WO2013051632A1 - Composé hétérocyclique fusionné contenant de l'azote - Google Patents

Composé hétérocyclique fusionné contenant de l'azote Download PDF

Info

Publication number
WO2013051632A1
WO2013051632A1 PCT/JP2012/075721 JP2012075721W WO2013051632A1 WO 2013051632 A1 WO2013051632 A1 WO 2013051632A1 JP 2012075721 W JP2012075721 W JP 2012075721W WO 2013051632 A1 WO2013051632 A1 WO 2013051632A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
optionally substituted
alkoxy
hydroxy
Prior art date
Application number
PCT/JP2012/075721
Other languages
English (en)
Japanese (ja)
Inventor
祐介 冨成
宏司 小野
重充 松本
泰祐 加藤
淳 蓮岡
今村　真一
Original Assignee
武田薬品工業株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 武田薬品工業株式会社 filed Critical 武田薬品工業株式会社
Publication of WO2013051632A1 publication Critical patent/WO2013051632A1/fr

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/32—Antioestrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D403/14—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 three or more hetero rings
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present invention has an excellent activity as an estrogen-related receptor alpha [Estrogen Related Receptor- ⁇ (in this specification, sometimes abbreviated as ERR ⁇ )] modulator, and a malignant tumor (eg, breast cancer, malignant lymphoma,
  • ERR ⁇ Estrogen Related Receptor- ⁇
  • a malignant tumor eg, breast cancer, malignant lymphoma
  • the present invention relates to a novel compound useful as a preventive or therapeutic agent for ERR ⁇ -related diseases such as multiple myeloma, prostate cancer, colon cancer, lung cancer, ovarian cancer, endometrial cancer).
  • Nuclear receptors are transcriptional regulators that regulate gene expression in a ligand-dependent manner in response to various stimuli such as physiological factors such as development and differentiation, or environmental factors. Form. These include classical nuclear receptors such as estrogen receptor (ER) with estrogen as a ligand, and orphan nuclear receptors whose ligands and physiological functions are unknown.
  • ER estrogen receptor
  • Estrogen-related receptor alpha belongs to the estrogen-related receptor subfamily (ERR subfamily) which is an orphan nuclear receptor closely related to ER. Other members of the ERR subfamily have been identified as ERR ⁇ and ERR ⁇ , all of which have high homology with ER in the DNA binding domain. The ER and ERR subfamilies are known to share target genes such as estrogen responsive genes.
  • Non-Patent Documents 1 to 4 Non-Patent Documents 1 to 4.
  • compounds that can modulate the activity of ERR ⁇ are directed against both ERR ⁇ and ER-related diseases by directly modulating the transcriptional effects of ERR ⁇ or by indirect effects on the ER signaling pathway. Can have a therapeutic effect.
  • ERR ⁇ modulators are found in various disease states (eg, cancer such as breast cancer, diabetes, hyperlipidemia, obesity, metabolic syndrome, arthritis, atherosclerosis, rheumatoid arthritis, atopic) It is expected to be useful in the treatment or prevention of dermatitis, osteoporosis, anxiety, depression, Parkinson's disease, Alzheimer's disease, etc. (Patent Documents 1, 2, Non-Patent Document 5).
  • cancer such as breast cancer
  • diabetes hyperlipidemia
  • obesity metabolic syndrome
  • arthritis atherosclerosis
  • rheumatoid arthritis atopic
  • Non-patent Documents 6 and 7 Recently, it has been reported that siRNA and low molecular weight compounds having ERR ⁇ inhibitory activity can provide good antitumor effects against estrogen receptor positive and negative breast cancer in a mouse model.
  • Patent Document 3 International Publication No. 2011/016501 includes a formula:
  • R 1 , R 2 and R 3 are each independently a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, an acyl group, or a substituent.
  • Y is —O—, —S— or —NR a — (wherein R a is a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic ring; A hydroxyl group that may be substituted with a group, an acyl group, or an optionally substituted alkyl group.);
  • Z is ⁇ O, ⁇ S or ⁇ NR b (wherein R b is a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, acyl A hydroxyl group which may be substituted with a group or an alkyl group which may have a substituent.);
  • Z 1 represents —OR d , —SR d or —NHR d (wherein R d independently represents a hydrogen atom, a hydrocarbon group which may have a substituent, or a substituent. An optionally substituted heterocyclic group or an acyl group. ]
  • R 4 represents a hydrogen atom or an alkyl group which may have a substituent;
  • R 5 , R 6 , R 7 and R 8 each independently have a hydrogen atom, a hydrocarbon group which may have a substituent, an amino group which may have a substituent, or a substituent.
  • X is —O—, —CO—, —O—CO—, —CO—O—, —SO 2 —, —SO—, —S—, —SO 2 —O—, —NR c1 —, —CO —NR c1 —, —NR c1 —CO—, —NR c1 —CO—NR c2 —, —O —CO—NR c1 —, —NR c1 —CO—O—, —SO 2 —NR c1 —, —NR c1 —SO 2 — or —NR c1 —SO 2 —NR c2
  • Patent Document 4 International Publication No. 2010/001169 describes a formula useful for the treatment of PIM kinase-related conditions and diseases:
  • R 1 is selected from carbocyclyl, aryl, heterocyclyl, which may be substituted with one or more R 2 , and R 2 is selected from C 1-6 alkyl, etc. Has been.
  • Patent Document 5 International Publication No. 1998/033797 includes a formula:
  • R 1 represents a hydrogen atom, lower alkyl, optionally substituted aryl, aryl fused with a non-aromatic hydrocarbon ring or non-aromatic heterocycle, optionally substituted aralkyl, substituted.
  • Z represents —S—, —SO—, —O—, —OCH 2 —, —CONH—, —CONHCH 2 —, —N (R 16 )-(Wherein R 16 is a hydrogen atom, alkyl, or aralkyl), or a single bond;
  • X 1 is — (CH 2 ) q—CO— (wherein q is an integer of 0 to 3), — (CH 2 ) r—CO—N (R 17 ) — (wherein R 17 is a hydrogen atom or lower alkyl, r is an integer of 0 to 3), —CH 2 NHSO 2 —, — (CH 2 ) s —N ( R 18) -CO- (wherein, R 18 is a hydrogen atom Other lower alkyl, s is an integer of 0 to 3), - CH 2 NHCOCH 2 O -, - CH 2 N (R
  • R 2 and R 3 are both a hydrogen atom, or an aryl optionally substituted on one side, an optionally substituted heteroaryl, or an optionally substituted cycloalkyl, the other being a hydrogen atom or lower alkyl;
  • R 4 , R 5 , G ring, J ring, and L ring are each independently an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted cycloalkyl, or cycloalkenyl;
  • a broken line (---) represents the presence or absence of a bond;
  • p represents an integer of 0 to 2), and a broken line (---) represents the presence or absence of a bond;
  • a wavy line ( ⁇ ) indicates that D is in a cis or trans relationship with E] (provided that when the bond between the carbon atom adjacent to D and the ring carbon atom is a single bond) , 1 is an alkylene, X 2 and X 3 is a single bond, X
  • Patent Document 6 International Publication No. 2010/036380 describes a formula useful as a kinase inhibitor:
  • X 5 and X 6 are CR 6 , N, CL 1 -R 1 or NL 1 -R 1 ; X 1 is C or N; X 2 and X 8 are independently N or CR 6 ; X 3 and X 7 are C or N; X 4 in formula IA or IC is C or N; X 4 in formula IB or ID is CR 6 , NH or N; R 1 is hydrogen L 1 is a bond, etc .; R 2 and R 3 are independently hydrogen, etc .; R 4 and R 5 are independently hydrogen, etc .; L is —NH—CR 7 R 8 —, -(CR 7 R 8 ) z-, -CO-, -CR 7 R 8 (CO)-, -O-, -SO- or -SO 2- ; z is an integer from 0 to 10; R 6 is R 7 and R 8 independently represent hydrogen or the like; R 9 represents hydrogen or the like; W represents CR 6 or N].
  • Patent Document 7 International Publication No. 2009/088986 describes a formula useful for the treatment of diseases and symptoms related to PI3 (phosphatidyl inositol 3) kinase activity:
  • Wd represents heterocycloalkyl, aryl or heteroaryl;
  • B represents the formula:
  • Wc is aryl, heteroaryl, heterocycloalkyl or cycloalkyl; q is an integer from 0 to 4; X is absent or — (CH (R 9 )) z—; z Is 1; Y is absent or —N (R 9 ) —; R 1 is hydrogen etc .; R 2 is alkyl etc .; R 3 is hydrogen etc; R 5 , R 6 , R 7 and R 8 independently represents hydrogen or the like; R 9 represents hydrogen or the like. The compound represented by this is described.
  • Patent Document 8 International Publication No. 2009/088990 has a formula useful for the treatment of diseases and symptoms related to PI3 (phosphatidyl inositol 3) kinase activity:
  • the compound represented by this is described.
  • Patent Document 9 (US Patent Application Publication No. 2009/0312319) includes a formula useful for the treatment of diseases and symptoms related to PI3 (phosphatidyl inositol 3) kinase activity:
  • Wd is heterocycloalkyl, aryl or heteroaryl
  • B is alkyl or the like
  • X is absent or — (CH (R 9 )) z—; z is 1
  • Y is absent , -N (R 9 )-;
  • R 1 represents hydrogen or the like;
  • R 3 represents hydrogen or the like;
  • R 5 , R 6 , R 7 and R 8 independently represent hydrogen or the like;
  • R 9 represents hydrogen or the like; Show. The compound represented by this is described.
  • Patent Document 10 International Publication No. 2011/077555 describes a formula:
  • X represents —CH— or N;
  • R 1 represents an optionally substituted hydrocarbon group or the like;
  • R 2 represents a hydrogen atom or an optionally substituted hydrocarbon group or the like;
  • R 3 represents hydrogen Atoms or hydrocarbon groups, etc .;
  • Patent Document 11 International Publication No. 2011/103130 includes a formula:
  • X represents —CH— or N
  • R 1 , R 4 and R 5 represent an optionally substituted hydrocarbon group, etc .
  • R 2 represents a hydrogen atom or an optionally substituted hydrocarbon group, etc.
  • R 3 represents a hydrogen atom or a hydrocarbon group. The compound represented by this is described.
  • Patent Document 12 International Publication No. 2011/103134 describes a formula:
  • X represents —CH— or N; R 1 and R 4 represent an optionally substituted hydrocarbon group, etc .; R 2 represents a hydrogen atom or an optionally substituted hydrocarbon group, etc .; R 3 represents a hydrogen atom or a hydrocarbon group.
  • X represents —CH— or N; R 1 and R 4 represent an optionally substituted hydrocarbon group, etc .; R 2 represents a hydrogen atom or an optionally substituted hydrocarbon group, etc .; R 3 represents a hydrogen atom or a hydrocarbon group.
  • Patent Document 13 International Publication No. 2011/149841 includes a formula:
  • X is N or CR 4 ; Y is N or CH; however, when Y is CH, X is CH; L is a bond or an optionally substituted hydrocarbon group, etc .; R 1 is H, —OH, —NH 2 etc .; R 2 and R 3 are optionally substituted hydrocarbon groups, etc .; R 4 is a hydrogen atom or optionally substituted hydrocarbon groups, etc .; R 5 is R 2 and R 5 may form a cycloalkyl; R 6 and R 7 represent H or F; The compound represented by this is described.
  • ERR ⁇ modulator have excellent activity as an ERR ⁇ modulator and treat ERR ⁇ related diseases such as malignant tumors (eg, breast cancer, malignant lymphoma, multiple myeloma, prostate cancer, colon cancer, lung cancer, ovarian cancer, endometrial cancer) or Development of novel compounds useful as preventive drugs and the like is desired.
  • malignant tumors eg, breast cancer, malignant lymphoma, multiple myeloma, prostate cancer, colon cancer, lung cancer, ovarian cancer, endometrial cancer
  • development of novel compounds useful as preventive drugs and the like is desired.
  • A represents a cyclic group which may have a substituent
  • L a is a bond, -O -, - CO -, - S -, - SO -, - SO 2 -, - NR L1 - or -NR L1 -CO-
  • the L b represents a C 1-3 alkylene group which may have a bond or a substituent
  • L c is a bond, -CO -, - O-CO -, - NR L2 -CO -, - SO 2 - or -NR L2 -SO 2 -
  • the R L1 and R L2 each independently have a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or a substituent.
  • G is the formula
  • Z 1 represents a nitrogen atom, a carbon atom or —CR Z1 —
  • Z 2 represents a nitrogen atom, a carbon atom or —CR Z2 —
  • Z 3 represents a nitrogen atom, a carbon atom or —CR Z3 —
  • Z 4 represents a nitrogen atom, a carbon atom or —CR Z4 —
  • R Z1 , R Z2 , R Z3 and R Z4 each independently represent a hydrogen atom or a substituent
  • R 4 represents a hydrogen atom or a substituent
  • R 5 represents a hydrogen atom or a hydrocarbon group optionally having substituent (s)
  • E is the formula
  • R 1 , R 2 , R 3 and R X may each independently have a hydrogen atom or a substituent;
  • R 1 represents a good hydrocarbon group, a heterocyclic group which may have a substituent, a hydroxy group which may have a substituent, an amino group which may have a substituent, or an acyl group.
  • R 2 together with the adjacent nitrogen atom may form a nitrogen-containing heterocyclic ring which may have a substituent.
  • a salt thereof in this specification, sometimes abbreviated as compound (I)).
  • A is (1) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a cyano group and a hydroxy group; (B) substituted with 1 to 3 substituents selected from a halogen atom, a cyano group, a hydroxy group, a tri-C 1-6 alkyl-silyl-C 1-6 alkoxy group and a C 3-10 cycloalkyl group An optionally substituted C 1-6 alkoxy group; (C) a halogen atom, (D) a cyano group, (E) a hydroxy group, (F) a carboxy group, (G) a C 1-6 alkoxy-carbonyl group, (H) a carbamoyl group, (I) a mono- or di-C 1-6 alkyl-carbamoyl group which may be substituted with 1 to 3 substituents selected from a hydroxy group and a cyano group (
  • L a is a bond hand;
  • L b is (1) a bond, or (2) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 hydroxy groups, (B) a carboxy group, (C) a C 1-6 alkoxy-carbonyl group, (D) a carbamoyl group, (E) a C 3-10 cycloalkyl group, and (f) 1 to 3 substituents selected from 4 to 6-membered non-aromatic heterocyclic groups optionally substituted with 1 to 3 hydroxy groups
  • a C 1-3 alkylene group optionally substituted by: The compound or a salt thereof according to any one of [1] to [2], wherein L c is a bond.
  • Z 1 is a nitrogen atom, a carbon atom or —CR Z1 —;
  • Z 2 is a carbon atom or —CR Z2 —;
  • Z 3 is a nitrogen atom, a carbon atom or —CR Z3 —;
  • Z 4 is a nitrogen atom or —CR Z4 —;
  • R Z1 , R Z2 , R Z3 and R Z4 are each independently a hydrogen atom or a C 1-6 alkoxy group;
  • R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
  • R 5 is a C 1-6 alkyl group.
  • R X is (1) a hydrogen atom; or (2) (a) a halogen atom, (B) a hydroxy group, (C) a mono- or di-C 1-6 alkyl-amino group, and (d) a 4- to 6-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6 alkyl groups
  • R 1 is (1) a hydrogen atom; (2) (a) a C 6-10 aryl group optionally substituted with an amino group, (B) a 4 to 6-membered group optionally substituted by 1 to 3 substituents selected from a C 1-6 alkyl group, a C 7-13 aralkyl group, a C 1-6 alkoxy-carbonyl group and an oxo group
  • R 2 is (1) a hydrogen atom; (2) hydroxy group, C 1-6 alkoxy group and a mono- - or di -C 1-6 alkyl - 1 to 3 substituents optionally substituted by a C 1-6 alkyl group selected from amino groups; Or (3) a C 7-13 aralkyl group; R 3 is a C 1-6 alkyl group optionally substituted by 1 to 3 mono- or di-C 1-6 alkyl-amino groups; Or R 1 and R 2 together with the adjacent nitrogen atom, (1) a cyano group, (2) a hydroxy group, (3) a C 1-6 alkoxy group optionally substituted by 1 to 3 hydroxy groups, (4) a halogen atom, hydroxy group, C 1-6 alkoxy group and a mono- - or di -C 1-6 alkyl - substituted by 1 selected from amino group to three substituents C 1-6 An
  • A is (1) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a cyano group and a hydroxy group, (B) substituted with 1 to 3 substituents selected from a halogen atom, a cyano group, a hydroxy group, a tri-C 1-6 alkyl-silyl-C 1-6 alkoxy group and a C 3-10 cycloalkyl group An optionally substituted C 1-6 alkoxy group, (C) a halogen atom, (D) a cyano group, (E) a hydroxy group, (F) a carboxy group, (G) a C 1-6 alkoxy-carbonyl group, (H) a carbamoyl group, (I) a mono- or di-C 1-6 alkyl-carbamoyl group which may be substituted with 1 to 3 substituents selected from a hydroxy group and a cyano group (
  • Z 1 is a nitrogen atom, a carbon atom or —CR Z1 —;
  • Z 2 is a carbon atom or —CR Z2 —;
  • Z 3 is a nitrogen atom, a carbon atom or —CR Z3 —;
  • Z 4 is a nitrogen atom or —CR Z4 —;
  • R Z1 , R Z2 , R Z3 and R Z4 are each independently a hydrogen atom or a C 1-6 alkoxy group;
  • R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
  • R 5 is a C 1-6 alkyl group.
  • a group represented by: E is the formula
  • X is —S— or —NR X —;
  • R X is (1) a hydrogen atom; or (2) (a) a halogen atom, (B) a hydroxy group, (C) a mono- or di-C 1-6 alkyl-amino group, and (d) a 4- to 6-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6 alkyl groups
  • R 1 is (1) a hydrogen atom; (2) (a) a C 6-10 aryl group optionally substituted with an amino group, (B) a 4 to 6-membered group optionally substituted by 1 to 3 substituents selected from a C 1-6 alkyl group, a C 7-13 aralkyl group, a C 1-6 alkoxy-carbonyl group and an oxo group
  • R 2 is (1) a hydrogen atom; (2) hydroxy group, C 1-6 alkoxy group and a mono- - or di -C 1-6 alkyl - 1 to 3 substituents optionally substituted by a C 1-6 alkyl group selected from amino groups; Or (3) a C 7-13 aralkyl group; R 3 is a C 1-6 alkyl group optionally substituted by 1 to 3 mono- or di-C 1-6 alkyl-amino groups; Or R 1 and R 2 together with the adjacent nitrogen atom, (1) a cyano group, (2) a hydroxy group, (3) a C 1-6 alkoxy group optionally substituted by 1 to 3 hydroxy groups, (4) a halogen atom, hydroxy group, C 1-6 alkoxy group and a mono- - or di -C 1-6 alkyl - substituted by 1 selected from amino group to three substituents C 1-6 An
  • A is (1) (a) a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a cyano group and a hydroxy group, (B) substituted with 1 to 3 substituents selected from a halogen atom, a cyano group, a hydroxy group, a tri-C 1-6 alkyl-silyl-C 1-6 alkoxy group and a C 3-10 cycloalkyl group An optionally substituted C 1-6 alkoxy group, (C) a halogen atom, (D) a cyano group, (E) a hydroxy group, (F) a carboxy group, (G) a C 1-6 alkoxy-carbonyl group, (H) a carbamoyl group, (I) a mono- or di-C 1-6 alkyl-carbamoyl group optionally substituted with 1 to 3 substituents selected from a hydroxy group and a cyano group (two
  • a C 3-10 cycloalkyl group which may be substituted with 1 to 3 C 1-6 alkyl groups and may be further condensed with a benzene ring;
  • L a is a bond hand;
  • L b is (1) a bond, or (2) (a) a C 1-6 alkyl group optionally substituted with 1 to 3 hydroxy groups, (B) a carboxy group, (C) a C 1-6 alkoxy-carbonyl group, (D) a carbamoyl group, (E) C 3-10 cycloalkyl groups, and (f) 1 to 3 to 1 selected from optionally oxetanyl group optionally substituted by a hydroxy group may be substituted with 1-3 substituent
  • Z 1 is a nitrogen atom, a carbon atom or —CH—;
  • Z 2 is a carbon atom or —CH—;
  • Z 3 is a nitrogen atom, a carbon atom or —CH—;
  • Z 4 is a nitrogen atom, —CH— or —C (C 1-6 alkoxy group) —;
  • R 4 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
  • R 5 is a C 1-6 alkyl group
  • E is the formula
  • X is —S— or —NR X —;
  • R X is (1) a hydrogen atom; or (2) (a) a halogen atom, (B) a hydroxy group, Substituted with 1 to 7 substituents selected from (c) a di-C 1-6 alkyl-amino group, and (d) a pyrrolidinyl group optionally substituted by 1 to 3 C 1-6 alkyl groups
  • R 1 is (1) a hydrogen atom; (2) (a) a phenyl group optionally substituted with an amino group, (B) a pyrrolidinyl group, a tetrahydrofuryl group, a piperidinyl group, a piperazinyl group each optionally substituted by 1 to 3 substituents selected from a C 1-6 alkyl group, a C 1-6 alkoxy-carbonyl group and an oxo group Group, or morpholinyl
  • R 2 is (1) a hydrogen atom; (2) a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a hydroxy group, a C 1-6 alkoxy group and a di-C 1-6 alkyl-amino group; or (3 ) A benzyl group; R 3 is a C 1-6 alkyl group optionally substituted by 1 to 3 di-C 1-6 alkyl-amino groups; Or R 1 and R 2 together with the adjacent nitrogen atom, (1) a cyano group, (2) a hydroxy group, (3) a C 1-6 alkoxy group optionally substituted by 1 to 3 hydroxy groups, (4) a C 1-6 alkyl group which may be substituted with
  • Z 3 is a nitrogen atom or —CH—;
  • Z 4 is a nitrogen atom or —CR Z4 —;
  • R Z4 is a hydrogen atom or a C 1-6 alkoxy group;
  • R 4 is a hydrogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
  • R 5 is a C 1-6 alkyl group.
  • R X is (1) a hydrogen atom; or (2) (a) a halogen atom, (B) a hydroxy group, Substituted with 1 to 7 substituents selected from (c) a di-C 1-6 alkyl-amino group, and (d) a pyrrolidinyl group optionally substituted by 1 to 3 C 1-6 alkyl groups
  • R 1 is (1) a hydrogen atom; (2) (a) a pyrrolidinyl group, piperidinyl group, piperazinyl group, or morpholinyl group each optionally substituted by 1 to 3 C 1-6 alkyl groups, (B) a pyridyl group, (C) a cyano group, (D) a hydroxy group, (E) a C 1-6 alkoxy group which may be substituted with 1 to 3 substituents selected from a hydroxy group and
  • R 2 is (1) a hydrogen atom; (2) a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a hydroxy group, a C 1-6 alkoxy group and a mono- or di-C 1-6 alkyl-amino group; Or (3) a benzyl group; R 3 is a C 1-6 alkyl group optionally substituted by 1 to 3 di-C 1-6 alkyl-amino groups; Or R 1 and R 2 together with the adjacent nitrogen atom, (1) a cyano group, (2) a hydroxy group, (3) a C 1-6 alkoxy group optionally substituted by 1 to 3 hydroxy groups, (4) a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a halogen atom, a hydroxy group and a di-C 1-6 alkyl-amino group
  • A is a phenyl group substituted with 1 to 3 substituents selected from a C 1-6 alkyl group substituted with 1 to 3 halogen atoms;
  • L a is a bond hand;
  • L b is a C 1-3 alkylene group;
  • L c is a bond;
  • G is the formula
  • a group represented by: E is the formula
  • R 1 is (1) (a) substituted with 1 to 3 substituents selected from pyrrolidinyl group substituted with 1 to 3 C 1-6 alkyl groups, and (b) di-C 1-6 alkylamino group An optionally substituted C 1-6 alkyl group; or (2) a C 2-10 alkynyl group;
  • R 2 is a hydrogen atom;
  • R 1 and R 2 may form an azetidine ring or a pyrrolidine ring each substituted with 1 to 3 hydroxy groups together with the adjacent nitrogen atom.
  • the compound or its salt of the said [1] description which is group represented by these.
  • [12] A medicament comprising the compound or salt thereof according to any one of [1] to [11].
  • a method for reverse action of ERR ⁇ comprising administering an effective amount of the compound or salt thereof according to any one of [1] to [11] to a mammal.
  • a method for preventing or treating cancer comprising administering an effective amount of the compound or salt thereof according to any one of [1] to [11] to a mammal.
  • the medicament according to [12] above which is a prophylactic or therapeutic agent for breast cancer, malignant lymphoma, multiple myeloma, prostate cancer, colon cancer, lung cancer, ovarian cancer or endometrial cancer.
  • Breast cancer, malignant lymphoma, multiple myeloma, prostate cancer, characterized by administering an effective amount of the compound or salt thereof according to any one of [1] to [11] to a mammal A method for preventing or treating colon cancer, lung cancer, ovarian cancer or endometrial cancer.
  • the compound of the present invention has excellent activity as an ERR ⁇ modulator (particularly an inverse agonist) and has excellent properties in terms of pharmacokinetics, for example, malignant tumors (eg, breast cancer, malignant lymphoma, It is useful as a prophylactic or therapeutic agent for ERR ⁇ -related diseases such as multiple myeloma, prostate cancer, colon cancer, lung cancer, ovarian cancer, endometrial cancer).
  • malignant tumors eg, breast cancer, malignant lymphoma
  • It is useful as a prophylactic or therapeutic agent for ERR ⁇ -related diseases such as multiple myeloma, prostate cancer, colon cancer, lung cancer, ovarian cancer, endometrial cancer).
  • halogen atom in the present specification means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom unless otherwise specified.
  • C 1-6 alkyl group means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethyl unless otherwise specified. It means propyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • C 1-6 alkoxy group in the present specification means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy and the like, unless otherwise specified. To do.
  • C 1-6 alkoxy-carbonyl group in the present specification is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert- It means butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.
  • C 1-6 alkyl-carbonyl group in the present specification is acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2 , 2-dimethylpropanoyl, hexanoyl, heptanoyl and the like.
  • C 1-6 alkoxycarbonimidoyl group in the present specification means (C 1-6 alkoxy) -C ( ⁇ NH) —.
  • R 3 is a hydrogen atom in the group represented by the formula
  • the group includes any of the tautomers described above.
  • Ea is intended to include all of its possible tautomers.
  • X represents —S—, —O— or —NR X —;
  • R 1 , R 2 , R 3 and R X each independently represent a hydrogen atom or an optionally substituted hydrocarbon group.
  • R 1 and R 2 together with the adjacent nitrogen atom may form a nitrogen-containing heterocyclic ring which may have a substituent.
  • hydrocarbon group of the “hydrocarbon group optionally having substituent (s)” represented by R 1 , R 2 , R 3 or R X , for example, a C 1-10 alkyl group, C 2-10 An alkenyl group, a C 2-10 alkynyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 4-10 cycloalkadienyl group, a C 6-14 aryl group, a C 7-13 aralkyl group, Examples thereof include a C 8-13 arylalkenyl group and a C 3-10 cycloalkyl-C 1-6 alkyl group.
  • C 1-10 alkyl group for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, hexyl , Isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl and decyl.
  • Examples of the C 2-10 alkenyl group include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1 -Pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl.
  • Examples of the C 2-10 alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1 -Hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 4-methyl-2-pentynyl, 1-heptynyl, 1-octynyl.
  • Examples of the C 3-10 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3 2.1] octyl, bicyclo [3.2.2] nonyl, bicyclo [3.3.1] nonyl, bicyclo [4.2.1] nonyl, bicyclo [4.3.1] decyl, and adamantyl. It is done.
  • Examples of the C 3-10 cycloalkenyl group include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, and 3-cyclohexen-1-yl.
  • Examples of the C 4-10 cycloalkadienyl group include 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, and 2,5-cyclohexadien-1-yl.
  • C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group and C 4-10 cycloalkadienyl group may each be condensed with a benzene ring.
  • condensed ring groups include , Indanyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl.
  • Examples of the C 6-14 aryl group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl, biphenylyl.
  • Examples of the C 7-13 aralkyl group include benzyl, phenethyl, naphthylmethyl, biphenylylmethyl, and phenylpropyl.
  • Examples of the C 8-13 arylalkenyl group include styryl.
  • Examples of the C 3-10 cycloalkyl-C 1-6 alkyl group include cyclopropylmethyl, cyclohexylmethyl, 1-cyclohexylethyl, and 2-cyclohexylethyl.
  • the C 1-10 alkyl group, C 2-10 alkenyl group and C 2-10 alkynyl group exemplified as the “hydrocarbon group” are 1 to 7 (preferably 1 to 3) at substitutable positions. It may have a substituent.
  • a substituent for example, (1) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a cyano group, (d) a C 1-6 alkoxy group, (e) a halogen atom, and (f) an amino group,
  • a C 3-10 cycloalkyl group eg, cyclopropyl, cyclohexyl
  • substituents selected from: (2) (a) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (b) a hydroxy group, (c) a cyano group, (d) a C 1-6 alkoxy group, (e) a halogen atom, and (f) an amino group
  • a C 6-14 aryl group eg, phenyl, naphthyl
  • a carbamoyl group which may be mono- or di-substituted with a substituent selected from: (11) a thiocarbamoyl group optionally mono- or disubstituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms; (12) a sulfamoyl group optionally mono- or disubstituted with a C 1-6 alkyl group optionally substituted with 1 to 3 halogen atoms; (13) a carboxy group; (14) hydroxy group; (15) (a) a halogen atom, (b) a carboxy group, (c) a C 1-6 alkoxy group optionally substituted with a tri-C 1-6 alkyl-silyl group (eg, trimethylsilyl), (d) a C 1-6 alkoxy-carbonyl group, (e) a hydroxy group, (f) a cyano group, (g) optionally substituted with 1 to 3 substituent
  • C 6-14 aryl group, C 7-13 aralkyl group and C 8-13 arylalkenyl group exemplified as the “hydrocarbon group” have 1 to 3 substituents at substitutable positions. It may be.
  • substituents for example, (1) groups exemplified as the substituents that the aforementioned C 1-10 alkyl group and the like may have; (2) (a) a halogen atom, (b) a cyano group, (c) a carboxy group, (d) a hydroxy group optionally substituted with a non-aromatic heterocyclic group (eg, piperidino, tetrahydropyranyl), (e) a C 1-6 alkoxy group, (f) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group, (g) a C 6-14 aryl group (eg, phenyl), (h) a C 1-6 alkoxy-carbonyl group, (i) a C 1-6 alkyl-carbonyloxy group (eg, acetyloxy, tert-butylcarbonyloxy), (j) a carbamoyl group, (k) an aromatic heterocyclic group optional
  • C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 4-10 cycloalkadienyl group and C 3-10 cycloalkyl-C 1-6 alkyl exemplified as the “hydrocarbon group” are exemplified.
  • the group may have 1 to 4 (preferably 1 to 3) substituents at substitutable positions.
  • substituents for example, (1) groups exemplified as the substituents that the aforementioned C 6-14 aryl group and the like may have; (2) an oxo group; Is mentioned. When there are two or more substituents, each substituent may be the same or different.
  • heterocyclic group in the “optionally substituted heterocyclic group” represented by R 1 , R 2 , R 3 or R X includes an aromatic heterocyclic group and a non-aromatic heterocyclic group. Can be mentioned.
  • the aromatic heterocyclic group is, for example, a 4 to 7 member (preferably 5 or 5) containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring constituent atom.
  • 6-membered) monocyclic aromatic heterocyclic group and condensed aromatic heterocyclic group examples include these 4- to 7-membered monocyclic aromatic heterocyclic groups and 5- or 6-membered aromatic heterocyclic rings containing 1 to 2 nitrogen atoms (eg, pyrrole).
  • Imidazole pyrazole, pyrazine, pyridine, pyrimidine), a 5-membered aromatic heterocyclic ring containing one sulfur atom (eg, thiophene), or a group having 1 to 2 condensed benzene rings.
  • Furyl eg, 2-furyl, 3-furyl
  • thienyl eg, 2-thienyl, 3-thienyl
  • pyridyl eg, 2-pyridyl, 3-pyridyl, 4-pyridyl
  • pyrimidinyl eg, 2-pyrimidinyl
  • 5-pyrimidinyl eg, 5-pyrimidinyl
  • pyridazinyl eg, 3-pyridazinyl, 4-pyridazinyl
  • pyrazinyl eg, 2-pyrazinyl
  • pyrrolyl eg, 2-pyrrolyl, 3-pyrrolyl
  • imidazolyl eg, 1 -Imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl
  • pyrazolyl eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl
  • non-aromatic heterocyclic group examples include 4 to 7 members (preferably 4 to 6 members) containing 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms in addition to carbon atoms as ring constituent atoms.
  • fused non-aromatic heterocyclic group examples include these 4- to 7-membered monocyclic non-aromatic heterocyclic groups and 5- or 6-membered aromatic or non-aromatic groups containing 1 to 2 nitrogen atoms.
  • Heterocycle eg, pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine
  • 5-membered aromatic or non-aromatic heterocycle containing one sulfur atom eg, thiophene
  • benzene ring etc.
  • Two condensed groups are mentioned.
  • Oxiranyl eg, 2-oxiranyl
  • oxetanyl eg, 2-oxetanyl, 3-oxetanyl
  • aziridinyl eg, 1-aziridinyl, 2-aziridinyl
  • azetidinyl eg, 1-azetidinyl, 2-azetidinyl, 3-azetidinyl
  • Pyrrolidinyl eg, 1-pyrrolidinyl, 2-pyrrolidinyl
  • piperidinyl eg, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl
  • homopiperidinyl eg, homopiperidino, 2-homopiperidinyl, 3-homopiperidinyl, 4- Homopiperidinyl
  • tetrahydropyridyl eg, 1,2,3,6-tetrahydropyridyl
  • aromatic heterocyclic group and “non-aromatic heterocyclic group” may have 1 to 3 substituents at substitutable positions.
  • examples of the substituent of the aromatic heterocyclic group include the C 6-14 aryl group exemplified as the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)”. What was illustrated as a substituent which you may have is mentioned. When there are two or more substituents, each substituent may be the same or different.
  • examples of the substituent of the non-aromatic heterocyclic group include a C 3-10 cycloalkyl group exemplified as the “hydrocarbon group” of the “hydrocarbon group which may have a substituent”. What was illustrated as a substituent which may be carried out is mentioned. When there are two or more substituents, each substituent may be the same or different.
  • the “hydroxy group optionally having substituent (s)” represented by R 1 , R 2 , R 3 or R X is, for example, a C 1-10 alkyl group optionally having substituent (s), C 2-10 alkenyl group, C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 6-14 aryl group, C 7-13 aralkyl group, C 8-13 arylalkenyl group, C 3-10 cyclo Examples thereof include a hydroxy group which may be substituted with a substituent selected from an alkyl-C 1-6 alkyl group, a C 1-6 alkyl-carbonyl group, a heterocyclic group and the like.
  • Examples of the 13 arylalkenyl group and C 3-10 cycloalkyl-C 1-6 alkyl group are “hydrocarbon groups” in the “hydrocarbon groups optionally having substituents” represented by R 1 and the like. The thing which was done is mentioned.
  • heterocyclic group examples include “aromatic heterocyclic group” and “non-aromatic heterocyclic group” exemplified as “heterocyclic group” of “optionally substituted heterocyclic group” represented by R 1 or the like. ".
  • C 1-10 alkyl groups C 2-10 alkenyl groups, C 3-10 cycloalkyl groups, C 3-10 cycloalkenyl groups, C 6-14 aryl groups, C 7-13 aralkyl groups, C 8-13 aryls 1 to 3 alkenyl groups, C 3-10 cycloalkyl-C 1-6 alkyl groups, C 1-6 alkyl-carbonyl groups, aromatic heterocyclic groups and non-aromatic heterocyclic groups each at a substitutable position It may have a substituent. When there are two or more substituents, each substituent may be the same or different.
  • Examples of the substituent for the C 3-10 cycloalkyl group, the C 3-10 cycloalkenyl group, the C 3-10 cycloalkyl-C 1-6 alkyl group, and the non-aromatic heterocyclic group are represented by R 1 and the like. Examples thereof include those exemplified as the substituent which the C 3-10 cycloalkyl group and the like exemplified as the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” may have.
  • examples of the substituent of the C 6-14 aryl group, C 7-13 aralkyl group, C 8-13 arylalkenyl group, and aromatic heterocyclic group include those represented by R 1 or the like.
  • examples of the substituent that the C 6-14 aryl group and the like exemplified as the “hydrocarbon group” of the “good hydrocarbon group” may have may be mentioned.
  • amino group optionally having substituent (s) represented by R 1 , R 2 , R 3 or R X , for example, a C 1-10 alkyl group optionally having substituent (s), A C 2-10 alkenyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 6-14 aryl group, a C 7-13 aralkyl group, a C 8-13 arylalkenyl group and a heterocyclic group; and An amino group which may be substituted with 1 or 2 substituents selected from an acyl group and the like is mentioned.
  • those exemplified as the “hydrocarbon group” in the “hydrocarbon group optionally having substituent (s)” represented by R 1 and the like can be mentioned.
  • heterocyclic group examples include “aromatic heterocyclic group” and “non-aromatic heterocyclic group” exemplified as “heterocyclic group” of “optionally substituted heterocyclic group” represented by R 1 or the like. ".
  • the alkenyl group, aromatic heterocyclic group and non-aromatic heterocyclic group each may have 1 to 3 substituents at substitutable positions. When there are two or more substituents, each substituent may be the same or different.
  • examples of the substituent of the C 1-10 alkyl group and the C 2-10 alkenyl group include the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by R 1 or the like. Examples of the substituent which the C 1-10 alkyl group may have may be mentioned.
  • examples of the substituent for the C 3-10 cycloalkyl group, the C 3-10 cycloalkenyl group, and the non-aromatic heterocyclic group include “an optionally substituted hydrocarbon group” represented by R 1 and the like. Examples of the substituent that the C 3-10 cycloalkyl group and the like exemplified as the “hydrocarbon group” in FIG.
  • examples of the substituent of the C 6-14 aryl group, C 7-13 aralkyl group, C 8-13 arylalkenyl group, and aromatic heterocyclic group include those represented by R 1 or the like.
  • examples of the substituent that the C 6-14 aryl group and the like exemplified as the “hydrocarbon group” of the “good hydrocarbon group” may have may be mentioned.
  • Examples of the “acyl group” represented by R 1 , R 2 , R 3 or R X or the “acyl group” as a substituent of the “amino group optionally having substituent (s)” include, for example, the formula: -COR A , -CO-OR A , -SO 2 R A , -SOR A , -CO-NR A 'R B ', -SO 2 -NR A 'R B ', -SO 2 -NR A '(COR B '), - CS-NR a' in R B '[wherein, R a is a hydrogen atom, a heterocyclic group which may have a hydrocarbon may have a substituent hydrogen group or a substituent R A ′ represents a hydrogen atom, a hydroxy group, a hydrocarbon group which may have a substituent or a heterocyclic group which may have a substituent; R B ′ represents a hydrogen atom, a substituent A hydrocarbon group which may
  • Examples of the “hydrocarbon group optionally having substituent (s)” and the “heterocyclic group optionally having substituent (s)” represented by R A , R A ′ or R B ′ include R 1 and the like. Examples thereof include the same “hydrocarbon groups optionally having substituents” and “heterocyclic groups optionally having substituents” shown.
  • nitrogen-containing heterocycle in the “nitrogen-containing heterocycle optionally having substituents” formed by R A ′ and R B ′ together with adjacent nitrogen atoms include, for example, other than carbon atoms as ring-constituting atoms. It contains at least one nitrogen atom, may further contain 1 to 2 heteroatoms selected from oxygen, sulfur and nitrogen atoms, and may contain a 4 to 8 member which may form a spiro ring. A nitrogen heterocycle is mentioned.
  • nitrogen-containing heterocycle examples include azetidine, pyrrolidine, pyrazoline, piperidine, piperazine, morpholine, thiomorpholine, azepane, diazepan, hexahydropyrrolo [3,4-b] pyrrole, 1,7-diazaspiro [4.4 Nonane, 2,8-diazaspiro [4.5] decane, 1,3,8-triazaspiro [4.5] decane.
  • a 4- to 8-membered nitrogen-containing heterocyclic ring which may form a spiro ring means a 4- to 8-membered nitrogen-containing heterocyclic ring (for example, at least one nitrogen atom other than a carbon atom as a ring-constituting atom).
  • a 4- to 8-membered nitrogen-containing heterocycle preferably pyrrolidine or piperidine, which may further contain 1 to 2 heteroatoms selected from oxygen, sulfur and nitrogen atoms, preferably C 3-6 A cycloalkane (for example, cyclopentane, cyclohexane) or a 4- to 6-membered heterocyclic ring (for example, 4 containing 1 to 2 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a carbon atom as a ring-constituting atom) Or a 6-membered heterocyclic ring, preferably a pyrrolidine or piperidine) ring that may form a spiro ring. Substituents may be present on one or both rings.
  • the nitrogen-containing heterocycle may have 1 to 3 (preferably 1 or 2) substituents at substitutable positions.
  • substituents include the substituent that the C 3-10 cycloalkyl group exemplified as the “hydrocarbon group” of the “hydrocarbon group optionally having substituent” may have What was illustrated is mentioned.
  • each substituent may be the same or different.
  • acyl group examples include (1) formyl group, (2) an optionally substituted C 1-6 alkyl-carbonyl group, (3) an optionally substituted C 2-6 alkenyl-carbonyl group, (4) an optionally substituted C 2-6 alkynyl-carbonyl group, (5) an optionally substituted C 3-6 cycloalkyl-carbonyl group, (6) an optionally substituted C 3-6 cycloalkenyl-carbonyl group, (7) an optionally substituted C 6-10 aryl-carbonyl group, (8) a heterocyclic carbonyl group which may have a substituent, (9) a carboxy group, (10) an optionally substituted C 1-6 alkoxy-carbonyl group, (11) an optionally substituted C 2-6 alkenyloxy-carbonyl group, (12) an optionally substituted C 2-6 alkynyloxy-carbonyl group, (13) an optionally substituted C 3-6 cycloalkyloxy-carbonyl group, (14) an optionally
  • C 2-6 alkenyl - carbonyl group for example, ethenyl, 1- propenylcarbonyl, 2-propenyl Carbonyl, 2-methyl-1-propenylcarbonyl, 1-butenylcarbonyl, 2-butenylcarbonyl, 3-butenylcarbonyl, 3-methyl-2-butenylcarbonyl, 1-pentenylcarbonyl, 2-pentenylcarbonyl, 3 -Pentenylcarbonyl, 4-pentenylcarbonyl, 4-methyl-3-pentenylcarbonyl, 1-hexenylcarbonyl, 2-hexenylcarbonyl, 3-hexenylcarbonyl, 4-hexenylcarbonyl, 5-hexenylcarbonyl.
  • C 2-6 alkynyl-carbonyl group” of the “optionally substituted C 2-6 alkynyl-carbonyl group” includes, for example, ethynylcarbonyl, 1-propynylcarbonyl, 2-propynylcarbonyl, 1- Butynylcarbonyl, 2-butynylcarbonyl, 3-butynylcarbonyl, 1-pentynylcarbonyl, 2-pentynylcarbonyl, 3-pentynylcarbonyl, 4-pentynylcarbonyl, 1-hexynylcarbonyl, 2-hexynyl Examples include carbonyl, 3-hexynylcarbonyl, 4-hexynylcarbonyl, and 5-hexynylcarbonyl.
  • C 3-6 also be cycloalkyl - carbonyl group
  • the "C 3-6 cycloalkyl group” for example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl Is mentioned.
  • C 3-6 cycloalkenyl optionally having - carbonyl group
  • the "C 3-6 cycloalkenyl group” for example, 2-cyclopropene-1-ylcarbonyl, 2- cyclobutene Examples include 1-ylcarbonyl, 2-cyclopenten-1-ylcarbonyl, 3-cyclopenten-1-ylcarbonyl, 2-cyclohexen-1-ylcarbonyl, and 3-cyclohexen-1-ylcarbonyl.
  • carbonyl group which may have a substituent C 6-10 aryl which may have a substituent C 6-10 aryl" - as a “C 6-10 arylcarbonyl group", for example, benzoyl, 1-naphthoyl, 2-naphthoyl.
  • heterocyclic carbonyl group of the “optionally substituted heterocyclic carbonyl group” includes, for example, (1) a 5- or 6-membered monocyclic aromatic heterocyclic ring (eg, furan, thiophene, pyrrole).
  • aromatic heterocycle eg, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indole, Isoindole, 1H-indazole, benzimi
  • C 2-6 alkenyloxy - carbonyl group Optionally substituted C 2-6 alkenyloxy - carbonyl group
  • the "C 2-6 alkenyloxy group” for example, ethenyl oxycarbonyl, 1-propenyloxy carbonyl, 2- Propenyloxycarbonyl, 1-butenyloxycarbonyl, 2-butenyloxycarbonyl, 3-butenyloxycarbonyl, 3-methyl-2-butenyloxycarbonyl, 1-pentenyloxycarbonyl, 2-pentenyloxycarbonyl, 3- Examples include pentenyloxycarbonyl, 4-pentenyloxycarbonyl, 1-hexenyloxycarbonyl, 2-hexenyloxycarbonyl, 3-hexenyloxycarbonyl, 4-hexenyloxycarbonyl, and 5-hexenyloxycarbonyl.
  • C 2-6 alkynyloxy-carbonyl group for example, ethynyloxy, 1- propynyloxy carbonyl, 2-propynyl Oxycarbonyl, 1-butynyloxycarbonyl, 2-butynyloxycarbonyl, 3-butynyloxycarbonyl, 1-pentynyloxycarbonyl, 2-pentynyloxycarbonyl, 3-pentynyloxycarbonyl, 4-pentynyloxy Examples include carbonyl, 1-hexynyloxycarbonyl, 2-hexynyloxycarbonyl, 3-hexynyloxycarbonyl, 4-hexynyloxycarbonyl and 5-hexynyloxycarbonyl.
  • C 3-6 cycloalkyloxy - carbonyl group -
  • the "C 3-6 cycloalkyloxy group” for example, cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyl Examples include oxycarbonyl and cyclohexyloxycarbonyl.
  • C 3-6 cycloalkenyloxy - carbonyl group Optionally substituted C 3-6 cycloalkenyloxy - carbonyl group.
  • the "C 3-6 cycloalkenyloxy group” for example, 2-cyclopropene-1-yl oxycarbonyl, 2-cyclobuten-1-yloxycarbonyl, 2-cyclopenten-1-yloxycarbonyl, 3-cyclopenten-1-yloxycarbonyl, 2-cyclohexen-1-yloxycarbonyl, 3-cyclohexen-1-yloxycarbonyl Can be mentioned.
  • C 6-10 aryloxy - carbonyl group -
  • C 6-10 aryloxycarbonyl group for example, phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxy And carbonyl.
  • heterocyclic oxycarbonyl group in the “optionally substituted heterocyclic oxycarbonyl group” include (1) a 5- or 6-membered monocyclic aromatic heterocyclic ring (eg, furan, thiophene).
  • C 1-6 alkyl-sulfonyl group in the “optionally substituted C 1-6 alkyl-sulfonyl group” means methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, unless otherwise specified.
  • C 1-6 alkyl-carbonyl groups C 2-6 alkenyl-carbonyl groups, C 2-6 alkynyl-carbonyl groups, C 3-6 cycloalkyl-carbonyl groups, C 3-6 cycloalkenyl-carbonyl groups, C 6 -10 aryl-carbonyl group, heterocyclic carbonyl group, C 1-6 alkoxy-carbonyl group, C 2-6 alkenyloxy-carbonyl group, C 2-6 alkynyloxy-carbonyl group, C 3-6 cycloalkyloxy-carbonyl Group, C 3-6 cycloalkenyloxy-carbonyl group, C 6-10 aryloxy-carbonyl group, C 1-6 alkyl-sulfonyl group and heterocyclic oxycarbonyl group each have 1 to 3 substituents at substitutable positions. It may have a substituent. When there are two or more substituents, each substituent may be the same or different.
  • substituent of the 2-6 alkynyloxy-carbonyl group and the C 1-6 alkyl-sulfonyl group include the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by R 1 and the like. Examples of the substituent that the exemplified C 1-10 alkyl group and the like may have are exemplified.
  • substituent for the ring oxycarbonyl group include the C 3-10 cycloalkyl group exemplified as the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by R 1 and the like.
  • substituent which may be present are as follows (provided that the heterocyclic ring of the heterocyclic carbonyl group and the heterocyclic oxycarbonyl group is an aromatic heterocyclic ring, excluding oxo).
  • C 6-10 aryl - carbonyl and C 6-10 aryloxy - Examples of the substituent of the carbonyl group, represented by such as R 1 in the "optionally substituted hydrocarbon group", "hydrocarbon Examples of the substituent that the C 6-14 aryl group exemplified as the “group” may have may be mentioned.
  • Examples of the “carbamoyl which may have a substituent” include, for example, a C 1-10 alkyl group, a C 2-10 alkenyl group, a C 3-10 cycloalkyl group, each of which may have a substituent, It may be substituted with one or two substituents selected from a C 3-10 cycloalkenyl group, a C 6-14 aryl group, a C 7-13 aralkyl group, a C 8-13 arylalkenyl group, a heterocyclic group, and the like.
  • a good carbamoyl group is mentioned.
  • those exemplified as the “hydrocarbon group” in the “hydrocarbon group optionally having substituent (s)” represented by R 1 and the like can be mentioned.
  • heterocyclic group examples include “aromatic heterocyclic group” and “non-aromatic heterocyclic group” exemplified as “heterocyclic group” of “optionally substituted heterocyclic group” represented by R 1 or the like. ".
  • the alkenyl group, aromatic heterocyclic group and non-aromatic heterocyclic group each may have 1 to 3 substituents at substitutable positions. When there are two or more substituents, each substituent may be the same or different.
  • examples of the substituent of the C 1-10 alkyl group and the C 2-10 alkenyl group include the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by R 1 or the like. Examples of the substituent which the C 1-10 alkyl group may have may be mentioned.
  • examples of the substituent for the C 3-10 cycloalkyl group, the C 3-10 cycloalkenyl group, and the non-aromatic heterocyclic group include “an optionally substituted hydrocarbon group” represented by R 1 and the like. Examples of the substituent that the C 3-10 cycloalkyl group and the like exemplified as the “hydrocarbon group” in FIG.
  • examples of the substituent of the C 6-14 aryl group, C 7-13 aralkyl group, C 8-13 arylalkenyl group, and aromatic heterocyclic group include those represented by R 1 or the like.
  • examples of the substituent that the C 6-14 aryl group and the like exemplified as the “hydrocarbon group” of the “good hydrocarbon group” may have may be mentioned.
  • nitrogen-containing heterocyclic ring optionally having substituent (s) formed by R 1 and R 2 together with the adjacent nitrogen atom is the “substituent group” formed by R A ′ and R B ′ together with the adjacent nitrogen atom. And the same as “nitrogen-containing heterocycle optionally having a”.
  • E is preferably a formula
  • X which is a group represented by the formula: is preferably —S— or —NR X —, more preferably —S—.
  • R X is preferably a hydrogen atom or an optionally substituted hydrocarbon group, more preferably (1) a hydrogen atom; or (2) (a) a halogen atom (preferably a fluorine atom), (b) a hydroxy group, (c) a mono- or di-C 1-6 alkyl-amino group (eg, dimethylamino), and (d) 1 to 3 C 1-6 alkyl groups (preferably methyl) A good 4- to 6-membered non-aromatic heterocyclic group (preferably pyrrolidinyl) A C 1-6 alkyl group (preferably methyl, ethyl, propyl, isobutyl) optionally substituted by 1 to 7 substituents selected from
  • R 1 is preferably a hydrogen atom, a hydrocarbon group which may have a substituent, or a heterocyclic group which may have a substituent, more preferably (1) hydrogen atom; (2) (a) a C 6-10 aryl group (preferably phenyl) optionally substituted with an amino group, (b) C 1-6 alkyl group (preferably methyl, ethyl), C 7-13 aralkyl group (preferably benzyl), C 1-6 alkoxy-carbonyl group (preferably tert-butoxycarbonyl) and oxo A 4- to 6-membered non-aromatic heterocyclic group (preferably pyrrolidinyl, tetrahydrofuryl, piperidinyl, piperazinyl, morpholinyl) optionally substituted by 1 to 3 substituents selected from the group, (c) a 5 to 9 member optionally substituted with a C 1-6 alkyl group (preferably methyl, ethyl) optionally substituted with a C 1-6
  • R 2 is preferably a hydrogen atom or an optionally substituted hydrocarbon group, more preferably (1) a hydrogen atom; (2) 1 to 3 substituents selected from a hydroxy group, a C 1-6 alkoxy group (preferably methoxy) and a mono- or di-C 1-6 alkyl-amino group (preferably dimethylamino) An optionally substituted C 1-6 alkyl group (preferably methyl, ethyl, propyl); or (3) a C 7-13 aralkyl group (preferably benzyl).
  • R 1 and R 2 together with the adjacent nitrogen atom (1) a cyano group, (2) a hydroxy group, (3) a C 1-6 alkoxy group (preferably methoxy, ethoxy) optionally substituted by 1 to 3 hydroxy groups, (4) selected from a halogen atom (preferably a fluorine atom), a hydroxy group, a C 1-6 alkoxy group (preferably methoxy) and a mono- or di-C 1-6 alkyl-amino group (preferably diethylamino)
  • a C 1-6 alkyl group (preferably methyl, ethyl, isopropyl) optionally substituted by 1 to 3 substituents, (5) a carboxy group, (6) C 1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, tert-butoxycarbonyl), (7) a carbamoyl group, (8) a C 1-6 alkyl-sulfonyl group (preferably ethylsulfonyl), (9)
  • R 1 and R 2 together with the adjacent nitrogen atom may form a 4- to 8-membered nitrogen-containing heterocyclic ring (preferably azetidine or pyrrolidine) which may be substituted with a hydroxy group. preferable.
  • R 3 is preferably an optionally substituted hydrocarbon group, more preferably 1 to 3 mono- or di-C 1-6 alkyl-amino groups (preferably diethylamino).
  • a C 1-6 alkyl group preferably methyl, ethyl which may be substituted with Of these, a C 1-6 alkyl group (preferably methyl) is preferable.
  • A represents a cyclic group which may have a substituent.
  • Examples of the “cyclic group” of the “cyclic group optionally having a substituent” represented by A include an aromatic group and a non-aromatic cyclic group.
  • aromatic group examples include an aromatic hydrocarbon group and an aromatic heterocyclic group.
  • aromatic hydrocarbon group is preferably a C 6-14 aryl group.
  • C 6-14 aryl group examples include those exemplified as the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by R 1 and the like.
  • aromatic heterocyclic group is the same as the “aromatic heterocyclic group” exemplified as the “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” represented by R 1 or the like. Is mentioned.
  • the aromatic group may have 1 to 3 substituents at substitutable positions. When there are two or more substituents, each substituent may be the same or different.
  • examples of the substituent of the aromatic group include a C 6-14 aryl group exemplified as the “hydrocarbon group” of the “hydrocarbon group which may have a substituent” represented by R 1 or the like. What was illustrated as a substituent which may be carried out is mentioned.
  • non-aromatic cyclic group examples include non-aromatic cyclic hydrocarbon groups and non-aromatic heterocyclic groups.
  • non-aromatic cyclic hydrocarbon group examples include C 3-10 cycloalkyl, C 3-10 cycloalkenyl, C 4-10 cycloalkadienyl, each of which may be condensed with a benzene ring. .
  • C 3-10 cycloalkyl C 3-10 cycloalkenyl, C 4-10 cycloalkadienyl, “hydrocarbon group of“ optionally substituted hydrocarbon group ”represented by R 1 or the like "”.
  • non-aromatic heterocyclic group is the same as the “non-aromatic heterocyclic group” exemplified as the “heterocyclic group” of the “heterocyclic group optionally having substituent (s)” represented by R 1 or the like. Can be mentioned.
  • the non-aromatic cyclic group may have 1 to 3 substituents at substitutable positions. When there are two or more substituents, each substituent may be the same or different.
  • the substituent of the non-aromatic cyclic group the C 3-10 cycloalkyl group exemplified as the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by R 1 or the like And those exemplified as the substituents that may be included.
  • A is preferably an optionally substituted C 6-10 aryl group (preferably phenyl, naphthyl), an optionally substituted 5- or 6-membered aromatic heterocyclic group ( Preferred is pyrazolyl, pyridyl), or a C 3-10 cycloalkyl group (preferably cyclohexyl, indanyl, tetrahydronaphthyl) which may have a substituent and may be condensed with a benzene ring.
  • C 6-10 aryl group preferably phenyl, naphthyl
  • an optionally substituted 5- or 6-membered aromatic heterocyclic group Preferred is pyrazolyl, pyridyl
  • a C 3-10 cycloalkyl group preferably cyclohexyl, indanyl, tetrahydronaphthyl
  • A is more preferably (1) (a) a C 1-6 alkyl group (preferably methyl, optionally substituted by 1 to 3 substituents selected from a halogen atom (preferably a fluorine atom), a cyano group and a hydroxy group; Ethyl, isopropyl, tert-butyl) (preferably trifluoromethyl), (b) a halogen atom (preferably a fluorine atom), a cyano group, a hydroxy group, a tri-C 1-6 alkyl-silyl-C 1-6 alkoxy group (preferably trimethylsilylethoxy) and a C 3-10 cycloalkyl group A C 1-6 alkoxy group (preferably methoxy, ethoxy, isopropoxy) (preferably trifluoromethoxy) optionally substituted with 1 to 3 substituents selected from (preferably cyclopropyl), (c) a halogen atom (preferably a fluorine atom, a chlorine atom, a
  • 1 to 3 preferably, C 1-6 alkyl group (preferably methyl) (preferably trifluoromethyl) optionally substituted with 1 to 3 halogen atoms (preferably fluorine atom)
  • 1 to 3 preferably a C 6-10 aryl group (preferably phenyl) which may be substituted with 1 to 2 substituents.
  • L a is a bond, -O -, - CO -, - S -, - SO -, - SO 2 -, - NR L1 - or -NR L1 -CO-;
  • the L b represents a C 1-3 alkylene group which may have a bond or a substituent;
  • L c is a bond, -CO -, - O-CO -, - NR L2 -CO -, - SO 2 - or -NR L2 -SO 2 -;
  • the R L1 and R L2 each independently have a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or a substituent.
  • a hydroxy group, an amino group which may have a substituent, or an acyl group is shown.
  • C 1-3 alkylene group of the "optionally substituted C 1-3 alkylene group” represented by L b, a methylene group, an ethylene group, a trimethylene group.
  • the “C 1-3 alkylene group” may have 1 to 3 substituents at substitutable positions. When there are two or more substituents, each substituent may be the same or different.
  • examples of the substituent of the C 1-3 alkylene group include a C 6-14 aryl group exemplified as the “hydrocarbon group” of the “hydrocarbon group which may have a substituent”. What was illustrated as a substituent which may be carried out is mentioned.
  • H hydrocarbon group optionally having substituent (s) represented by R L1 or R L2
  • Heterocyclic group optionally having substituent (s) “Hydroxy group optionally having substituent (s)”
  • L a is preferably a bond.
  • L b is preferably (1) a bond; or (2) (a) a C 1-6 alkyl group (preferably methyl, ethyl) optionally substituted by 1 to 3 hydroxy groups, (b) a carboxy group, (c) a C 1-6 alkoxy-carbonyl group (preferably isobutoxycarbonyl), (d) a carbamoyl group, (e) a C 3-10 cycloalkyl group (preferably cyclopropyl), and (f) a 4- to 6-membered non-aromatic heterocyclic group (preferably substituted with 1 to 3 hydroxy groups) (preferably , Oxetanyl)
  • a C 1-3 alkylene group preferably methylene, ethylene
  • they are a bond or a C 1-3 alkylene group (preferably methylene). Of these, a C 1-3 alkylene group (preferably methylene) is preferable.
  • L c is preferably a bond.
  • -L a -L b -L c- is preferably a linker connecting A and G with a maximum of 6 atoms or less, more preferably a bond, a C 1-3 alkylene group (preferably methylene, Ethylene). Of these, a C 1-3 alkylene group (preferably methylene) is preferable.
  • G is a formula
  • Z 1 represents a nitrogen atom, a carbon atom or —CR Z1 —
  • Z 2 represents a nitrogen atom, a carbon atom or —CR Z2 —
  • Z 3 represents a nitrogen atom, a carbon atom or —CR Z3 —
  • Z 4 represents a nitrogen atom, a carbon atom or —CR Z4 —
  • R Z1 , R Z2 , R Z3 and R Z4 each independently represent a hydrogen atom or a substituent
  • R 4 represents a hydrogen atom or a substituent
  • R 5 represents a hydrogen atom or a hydrocarbon group which may have a substituent.
  • Z 1 , Z 2 , Z 3 and Z 4 is a carbon atom, and E is bonded to the carbon atom. That is, when Z 1 is a carbon atom, Z 2 is a nitrogen atom or —CR Z2 —, Z 3 is a nitrogen atom or —CR Z3 —, and Z 4 is a nitrogen atom or —CR Z4 —. When Z 2 is a carbon atom, Z 1 is a nitrogen atom or —CR Z1 —, Z 3 is a nitrogen atom or —CR Z3 —, and Z 4 is a nitrogen atom or —CR Z4 —.
  • Z 1 is a nitrogen atom or —CR Z1 —
  • Z 2 is a nitrogen atom or —CR Z2 —
  • Z 4 is a nitrogen atom or —CR Z4 —
  • Z 4 is a carbon atom
  • Z 1 is a nitrogen atom or —CR Z1 —
  • Z 2 is a nitrogen atom or —CR Z2 —
  • Z 3 is a nitrogen atom or —CR Z3 —.
  • R Z1 , R Z2 , R Z3 , R Z4 and R 4 are “hydrocarbon groups” of the “hydrocarbon group optionally having substituents” represented by R 1 and the like.
  • R 1 substituents represented by R 1 and the like.
  • substituents represented by R 1 and the like.
  • substituents represented by R 1 and the like.
  • substituents that the C 3-10 cycloalkyl group and the like may have are exemplified.
  • R Z1 , R Z2 , R Z3 and R Z4 is preferably a C 1-6 alkoxy group (preferably methoxy).
  • R Z1 , R Z2 , R Z3 and R Z4 are preferably each independently a hydrogen atom or a C 1-6 alkoxy group (preferably methoxy).
  • Z 1 is preferably a nitrogen atom, a carbon atom or —CR Z1 —, more preferably a nitrogen atom, a carbon atom or —CH—.
  • Z 2 is preferably a carbon atom or —CR Z2 —, and more preferably a carbon atom or —CH—.
  • Z 3 is preferably a nitrogen atom, a carbon atom or —CR Z3 —, more preferably a nitrogen atom, a carbon atom or —CH—.
  • Z 4 is preferably a nitrogen atom or —CR Z4 —, more preferably a nitrogen atom, —CH— or —C (C 1-6 alkoxy group) —.
  • (Z 1 , Z 2 , Z 3 , Z 4 ) is preferably (—CH—, carbon atom, —CH—, —CH—), (—CH—, carbon atom, —CH—, —C ( OMe)-), (—CH—, —CH—, carbon atom, —CH—), (—CH—, carbon atom, nitrogen atom, —CH—), (carbon atom, —CH—, —CH—, —CH—), (—CH—, carbon atom, —CH—, nitrogen atom), or (nitrogen atom, carbon atom, nitrogen atom, —CH—).
  • (—CH—, carbon atom, —CH—, —CH—) is preferable.
  • the substituent represented by R 4 is preferably a halogen atom (preferably a bromine atom), a C 1-6 alkyl group (preferably methyl) or a C 1-6 alkoxy group (preferably methoxy).
  • R 4 is preferably a hydrogen atom, a halogen atom (preferably a bromine atom), a C 1-6 alkyl group (preferably methyl) or a C 1-6 alkoxy group (preferably methoxy). Of these, a hydrogen atom is preferable.
  • Examples of the hydrocarbon group optionally having a substituent represented by R 5 include those exemplified as R 1 and the like. Of these, a C 1-6 alkyl group (preferably methyl) is preferable.
  • R 5 is preferably a C 1-6 alkyl group (preferably methyl).
  • G is preferably a formula
  • (Z 1 , Z 2 , Z 3 , Z 4 ) is preferably (—CH—, carbon atom, —CH—, —CH—), and R 4 is preferably a hydrogen atom.
  • the group represented by the formula Ga is a formula
  • Z 3 is a nitrogen atom or —CH—;
  • Z 4 is a nitrogen atom or —CR Z4 —;
  • R Z4 is a hydrogen atom or a C 1-6 alkoxy group;
  • R 4 is a hydrogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
  • R 5 is a C 1-6 alkyl group.
  • G is more preferably the formula
  • Compound IA is (1) (a) a C 1-6 alkyl group (preferably methyl, optionally substituted by 1 to 3 substituents selected from a halogen atom (preferably a fluorine atom), a cyano group and a hydroxy group; Ethyl, isopropyl, tert-butyl) (preferably trifluoromethyl), (b) a halogen atom (preferably a fluorine atom), a cyano group, a hydroxy group, a tri-C 1-6 alkyl-silyl-C 1-6 alkoxy group (preferably trimethylsilylethoxy) and a C 3-10 cycloalkyl group A C 1-6 alkoxy group (preferably methoxy, ethoxy, isopropoxy) (preferably trifluoromethoxy) optionally substituted with 1 to 3 substituents selected from (preferably cyclopropyl), (c) a halogen atom (
  • a group represented by: Z 1 is a nitrogen atom, a carbon atom or —CR Z1 —;
  • Z 2 is a carbon atom or —CR Z2 —;
  • Z 3 is a nitrogen atom, a carbon atom or —CR Z2 —;
  • Z 4 is a nitrogen atom or —CR Z4 —;
  • R Z1 , R Z2 , R Z2 and R Z4 are each independently a hydrogen atom or a C 1-6 alkoxy group (preferably methoxy);
  • R 4 is a hydrogen atom, a halogen atom (preferably a bromine atom), a C 1-6 alkyl group (preferably methyl) or a C 1-6 alkoxy group (preferably methoxy);
  • R 5 is a C 1-6 alkyl group (preferably methyl);
  • E is the formula
  • a group represented by: X is —S— or —NR X —; R X is (1) a hydrogen atom; or (2) (a) a halogen atom (preferably a fluorine atom), (b) a hydroxy group, (c) a mono- or di-C 1-6 alkyl-amino group (eg, dimethylamino), and (d) 1 to 3 C 1-6 alkyl groups (preferably methyl)
  • a good 4- to 6-membered non-aromatic heterocyclic group preferably pyrrolidinyl
  • a C 1-6 alkyl group preferably methyl, ethyl, propyl, isobutyl
  • R 1 is (1) hydrogen atom; (2) (a) a C 6-10 aryl group (preferably phenyl) optionally substituted with an amino group, (b) C 1-6 alkyl group (preferably methyl, ethyl), C 7-13 aralkyl group (preferably benzy
  • R 1 and R 2 together with the adjacent nitrogen atom, (1) a cyano group, (2) a hydroxy group, (3) a C 1-6 alkoxy group (preferably methoxy, ethoxy) optionally substituted by 1 to 3 hydroxy groups, (4) selected from a halogen atom (preferably a fluorine atom), a hydroxy group, a C 1-6 alkoxy group (preferably methoxy) and a mono- or di-C 1-6 alkyl-amino group (preferably diethylamino)
  • a C 1-6 alkyl group (preferably methyl, ethyl, isopropyl) optionally substituted by 1 to 3 substituents, (5) a carboxy group, (6) C 1-6 alkoxy-carbonyl group (preferably methoxycarbonyl, tert-butoxycarbonyl), (7) a carbamoyl group, (8) a C 1-6 alkyl-sulfonyl group (preferably ethylsulfonyl), (
  • [Compound I-A1] (Z 1 , Z 2 , Z 3 , Z 4 ) is (—CH—, carbon atom, —CH—, —CH—), (—CH—, carbon atom, —CH—, —C (OMe) —) , (—CH—, —CH—, carbon atom, —CH—), (—CH—, carbon atom, nitrogen atom, —CH—), (carbon atom, —CH—, —CH—, —CH—) (Compound IA), (—CH—, carbon atom, —CH—, nitrogen atom), or (nitrogen atom, carbon atom, nitrogen atom, —CH—).
  • A is a C 1-6 alkyl group (preferably methyl) (preferably trifluoromethyl) optionally substituted with 1 to 3 halogen atoms (preferably a fluorine atom)
  • L a is a bond hand;
  • L b is a C 1-3 alkylene group (preferably methylene);
  • L c is a bond;
  • G is the formula
  • a group represented by: E is the formula
  • Compound (I) may be a salt, and the salt of compound (I) is preferably a pharmacologically acceptable salt.
  • the salt of compound (I) include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, and a salt with a basic or acidic amino acid.
  • salts with inorganic bases include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt; magnesium salt; aluminum salt; ammonium salt.
  • salt with an organic base examples include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine and the like.
  • salt with inorganic acid examples include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • the salt with organic acid include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluenesulfonic acid and the like.
  • salts with basic amino acids include salts with arginine, lysine, ornithine and the like.
  • salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • the salt of compound (I) is preferably a salt with an inorganic acid (preferably hydrochloric acid) or an organic acid (preferably fumaric acid).
  • Compound (I) may be a prodrug, and as a prodrug of compound (I), a compound that is converted into compound (I) by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically A compound that undergoes oxidation, reduction, hydrolysis or the like and changes to compound (I), or a compound that undergoes hydrolysis or the like by gastric acid or the like and changes to compound (I).
  • a compound in which the amino group of the compound (I) is acylated, alkylated or phosphorylated eg, the amino group of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated
  • the amino group of the compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated
  • 5-methyl-2-oxo-1,3-dioxolen-4-yl methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylated compound
  • compound Compounds wherein the hydroxy group of (I) is acylated, alkylated, phosphorylated, borated eg, the hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succiny
  • the prodrug of compound (I) is a compound that changes to compound (I) under physiological conditions as described in Hirokawa Shoten 1990, “Drug Development”, Volume 7, Molecular Design, pages 163 to 198. It may be.
  • Compound (I) may be labeled with an isotope (eg, 2 H, 3 H, 14 C, 35 S, 125 I, 11 C, 18 F) or the like.
  • an isotope eg, 2 H, 3 H, 14 C, 35 S, 125 I, 11 C, 18 F
  • the compound (I) labeled or substituted with an isotope can be used, for example, as a tracer (PET tracer) used in positron emission tomography (PET), and is useful in fields such as medical diagnosis.
  • PET tracer positron emission tomography
  • compound (I) may be an anhydride or a hydrate.
  • Compound (I) may be a solvate or a solvate. Further, compound (I) may be a deuterium converter.
  • the compound (I) may be a crystal, and it is included in the compound (I) regardless of whether the crystal form is single or a crystal form mixture.
  • the crystal can be produced by crystallization by applying a crystallization method known per se.
  • Compound (I) may be a pharmaceutically acceptable cocrystal or cocrystal salt.
  • a co-crystal or co-crystal salt is composed of two or more unique solids at room temperature, each having different physical properties (eg structure, melting point, heat of fusion, hygroscopicity and stability). Means crystalline material.
  • the cocrystal or cocrystal salt can be produced according to a cocrystallization method known per se.
  • compound (I) contains an isomer such as an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, a geometric isomer, etc.
  • an isomer such as an optical isomer, a stereoisomer, a positional isomer, a rotational isomer, a geometric isomer, etc.
  • either one of the isomers or a mixture is combined with compound (I).
  • compound (I) there exists a geometric isomer based on the double bond of the moiety where E is bonded to ring G, and the geometric isomer based on the double bond (E-form and Z-form)
  • E-form and Z-form One and mixtures thereof are also encompassed in Compound (I).
  • E is the formula
  • isomers due to conformation may be produced, and such isomers or mixtures thereof are also included in the compound (I) of the present invention.
  • Each of these isomers can be obtained as a single product by a synthesis method and a separation method known per se (eg, concentration, solvent extraction, column chromatography, recrystallization).
  • a separation method known per se eg, concentration, solvent extraction, column chromatography, recrystallization.
  • the optical isomer resolved from the compound is also encompassed in compound (I).
  • the optical isomer can be produced by a method known per se. Specifically, an optically active synthetic intermediate is used, or an optical isomer is obtained by optical resolution of the final racemate according to a conventional method.
  • optical resolution method a method known per se, for example, a fractional recrystallization method, a chiral column method, or a diastereomer method is used.
  • 1) Fractional recrystallization method Racemate and optically active compound (eg, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine) to form a salt, which is separated by fractional recrystallization, and if desired, a free optical isomer is obtained through a neutralization step.
  • optically active compound eg, (+)-mandelic acid, ( ⁇ )-mandelic acid, (+)-tartaric acid, ( ⁇ )-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-
  • Chiral column method A method in which a racemate or a salt thereof is separated by applying to an optical isomer separation column (chiral column).
  • an optical isomer separation column chiral column
  • a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation), CHIRAL series (manufactured by Daicel Chemical Industries), and water, various buffer solutions (eg, phosphate buffer). Liquid) and an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine) are developed as a single or mixed solution to separate optical isomers.
  • an organic solvent eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine
  • Diastereomer method A mixture of racemates is converted into a mixture of diastereomers by a chemical reaction with an optically active reagent, and this mixture is subjected to normal separation means (eg, fractional recrystallization method, chromatography method) and the like.
  • normal separation means eg, fractional recrystallization method, chromatography method
  • the compound (I) when the compound (I) has a hydroxyl group or a primary or secondary amino group in the molecule, the compound and an optically active organic acid (eg, MTPA [ ⁇ -methoxy- ⁇ - (trifluoromethyl) phenylacetic acid] , (-)-Menthoxyacetic acid) and the like are subjected to a condensation reaction, whereby ester or amide diastereomers are obtained, respectively.
  • an amide or ester diastereomer when the compound (I) has a carboxyl group in the molecule, an amide or ester diastereomer is obtained by subjecting the compound and an optically active amine or optically active alcohol to a condensation reaction. The separated diastereomer is converted to the optical isomer of the original compound by subjecting it to an acid hydrolysis or basic hydrolysis reaction.
  • Compound (I) or a prodrug thereof has low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity)
  • a mammal eg, human, mouse
  • a pharmaceutical composition sometimes referred to herein as “the pharmaceutical of the present invention”.
  • Rats, hamsters, rabbits, dogs, cats, cows, horses, pigs, sheep, monkeys can be used as preventive or therapeutic agents for various diseases described below.
  • the pharmacologically acceptable carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations , Solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
  • excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light
  • excipients include anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminate metasilicate.
  • lubricant examples include magnesium stearate, calcium stearate, talc and colloidal silica.
  • Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples include propylmethylcellulose and polyvinylpyrrolidone.
  • disintegrant examples include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropyl cellulose.
  • Suitable examples of the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Is mentioned.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone , Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate
  • polyvinyl alcohol, polyvinylpyrrolidone Hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
  • Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.
  • buffer solutions such as phosphate, acetate, carbonate and citrate.
  • Benzyl alcohol is a preferred example of the soothing agent.
  • Preferable examples of the preservative include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.
  • antioxidant examples include sulfite and ascorbate.
  • the colorant examples include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (Eg, the aluminum salt of the water-soluble edible tar dye), natural dyes (eg, ⁇ -carotene, chlorophyll, bengara) and the like.
  • water-soluble edible tar dyes eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.
  • water-insoluble lake dyes Eg, the aluminum salt of the water-soluble edible tar dye
  • natural dyes eg, ⁇ -carotene, chlorophyll, bengara
  • Suitable examples of sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.
  • Examples of the pharmaceutical dosage form of the present invention include tablets (including sublingual tablets and orally disintegrating tablets), capsules (including soft capsules and microcapsules), granules, powders, troches, syrups, emulsions, Oral preparations such as suspensions; and injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, infusions), external preparations (eg, transdermal preparations, ointments), Examples include suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), ophthalmic preparations and the like, and these are safe orally or parenterally. Can be administered.
  • tablets including sublingual tablets and orally disintegrating tablets
  • capsules including soft capsules and microcapsules
  • granules powders, troches, syrups, emulsions, Oral preparations such as suspensions
  • injections
  • compositions may be controlled-release preparations (eg, sustained-release microcapsules) such as immediate-release preparations or sustained-release preparations.
  • the medicament of the present invention can be produced by a method commonly used in the field of pharmaceutical technology, for example, a method described in the Japanese Pharmacopoeia.
  • the content of the compound of the present invention in the medicament of the present invention varies depending on the dosage form, the dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight.
  • the compound of the present invention exhibits excellent activity as an estrogen-related receptor alpha (ERR ⁇ ) modulator (particularly an inverse agonist).
  • ERP ⁇ estrogen-related receptor alpha
  • ERR ⁇ modulator means a compound having a function of regulating various actions of ERR ⁇ , and includes ERR ⁇ agonist (agonist), ERR ⁇ antagonist (antagonist), ERR ⁇ inverse agonist (inverse agonist), and the like. .
  • ERR ⁇ inverse agonist means a compound that inhibits the original function of ERR ⁇ .
  • the compound of the present invention and the medicament of the present invention are ERR ⁇ related to mammals (eg, humans, mice, rats, hamsters, rabbits, dogs, cats, cows, horses, pigs, sheep, monkeys, preferably humans). Effective for prevention and treatment of diseases.
  • mammals eg, humans, mice, rats, hamsters, rabbits, dogs, cats, cows, horses, pigs, sheep, monkeys, preferably humans. Effective for prevention and treatment of diseases.
  • the compound of the present invention has high metabolic stability.
  • the compound of the present invention is highly soluble and exhibits a high medicinal effect in vivo.
  • (A) Malignant tumors eg, colon cancer (eg, familial colorectal cancer, hereditary non-polyposis colorectal cancer, gastrointestinal stromal tumor), lung cancer (eg, non-small cell lung cancer, small cell lung cancer, malignant mesothelioma) , Mesothelioma, pancreatic cancer (eg, pancreatic duct cancer), gastric cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenosquamous carcinoma), breast cancer (eg, invasive ductal carcinoma, non-invasive ductal carcinoma, inflammation) Breast cancer), ovarian cancer (eg, epithelial ovarian cancer, extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low-grade tumor), prostate cancer (eg, hormone-dependent prostate cancer, hormone-independent prostate cancer) ), Liver cancer (eg, primary liver cancer, extra liver cancer, extra liver cancer, extra liver cancer, extra
  • brain tumors e.g. pineal astrocytoma, ciliary astrocytoma, diffuse astrocytoma, anaplastic astrocytoma), melanoma (e.g. Norma), sarcoma, bladder cancer, blood cancer (e.g., multiple myeloma, a disease or condition associated with malignant lymphomas));
  • B Hyperglycemia, insulin insensitivity, diabetes, obesity, hyperlipidemia, hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, hypertension, hyperinsulinemia, hyperuricemia Diseases or conditions associated with metabolic syndrome, including diseases or combinations thereof;
  • C diseases or conditions associated with bone or cartilage including arthritis, osteoarthritis and rheumatoid arthritis;
  • D inflammatory diseases, conditions or conditions resulting from the release of pro-inflammatory cytokines including rheumatoid arthritis, atherosclerosis and atopic dermatitis; and
  • the compound of the present invention is a cancer preventive or therapeutic agent, particularly a solid cancer in which increased expression of ERR ⁇ is confirmed (eg, breast cancer, malignant lymphoma, multiple myeloma, prostate cancer, colon cancer, lung cancer, ovarian cancer, intrauterine It is useful as a preventive or therapeutic agent for membrane cancer).
  • a cancer preventive or therapeutic agent particularly a solid cancer in which increased expression of ERR ⁇ is confirmed (eg, breast cancer, malignant lymphoma, multiple myeloma, prostate cancer, colon cancer, lung cancer, ovarian cancer, intrauterine It is useful as a preventive or therapeutic agent for membrane cancer).
  • prevention of a disease refers to, for example, a patient who has not developed the disease, which is expected to have a high risk of onset due to some factor related to the disease, or a subjective symptom. This means that the compound of the present invention is administered to a patient who does not have the disease, or the compound of the present invention is administered to a patient who is concerned about recurrence of the disease after treatment of the disease.
  • the dose of the compound of the present invention to a mammal varies depending on the administration subject, administration route, target disease, symptom, and the like. 0.01 to 100 mg / kg body weight, preferably 0.05 to 30 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight, more preferably 0.5 to 10 mg / kg body weight. It is desirable to administer 1 to 3 times a day.
  • the compound of the present invention when orally administered to an adult prostate cancer patient, it is usually about 0.01 to 100 mg / kg body weight, preferably 0.1 to 30 mg / kg body weight, more preferably 0.
  • the dosage is 5 to 10 mg / kg body weight, and it is desirable to administer this amount once to three times a day.
  • the compound of the present invention is a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, a therapeutic agent for hyperlipidemia, an antihypertensive agent, an anti-obesity agent, a diuretic agent, a chemotherapeutic agent, an immunotherapeutic agent, an action of cell growth factor and its receptor.
  • Can be used in combination with drugs such as anti-thrombotic agents, antithrombotic agents, osteoporosis therapeutic agents, and anti-dementia agents (hereinafter abbreviated as concomitant drugs).
  • the administration time of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject at the same time or may be administered with a time difference.
  • the compound of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.
  • diabetes therapeutic agents include insulin preparations (eg, animal insulin preparations extracted from bovine and porcine pancreas; human insulin preparations synthesized by genetic engineering using E. coli or yeast; insulin zinc; protamine insulin zinc; Insulin fragments or derivatives (eg, INS-1), oral insulin preparations), insulin resistance improvers (eg, pioglitazone or its hydrochloride, rosiglitazone or its maleate), PPAR ⁇ agonists, PPAR ⁇ antagonists, PPAR ⁇ / ⁇ Dual agonists, ⁇ -glucosidase inhibitors (eg, voglibose, acarbose, miglitol, emiglitate), biguanides (eg, phenformin, metformin, buformin or their salts (eg, hydrochloride, fumarate, succinate)) , Insulin Secretion enhancer [sulfonylurea (eg, tolbutamide, glibenclamide,
  • Examples of therapeutic agents for diabetic complications include aldose reductase inhibitors (eg, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, CT-112), neurotrophic factors and their increasing agents (eg, NGF, NT-3, BDNF, neurotrophin production / secretion promoters described in WO01 / 14372 (eg, 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) -5- [3- (2-methylphenoxy) propyl] oxazole)), nerve regeneration promoter, PKC inhibitor (eg, ruboxistaurin mesylate), AGE inhibitor (eg, ALT946, pimagedin, N-phenacylthiazo) Lithium bromide (ALT766), ALT-711, EXO-226, pyridoline (Pyridorin), pyridoxamine), active oxygen scavenger (eg, thi
  • HMG-CoA reductase inhibitors eg, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin or salts thereof (eg, sodium salt, calcium salt)
  • Squalene synthase inhibitors eg, fibrate compounds (eg, bezafibrate, clofibrate, simfibrate, clinofibrate), ACAT inhibitors (eg, Avasimibe, eflucimibe), anion exchange resins (eg, cholestyramine) ), Probucol, nicotinic acid drugs (eg, nicomol, niceritrol), ethyl icosapentate, plant sterols (eg, soysterol, gamma-oryzanol).
  • HMG-CoA reductase inhibitors eg, pravastatin, simvastatin, lov
  • antihypertensive agents include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril), angiotensin II receptor antagonists (eg, candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan, 1- [ [2 '-(2,5-Dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethoxy-1H-benzimidazole-7 -Carboxylic acid), calcium antagonists (eg, manidipine, nifedipine, amlodipine, efonidipine, nicardipine), potassium channel openers (eg, lebucromakalim, L-27152, AL 0671, NIP-121) and clonidine.
  • Anti-obesity agents include, for example, central anti-obesity drugs (eg, dexfenfluramine, fenfluramine, phentermine, sibutramine, ampepramon, dexamphetamine, mazindol, phenylpropanolamine, clobenzorex; MCH receptor antagonist Drugs (eg, SB-568849; SNAP-7941; compounds described in WO01 / 82925 and WO01 / 87834); neuropeptide Y antagonists (eg, CP-422935); cannabinoid receptor antagonists (eg, SR-141716, SR-147778); ghrelin antagonist), pancreatic lipase inhibitor (eg, orlistat, ATL-962), ⁇ 3 agonist (eg, AJ-9677), peptidic appetite suppressant (eg, leptin, CNTF (ciliary nerve) Nutritional factors)), cholecystokinin agonists (e
  • diuretic examples include xanthine derivatives (eg, sodium salicylate theobromine, calcium salicylate theobromine), thiazide preparations (eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide.
  • xanthine derivatives eg, sodium salicylate theobromine, calcium salicylate theobromine
  • thiazide preparations eg, etiazide, cyclopenthiazide, trichloromethiazide, hydrochlorothiazide, hydroflumethiazide, benchylhydrochlorothiazide, pentfurizide, polythiazide.
  • Methiclotiazide e.g., Methiclotiazide
  • anti-aldosterone preparations e.g, spironolactone, triamterene
  • carbonic anhydrase inhibitors e.g, acetazolamide
  • chlorobenzenesulfonamide preparations eg, chlorthalidone, mefluside, indapamide
  • azosemide isosorbide
  • ethacrynic acid Piretanide
  • bumetanide furosemide.
  • chemotherapeutic agents include alkylating agents (eg, nitrogen mustard, nitrogen mustard hydrochloride-N-oxide, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carbocon, improsulfan tosylate, busulfan, nimustine hydrochloride) , Mitobronitol, melphalan, dacarbazine, ranimustine, estramustine phosphate sodium, triethylenemelamine, carmustine, lomustine, streptozocin, piprobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, dibromustine hydrochloride Pidium, fotemustine, prednimustine, pumitepa, ribomustine, temozolomide, treosulphane, trof Sufamide, dinostatin st
  • immunotherapeutic agents include picibanil, krestin, schizophyllan, lentinan, ubenimex, interferon, interleukin, macrophage colony stimulating factor, granulocyte colony stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, corynebacterium parvum, levamisole , Polysaccharide K, procodazole, and anti-CTLA4 antibody.
  • agents that inhibit the action of cell growth factors and their receptors include anti-VEGF antibodies (eg, Bevacizumab), anti-HER2 antibodies (eg, Trastuzumab, Pertuzumab), anti-EGFR antibodies (eg, Cetuximab, Panitumumab, Matuzumab, Nimotuzumab), anti-VEGFR antibody, anti-HGF antibody, Imatinib mesylate, Erlotinib, Gefitinib, Sorafenib, Sunitinib, Dasatinib, Lapatinib, Vatalanib, 4- (4-fluoro-2-methyl-1H-indol-5-yloxy) -6- Methoxy-7- [3- (1-pyrrolidinyl) propoxy] quinazoline (AZD-2171), Lestaurtinib, Pazopanib, Canertinib, Tandutinib, 3- (4-bromo-2,6-difluor
  • Antithrombotic agents include, for example, heparin (eg, heparin sodium, heparin calcium, dalteparin sodium), warfarin (eg, warfarin potassium), antithrombin drug (eg, argatroban), thrombolytic agent (Eg, urokinase, tisokinase,reteplase, nateplase, monteplase, pamitepase), platelet aggregation inhibitors (eg, ticlopidine hydrochloride, cilostazol) cilostazol), ethyl icosapentate, beraprost sodium, sarpogrelate hydrochloride).
  • heparin eg, heparin sodium, heparin calcium, dalteparin sodium
  • warfarin eg, warfarin potassium
  • antithrombin drug eg, argatroban
  • thrombolytic agent Eg, urokinase,
  • osteoporosis therapeutic agents include alfacalcidol, calcitriol, elcatonin, salmon calcitonin salmon, estriol, ipriflavone, risedronate disodium (risedronate) disodium), pamidronate disodium, alendronate sodium hydrate, reminderonate disodium.
  • anti-dementia agents examples include tacrine, donepezil, rivastigmine, and galanthamine.
  • drugs that have been shown to improve cachexia in animal models and clinically: cyclooxygenase inhibitors (eg, indomethacin), progesterone derivatives (eg, megestrol acetate), carbohydrate steroids (eg, dexamethasone), metoclopramide Drugs, tetrahydrocannabinols, fat metabolism improvers (eg, eicosapentaenoic acid), growth hormone, IGF-1, or cachexia-inducing factors TNF- ⁇ , LIF, IL-6, oncostatin An antibody against M can also be used in combination with the compound of the present invention.
  • cyclooxygenase inhibitors eg, indomethacin
  • progesterone derivatives eg, megestrol acetate
  • carbohydrate steroids eg, dexamethasone
  • metoclopramide Drugs etrahydrocannabinols
  • fat metabolism improvers eg,
  • the above concomitant drugs may be used in combination of two or more at an appropriate ratio.
  • the amount of each agent can be reduced within a safe range in consideration of the opposite effect of those agents. Thus, the adverse effects that would be caused by these agents can be safely prevented.
  • the compound of the present invention can be used in combination with non-drug therapy.
  • non-drug therapy (1) surgery; (2) pressor chemotherapy using angiotensin II or the like; (3) gene therapy; (4) hyperthermia; (5) cryotherapy; (6) Laser ablation method; (7) radiotherapy; (8) immunotherapy.
  • Compound (I) can be produced, for example, by the method shown by the following reaction formula or a method analogous thereto.
  • the compound in the reaction formula may form a salt. Examples of such a salt include the same salts as those of the aforementioned compound (I).
  • the compound obtained in each step in the reaction formula can be used in the next reaction as a reaction mixture or as a crude product, but is concentrated, extracted, recrystallized, distilled, chromatographed from the reaction mixture according to a conventional method. It may be used after isolation and purification by known means such as.
  • a schematic diagram of the reaction formula is shown below, and each symbol of the compound in the schematic diagram has the same meaning as described above.
  • Step 1-1 This step is a step for producing compound (IV) by reacting compound (II) with compound (III) in the presence of a base.
  • the starting compound (II) is commercially available, or a method known per se [for example, Journal of the Chemical Society, 1644 (1956); Journal of the Chemical Society, 389 (1954); Journal of the American Chemical Society, 81, 6498 (1959); Journal of the American Chemical Society, 57, 2627 (1935)] or a method analogous thereto.
  • the starting compound (III) is commercially available, or a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (Richard C. Larock) And the method according to these methods.
  • the amount of compound (II) to be used is generally 0.1 to 10 molar equivalents relative to compound (III).
  • Bases include primary amines, secondary amines (eg, piperidine), organic bases such as tertiary amines, and salts thereof; or potassium fluoride, cesium fluoride, ammonium acetate, sodium hydride, potassium carbonate, carbonic acid Examples thereof include inorganic bases such as cesium and potassium tert-butoxide.
  • the amount of the base to be used is generally 0.1 to 10 molar equivalents, preferably 0.5 to 5 molar equivalents, relative to compound (III). This reaction is usually performed in an inert solvent.
  • the inert solvent examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetonitrile, and the like. Is mentioned. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Step 1-2 This step is a step of producing compound (V) by reacting compound (IV) with Lawesson's reagent or P 2 S 5 .
  • the amount of Lawesson reagent or P 2 S 5 to be used is generally 1-10 molar equivalents, preferably 1-5 molar equivalents, relative to compound (IV).
  • This reaction is usually performed in an inert solvent.
  • the inert solvent include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, methanol, ethanol, N, N-dimethylformamide, dimethyl sulfoxide and the like. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Step 1-3 When R 3 of compound (V) is a hydrogen atom, compound (V) and an amine represented by the formula: R 1 R 2 NH (wherein each symbol is as defined above) or a salt thereof Compound (Ia) can be produced by reacting.
  • the amount of the amine represented by the formula: R 1 R 2 NH or a salt thereof to be used is generally 1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, relative to compound (V). This reaction is usually performed in an inert solvent.
  • inert solvent examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetonitrile, and the like. It is done. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • This reaction is performed under microwave irradiation as necessary.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • an inorganic base such as sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide or the like is added to the reaction system. Progress can be accelerated.
  • the amount of the inorganic base used is usually 1 molar equivalent or more with respect to the amine salt represented by the formula: R 1 R 2 NH.
  • the amine represented by the formula: R 1 R 2 NH or a salt thereof a commercially available one can be used, or it can be produced by a method known per se.
  • Step 1-4 When R 3 of compound (V) is not a hydrogen atom, compound (V) is reacted with an amine represented by the formula: R 1 NH 2 (wherein each symbol is as defined above) or a salt thereof. Thus, compound (Ib) can be produced. This reaction can be carried out by the same method as in the above step 1-3.
  • the amine represented by the formula: R 1 NH 2 or a salt thereof is commercially available, or can be produced by a method known per se.
  • Step 1-5 This step is a step for producing compound (V) by reacting compound (VI) with compound (III) in the presence of a base.
  • the starting compound (VI) is commercially available, or a method known per se [for example, the method described in European Journal of Medicinal Chemistry, 44, 2038 (2009); European Journal of Medicinal Chemistry, 44, 3272 (2009) ] Or a method according to these methods. This reaction can be carried out by the same method as in the above step 1-1.
  • Compound (Ia) and Compound (Ib) can also be produced by the following production method or a method analogous thereto.
  • Step 2-1 When R 3 of compound (VI) is a hydrogen atom, compound (VII) can be produced by reacting compound (VI) with an amine represented by the formula: R 1 R 2 NH or a salt thereof. it can. This reaction can be carried out by the same method as in Step 1-3 of Production Method 1 described above.
  • Step 2-2 This step is a step for producing compound (Ia) by reacting compound (VII) with compound (III) in the presence of a base. This reaction can be carried out by the same method as in Step 1-1 of Production Method 1 described above.
  • Step 2-3 When R 3 of compound (VI) is not a hydrogen atom, compound (VIII) can be produced by reacting compound (VI) with an amine represented by the formula: R 1 NH 2 or a salt thereof. This reaction can be carried out by the same method as in Step 1-3 of Production Method 1 described above.
  • Step 2-4 This step is a step for producing compound (Ib) by reacting compound (VIII) with compound (III) in the presence of a base. This reaction can be carried out by the same method as in Step 1-1 of Production Method 1 described above.
  • Compound (Ia) can also be produced by the following production method or a method analogous thereto.
  • J represents a leaving group, and other symbols are as defined above.
  • the leaving group represented by J include a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), C 1-6 alkyl- (which may be substituted with 1 to 3 halogen atoms).
  • a C 6-14 aryl-sulfonyloxy group eg, methanesulfonyloxy group, toluenesulfonyloxy group, trifluoromethanesulfonyloxy group
  • 2 2,2-trichloroethane imidate group and the like e.g, fluorine atom, chlorine atom, bromine atom, iodine atom
  • C 1-6 alkyl- which may be substituted with 1 to 3 halogen atoms
  • a C 6-14 aryl-sulfonyloxy group eg, methanesulfonyloxy group, toluene
  • Step 3-1 This step is a step for producing a compound (IX) by reacting the compound (V ′) with a compound represented by the formula: CH 3 —J.
  • the amount of the compound represented by the formula: CH 3 —J to be used is generally 1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, relative to compound (V ′). This reaction is usually performed in an inert solvent in the presence of a base.
  • the inert solvent examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide and the like. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • tertiary amines or inorganic bases such as sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide, and the like can be used. Of these, potassium carbonate is preferable.
  • the amount of the base to be used is generally 1-10 molar equivalents, preferably 1-5 molar equivalents, relative to compound (V ′).
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • Step 3-2 This step is a step for producing compound (Ia) by reacting compound (IX) with an amine represented by the formula: R 1 R 2 NH or a salt thereof.
  • the amount of the amine represented by the formula: R 1 R 2 NH or a salt thereof to be used is generally 1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, relative to compound (IX). This reaction is usually performed in an inert solvent.
  • inert solvent examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetonitrile, and the like. It is done. Two or more of these solvents may be mixed and used at an appropriate ratio. This reaction is performed in the presence of methyl acrylate as necessary.
  • the amount of methyl acrylate to be used is generally 1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, relative to compound (IX).
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • an inorganic base such as sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide or the like is added to the reaction system. Progress can be accelerated.
  • the amount of the inorganic base used is usually 1 molar equivalent or more with respect to the amine salt represented by the formula: R 1 R 2 NH.
  • the amine represented by the formula: R 1 R 2 NH or a salt thereof a commercially available one can be used, or it can be produced by a method known per se.
  • Step 4-1 This step is a step for producing compound (Ic) by reacting compound (Id) with a compound represented by the formula: R 2 -J.
  • the amount of the compound represented by the formula: R 2 -J to be used is generally 1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, relative to compound (Id).
  • This reaction is usually performed in an inert solvent in the presence of a base.
  • the inert solvent include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide and the like. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • inorganic bases such as sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide and the like can be used. Of these, potassium carbonate is preferable.
  • the amount of the base to be used is generally 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (Id).
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • As the compound represented by the formula: R 2 -J a commercially available product can be used, or it can be produced by a method known per se.
  • Step 5-1 This step is a step for producing compound (Ie) by reacting compound (Id) with a compound represented by the formula: R 3 -J.
  • This reaction can be carried out by the same method as in Step 4-1 of Production Method 4 described above.
  • the compound represented by the formula: R 3 -J a commercially available compound can be used, or it can be produced by a method known per se.
  • X is -NR X -
  • Compound (Ig) among the compounds (Ib), X is -NR X - and a compound wherein R 1 is a hydrogen atom (If) is the following production methods Or it can manufacture also by the method according to these.
  • Step 6-1 This step is a step for producing a compound (XII) by reacting an isocyanate derivative (X) with an aminoacetonitrile derivative (XI) or a salt thereof.
  • Isocyanate derivatives (X) and aminoacetonitrile derivatives (XI) are commercially available, or are known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd”. Ed. “(By Richard C. Larock)] or a method analogous thereto.
  • the amount of aminoacetonitrile derivative (XI) or a salt thereof used is usually 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to the isocyanate derivative (X).
  • This reaction is usually performed in an inert solvent.
  • the inert solvent include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide and the like. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • an organic base eg, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -undec-7
  • inorganic bases eg, potassium carbonate, cesium carbonate
  • the amount of such base to be used is generally 0.5 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to the salt of aminoacetonitrile derivative (XI).
  • Step 6-2 This step is a step for producing compound (XIII) by reacting compound (XII) with a base.
  • a base for example, triethylamine, 1,8-diazabicyclo [5.4.0] -undec-7-ene, potassium carbonate, cesium carbonate, sodium hydride, potassium tert-butoxide and the like can be used. Sodium and potassium tert-butoxide are preferred.
  • the amount of the base to be used is generally 1 to 20 molar equivalents, preferably 1 to 10 molar equivalents, relative to compound (XII). This reaction is usually performed in an inert solvent.
  • inert solvent examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetonitrile, and the like. Is mentioned. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Compound (XIII) can also be produced from compound (X) in one step without going through compound (XII).
  • Step 6-3 This step is a step for producing compound (If) by reacting compound (XIII) with compound (III) in the presence of a base. This reaction can be carried out by the same method as in Step 1-1 of Production Method 1 described above.
  • Step 6-4 In this step, compound (Ig) is produced by reacting compound (If) with an amine represented by the formula: R 1 NH 2 or a salt thereof. This reaction can be carried out by the same method as in Step 1-3 of Production Method 1 described above.
  • X is —NR X — and R 2 is a hydrogen atom.
  • X is —NR X — and R 1 and R 2 are hydrogen atoms.
  • Compound (Ih) can also be produced by the following production method or a method analogous thereto.
  • Step 7-1 This step is a step for producing compound (Ih) by reacting compound (XIII ′) with compound (III) in the presence of a base.
  • the starting compound (XIII ′) can be produced through Step 6-2 using benzoyl isocyanate as the isocyanate derivative (X) in Step 6-1 of Production Method 6 described above. This reaction can be carried out by the same method as in Step 1-1 of Production Method 1 described above.
  • Step 7-2 This step is a step for producing compound (Ii) by reacting compound (Ih) with an amine represented by the formula: R 1 NH 2 or a salt thereof. This reaction can be carried out by the same method as in Step 1-3 of Production Method 1 described above.
  • Step 8-1 compound (If) is produced by reacting compound (Ij) with a compound represented by the formula: R X -J.
  • This reaction can be carried out by the same method as in Step 4-1 of Production Method 4 described above.
  • the starting compound (Ij) can be produced through Step 6-2 and Step 6-3 using H 2 NCH 2 CN as the aminoacetonitrile derivative (XI) in Step 6-1 of Production Method 6 described above.
  • R X -J a commercially available product can be used, or it can be produced by a method known per se.
  • Step 9-1 This step is a step for producing compound (Ik) by reacting compound (Ij) with an amine represented by the formula: R 1 NH 2 or a salt thereof.
  • the starting compound (Ij) can be produced through Step 6-2 and Step 6-3 using H 2 NCH 2 CN as the aminoacetonitrile derivative (XI) in Step 6-1 of Production Method 6 described above.
  • This reaction can be carried out by the same method as in Step 1-3 of Production Method 1 described above.
  • Step 9-2 This step is a step for producing compound (Ig) by reacting compound (Ik) with a compound represented by the formula: R X -J. This reaction can be carried out by the same method as in Step 4-1 of Production Method 4 described above.
  • Compound (III) can also be produced by the following production method or a method analogous thereto.
  • Step 10-1 This step is a step of producing compound (XVI) by reacting compound (XIV) with compound (XV) in the presence of a base.
  • Compound (XIV) and Compound (XV) are commercially available, or a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” ( The method described by Richard C. Larock), or the like.
  • the amount of compound (XV) to be used is generally 0.1 to 10 molar equivalents relative to compound (XIV).
  • Bases include primary amines, secondary amines (eg piperidine), tertiary amines or salts thereof; potassium fluoride, cesium fluoride, ammonium acetate, sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide And inorganic bases such as
  • the amount of the base to be used is generally 0.1-10 molar equivalents relative to compound (XIV). This reaction is usually performed in an inert solvent.
  • the inert solvent examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetonitrile, and the like. Is mentioned. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Step 10-2 This step is a step for producing compound (III) by subjecting compound (XVI) to an oxidation reaction.
  • the oxidation reaction can be carried out in the presence of dimethyl sulfoxide, an activator and a base, but a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed. "(By Richard C. Larock)] or similar methods.
  • the activator include sulfur trioxide pyridine complex, oxalyl chloride, trifluoroacetic anhydride and the like.
  • the amount of the activator to be used is generally 1 to 10 molar equivalents relative to compound (XVI).
  • Examples of the base include tertiary amines such as triethylamine and N, N-diisopropylethylamine.
  • the amount of the base to be used is generally 1-50 molar equivalents relative to compound (XVI).
  • This reaction is usually performed in an inert solvent.
  • examples of the inert solvent include tetrahydrofuran, dichloromethane and the like. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Compound (III) can also be produced by the following production method or a method analogous thereto.
  • Step 11-1 This step is a step for producing compound (XVII) by subjecting compound (XIV) to an oxidation reaction. This reaction can be carried out by the same method as in Step 10-2 of Production Method 10 described above.
  • Step 11-2 This step is a step for producing compound (III) by reacting compound (XVII) with compound (XV) in the presence of a base. This reaction can be carried out by the same method as in Step 10-1 of Production Method 10 described above.
  • Compound (III) can also be produced by the following production method or a method analogous thereto.
  • Step 12-1 This step is a step for producing compound (XIX) by reacting compound (XVIII) with compound (XV) in the presence of a base.
  • Compound (XVIII) may be a commercially available product, or a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (By Richard C. Larock) ) Etc.] or a method analogous thereto. This reaction can be carried out by the same method as in Step 10-1 of Production Method 10 described above.
  • Step 12-2 This step is a step for producing compound (XX) by reacting compound (XIX) with a metal cyano compound.
  • metal cyano compound examples include copper cyanide and the like, and methods known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (Richard C. Can also be produced by a method described in Larock) or a method analogous thereto.
  • the amount of the metal cyano compound to be used is generally 0.5-50 molar equivalents relative to compound (XIX). This reaction is usually performed in an inert solvent.
  • Step 12-3 This step is a step for producing compound (III) by subjecting compound (XX) to a reduction reaction.
  • the reduction reaction can be carried out in the presence of diisobutylaluminum hydride or in the presence of platinum oxide in formic acid, but a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), It can also be carried out by the method described in “Comprehensive Organic Transformations, 2nd Ed.” (By Richard C. Larock) or a method analogous thereto.
  • the amount of diisobutylaluminum hydride to be used is generally 1 to 10 molar equivalents relative to compound (XX). When diisobutylaluminum hydride is used, the reduction reaction is usually performed in an inert solvent.
  • the inert solvent examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene and the like. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the amount of platinum oxide to be used is generally 0.01-100 molar equivalents relative to compound (XX).
  • the amount of formic acid used is usually 1 to 1000 molar equivalents.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Compound (III) can also be produced by the following production method or a method analogous thereto.
  • Step 13-1 This step is a step of producing compound (XXI) by subjecting compound (XIX) to a vinyl group coupling reaction.
  • Compound (XIX) is commercially available, or a method known per se [eg, “Advanced Organic Chemistry, 4th Ed.” (Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (Richard C. Larock) ) Etc.] or a method analogous thereto.
  • the vinyl group coupling reaction can be carried out in the presence of tributyl (ethenyl) stannane and tetrakistriphenylphosphine palladium, but a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March) , "Comprehensive Organic Transformations, 2nd Ed.” (By Richard C. Larock)] or a method analogous thereto.
  • the amount of tributyl (ethenyl) stannane to be used is generally 1-10 molar equivalents relative to compound (XIX).
  • the amount of tetrakistriphenylphosphine palladium to be used is generally 0.01 to 10 molar equivalents relative to compound (XIX).
  • This reaction is usually performed in an inert solvent.
  • the inert solvent include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetonitrile, and the like. Is mentioned. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Step 13-2 This step is a step for producing compound (III) by subjecting compound (XXI) to an oxidative cleavage reaction.
  • the oxidative cleavage reaction can be performed in the presence of osmium tetroxide and sodium periodate, but a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed. "(By Richard C. Larock)] or similar methods.
  • the amount of osmium tetroxide to be used is generally 0.01 to 10 molar equivalents relative to compound (XXI).
  • the amount of sodium periodate to be used is generally 1-100 molar equivalents relative to compound (XXI).
  • This reaction is usually performed in an inert solvent.
  • the inert solvent include water, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, Examples include acetonitrile. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Compound (III) can also be produced by the following production method or a method analogous thereto.
  • Step 14-1 This step is a step for producing compound (III) by subjecting compound (XXII) to a reduction reaction.
  • Compound (XXII) may be a commercially available product, or a method known per se [eg, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (By Richard C. Larock) ) Etc.] or a method analogous thereto.
  • the reduction reaction can be carried out in the presence of diisobutylaluminum hydride, but a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” ( (The method described by Richard C.
  • the amount of diisobutylaluminum hydride to be used is generally 1-10 molar equivalents relative to compound (XXII).
  • diisobutylaluminum hydride is usually carried out in an inert solvent.
  • the inert solvent include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene and the like. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Compound (XVI) can also be produced by the following production method or a method analogous thereto.
  • Step 15-1 This step is a step for producing compound (XXIII) by subjecting compound (XXII) to a hydrolysis reaction.
  • the hydrolysis reaction can be carried out in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, but a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March) , “Comprehensive Organic Transformations, 2nd Ed.” (By Richard C. Larock)] or a method analogous thereto.
  • the amount of the base to be used is generally 1-100 molar equivalents relative to compound (XXII). This reaction is usually performed in an inert solvent.
  • the inert solvent examples include water, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, Examples include acetonitrile. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Step 15-2 This step is a step for producing compound (XVI) by subjecting compound (XXIII) to a reduction reaction.
  • the reduction reaction can be carried out in the presence of isobutyl chloroformate, a base, and sodium borohydride, but a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed. ”(By Richard C. Larock)] or a method analogous thereto.
  • the amount of isobutyl chloroformate to be used is generally 1-10 molar equivalents relative to compound (XXIII).
  • Bases include primary amines, secondary amines (eg piperidine), tertiary amines or salts thereof; potassium fluoride, cesium fluoride, ammonium acetate, sodium hydride, potassium carbonate, cesium carbonate, potassium tert-butoxide And inorganic bases such as
  • the amount of the base to be used is generally 1-100 molar equivalents relative to compound (XXIII).
  • the amount of sodium borohydride to be used is generally 1-10 molar equivalents relative to compound (XXIII). This reaction is usually performed in an inert solvent.
  • the inert solvent examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and the like. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Compound (XXVIII), which is a group represented by the following formula, can also be produced by the following production method or a method analogous thereto.
  • R 6 represents a hydrogen atom or a hydrocarbon group which may have a substituent. Other symbols are as defined above.
  • Step 16-1 This step is a step for producing compound (XXV) by reacting compound (XXIV) with hydrazine or hydrazine monohydrate.
  • Compound (XXIV) is commercially available, or a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (By Richard C. Larock) ) Etc.] or a method analogous thereto.
  • This reaction is a method known per se [eg, the method described in “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (By Richard C. Larock)) or It can also be performed according to a similar method.
  • the amount of hydrazine or hydrazine monohydrate to be used is generally 1 to 10 molar equivalents relative to compound (XXIV).
  • This reaction is usually performed in an inert solvent.
  • the inert solvent include water, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, Examples include acetonitrile. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Step 16-2 This step is a step of producing compound (XXVI) by subjecting compound (XXV) to a cyclization reaction.
  • This reaction can be carried out by irradiating microwaves in the presence of a base, but a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed. "(By Richard C. Larock)] or similar methods.
  • Bases include primary amines, secondary amines (eg, piperidine), tertiary amines, pyridine or salts thereof; potassium fluoride, cesium fluoride, ammonium acetate, sodium hydride, potassium carbonate, cesium carbonate, potassium tert -Inorganic bases such as butoxide.
  • the amount of the base to be used is generally 1-1000 molar equivalents relative to compound (XXV). This reaction is usually performed in the absence of a solvent or in an inert solvent.
  • the inert solvent examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetonitrile, and the like. Is mentioned. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Step 16-3 This step is a step for producing compound (XXVII) by reacting compound (XXVI) with compound (XV).
  • Compound (XV) is commercially available, or a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (By Richard C. Larock) ) Etc.] or a method analogous thereto.
  • the amount of compound (XV) to be used is generally 1 to 10 molar equivalents relative to compound (XXVI). This reaction is usually performed in an inert solvent.
  • the inert solvent examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetonitrile, and the like. Is mentioned. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Step 16-4 This step is a step for producing compound (XXVIII) by reacting compound (XXVII) with a compound represented by the formula: R 5 -J.
  • the compound represented by R 5 -J is commercially available, or a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” ( The method described by Richard C. Larock), or the like. This reaction can be carried out by the same method as in Step 4-1 of Production Method 4 described above.
  • Step 17-1 This step is a step of producing compound (XXX) by reacting compound (XXIX) with compound (XV) in the presence of a base.
  • Compound (XXIX) is commercially available, or a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (By Richard C. Larock) ) Etc.] or a method analogous thereto.
  • This reaction can be carried out by the same method as in Step 10-1 of Production Method 10 described above.
  • Step 17-2 This step is a step for producing compound (XXXI) by subjecting compound (XXX) to an amidation reaction.
  • the amidation reaction can be carried out in the presence of ammonia, but a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (Richard C [Methods described by Larock)] or similar methods.
  • the amount of ammonia to be used is generally 1-1000 molar equivalents relative to compound (XXX). This reaction is usually performed in an inert solvent.
  • the inert solvent examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetonitrile, and the like. Is mentioned. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Step 17-3 This step is a step of producing compound (XXXII) by subjecting compound (XXXI) to a reduction reaction.
  • the reduction reaction can be carried out in a hydrogen atmosphere in the presence of palladium carbon, but a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed. (Method described in Richard C. Larock)] or a method similar thereto.
  • the amount of palladium carbon to be used is generally 0.01-10 molar equivalents relative to compound (XXXI). This reaction is usually performed in an inert solvent.
  • the inert solvent examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetonitrile, and the like. Is mentioned. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Step 17-4 This step is a step of producing compound (XXXIII) by subjecting compound (XXXII) to a cyclization reaction.
  • this reaction can be carried out in the presence of urea, a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (Richard C. (The method described in Larock)] or a method similar to these.
  • the amount of urea used is usually 1 to 1000 molar equivalents relative to compound (XXXII). This reaction is usually performed in the absence of a solvent or in an inert solvent.
  • the inert solvent examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetonitrile, and the like. Is mentioned. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Step 17-5 This step is a step for producing compound (XXXIV) by reacting compound (XXXIII) with phosphorus oxychloride.
  • This reaction is a method known per se [eg, the method described in “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed.” (By Richard C. Larock)) or It can also be performed according to a similar method.
  • the amount of phosphorus oxychloride to be used is generally 1-1000 molar equivalents relative to compound (XXXIII). This reaction is usually performed in the absence of a solvent or in an inert solvent.
  • the inert solvent examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile, and the like. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Step 17-6 This step is a step for producing compound (XXXV) by subjecting compound (XXXIV) to a reduction reaction.
  • the reduction reaction can be performed in a hydrogen atmosphere, in the presence of palladium on carbon, and a base, but a method known per se [for example, “Advanced Organic Chemistry, 4th Ed.” (By Jerry March), “Comprehensive Organic Transformations, 2nd Ed. "(By Richard C. Larock)] or similar methods.
  • the amount of palladium carbon to be used is generally 0.01-10 molar equivalents relative to compound (XXXIV).
  • the amount of the base to be used is generally 1-100 molar equivalents relative to compound (XXXIV). This reaction is usually performed in an inert solvent.
  • the inert solvent examples include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, N, N-dimethylformamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, acetonitrile, and the like. Is mentioned. Two or more of these solvents may be mixed and used at an appropriate ratio.
  • the reaction temperature is usually ⁇ 100 to 200 ° C.
  • the reaction time is not particularly limited, but is usually 0.1 to 100 hours, preferably 0.5 to 72 hours.
  • Compound (I) (for example, compounds (Ia) to (Ik) obtained by the above-described method) is further subjected to per se known means to further introduce substituents and convert functional groups, and within the scope of the present invention.
  • the included compounds can also be prepared.
  • For the substituent conversion a known general method is used.
  • halogenation conversion to a carboxy group by hydrolysis of an ester, conversion to a carbamoyl group by amidation of a carboxy group, conversion to a hydroxymethyl group by reduction of the carboxy group
  • Conversion conversion to alcohol form by reduction or alkylation of carbonyl group, reductive amination of carbonyl group, oximation of carbonyl group, acylation / urealation / sulfonylation / alkylation of amino group, active halogen by amine
  • Amination of nitro group conversion to amino group by reduction of nitro group, acylation, carbamate formation, sulfonylation, alkylation of hydroxy group.
  • a protective group is introduced into the reactive substituent in advance by a publicly known means as necessary.
  • the protecting group can be removed by means known per se to produce compounds within the scope of the present invention.
  • R a represents a hydrogen atom, a hydrocarbon group which may have a substituent, a heterocyclic group which may have a substituent, or a substituent; A hydroxy group which may have, an amino group which may have a substituent, or an acyl group.
  • ERR ⁇ modulator especially an inverse agonist
  • Haldrocarbon group optionally having substituent (s) represented by R a
  • heterocyclic group optionally having substituent (s) “hydroxy group optionally having substituent (s)”
  • amino group optionally having substituent (s) and “acyl group”
  • hydrocarbon group optionally having substituent (s) represented by R 1 and the like, “having substituents” Examples thereof include the same as those of “an optionally substituted heterocyclic group”, “an optionally substituted hydroxy group”, “an optionally substituted amino group” and “acyl group”.
  • Example 1 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (methylamino) -1,3-thiazole-2 ( 5H) -ON
  • B) 1- [2,4-Bis (trifluoromethyl) benzyl] -1H-indazole-5-carbaldehyde 1H-indazole-5-carbaldehyde (41.8 g) in DMF (600 mL) in potassium carbonate (47.6 g) and 1- (Bromomethyl) -2,4-bis (trifluoromethyl) benzene (95.0 g) in DMF (100 mL) were added.
  • Example 2 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- ⁇ [2- (1-methylpyrrolidin-2-yl ) Ethyl] amino ⁇ -1,3-thiazol-2 (5H) -one 4-thioxo-1,3-thiazolidin-2-one (3.48 g) and 2- (1-methylpyrrolidin-2-yl) ethanamine ( After stirring a solution of 3.35 g) in ethanol (150 mL) at room temperature for 2 hours, 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazole-5-carbaldehyde (9.71 g) and potassium tert- Butoxide (2.93 g) was added.
  • the reaction mixture was stirred under reflux conditions for 5 hours, cooled to room temperature, and saturated aqueous ammonium chloride solution was added. After concentration under reduced pressure, extraction was performed with an ethyl acetate / THF mixed solvent. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, THF), washed with diethyl ether, and recrystallized from ethyl acetate / THF to give the title compound (3.0 g).
  • Example 3 (5Z) -4- (Methylamino) -5-( ⁇ 2- [2- (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -1,3-thiazole-2 (5H)- on A) 2- [2- (Trifluoromethyl) benzyl] -2H-indazole-5-carbaldehyde 1H-indazole-5-carbaldehyde (8.76 g) and potassium carbonate (9.94 g) dissolved in DMF (59.9 mL) 1- (Bromomethyl) -2- (trifluoromethyl) benzene (17.19 g) was added.
  • Example 4 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -3-bromo-2H-indazol-5-yl ⁇ methylidene) -4- (methylamino) -1,3- Thiazole-2 (5H) -one
  • 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazole- N-bromosuccinimide (783 mg) was added to a solution of 5-carbaldehyde (1.49 g) in DMF (6.8 mL).
  • Example 5 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- ⁇ [2- (diethylamino) ethyl] amino ⁇ -1 , 3-thiazol-2 (5H) -one 4-thioxo-1,3-thiazolidin-2-one (3.38 g) and N, N-diethylethane-1,2-diamine (2.95 g) in ethanol (200 mL ) After the solution was stirred at room temperature for 2 hours, 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazole-5-carbaldehyde (9.47 g) and potassium tert-butoxide (2.85 g) were added.
  • Example 6 (5Z) -5-( ⁇ 1- [2,4-Bis (trifluoromethyl) benzyl] -1H-indazol-6-yl ⁇ methylidene) -4- (methylamino) -1,3-thiazole-2 ( 5H) -ON
  • B) 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazole-6-carbaldehyde 1H-indazole-6-carbaldehyde (1.27 g) in DMF (9 mL) in potassium carbonate (1.44 g) and 1- (bromomethyl) -2,4-bis (trifluoromethyl) benzene (1.79 mL) were added.
  • Example 7 4- (5- ⁇ (Z)-[4- (methylamino) -2-oxo-1,3-thiazol-5 (2H) -ylidene] methyl ⁇ -1H-indazol-1-yl) -2- ( (Trifluoromethyl) benzonitrile A) 4- (5-Formyl-1H-indazol-1-yl) -2- (trifluoromethyl) benzonitrile B) 4- (5-Formyl-2H-indazol-2-yl) -2- (trifluoromethyl) benzonitrile 1H-indazole-5-carbaldehyde (1.46 g) and 4-fluoro-2- (trifluoromethyl ) Potassium carbonate (1.66 g) was added to a solution of benzonitrile (1.66 g) in DMSO (100 mL).
  • Example 8 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (dimethylamino) -1,3-thiazole-2 ( 5H) -one (5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (methylamino) -1,3- To a solution of thiazol-2 (5H) -one (275.0 mg) in DMF (2.8 mL) were added potassium carbonate (157.6 mg) and methyl iodide (0.0706 mL).
  • reaction mixture was stirred at 60 ° C. overnight, poured into water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • reaction mixture was stirred at 60 ° C. overnight, poured into water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the reaction mixture was poured into a saturated aqueous solution of potassium sodium tartrate and the solvent was distilled off under reduced pressure. Water / ethyl acetate was added to the residue, and the organic layer was separated. The extract was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound (1.89 g).
  • Example 17 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4-[(2-hydroxyethyl) (methyl) amino]- 1,3-thiazol-2 (5H) -one (5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- ( To a solution of methylsulfanyl) -1,3-thiazol-2 (5H) -one (17 mg) in methanol (3 mL) was added 2- (methylamino) ethanol (8 mg), and the mixture was stirred for 1 hour under reflux conditions.
  • Example 18 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (diethylamino) -1,3-thiazole-2 (5H ) -One (5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (methylsulfanyl) -1,3-thiazole To a solution of -2 (5H) -one (102 mg) in THF (3 mL) was added diethylamine (292 mg) at room temperature, and the reaction mixture was stirred at 50 ° C for 2 hours.
  • the reaction mixture was stirred at room temperature for 1.5 hours, an aqueous citric acid solution was added dropwise, the mixture was further stirred for 30 minutes, made basic with 1M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (99.2 mg).
  • Example 20 4- (4- ⁇ (Z)-[4- (methylamino) -2-oxo-1,3-thiazol-5 (2H) -ylidene] methyl ⁇ -1H-indazol-1-yl) -3- ( (Trifluoromethyl) benzonitrile 1H-indazole-4-carbaldehyde (692.2 mg) in DMSO (5 mL) solution in lithium carbonate (700.5 mg) and 4-fluoro-3- (trifluoromethyl) benzonitrile (1.34 g) Was added. The reaction mixture was stirred at 100 ° C. for 6 hours, poured into water, and extracted with ethyl acetate.
  • Example 21 4- (4- ⁇ (Z)-[4- (methylamino) -2-oxo-1,3-thiazol-5 (2H) -ylidene] methyl ⁇ -2H-indazol-2-yl) -3- ( (Trifluoromethyl) benzonitrile 1H-indazole-4-carbaldehyde (692.2 mg) in DMSO (5 mL) solution in lithium carbonate (700.5 mg) and 4-fluoro-3- (trifluoromethyl) benzonitrile (1.34 g) Was added. The reaction mixture was stirred at 100 ° C. for 6 hours, poured into water, and extracted with ethyl acetate.
  • Example 22 4- (4- ⁇ (Z)-[4- (methylamino) -2-oxo-1,3-thiazol-5 (2H) -ylidene] methyl ⁇ -1H-indazol-1-yl) -3- ( To a solution of ethyl trifluoromethyl) benzenecarboxymate 1H-indazole-4-carbaldehyde (692.2 mg) in DMSO (5 mL), lithium carbonate (700.5 mg) and 4-fluoro-3- (trifluoromethyl) benzonitrile ( 1.34 g) was added. The reaction mixture was stirred at 100 ° C. for 6 hours, poured into water, and extracted with ethyl acetate.
  • reaction mixture was concentrated by blowing air at 60 ° C., and the resulting residue was dissolved in DMSO and purified by preparative HPLC (column: YMC combiprep pro C18 RS, solvent: 10 mM NH 4 HCO 3 / MeCN).
  • the obtained eluate containing the title compound was concentrated by blowing air at 60 ° C. to obtain the title compound (7.9 mg).
  • Example 33 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (3-hydroxypyrrolidin-1-yl) -1, 3-thiazol-2 (5H) -one (5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (methylsulfanyl
  • THF a solution of -1,3-thiazol-2 (5H) -one (4.50 g) in THF (30 mL) was added a solution of pyrrolidin-3-ol (0.86 g) in THF (10 mL).
  • Example 34 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (3-hydroxyazetidin-1-yl) -1 , 3-Thiazol-2 (5H) -one (5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (methyl Add azetidin-3-ol hydrochloride (2.78 g) to a solution of sulfanyl) -1,3-thiazol-2 (5H) -one (1.50 g) in DMF (25 mL) and pyridine (5.00 mL) at room temperature.
  • Example 35 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4-[(3-hydroxypropyl) amino] -1,3 -Thiazol-2 (5H) -one 4-Thioxo-1,3-thiazolidin-2-one (11 mg) in ethanol (0.5 mL) was added to 3-aminopropan-1-ol (6 mg) and triethylamine (8 mg] and stirred at room temperature for 6 hours, and then 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazole-5-carbaldehyde (30 mg) in ethanol (0.5 mL) and potassium tert -Butoxide (9 mg) was added, and the mixture was stirred at 80 ° C.
  • Example 36 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- ⁇ [2- (2-hydroxyethoxy) ethyl] amino ⁇ -1,3-thiazol-2 (5H) -one (5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4 2- (2-Aminoethoxy) ethanol (314 mg) was added to a solution of-(methylsulfanyl) -1,3-thiazol-2 (5H) -one (1.50 g) in THF (50 mL), and 2 Stir for hours.
  • Example 37 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (prop-2-yn-1-ylamino) -1 , 3-Thiazol-2 (5H) -one (5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (methyl Sulfanyl) -1,3-thiazol-2 (5H) -one (1.5 g) was dissolved in THF, and prop-2-yn-1-amine (0.958 mL) was added.
  • Example 40 4-[(5- ⁇ (Z)-[4- (Methylamino) -2-oxo-1,3-thiazol-5 (2H) -ylidene] methyl ⁇ -2H-indazol-2-yl) methyl]- Ethyl 3- (trifluoromethyl) benzenecarboxymate 4-[(5-formyl-2H-indazol-2-yl) methyl] -3- (trifluoromethyl) benzonitrile (187.4 mg) and 4- (methylamino To a solution of) -1,3-thiazol-2 (5H) -one (111.1 mg) in ethanol (2.8 mL) was added potassium tert-butoxide (93.6 mg).
  • Example 45 (5Z) -5-( ⁇ 2-[(4'-Methoxybiphenyl-2-yl) methyl] -2H-indazol-5-yl ⁇ methylidene) -4- (methylamino) -1,3-thiazole-2 (5H) -one (5Z) -5- ⁇ [2- (2-bromobenzyl) -2H-indazol-5-yl] methylidene ⁇ -4- (methylamino) -1,3-thiazole-2 (5H) -On (77.8 mg), (4-methoxyphenyl) boronic acid (33.2 mg) and cesium carbonate (118.6 mg) were suspended in dimethoxyethane (0.73 mL) / water (0.18 mL), and [1, 1'-Bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (1: 1) (14.9 mg) was added.
  • the reaction mixture was stirred for 2.5 hours under reflux with heating, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate / hexane). Further, the mixture was fractionated by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% TFA)), a saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized from ethyl acetate / methanol / hexane to give the title compound (33.1 mg).
  • Example 47 (5Z) -5-[(2- ⁇ 2-hydroxy-1- [2- (trifluoromethyl) phenyl] ethyl ⁇ -2H-indazol-5-yl) methylidene] -4- (methylamino) -1, 3-thiazol-2 (5H) -one (5- ⁇ (Z)-[4- (methylamino) -2-oxo-1,3-thiazol-5 (2H) -ylidene] methyl ⁇ -2H-indazole-
  • 2-yl) [2- (trifluoromethyl) phenyl] acetic acid (102.4 mg,) in THF (1.11 mL) was ice-cooled, and triethylamine (0.0465 ml) and isobutyl chloroformate (0.0433 ml) were added dropwise.
  • Example 53 2-[(5- ⁇ (Z)-[4- (Methylamino) -2-oxo-1,3-thiazol-5 (2H) -ylidene] methyl ⁇ -2H-indazol-2-yl) methyl] benzoic acid Methyl 2-[(5- ⁇ (Z)-[4- (Methylamino) -2-oxo-1,3-thiazol-5 (2H) -ylidene] methyl ⁇ -2H-indazol-2-yl) methyl ] To a solution of benzoate (344.1 mg) in methanol (4.23 mL) was added 2M aqueous sodium hydroxide solution (0.847 mL).
  • Example 56 (5E) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (methylamino) -1,3-thiazole-2 ( 5H) -one (5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (methylamino) -1,3- Thiazol-2 (5H) -one (74.2 mg) was dissolved in methanol (80 mL) / acetonitrile (80 mL) and allowed to stand under sunlight for 3 days.
  • the reaction mixture was stirred at 0 ° C. for 5 min, and sodium borohydride (25.2 mg) was added. Further, after stirring at 0 ° C. for 1 hour, methanol was added, and the mixture was purified by silica gel column chromatography (NH, ethyl acetate / hexane and methanol / ethyl acetate), recrystallized from ethyl acetate / hexane, and the title compound (16.0 mg) and (5Z) -5-[(2- ⁇ 2-hydroxy-1- [2- (trifluoromethyl) phenyl] ethyl ⁇ -2H-indazol-5-yl) methylidene] -4- (methylamino) -1,3-thiazol-2 (5H) -one (3.5 mg) was obtained.
  • Example 58 2- (5- ⁇ (Z)-[4- (Methylamino) -2-oxo-1,3-thiazol-5 (2H) -ylidene] methyl ⁇ -2H-indazol-2-yl) -2- [ 2- (Trifluoromethyl) phenyl] acetamide (5- ⁇ (Z)-[4- (methylamino) -2-oxo-1,3-thiazole-5 (2H) -ylidene] methyl ⁇ -2H-indazole- 2-yl) [2- (trifluoromethyl) phenyl] acetic acid (190 mg) and 1H-benzo [d] [1,2,3] triazol-1-ol ammonium salt (94 mg) in DMF (2.07 mL) And N 1 -((ethylimino) methylene) -N 3 , N 3 -dimethylpropane-1,3-diamine hydrochloride (119 mg) was added.
  • the reaction mixture was stirred at room temperature for 4 hours, poured into 1M hydrochloric acid, and extracted with ethyl acetate.
  • the extract was washed with water, 1M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate / hexane) and recrystallized from ethyl acetate / methanol / hexane to give the title compound (80 mg).
  • the reaction mixture was stirred at room temperature for 3 hours, 1M hydrochloric acid was added, the mixture was further stirred for 30 minutes, and extracted with ethyl acetate.
  • the extract was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (80.4 mg).
  • Methyl 2- (trifluoromethyl) -4- ⁇ [2- (trimethylsilyl) ethoxy] methoxy ⁇ benzoate Methyl 4-hydroxy-2- (trifluoromethyl) benzoate (6.98 g, EP2243779 A1, 2010) and ⁇ 2-[(Chloromethoxy) methoxy] ethyl ⁇ (trimethyl) silane (6.17 mL) was added to a solution of cesium carbonate (11.4 g) in acetonitrile (70 mL). The reaction mixture was stirred at room temperature overnight, the solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate.
  • reaction mixture was diluted with diethyl ether (200 mL), water (3 mL) was slowly added dropwise under ice-cooling, 4M aqueous sodium hydroxide solution (3 mL), and water (9 mL) were further added dropwise.
  • the resulting reaction mixture was stirred vigorously at room temperature for 2 hours, the precipitate was filtered off, and the mother liquor was concentrated under reduced pressure to give the title compound (6.83 g).
  • Example 65 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (3-hydroxypiperidin-1-yl) -1, 3-thiazol-2 (5H) -one (5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (methylsulfanyl Piperidin-3-ol hydrochloride (826 mg) was added to a mixed solution of) -1,3-thiazol-2 (5H) -one (300 mg) in DMF (10 mL) and pyridine (1 mL) at room temperature, Stir at 60 ° C.
  • Example 66 (5Z) -4-azetidin-1-yl-5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -1,3-thiazole-2 (5H) -one (5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (methylsulfanyl) -1,3
  • a solution of -thiazol-2 (5H) -one (300 mg) and triethylamine (61 mg) in THF (5 mL) was added azetidine (34 mg) at room temperature.
  • Example 68 4-[(5- ⁇ (Z)-[4- (Methylamino) -2-oxo-1,3-thiazol-5 (2H) -ylidene] methyl ⁇ -2H-indazol-2-yl) methyl]- 3- (Trifluoromethyl) benzoic acid
  • the title compound (119.7 mg) and 4-[(5- ⁇ (Z)-[4- (methylamino) -2-oxo Methyl-1,3-thiazol-5 (2H) -ylidene] methyl ⁇ -2H-indazol-2-yl) methyl] -3- (trifluoromethyl) benzoate was obtained.
  • Example 70 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (3-hydroxy-3-methylpyrrolidin-1-yl ) -1,3-thiazol-2 (5H) -one (5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4 Iodine in a solution of-(methylsulfanyl) -1,3-thiazol-2 (5H) -one (300 mg), triethylamine (134 mg) and 3-methylpyrrolidin-3-ol (121 mg) in THF (5 mL) (168 mg) was added at room temperature.
  • Example 87 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4-[(3R) -3-hydroxypyrrolidin-1-yl ] -1,3-thiazol-2 (5H) -one (5Z) -4- (methylsulfanyl) -5-( ⁇ 2- [2- (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ (3R) -pyrrolidin-3-ol (35 mg) was added to a solution of methylidene) -1,3-thiazol-2 (5H) -one (200 mg) and methyl acrylate (172 mg) in THF (5 mL) at room temperature. And stirred at 60 ° C. for 2 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel chromatography (NH, ethyl acetate /
  • Example 89 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (3-methoxypyrrolidin-1-yl) -1, 3-thiazol-2 (5H) -one
  • 5Z -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (methylsulfanyl ) -1,3-thiazol-2 (5H) -one (200 mg) and methyl acrylate (172 mg) in DMF (5 mL) and pyridine (1 mL) were mixed with 3-methoxypyrrolidine hydrochloride (165 mg) was added and allowed to react overnight at room temperature.
  • Example 90 8-[(5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -2-oxo-2,5-dihydro-1, 3-thiazol-4-yl] -2,8-diazaspiro [4.5] decane-1,3-dione
  • Example 94 (5Z) -4-[(3-Aminopropyl) amino] -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -1,3 -Thiazol-2 (5H) -one hydrochloride tert-butyl (3- ⁇ [(5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ Methylidene) -2-oxo-2,5-dihydro-1,3-thiazol-4-yl] amino ⁇ propyl) carbamate (670 mg) and 4M hydrogen chloride / ethyl acetate solution (10 mL) at room temperature After stirring for 3 hours, the precipitate was filtered and washed with ethyl acetate to obtain the title compound (598 mg).
  • Example 95 N- (3- ⁇ [(5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -2-oxo-2,5- Dihydro-1,3-thiazol-4-yl] amino ⁇ propyl) methanesulfonamide (5Z) -4-[(3-aminopropyl) amino] -5-( ⁇ 2- [2,4-bis (trifluoro Methyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -1,3-thiazol-2 (5H) -one Hydrochloride (150 mg) in THF (4 mL) in triethylamine (0.187 mL) and methane chloride Sulfonyl (0.031 mL) was added.
  • Example 99 N- (3- ⁇ [(5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -2-oxo-2,5- Dihydro-1,3-thiazol-4-yl] (methyl) amino ⁇ propyl) acetamide N- (3- ⁇ [(5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -2-oxo-2,5-dihydro-1,3-thiazol-4-yl] amino ⁇ propyl) acetamide (220 mg) in a solution of THF (2 mL) A solution of potassium (80 mg) and methyl iodide (0.025 mL) in THF (2 mL) was added.
  • Example 100 (5Z) -4-[(3R) -3-Aminopyrrolidin-1-yl] -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene ) -1,3-thiazol-2 (5H) -one tert-butyl ⁇ (3R) -1-[(5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H -Indazol-5-yl ⁇ methylidene) -2-oxo-2,5-dihydro-1,3-thiazol-4-yl] pyrrolidin-3-yl ⁇ carbamate (500 mg) and 4M hydrogen chloride / ethyl acetate solution ( 5 mL) was stirred at room temperature for 3 hours, and then the solvent was distilled off under reduced pressure.
  • Example 103 (5Z) -4- (3-Aminoazetidin-1-yl) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -1 , 3-thiazol-2 (5H) -one in 4M hydrogen chloride / ethyl acetate solution (10 mL) was added ) Benzyl] -2H-indazol-5-yl ⁇ methylidene) -2-oxo-2,5-dihydro-1,3-thiazol-4-yl] azetidin-3-yl ⁇ carbamate (220 mg) Stir for 3 hours at ° C.
  • the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution under ice-cooling, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (NH, ethyl acetate / methanol) to give the title compound (7 mg).
  • Example 104 N- ⁇ (3R) -1-[(5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -2-oxo-2 , 5-Dihydro-1,3-thiazol-4-yl] pyrrolidin-3-yl ⁇ -N 2 , N 2 -dimethylglycinamide (5Z) -4-[(3R) -3-aminopyrrolidin-1-yl ] -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -1,3-thiazol-2 (5H) -one (200 mg) To the THF (2 mL) solution was added N, N-dimethylglycine (48 mg), diisopropylethylamine (0.08 mL) and 2- (7-aza-1H-benz
  • the reaction mixture was stirred at 60 ° C. overnight, and the solvent was evaporated under reduced pressure.
  • the residue was dissolved in ethyl acetate / water and the organic layer was separated.
  • the extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (NH, methanol / ethyl acetate), washed with diethyl ether, and recrystallized from ethyl acetate / heptane to give the title compound (4.29 g).
  • Example 109 1- ⁇ 1-[(5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -2-oxo-2,5-dihydro -1,3-thiazol-4-yl] pyrrolidin-3-yl ⁇ -3-ethyl-1-methylurea in a solution of ethyl isocyanate (0.025 mL) in THF (4 mL) (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- [3- (methylamino) pyrrolidin-1-yl] -1,3-thiazol-2 (5H ) -One (150 mg) was added.
  • reaction mixture was stirred at room temperature overnight, and the reaction mixture was purified by silica gel column chromatography (NH, methanol / ethyl acetate) and recrystallized from ethyl acetate / heptane to give the title compound (43.3 mg).
  • Example 111 2- [2,4-Bis (trifluoromethyl) benzyl] -6- ⁇ (Z)-[4- (3-hydroxypyrrolidin-1-yl) -2-oxo-1,3-thiazole-5 (2H ) -Ilidene] methyl ⁇ -1-methyl-1,2-dihydro-3H-indazol-3-one 2- [2,4-bis (trifluoromethyl) benzyl] -1-methyl-3-oxo-2, To a solution of 3-dihydro-1H-indazole-6-carbaldehyde (264 mg) and piperidine (0.065 mL) in acetic acid (3 mL), add 4-thioxo-1,3-thiazolidin-2-one (87 mg) It was.
  • the reaction mixture was stirred at 100 ° C. for 1 hour, cooled to room temperature, ethyl acetate / water was added, and the organic layer was separated. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • potassium carbonate (0.109 g) and methyl iodide (0.041 mL) were added.
  • the reaction mixture was stirred at room temperature for 2 hours, ethyl acetate / water was added, and the organic layer was separated.
  • the extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • Example 114 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- ⁇ [2- (diethylamino) ethyl] amino ⁇ -1 , 3-Thiazol-2 (5H) -one 1/2 fumarate (5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene ) -4- ⁇ [2- (Diethylamino) ethyl] amino ⁇ -1,3-thiazol-2 (5H) -one (100 mg) in ethanol (1 mL) was added with fumaric acid (20.4 mg).
  • Example 118 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- (3-ethoxypyrrolidin-1-yl) -1, 3-thiazol-2 (5H) -one tert-butyl 3-ethoxypyrrolidine-1-carboxylate (230 mg) in ethyl acetate (3 mL) and 4M hydrogen chloride / ethyl acetate solution (3 mL) under ice-cooling The mixture was stirred for 2 hours.
  • Example 120 2- ⁇ 5-Fluoro-2-[(5- ⁇ (Z)-[4- (methylamino) -2-oxo-1,3-thiazole-5 (2H) -ylidene] methyl ⁇ -2H-indazole- 2-yl) methyl] phenyl ⁇ -2-methylpropanenitrile
  • Example 121 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- [4- (1H-imidazol-1-yl) piperidine -1-yl] -1,3-thiazol-2 (5H) -one (5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ (Methylidene) -4- (methylsulfanyl) -1,3-thiazol-2 (5H) -one (400 mg) in THF (4 mL) in methyl acrylate (0.366 mL), triethylamine (0.334 mL) and 4- (1H-imidazol-1-yl) piperidine hydrochloride (150 mg) was added.
  • the reaction mixture was stirred at 60 ° C. overnight, and the solvent was evaporated under reduced pressure.
  • the residue was dissolved in ethyl acetate / water and the organic layer was separated.
  • the extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), washed with diethyl ether, and recrystallized from ethyl acetate / heptane to give the title compound (1.35 g).
  • Example 125 (5Z) -5-( ⁇ 2- [2,4-Bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4- ⁇ [2- (diethylamino) ethyl] amino ⁇ -1 , 3-Thiazol-2 (5H) -one dihydrochloride (5Z) -5-( ⁇ 2- [2,4-bis (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene) -4 6N hydrochloric acid (0.094 mL) was added to a solution of- ⁇ [2- (diethylamino) ethyl] amino ⁇ -1,3-thiazol-2 (5H) -one (208 mg) in ethanol (1 mL).
  • N-methyl-N-piperidin-4-ylacetamide hydrochloride The title compound was obtained from tert-butyl 4- [acetyl (methyl) amino] piperidine-1-carboxylate by the same method as in Step A of Example 90. It was. 1 H NMR (300 MHz, DMSO-d 6 ) ⁇ 1.52-1.80 (2H, m), 1.87-2.10 (5H, m), 2.63-2.83 (3H, m), 2.87-3.07 (2H, m), 3.22 -3.36 (2H, m), 3.83-4.62 (1H, m), 9.00 (2H, brs).
  • Example 133 (5Z) -5-[(2- ⁇ (3-Hydroxyoxetane-3-yl) [2- (trifluoromethyl) phenyl] methyl ⁇ -2H-indazol-5-yl) methylidene] -4- (methylamino ) -1,3-thiazol-2 (5H) -one (5Z) -5-( ⁇ 2- [4-bromo-2- (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ methylidene)-
  • a solution of 4- (methylamino) -1,3-thiazol-2 (5H) -one (201.7 mg) in THF (2.04 mL) was cooled to ⁇ 78 ° C., and 60% sodium hydride (16.29 mg) was added.
  • the reaction mixture was stirred at ⁇ 78 ° C. for 10 minutes, and 1.6M n-butyllithium hexane solution (0.305 mL) was slowly added dropwise over 10 minutes. After further stirring for 10 minutes, oxetan-3-one (44.0 mg) was added, and the temperature was raised to room temperature. The reaction mixture was stirred at room temperature for 2 hours, poured into 1M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (methanol / ethyl acetate), further separated by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% TFA)), and saturated hydrogen carbonate was obtained in the obtained fraction. An aqueous sodium solution was added, and the mixture was extracted with ethyl acetate.
  • Example 134 (5Z) -5-[(2- ⁇ [4-Bromo-2- (trifluoromethyl) phenyl] (3-hydroxyoxetane-3-yl) methyl ⁇ -2H-indazol-5-yl) methylidene] -4 -(Methylamino) -1,3-thiazol-2 (5H) -one
  • 5Z -5-( ⁇ 2- [4-bromo-2- (trifluoromethyl) benzyl] -2H-indazol-5-yl ⁇ Methylidene) -4- (methylamino) -1,3-thiazol-2 (5H) -one (201.7 mg) in THF (2.04 mL) was cooled to -78 ° C and 60% sodium hydride (16.29 mg ) Was added.
  • reaction mixture was stirred at ⁇ 78 ° C. for 10 minutes, and 1.6M n-butyllithium hexane solution (0.305 mL) was slowly added dropwise over 10 minutes. After further stirring for 10 minutes, oxetan-3-one (44.0 mg) was added, and the temperature was raised to room temperature. The reaction mixture was stirred at room temperature for 2 hours, poured into 1M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
  • the residue was purified by silica gel column chromatography (methanol / ethyl acetate), further separated by HPLC (C18, mobile phase: water / acetonitrile (containing 0.1% TFA)), and saturated hydrogen carbonate was obtained in the obtained fraction. An aqueous sodium solution was added, and the mixture was extracted with ethyl acetate.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Obesity (AREA)
  • Rheumatology (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Endocrinology (AREA)
  • Cardiology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Pulmonology (AREA)
  • Emergency Medicine (AREA)
  • Vascular Medicine (AREA)
  • Psychology (AREA)
  • Addiction (AREA)
  • Child & Adolescent Psychology (AREA)
  • Urology & Nephrology (AREA)
  • Oncology (AREA)
  • Dermatology (AREA)

Abstract

La présente invention concerne un nouveau composé qui a une excellente activité en tant que modulateur du ERRá et qui est utile comme agent thérapeutique ou prophylactique pour des maladies apparentées au ERRá telles que les cancers ou similaires. La présente invention concerne un composé représenté par la formule (I) ou un sel de celui-ci. (Dans la formule (I), A représente un groupe cyclique facultativement substitué ; La représente une liaison ou similaire ; Lb représente un alkylène en C1-3 ou similaire ; Lc représente une liaison ou similaire ; G représente un groupe représenté par la formule Ga ou Gb (Z1, Z2, Z3 et Z4 représentant chacun indépendamment un atome d'azote, un atome de carbone, -CH- ou similaires ; R4 représentant un atome d'hydrogène ou similaire ; et R5 représentant un atome d'hydrogène ou similaire) ; et E représente un groupe représenté par la formule Ea ou Eb (X représentant -S- ou similaire ; et R1, R2 et R3 représentant chacun indépendamment un atome d'azote ou similaire).
PCT/JP2012/075721 2011-10-04 2012-10-03 Composé hétérocyclique fusionné contenant de l'azote WO2013051632A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2011220388 2011-10-04
JP2011-220388 2011-10-04

Publications (1)

Publication Number Publication Date
WO2013051632A1 true WO2013051632A1 (fr) 2013-04-11

Family

ID=48043786

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2012/075721 WO2013051632A1 (fr) 2011-10-04 2012-10-03 Composé hétérocyclique fusionné contenant de l'azote

Country Status (2)

Country Link
JP (1) JPWO2013051632A1 (fr)
WO (1) WO2013051632A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015082587A1 (fr) 2013-12-05 2015-06-11 Bayer Cropscience Ag Dérivés de n-cycloalkyl-n-{[2- (cycloalkyl-1-substitué)phényl]méthylène}-(thio)carboxamide
WO2015082586A1 (fr) 2013-12-05 2015-06-11 Bayer Cropscience Ag Dérivés de n-cycloalkyl-n-{[2- (cycloalkyl-1-substitué)phényl]méthylène}-(thio)carboxamide
KR20190086715A (ko) * 2016-11-14 2019-07-23 신톤 바이오파머슈티칼즈 비.브이. 단일-보호된 알파, 오메가-디아미노 알칸의 제조 방법

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011016501A1 (fr) * 2009-08-04 2011-02-10 武田薬品工業株式会社 Agent prophylactique ou thérapeutique pour le cancer
WO2011075565A1 (fr) * 2009-12-18 2011-06-23 Janssen Pharmaceutica Nv Aminothiazolone indazoles substitués comme modulateurs des récepteurs alpha liés aux œstrogènes
WO2011103130A1 (fr) * 2010-02-17 2011-08-25 Janssen Pharmaceutica Nv Aminothiazolones en tant que modulateurs de récepteur alpha associé aux œstrogènes
WO2011103134A1 (fr) * 2010-02-17 2011-08-25 Janssen Pharmaceutica Nv Aminothiazolones en tant que modulateurs de récepteur alpha associé aux œstrogènes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011016501A1 (fr) * 2009-08-04 2011-02-10 武田薬品工業株式会社 Agent prophylactique ou thérapeutique pour le cancer
WO2011075565A1 (fr) * 2009-12-18 2011-06-23 Janssen Pharmaceutica Nv Aminothiazolone indazoles substitués comme modulateurs des récepteurs alpha liés aux œstrogènes
WO2011103130A1 (fr) * 2010-02-17 2011-08-25 Janssen Pharmaceutica Nv Aminothiazolones en tant que modulateurs de récepteur alpha associé aux œstrogènes
WO2011103134A1 (fr) * 2010-02-17 2011-08-25 Janssen Pharmaceutica Nv Aminothiazolones en tant que modulateurs de récepteur alpha associé aux œstrogènes

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015082587A1 (fr) 2013-12-05 2015-06-11 Bayer Cropscience Ag Dérivés de n-cycloalkyl-n-{[2- (cycloalkyl-1-substitué)phényl]méthylène}-(thio)carboxamide
WO2015082586A1 (fr) 2013-12-05 2015-06-11 Bayer Cropscience Ag Dérivés de n-cycloalkyl-n-{[2- (cycloalkyl-1-substitué)phényl]méthylène}-(thio)carboxamide
KR20190086715A (ko) * 2016-11-14 2019-07-23 신톤 바이오파머슈티칼즈 비.브이. 단일-보호된 알파, 오메가-디아미노 알칸의 제조 방법
KR102614466B1 (ko) 2016-11-14 2023-12-14 비온디스 비.브이. 단일-보호된 알파, 오메가-디아미노 알칸의 제조 방법

Also Published As

Publication number Publication date
JPWO2013051632A1 (ja) 2015-03-30

Similar Documents

Publication Publication Date Title
TWI460176B (zh) 吲哚化合物
JP5000490B2 (ja) チエノピリミドン化合物
US20100029619A1 (en) Fused heterocyclic compound
JP6224004B2 (ja) 複素環化合物
US20090286791A1 (en) Amide Compounds
WO2013061962A1 (fr) Composé bicyclique
AU2011246004A1 (en) Bicyclic compound derivatives and their use as ACC inhibitors.
JPWO2008090944A1 (ja) スピロ環化合物
WO2013051632A1 (fr) Composé hétérocyclique fusionné contenant de l'azote
US20130040951A9 (en) Prophylactic or therapeutic agent for cancer
US8772277B2 (en) Nitrogen-containing heterocyclic compound
EP2371826A1 (fr) Nouveau composé cyclique condensé et utilisation de celui-ci
JP2009196966A (ja) ピラゾリジンジオン誘導体
WO2011055770A1 (fr) Composé à hétérocycle condensé
US9073864B2 (en) Aromatic ring compound
US9505772B2 (en) Aromatic ring compound
TWI454473B (zh) 稠環化合物及其用途
TW201536758A (zh) 雜環化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12838458

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2013537542

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12838458

Country of ref document: EP

Kind code of ref document: A1