBS N-bromosuccinimide
  • Etc Etc .
  • the radical initiator used is an azo compound such as azobisisobutyronitrile (AIBN); 4-4′-azobis-4-cyanopentanoic acid (ACPA) Water-soluble radical initiators such as triethylboron in the presence of air or oxygen, and benzoyl peroxide.
  • AIBN azobisisobutyronitrile
  • ACPA 4-4′-azobis-4-cyanopentanoic acid
  • Water-soluble radical initiators such as triethylboron in the presence of air or oxygen, and benzoyl peroxide.
  • the radical reaction reagent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, and samarium iodide.
  • Examples of Wittig reagents used include alkylidene phosphoranes.
  • the alkylidene phosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.
  • the reagents used include phosphonoacetate esters such as methyl dimethylphosphonoacetate and ethyl ethyl diethylphosphonoacetate; bases such as alkali metal hydrides and organolithiums Can be mentioned.
  • a reagent used includes a combination of a Lewis acid and an acid chloride, or a Lewis acid and an alkylating agent (eg, alkyl halides, alcohols, olefins, etc.).
  • a Lewis acid and an acid chloride or a Lewis acid and an alkylating agent (eg, alkyl halides, alcohols, olefins, etc.).
  • an organic acid or an inorganic acid can be used in place of the Lewis acid
  • an acid anhydride such as acetic anhydride can be used in place of the acid chloride.
  • a nucleophile eg, amines, imidazole, etc.
  • a base eg, organic bases, etc.
  • a nucleophilic addition reaction with a carbanion In each step, a nucleophilic addition reaction with a carbanion, a nucleophilic 1,4-addition reaction with a carbanion (Michael addition reaction), or a nucleophilic substitution reaction with a carbanion, a base used to generate a carbanion Examples thereof include organic lithiums, metal alkoxides, inorganic bases, and organic bases.
  • examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide; alkylmagnesium halides such as methylmagnesium bromide.
  • the Grignard reagent can be prepared by a method known per se, for example, by reacting alkyl halide or aryl halide with metal magnesium using ether or tetrahydrofuran as a solvent.
  • reagents include an active methylene compound (eg, malonic acid, diethyl malonate, malononitrile, etc.) sandwiched between two electron-withdrawing groups and a base (eg, organic bases, Metal alkoxides and inorganic bases) are used.
  • active methylene compound eg, malonic acid, diethyl malonate, malononitrile, etc.
  • a base eg, organic bases, Metal alkoxides and inorganic bases
  • phosphoryl chloride and an amide derivative eg, N, N-dimethylformamide, etc.
  • examples of the azidation agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, and sodium azide.
  • DPPA diphenylphosphoryl azide
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
  • examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid and the like.
  • examples of the carbonyl compound used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone.
  • examples of amines used include primary amines such as ammonia and methylamine; secondary amines such as dimethylamine and the like.
  • azodicarboxylic acid esters eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.
  • triphenylphosphine eg, triphenylphosphine
  • the reagents used include acyl halides such as acid chloride and acid bromide; acid anhydrides, active ester compounds, and sulfate ester compounds. And activated carboxylic acids.
  • carboxylic acid activators include carbodiimide condensing agents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD); 4- (4,6-dimethoxy-1,3,5- Triazine condensing agents such as triazin-2-yl) -4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenyl Azide phosphate (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukayama reagent); thionyl chloride; haloformates such as ethyl chloroformate Lower alkyl; O- (7-azabenzotriazol-1-yl) -N, N, N ′, N
  • additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP) may be further added to the reaction.
  • HOBt 1-hydroxybenzotriazole
  • HOSu N-hydroxysuccinimide
  • DMAP dimethylaminopyridine
  • the metal catalyst used is palladium acetate (II), tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), dichlorobis (triethyl).
  • Palladium compounds such as phosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride; tetrakis (triphenylphosphine) nickel (0 Nickel compounds such as tris (triphenylphosphine) rhodium (III) chloride; cobalt compounds; copper compounds such as copper oxide and copper (I) iodide; platinum compounds and the like.
  • a base may be added to the reaction, and examples of such a base include inorganic bases.
  • diphosphorus pentasulfide is typically used as the thiocarbonylating agent.
  • 2,4-bis (4-methoxyphenyl) is used.
  • Reagents having 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure such as -1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson reagent) May be used.
  • halogenating agents used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. Is mentioned.
  • the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.
  • the halogenating agent used is an acid halide of hydrohalic acid and an inorganic acid.
  • bromination such as phosphorus chloride include 48% hydrobromic acid.
  • a method of obtaining an alkyl halide from alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide may be used.
  • a method of synthesizing an alkyl halide through a two-step reaction in which an alcohol is converted into a sulfonate ester and then reacted with lithium bromide, lithium chloride, or sodium iodide may be used.
  • examples of the reagent used include alkyl halides such as ethyl bromoacetate; phosphites such as triethyl phosphite and tri (isopropyl) phosphite.
  • examples of the sulfonylating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic acid anhydride, and p-toluenesulfonic acid anhydride.
  • each step when a hydrolysis reaction is performed, an acid or a base is used as a reagent.
  • acid hydrolysis reaction of tert-butyl ester is performed, formic acid or triethylsilane may be added to reductively trap tert-butyl cations produced as a by-product.
  • examples of the dehydrating agent used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N, N'-dicyclohexylcarbodiimide, alumina, and polyphosphoric acid.
  • Compound (I) can be produced from compound (2) by the following method.
  • R 5 represents an optionally substituted C 1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), and B 1 represents a boron group (eg, a boronic acid group) (—B (OH) 2 ), a boronic acid ester group (—B (OR ′) 2 ; R ′ represents a C 1-6 alkyl group) or a cyclic group thereof (eg, 4, 4, 5, 5- Tetramethyl-1,3,2-dioxaborolan-2-yl, etc.), Y 1 is a leaving group (eg, halogen atom such as chlorine, bromine, iodine, sulfonyloxy group, or boronic acid group (—B (OH)) 2 )) and the other symbols are as defined above.
  • B 1 represents a boron group (eg, a boronic acid group) (—B (OH) 2 ), a
  • an optionally halogenated C 1-6 alkylsulfonyloxy group for example, methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.
  • a C 6-14 arylsulfonyloxy group [eg, C 1-6 alkyl group (eg, methyl, etc.), C 1-6 alkoxy group (eg, methoxy, etc.) and a substituent selected from 1 to 3 C 6-14 arylsulfonyloxy group and the like which may be present, and examples thereof include benzenesulfonyloxy, m-nitrobenzenesulfonyloxy, p-toluenesulfonyloxy, naphthylsulfonyloxy and the like.
  • the compound (6-1) When the group —X—Y—R 4 in the compound (6-1) is a protecting group, the compound (6-1) may be subjected to a deprotection reaction to be derivatized into the compound (7).
  • a compound (6-2) into which a group —X—Y—R 4 different from the above-described protecting group is introduced may be obtained by a hydration reaction, a ureaization reaction, or a carbamate reaction. Further, it may be derived to the compound (6-3) into which the group -XYR 4 -Y 1 having the leaving group Y 1 has been introduced by the amidation reaction, urea reaction or carbamate reaction. Thereafter, the compound (6-2) may be obtained by a coupling reaction.
  • the raw material compound and / or production intermediate of compound (I) may form a salt, and is not particularly limited as long as the reaction is achieved.
  • a salt that compound (I) or the like may form The same salt or the like is used.
  • the configurational isomer (E, Z form) of compound (I) can be isolated and purified by usual separation means such as extraction, recrystallization, distillation, chromatography, etc., when isomerization occurs. Pure compounds can be produced.
  • the corresponding pure isomer can also be obtained by proceeding with isomerization of the double bond by an acid catalyst, a transition metal complex, a metal catalyst, a radical species catalyst, light irradiation or a strong base catalyst.
  • the compound (I) may have a stereoisomer depending on the kind of the substituent, and this isomer alone or a mixture thereof is also included in the present invention.
  • Compound (I) may be a hydrate or non-hydrate.
  • deprotection reaction, acylation reaction, alkylation reaction, hydrogenation reaction, oxidation reaction, reduction reaction, carbon chain extension reaction, halogenation reaction, substituent exchange reaction, coupling reaction Compound (I) can be synthesized by carrying out a nucleophilic addition reaction with a carbanion, a Grignard reaction, and a deoxygenating fluorination reaction alone or in combination of two or more thereof.
  • the desired product When the desired product is obtained in the free state by the above reaction, it may be converted into a salt according to a conventional method. When it is obtained as a salt, it is converted into a free form or other salt according to a conventional method. You can also.
  • the compound (I) thus obtained can be isolated and purified from the reaction solution by known means such as phase transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography and the like.
  • compound (I) exists as a configurational isomer (configuration isomer), diastereomer, conformer or the like, each can be isolated by the separation and purification means as desired.
  • the compound (I) when the compound (I) is a racemate, it can be separated into a d-form and an l-form by ordinary optical resolution means.
  • reaction mixture obtained by a method known per se, such as extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, It can be isolated and purified by using means such as layer chromatography, preparative high performance liquid chromatography (preparative HPLC), medium pressure preparative liquid chromatography (medium pressure preparative LC) and the like.
  • Compound (I) which is a salt is in accordance with a method known per se, for example, when compound (I) is a basic compound, by adding an inorganic acid or an organic acid, or compound (I) is an acidic compound In some cases, it can be prepared by adding an organic base or an inorganic base.
  • compound (I) may have optical isomers, any of these individual optical isomers and mixtures thereof are naturally included in the scope of the present invention. If desired, these isomers are known per se. According to the means, it can be optically divided or manufactured separately.
  • compound (I) exists as a configurational isomer (configuration isomer), diastereomer, conformer, etc., each can be isolated by the above-described separation and purification means, if desired.
  • the compound (I) is a racemate, it can be separated into an S form and an R form by an ordinary optical resolution means.
  • a stereoisomer exists in the compound (I), the case where this isomer is used alone or a mixture thereof is also included in the present invention.
  • Compound (I) may be a prodrug.
  • a prodrug is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, a compound that is enzymatically oxidized, reduced, hydrolyzed, etc., and converted to compound (I)
  • it refers to a compound that undergoes hydrolysis or the like due to gastric acid or the like and changes to compound (I).
  • Compound (I) prodrugs include compounds in which the amino group of compound (I) is acylated, alkylated and phosphorylated (for example, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated) , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compounds, etc.); Compounds wherein the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, borated (for example, the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated , Alanylated, dimethylaminomethylcarbonylated compounds,
  • Compound (I) or a prodrug thereof can have an excellent Nrf2 activation action in vivo and is used as a prophylactic or therapeutic agent for diseases involving oxidative stress. Can be useful.
  • the compound of the present invention has excellent pharmacokinetics (eg, oral absorption, blood half-life, intracerebral transfer, metabolic stability) and toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity) Can be expected to have a low drug interaction, carcinogenicity), as it is as a pharmaceutical, or as a pharmaceutical composition mixed with a pharmaceutically acceptable carrier or the like, a mammal (eg, human, monkey, cow, horse) , Pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, goats) and can be safely administered orally or parenterally.
  • a mammal eg, human, monkey, cow, horse
  • Parenter includes intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ophthalmic, intracerebral, intrarectal, intravaginal, intraperitoneal, intratumoral, proximal to tumor, etc. Includes direct lesion administration.
  • oxidative stress is involved, and diseases caused by oxidative stress, such as hepatic diseases (eg, hepatitis (eg, nonalcoholic steatohepatitis, fatty liver, alcoholic hepatitis) , Hepatitis B, hepatitis C), cirrhosis, acetaminophen-induced liver disease), cardiovascular disease (eg, heart failure, pulmonary arterial hypertension, myocardial infarction, arteriosclerosis, angina, cerebral infarction, cerebral hemorrhage, Aortic aneurysm, aortic dissection, nephrosclerosis (eg, hypertensive nephrosclerosis), obstructive arteriosclerosis), pulmonary disease (eg, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis, cystic fibrosis) , Asthma, pneumonia, aspiration pneumonia, interstitial hepatic diseases (eg, hepatitis (e
  • the compound of the present invention is based on Nrf2 activation action, and hepatitis (eg, non-alcoholic steatohepatitis (NASH)), cardiovascular disease (eg, heart failure or pulmonary arterial hypertension), lung disease (eg, chronic Obstructive pulmonary disease (COPD)), kidney disease (eg, chronic kidney disease (CKD) or acute kidney injury (AKI)), central nervous system disease (eg, Parkinson's disease), mitochondrial disease (eg, Friedreich ataxia) , Mitochondrial myopathy), autoimmune diseases (for example, multiple sclerosis), and the like.
  • NASH non-alcoholic steatohepatitis
  • COPD chronic Obstructive pulmonary disease
  • kidney disease eg, chronic kidney disease (CKD) or acute kidney injury (AKI)
  • central nervous system disease eg, Parkinson's disease
  • mitochondrial disease eg, Friedreich ataxia
  • Mitochondrial myopathy Mitochondrial myopathy
  • autoimmune diseases for example, multiple s
  • the dose of the compound of the present invention varies depending on the administration route, symptoms and the like. For example, when orally administered to a patient with hepatitis (adult, body weight 40 to 80 kg, eg 60 kg), for example, 0.001 to 1000 mg / kg body weight per day.
  • the daily dose is preferably 0.01 to 100 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight per day. This amount can be administered in 1 to 3 divided doses per day.
  • the medicament containing the compound of the present invention can be obtained by using the compound of the present invention alone or a pharmaceutically acceptable carrier according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia). Can be used as a pharmaceutical composition.
  • Examples of the medicament containing the compound of the present invention include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules) ), Lozenges, syrups, solutions, emulsions, suspensions, controlled-release preparations (eg, immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, film-forms (eg , Orally disintegrating film, oral mucosa adhesive film), injection (eg, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), infusion, transdermal preparation, ointment, lotion Preparations, patches, suppositories (eg, anal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc., orally or parenterally (eg, intravenous
  • the “pharmaceutically acceptable carrier” various organic or inorganic carriers commonly used as starting materials are used.
  • excipients in solid preparations, excipients, lubricants, binders and disintegrants are used, and in liquid preparations, solvents, solubilizers, suspending agents, isotonic agents, buffering agents, and the like Soothing agents and the like are used.
  • preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
  • the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light anhydrous silicic acid.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, and colloidal silica.
  • Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, and sodium carboxymethylcellulose.
  • Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, and L-hydroxypropyl cellulose.
  • Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.
  • suspending agent for example, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, for example, polyvinyl alcohol, polyvinylpyrrolidone
  • hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin and D-mannitol.
  • Examples of the buffer include phosphate, acetate, carbonate, citrate buffer.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the preservative include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, and sorbic acid.
  • Examples of the antioxidant include sulfite, ascorbic acid, and ⁇ -tocopherol.
  • the pharmaceutical composition varies depending on the dosage form, administration method, carrier and the like, but the compound of the present invention is usually 0.01 to 100% (w / w), preferably 0.1 to 95% (w / w) based on the total amount of the preparation. It can manufacture in accordance with a conventional method by adding in the ratio of w).
  • the compound of the present invention may be used in combination with other active ingredients (hereinafter abbreviated as concomitant drugs).
  • a compound or a salt thereof that can have a preventive and / or therapeutic effect on an oxidative stress disease can be appropriately mixed depending on the disease to be treated.
  • examples of compounds or salts thereof that can have preventive and / or therapeutic effects on oxidative stress diseases include cardiotonic drugs such as digoxin, ⁇ agonists such as dobutamine, ⁇ inhibitors such as carvedilol, nitroglycerin, prosta Vasodilators such as cyclin and riociguat, angiotensin converting enzyme inhibitors such as ramipril, angiotensin II receptor antagonists such as candesartan, diuretics such as hydrochlorothiazide and furosemide, calcium receptor antagonists such as amlodipine, and mineralocorticoids such as eplerenone Receptor antagonists, endothelin receptor antagonists such as bosentan, anticoagulants such as rivaroxaban, antiplatelet drugs such as clopid
  • the compound of the present invention By combining the compound of the present invention and a concomitant drug, (1) The dose can be reduced compared to the case where the compound of the present invention or the concomitant drug is administered alone. (2) A drug to be used in combination with the compound of the present invention can be selected according to the patient's symptoms (mild, severe, etc.), (3) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the treatment period can be set longer. (4) By selecting a concomitant drug having a different mechanism of action from the compound of the present invention, the therapeutic effect can be sustained. (5) By using the compound of the present invention and the concomitant drug in combination, an excellent effect such as a synergistic effect can be obtained.
  • the combination agent of the present invention the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention or the pharmaceutical composition thereof and the concomitant drug or the pharmaceutical composition thereof are simultaneously administered to the administration subject. Alternatively, administration may be performed with a time difference.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration mode of the concomitant drug of the present invention is not particularly limited as long as the compound of the present invention and the concomitant drug are combined at the time of administration.
  • Examples of such administration forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and (2) formulating the compound of the present invention and the concomitant drug separately.
  • the concomitant drug of the present invention has low toxicity.
  • the compound of the present invention or (and) the above concomitant drug is mixed with a pharmacologically acceptable carrier according to a known method, for example, a pharmaceutical composition such as a tablet (sugar-coated tablet, (Including film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release agents, etc., orally or parenterally (eg, topical, rectal, intravenous administration) ) Can be safely administered.
  • An injection can be administered intravenously, intramuscularly, subcutaneously, or into an organ, or directly to a lesion.
  • Examples of the pharmacologically acceptable carrier that may be used in the production of the concomitant drug of the present invention include various organic or inorganic carrier substances commonly used as a pharmaceutical material.
  • excipients lubricants, binders and disintegrants can be used.
  • solvents, solubilizers, suspending agents, tonicity agents, buffers, soothing agents, and the like can be used.
  • additives such as usual preservatives, antioxidants, colorants, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, and light anhydrous silicic acid.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, and colloidal silica.
  • Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, and sodium carboxymethylcellulose.
  • Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, and L-hydroxypropyl cellulose.
  • Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil.
  • examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, and sodium citrate.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; for example, polyvinyl alcohol, polyvinylpyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate
  • polyvinyl alcohol polyvinylpyrrolidone
  • hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose.
  • Examples of the isotonic agent include glucose, D-sorbitol, sodium chloride, glycerin and D-mannitol.
  • Examples of the buffer include phosphate, acetate, carbonate, citrate buffer.
  • Examples of soothing agents include benzyl alcohol.
  • Examples of the preservative include paraoxybenzoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, and sorbic acid.
  • Examples of the antioxidant include sulfite, ascorbic acid, and ⁇ -tocopherol.
  • the compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation, More preferably, it is about 0.5 to 20% by weight.
  • the content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the whole preparation. About 0.5 to 20% by weight.
  • the content of additives such as carriers in the combination agent of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. .
  • the same content may be used when the compound of the present invention and the concomitant drug are formulated separately.
  • room temperature usually indicates about 10 ° C. to about 35 ° C.
  • the ratio shown in the mixed solvent is a volume ratio unless otherwise specified.
  • % indicates “% by weight”.
  • Elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography) unless otherwise specified. In TLC observation, 60 F254 manufactured by Merck was used as a TLC plate, and a solvent used as an elution solvent in column chromatography was used as a developing solvent. A UV detector was used for detection.
  • silica gel column chromatography aminopropylsilane-bonded silica gel was used when NH was described, and 3- (2,3-dihydroxypropoxy) propylsilane-bonded silica gel was used when Diol was described.
  • HPLC high performance liquid chromatography
  • octadecyl-bonded silica gel was used. The ratio of elution solvent indicates a volume ratio unless otherwise specified.
  • a peak from which H 2 O is eliminated may be observed as a fragment ion.
  • a free molecular ion peak or a fragment ion peak is usually observed.
  • the unit of sample concentration (c) in optical rotation ([ ⁇ ] D ) is g / 100 mL.
  • the calculated value (Calcd) and the actual measurement value (Found) are described.
  • the powder X-ray diffraction pattern was measured using Rigaku Ultima IV Cu-K ⁇ characteristic X-rays and described characteristic peaks.
  • the reaction mixture was stirred at room temperature for 1 hour, and then the reaction solution was concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane), and ethyl 3- (1,4-dimethyl-1H-benzo [d] [1,2,3] triazol-5-yl) -3 -(2- (4-Propylbenzoyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) propanoate (3.35 g) was obtained.
  • Ethyl 3- (1-ethyl-4-methyl-1H-benzotriazol-5-yl) -3- (1,2,3,4-tetrahydroisoquinolin-7-yl) propanoate hydrochloride (150 mg) and THF ( 3 ml), TEA (0.146 ml) and 4-ethylbenzoyl chloride (88 mg) were added at 0 ° C., and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere.
  • the mixture was purified with NH silica gel (ethyl acetate), the obtained residue (184 mg) was dissolved in THF (1 ml) and MeOH (1 ml), 2M aqueous sodium hydroxide solution (1 ml) was added, and the mixture was stirred at room temperature. Stir for 1 hour. 1M hydrochloric acid was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by HPLC (L-Column 2 ODS, mobile phase: water / acetonitrile (containing 0.1% TFA)) to obtain the title compound (143 mg).
  • Methyl 4-bromo-1H-indazole-7-carboxylate Methyl 2-amino-4-bromo-3-methylbenzoate (1.80 g) and AcOH (20 ml) in a mixture of sodium nitrite (0.763 g) A water (4.00 ml) solution was added at 0 ° C. The mixture was stirred at room temperature for 1 hour. Water was added to the mixture and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example 170 3- (1,4-Dimethyl-1H-benzotriazol-5-yl) -3- (2- (4-ethylbenzoyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) propanoic acid (optical) Isomer, tR1) Racemic 3- (1,4-dimethyl-1H-benzotriazol-5-yl) -3- (2- (4-ethylbenzoyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) propanoic acid
  • SFC columnumn: CHIRALCEL ADH (trade name), 20 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile
  • Example 171 3- (1,4-Dimethyl-1H-benzotriazol-5-yl) -3- (2- (4-ethylbenzoyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) propanoic acid (optical) Isomer, tR2) Racemic 3- (1,4-dimethyl-1H-benzotriazol-5-yl) -3- (2- (4-ethylbenzoyl) -1,2,3,4-tetrahydroisoquinolin-7-yl) propanoic acid
  • SFC columnumn: CHIRALCEL ADH (trade name), 20 mmID x 250 mmL, manufactured by Daicel Chemical Industries, mobile
  • the mixture was stirred at 60 ° C. for 2 hours under a nitrogen atmosphere.
  • a saturated aqueous ammonium chloride solution was added to the mixture at room temperature, and the mixture was extracted twice with ethyl acetate.
  • the organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain an ester.
  • the obtained ester was dissolved in THF (2 ml), MeOH (1 ml), 2M aqueous sodium hydroxide solution (2 ml), and stirred at room temperature for 1 hour. Hydrochloric acid was added to the reaction solution and concentrated.
  • Methyl 4- (benzyloxy) -2- (2,2-dimethoxyethoxy) benzoate Methyl 4- (benzyloxy) -2-hydroxybenzoate (6.9 g) and 2-bromo-1,1-dimethoxyethane
  • a mixture of (6.32 ml), potassium carbonate (7.38 g) and DMF (44.5 ml) was stirred at 100 ° C. overnight. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Methyl 4-bromo-3-hydroxy-2- (2-hydroxyethyl) benzoate Methyl 2-allyl-4-bromo-3-hydroxybenzoate (1.5 g), THF (26 ml) and water (26 ml Sodium periodate (2.367 g) was added in portions at 0 ° C. After stirring at the same temperature for 5 minutes, osmium tetroxide (1 g) was added and stirred at 0 ° C. for 4 hours. The reaction solution was filtered, saturated brine was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Methyl 7-bromo-2,3-dihydro-1-benzofuran-4-carboxylate Methyl 4-bromo-3-hydroxy-2- (2-hydroxyethyl) benzoate (1.1 g) and triphenylphosphine (1.2 To a mixture of g) and toluene (20 ml) was added diisopropyl azodicarboxylate (40% toluene solution) (2.53 ml) at room temperature. The mixture was stirred at 50 ° C. for 1 hour under a nitrogen atmosphere.
  • the mixture was stirred at 90 ° C. for 16 hours under a nitrogen atmosphere.
  • the reaction mixture was cooled to room temperature and filtered through celite. Water was added to the filtrate and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (4.22 g) as a colorless oil.
  • Example 219 3- (1,4-Dimethyl-1H-benzotriazol-5-yl) -3- (2- (2-methyl-2-phenylpropanoyl) -2,3,4,5-tetrahydro-1H-2- Benzazepine-8-yl) propanoic acid ethyl 3- (1,4-dimethyl-1H-benzotriazol-5-yl) -3- (2,3,4,5-tetrahydro-1H-2-benzoazepine-8 2-Iyl-2-phenylpropanoyl chloride (85 mg) was added to a mixture of -yl) propanoate hydrochloride (100 mg), DIPEA (0.163 ml) and acetonitrile (2 ml) at room temperature and stirred overnight.
  • reaction solution was purified by silica gel column chromatography (ethyl acetate / hexane). A mixture of the obtained ester, 1M aqueous sodium hydroxide solution (4.00 ml), THF (4 ml) and MeOH (2 ml) was stirred at room temperature overnight. 1M hydrochloric acid was added to the reaction solution and concentrated. The precipitated solid was collected by filtration to give the title compound (222 mg).
  • reaction solution was purified by silica gel column chromatography (ethyl acetate / hexane). A mixture of the obtained ester, THF (2 ml), MeOH (2 ml) and 1M aqueous sodium hydroxide solution (2.00 ml) was stirred at room temperature for 1 hour. 1M hydrochloric acid was added to the reaction solution and concentrated. The precipitated crystals were collected by filtration to give the title compound (158 mg).
  • Example compounds are shown in Table 1-1 to Table 1-49 below. MS in the table indicates actual measurement. Examples 2 to 24, 27 to 116, 119 to 130, 132 to 142, 144 to 154, 157, 158, 160 to 168 in the following table are prepared according to the methods shown in the above examples or a method analogous thereto. 172, 173, 175 to 179, 182, 184 to 186, 188 to 190, 193 to 199, 201 to 210, 212 to 216, 218, 220 to 232 mm.
  • reaction solution B 4-Bromo-6-iodo-N, 3-dimethyl-2-nitroaniline 4-Bromo-N, 3-dimethyl-2-nitroaniline (300 g) in acetic acid (1.5 L) solution -Iodosuccinimide (386 g) was added at room temperature. The reaction solution was stirred at 70-75 ° C. for 1.5 hours to obtain a reaction solution A. Similarly, N-iodosuccinimide (386 g) was slowly added to a solution of 4-bromo-N, 3-dimethyl-2-nitroaniline (300 g) in acetic acid (1.5 L) at room temperature. The reaction solution was stirred at 70-75 ° C. for 1.5 hours to obtain a reaction solution B.
  • Reaction liquids A and B were added to ice water (5 L) and extracted with ethyl acetate. The organic layer was separated, washed with a saturated aqueous sodium carbonate solution, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (433 g).
  • reaction solution B was stirred at 50-55 ° C. for 1 hour to obtain a reaction solution B.
  • the reaction solutions A and B were filtered, and the filtrate was diluted with ethyl acetate, washed with a saturated aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain an aniline derivative (352 g).
  • the reaction mixture was diluted with ethyl acetate and washed with 10% aqueous sodium hydrogen carbonate solution, and the organic layer was separated and concentrated.
  • the crude product was dissolved in a mixed solvent of EtOH (0.5 ml) and THF (0.5 ml), 2M aqueous sodium hydroxide solution (0.5 ml) was added, and the mixture was stirred at room temperature for 2 hr.
  • the mixture was neutralized with 2M aqueous hydrochloric acid (0.5 ml) and concentrated.
  • the crude product was purified by preparative HPLC using acetonitrile / water containing 0.1% TFA as an eluent to obtain the title compound (20 mg).
  • Example 236 3- (2- (2-Ethyl-4-methyl-1,3-thiazol-5-carbonyl) -3,4-dihydro-1H-isoquinolin-7-yl) -3- (7-methoxy-1,4 -Dimethylbenzotriazol-5-yl) propanoic acid ethyl 3- (7-methoxy-1,4-dimethyl-1H-benzotriazol-5-yl) -3- (1,2,3,4-tetrahydroisoquinoline-7 -Yl) propanoate hydrochloride (33 mg), 2-ethyl-4-methyl-1,3-thiazole-5-carboxylic acid (17 mg), TEA (20 mg), and 1-hydroxy-1H-benzotriazole ( To a 14 mg) DMF solution (1 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (16 mg) was added and stirred at room temperature for 15 hours.
  • the reaction mixture was diluted with ethyl acetate and washed with 10% aqueous sodium hydrogen carbonate solution, and the organic layer was separated and concentrated.
  • the crude product was dissolved in a mixed solvent of EtOH (0.5 ml) and THF (0.5 ml), 2M aqueous sodium hydroxide solution (0.5 ml) was added, and the mixture was stirred at room temperature for 2 hr.
  • the mixture was neutralized with 2M aqueous hydrochloric acid (0.5 ml) and concentrated.
  • the crude product was purified by preparative HPLC using acetonitrile / water containing 0.1% TFA as an eluent to obtain the title compound (16.9 mg).
  • Example 237 3- (2- (6-Ethyl-2-methylpyridine-3-carbonyl) -3,4-dihydro-1H-isoquinolin-7-yl) -3- (7-methoxy-1,4-dimethylbenzotriazole- 5-yl) propanoic acid trifluoroacetate ethyl 3- (7-methoxy-1,4-dimethyl-1H-benzotriazol-5-yl) -3- (1,2,3,4-tetrahydroisoquinoline-7- Yl) propanoate hydrochloride (33 mg), 6-ethyl-2-methylpyridine-3-carboxylic acid (17 mg), TEA (20 mg), and 1-hydroxy-1H-benzotriazole (14 mg) in DMF 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide (16 mg) was added to (1 ml) and stirred at room temperature for 15 hours.
  • the reaction mixture was diluted with ethyl acetate and washed with 10% aqueous sodium hydrogen carbonate solution, and the organic layer was separated and concentrated.
  • the crude product was dissolved in a mixed solvent of EtOH (0.5 ml) and THF (0.5 ml), 2M aqueous sodium hydroxide solution (0.5 ml) was added, and the mixture was stirred at room temperature for 2 hr.
  • the mixture was neutralized with 2M aqueous hydrochloric acid (0.5 ml) and concentrated.
  • the crude product was purified by preparative HPLC using acetonitrile / water containing 0.1% TFA as an eluent to obtain the title compound (15 mg).
  • Example 238 (2- (1-Ethyl-5-fluoro-3-methylpyrazole-4-carbonyl) -3,4-dihydro-1H-isoquinolin-7-yl) -3- (7-methoxy-1,4- Dimethylbenzotriazol-5-yl) propanoic acid ethyl 3- (7-methoxy-1,4-dimethyl-1H-benzotriazol-5-yl) -3- (1,2,3,4-tetrahydroisoquinoline-7- Yl) propanoate hydrochloride (33 mg), 1-ethyl-5-fluoro-3-methylpyrazole-4-carboxylic acid (18 mg), TEA (20 mg), and 1-hydroxy-1H-benzotriazole (14 mg) 1) -DMF solution (1 ml) was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (16 mg) and stirred at room temperature for 15 hours.
  • the reaction mixture was diluted with ethyl acetate and washed with 10% aqueous sodium hydrogen carbonate solution, and the organic layer was separated and concentrated.
  • the crude product was dissolved in a mixed solvent of EtOH (0.5 ml) and THF (0.5 ml), 2M aqueous sodium hydroxide solution (0.5 ml) was added, and the mixture was stirred at room temperature for 2 hr.
  • the mixture was neutralized with 2M aqueous hydrochloric acid (0.5 ml) and concentrated.
  • the crude product was purified by preparative HPLC using acetonitrile / water containing 0.1% TFA as an eluent to obtain the title compound (13 mg).
  • Example 244 3- (2- (2,6-Difluoro-4-methoxybenzoyl) -3,4-dihydro-1H-isoquinolin-7-yl) -3- (7-methoxy-1,4-dimethylbenzotriazole-5- Yl) ethyl propanoate 3- (7-methoxy-1,4-dimethyl-1H-benzotriazol-5-yl) -3- (1,2,3,4-tetrahydroisoquinolin-7-yl) propanoate hydrochloride ( 33 mg), 2,6-difluoro-4-methoxybenzoic acid (17 mg), TEA (20 mg), and 1-hydroxy-1H-benzotriazole (14 mg) in 1 ml DMF solution (1 ml) -3- (3-Dimethylaminopropyl) carbodiimide (16 mg) was added and stirred at room temperature for 15 hours.
  • the reaction mixture was diluted with ethyl acetate and washed with 10% aqueous sodium hydrogen carbonate solution, and the organic layer was separated and concentrated.
  • the crude product was dissolved in a mixed solvent of EtOH (0.5 ml) and THF (0.5 ml), 2M aqueous sodium hydroxide solution (0.5 ml) was added, and the mixture was stirred at room temperature for 2 hr. The mixture was neutralized with 2M aqueous hydrochloric acid and concentrated.
  • the crude product was purified by preparative HPLC using acetonitrile / water containing 0.1% TFA as an eluent to obtain the title compound (13 mg) as a colorless solid.
  • Example compounds are shown in Tables 2-1 to 2-5 below. MS in the table indicates actual measurement. The compounds of Examples 239 to 243 and 245 to 258 in the following table were produced according to the method shown in Example 235 or a method analogous thereto.
  • Example compounds are shown in Table 2-6 below.
  • the compounds of Examples 259 to 262 in the table below can be produced according to the method shown in Example 235 or a method analogous thereto.
  • Test Example 1 Measurement of Nrf2-Keap1 binding inhibitory activity The inhibitory activity of a test compound against the binding between Nrf2 and Keap1 was measured by a time-resolved fluorescence Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET) method.
  • TR-FRET Time Resolved Fluorescence Resonance Energy Transfer
  • Keap1 protein 2 ⁇ L of compound diluted in assay buffer (25 mM HEPES, pH 7.5, 150 mM NaCl, 0.01% Tween-20) 2 nM biotinylated human Keap1 protein (Kelch domain) 2 ⁇ L, 14 nM TAMRA labeled Nrf2 peptide (TAMRA) -Abu (4) -VWYTDIRMRDWM-OH) 2 ⁇ L and 2 nM Tb-labeled streptavidin 2 ⁇ L were added. Some wells were used as control wells without the addition of Keap1 protein.
  • Test Example 2 Effect of Compound on Rat Kidney Gene The amount of mRNA expression in the kidney of Nqo1 gene as an Nrf2 target gene was examined.
  • the compound was prepared in a suspension of 0.5% methylcellulose (MC, METOLOSE, Shin-Etsu Chemical Co., Ltd.) and was orally administered to male SD rats (Claire Japan) at a volume of 5 mL / kg. 17 hours after administration, the animals were euthanized under anesthesia and the kidneys were sampled.
  • Total RNA was extracted from collected kidneys using an extraction kit QIAsymphony RNA kit (Qiagen, catalog number 931636).
  • CNDA was prepared from the obtained total RNA using a cDNA synthesis kit SuperScript IV VILO Master Mix (Thermo Fisher, catalog number 11754-250).
  • the obtained cDNA was subjected to real-time quantitative PCR using Taqman Fast Advanced Master Mix (Applied Biosystems, Catalog No. 1609101) and the primers and probes shown below, and 7900HT Fast Real-Time PCR Systems (Applied Biosystems) ).
  • Table 4 shows the changes when the mRNA expression level of Nqo1 in the kidney of a rat administered with 0.5% MC aqueous solution as a vehicle is 1.
  • Formulation Example A pharmaceutical containing the compound of the present invention as an active ingredient can be produced, for example, according to the following formulation.
  • Tablet (1) 10 mg of the compound obtained in Example 1 (2) Lactose 35mg (3) Corn starch 150mg (4) Microcrystalline cellulose 30mg (5) Magnesium stearate 5mg 1 tablet 230mg The total amount of (1), (2) and (3) above was mixed with 20 mg of (4) and 2.5 mg of (5), and then granulated, and the remaining (4) was added to 10 mg and (5) in this granule. Of 2.5 mg and pressure-molded to obtain tablets.
  • diseases having an excellent Nrf2 activation action and involving oxidative stress particularly hepatitis (eg, non-alcoholic steatohepatitis (NASH)), cardiovascular disease (eg, heart failure or pulmonary artery) Hypertension), lung disease (eg, chronic obstructive pulmonary disease (COPD)), kidney disease (eg, chronic kidney disease (CKD) or acute kidney injury (AKI)), central nervous system disease (eg, Parkinson's disease)
  • hepatitis eg, non-alcoholic steatohepatitis (NASH)
  • cardiovascular disease eg, heart failure or pulmonary artery
  • lung disease eg, chronic obstructive pulmonary disease (COPD)
  • kidney disease eg, chronic kidney disease (CKD) or acute kidney injury (AKI)
  • central nervous system disease eg, Parkinson's disease
  • mitochondrial diseases eg, Friedreich's ataxia, mitochondrial myopathy
  • autoimmune diseases eg, multiple sclerosis

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Abstract

L'invention concerne un composé qui a une activité d'activation de Nrf2 et qui est supposé être utile en tant qu'agent prophylactique ou thérapeutique pour des maladies associées au stress oxydatif, en particulier l'hépatite (par exemple, la stéatohépatite non alcoolique (NASH)), des maladies cardiovasculaires (par exemple, une insuffisance cardiaque ou une hypertension artérielle pulmonaire), des maladies pulmonaires (par exemple, une maladie pulmonaire obstructive chronique (COPD)), des maladies rénales (par exemple, une maladie rénale chronique (CKD) ou une lésion rénale aiguë (AKI)), des maladies du système nerveux central (par exemple, la maladie de Parkinson), des maladies mitochondriales (par exemple l'ataxie de Friedreich, la myopathie mitochondriale), des maladies auto-immunes (par exemple, la sclérose en plaques) et analogues. La présente invention concerne un composé représenté par la formule (I) [dans laquelle chaque symbole est tel que défini dans la description] ou un sel de celui-ci.
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US11427601B1 (en) 2018-08-20 2022-08-30 Janssen Pharmaceutica Nv Inhibitors of KEAP1-Nrf2 protein-protein interaction
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RU2798235C9 (ru) * 2018-12-05 2023-09-20 Скохиа Фарма, Инк. Макроциклическое соединение и его применение
JP2022510736A (ja) * 2018-12-05 2022-01-27 株式会社スコヒアファーマ 大環状化合物とその使用
WO2020116660A1 (fr) * 2018-12-05 2020-06-11 Scohia Pharma, Inc. Composé macrocyclique et son utilisation
RU2798235C2 (ru) * 2018-12-05 2023-06-19 Скохиа Фарма, Инк. Макроциклическое соединение и его применение
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WO2020241853A1 (fr) 2019-05-31 2020-12-03 宇部興産株式会社 Dérivé de benzotriazole
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